Download NCIC CTG Generic "Working" Protocol

PROTOCOL DATE: 2010-SEP-24
NCIC CTG TRIAL: SC.23
HEALTH CANADA SUBMISSION
AMENDMENT #1: 2013-DEC-19
NCIC CLINICAL TRIALS GROUP (NCIC CTG)
A PHASE III DOUBLE-BLIND STUDY OF DEXAMETHASONE VERSUS PLACEBO IN THE
PROPHYLAXIS OF RADIATION-INDUCED PAIN FLARE FOLLOWING PALLIATIVE
RADIOTHERAPY FOR BONE METASTASES
NCIC CTG Protocol Number: SC.23
STUDY CHAIR:
CANADIAN CO-CHAIR:
Edward Chow
Alysa Fairchild
CORRELATIVE BIOLOGY CO-CHAIR:
Carlo DeAngelis
TRIAL COMMITTEE:
Jackson Wu
Abdenour Nabid
SENIOR INVESTIGATOR:
BIOSTATISTICIAN:
SYMPTOM CONTROL
COMMITTEE COORDINATOR:
QUALITY OF LIFE COORDINATOR:
STUDY COORDINATOR:
SPONSOR:
Ralph Meyer
Bingshu Chen
Rebecca Wong
Michael Brundage
Carolyn Wilson
NCIC CTG
(For contact information of study personnel see Final Page.)
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PROTOCOL DATE: 2010-SEP-24
NCIC CTG TRIAL: SC.23
TABLE OF CONTENTS
STUDY ACKNOWLEDGMENT/DISCLOSURE ....................................................................................... 1
TREATMENT SCHEMA ............................................................................................................................. 2
1.0
1.1
1.2
OBJECTIVES .................................................................................................................................. 3
Primary Objective ............................................................................................................................ 3
Secondary Objectives ....................................................................................................................... 3
2.0
2.1
2.2
2.3
2.4
2.5
2.6
BACKGROUND INFORMATION AND RATIONALE ............................................................... 4
The Burden of Cancer Bone Metastases........................................................................................... 4
Outcome Measures for Assessing Bone Pain and Its Response to Treatment .................................. 4
Reported Experience of Pain Flare ................................................................................................... 4
Dexamethasone for Pain Flare Prevention ....................................................................................... 6
Correlative Biology .......................................................................................................................... 8
Quality of Life ................................................................................................................................ 10
3.0
3.1
3.2
3.3
3.4
3.5
3.6
BACKGROUND THERAPEUTIC INFORMATION................................................................... 14
Name and Chemical Information ................................................................................................... 14
Chemical Structure ......................................................................................................................... 14
Mechanism of Action ..................................................................................................................... 14
Expected Toxic Effects .................................................................................................................. 14
Pharmaceutical Data ....................................................................................................................... 14
Administration................................................................................................................................ 15
4.0
4.1
4.2
TRIAL DESIGN ............................................................................................................................ 16
Stratification ................................................................................................................................... 16
Randomization ............................................................................................................................... 16
5.0
5.1
5.2
STUDY POPULATION ................................................................................................................ 17
Eligibility Criteria........................................................................................................................... 17
Ineligibility Criteria ........................................................................................................................ 18
6.0
PRE-TREATMENT EVALUATION ............................................................................................ 20
7.0
7.1
7.2
7.3
ENTRY/RANDOMIZATION PROCEDURES............................................................................. 21
Entry Procedures ............................................................................................................................ 21
Stratification ................................................................................................................................... 21
Randomization ............................................................................................................................... 21
8.0
8.1
8.2
8.3
TREATMENT PLAN .................................................................................................................... 22
Treatment Plan for the Prevention of Pain Flare Induced by Palliative Radiotherapy
for Bony Metastases ....................................................................................................................... 22
Radiation Treatment Plan ............................................................................................................... 23
Concomitant Therapy ..................................................................................................................... 24
9.0
9.1
9.2
9.3
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ....................................... 25
Evaluation During and After Protocol Treatment........................................................................... 25
Format of Patient Evaluations ........................................................................................................ 26
Minimum Data to Collect ............................................................................................................... 28
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10.0
10.1
10.2
10.3
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .................................................. 29
Evaluability .................................................................................................................................... 29
Definitions of Pain Flare, Response and Progression ..................................................................... 29
Evaluation of Response-Related Endpoints.................................................................................... 31
11.0
11.1
11.2
11.3
11.4
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 32
Definition of a Reportable Serious Adverse Event ......................................................................... 32
Serious Adverse Event Reporting Instructions ............................................................................... 32
NCIC CTG Responsibility for Reporting Serious Adverse Events to Health Canada
(Office of Clinical Trials) ............................................................................................................... 33
Reporting Safety Reports to Local Research Ethics Boards ........................................................... 33
12.0
12.1
12.2
12.3
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..... 35
Criteria for Discontinuing Protocol Treatment ............................................................................... 35
Therapy After Protocol Treatment is Stopped ................................................................................ 35
Follow-Up Off Protocol Treatment ................................................................................................ 35
13.0
13.1
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ........................................ 36
Specimen Collection ...................................................................................................................... 36
14.0
14.1
14.2
14.3
14.4
14.5
STATISTICAL CONSIDERATIONS ........................................................................................... 37
Clinical Study of Pain Flare Incidence ........................................................................................... 37
Cytokine Changes .......................................................................................................................... 38
Markers of Bone Turnover ............................................................................................................. 39
Analysis of Single Nucleotide Polymorphisms (SNPs) in DNA Obtained from Saliva Specimens 39
Quality of Life Analysis ................................................................................................................. 39
15.0
15.1
15.2
15.3
PUBLICATION POLICY .............................................................................................................. 40
Authorship of Papers, Meeting Abstracts, Etc................................................................................ 40
Responsibility for Publication ........................................................................................................ 40
Submission of Material for Presentation or Publication ................................................................. 40
16.0
16.1
16.2
16.3
16.4
16.5
16.6
16.7
16.8
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ............................................... 41
Institution Eligibility for Participation ............................................................................................ 41
Investigator Qualifications ............................................................................................................. 41
REB (Research Ethics Board) Approval for Protocols ................................................................... 41
Informed Consent ........................................................................................................................... 43
Retention of Patient Records and Study Files ................................................................................ 43
Centre Performance Monitoring ..................................................................................................... 43
On-Site Monitoring/Auditing ......................................................................................................... 44
Case Report Forms ......................................................................................................................... 44
17.0
REFERENCES .............................................................................................................................. 45
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APPENDIX I APPENDIX II APPENDIX III APPENDIX IV APPENDIX V APPENDIX VI APPENDIX VII APPENDIX VIII APPENDIX IX -
PATIENT EVALUATION FLOW SHEET................................................................. 49
PERFORMANCE STATUS SCALES/SCORES ........................................................ 50
DRUG DISTRIBUTION, SUPPLY AND CONTROL ............................................... 51
DOCUMENTATION FOR STUDY ............................................................................ 53
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .............. 55
CORRELATIVE STUDIES AND SAMPLE COLLECTION INSTRUCTIONS ....... 56
QUALITY OF LIFE ASSESSMENT .......................................................................... 57
DAILY PATIENT DIARY .......................................................................................... 60
BLINDING / UNBLINDING....................................................................................... 61
LIST OF CONTACTS ................................................................................................................................ 62
LIST OF PATIENT REPORTED OUTCOMES ........................................................................................ 63
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NCIC CTG TRIAL: SC.23
STUDY ACKNOWLEDGMENT/DISCLOSURE
I understand that this protocol contains information that is confidential and proprietary to NCIC CTG.
I have read the protocol and agree that it contains all necessary details for carrying out the study as described. I
will conduct this protocol as outlined therein, and according to Good Clinical Practice and any applicable local
regulations. I will make a reasonable effort to complete the study within the time designated. I confirm that I
and study personnel participating under my supervision have adequate resource to fulfill their responsibilities
as outlined in this protocol. I will maintain documentation of any investigator responsibilities assigned to
participating study personnel. I confirm that all data will be submitted in a timely manner and will be accurate,
complete and supported by source documents.
I will provide copies of the protocol and access to all information furnished by NCIC CTG to study personnel
under my supervision. I will discuss this material with them to ensure that they are fully informed about the
investigational product and the study.
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s)
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of this
protocol may not be used in any other clinical trial and may not be disclosed to any other person or entity
without the prior written permission of NCIC CTG. The foregoing shall not apply to disclosure required by
governmental regulations or laws; however, I will give prompt notice to NCIC CTG of any such disclosure.
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to
protect the best interests of the study subjects, however I will give prompt notice to NCIC CTG. The study may
be terminated at any time by NCIC CTG with or without cause.
Any supplemental information that may be added to this document is also confidential and proprietary to NCIC
CTG and must be kept in confidence in the same manner as the contents of this protocol.
___________________________________________________
Investigator
(printed name and signature)
_________________________
Date
Protocol Number: NCIC CTG SC.23
CENTRE: ___________________________________________
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NCIC CTG TRIAL: SC.23
AMEND #1: 2013-DEC-19
TREATMENT SCHEMA
Study Population:
Patients with non-hematologic cancer and painful bone metastases planned for a single 8 Gy treatment of
palliative radiotherapy to no more than two sites.
Stratification:





Baseline worst pain score (2-4 vs. 5-6 vs. 7-10)
Primary cancer site (breast vs. prostate vs. lung vs. other)
Number of painful sites receiving radiation treatment (1 vs. 2)
Centre
Change in drug formulation
Schema
Painful bone
metastases
requiring
treatment
with
palliative
radiotherapy
R
A
N Arm 1
D
O
M
I
Z Arm 2
E
2 x 4 mg
dexamethasone (dex)
capsules taken once
daily for 5 days
One dose
at least
one hour
prior to
RT (Day
2 placebo capsules
taken once daily for 5  0)
days

Single fraction
8 Gy palliative
RT to painful
bone
metastasis(es)
(Day 0)
One
dose
daily
for 4
days
(Days
1-4)
Continue
on-study
followup for
6 days
(Days
5-10)
Single
long-term
follow-up
contact
(Day 42)
Planned Sample Size: 298
Primary Endpoint:
 Reduction in incidence of radiation-induced pain flare from the time of radiotherapy treatment to ten days
after the completion of treatment
Secondary Endpoints:
•
Reduction in incidence of radiation-induced pain flare from the time of radiotherapy treatment to five days
after the completion of treatment
•
•
•
•
•
•
•
•
Reduction in incidence of radiation-induced pain flare from Day 6 to Day 10 after radiotherapy treatment
•
Correlation of pain flare with baseline levels of bone turnover markers
Correlation of dexamethasone prophylaxis failure with rapid metabolism of the drug, intrinsic
glucocorticoid receptor defects and single nucleotide polymorphisms (SNPs)

Change in median pain score over ten days
Change in median analgesic use over ten days
Response to radiation treatment at six weeks after treatment
Adverse events
Quality of life
Validation of the EORTC QLQ-BM22 (Bone Metastases) module
Correlation of pain flare and its prophylaxis by dexamethasone with changes in levels of inflammatory
cytokines
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1.0
1.1
OBJECTIVES
Primary Objective
To compare the effectiveness of prophylactic dexamethasone versus placebo in protecting against
radiation-induced pain flare associated with a single course of treatment consisting of 8 Gy by
examining the difference in incidence of pain flare in the first ten days after therapy.
•
1.2
Secondary Objectives
•
To compare in patients treated with dexamethasone versus placebo:
-
the incidences of pain flare occurring on Days 0-5 and Days 6-10 after receiving radiation
therapy
-
the change in median pain score over the ten days after radiation therapy
the change in median analgesic intake over the ten days after radiation therapy
the responses to radiation therapy at six weeks after treatment
the nature, severity and frequencies of adverse events
quality of life
•
•
To validate the EORTC QLQ-BM22 module with the EORTC QLQ-C15-PAL.
•
To investigate if pain flare is correlated with baseline levels of the bone turnover markers
pyridinoline and N-telopeptide.
•
To investigate if the mechanism of dexamethasone prophylaxis of pain flare is mediated through a
decrease in a surge of inflammatory cytokines.
•
To investigate if failure of dexamethasone prophylaxis is due to rapid metabolism of the drug,
intrinsic glucocorticoid receptor defects or variations in single nucleotide polymorphisms (SNPs).
To investigate if pain flare following palliative radiotherapy is correlated with a surge of
inflammatory cytokines.
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2.0
BACKGROUND INFORMATION AND RATIONALE
2.1
The Burden of Cancer Bone Metastases
An estimated 171,000 new cases of cancer will occur in Canada in 2009 [Canadian Cancer Society 2009].
Bone metastases develop in approximately 30-70% of newly diagnosed cancer patients [Foley 1985] .
Two-thirds to three-quarters of patients with advanced breast or prostate cancer are affected; lung,
thyroid, and renal carcinoma metastasize to bone in 30% to 40% of patients [Coleman 2006] . Bone
metastases are the most common cause of intractable malignancy-related pain [Foley 1985], and the site
of metastasis most likely to require palliative radiotherapy (RT) [Lutz 2007] . Complications of bone
metastases can include hypercalcemia, pathologic fracture and spinal cord compression [British
Association of Surgical Oncology 1999] . Immobility, anxiety, depression and severely diminished quality of
life (QOL) are reported by patients [Malawer 1993] . Although 80-90% of patients experience
improvement in pain with RT, the onset of relief can be delayed and its duration is variable [Bates
1992] . With advances in systemic treatment, survival of patients with bone metastases has improved
substantially. Certain subsets of patients (e.g. breast and prostate cancer patients with bone-only
disease) have life expectancies that range from two to five years [Harrington 1988]. Successful
management of symptoms secondary to bone metastases is essential to reduce pain and skeletal
complications, and to maximize QOL.
2.2
Outcome Measures for Assessing Bone Pain and Its Response to Treatment
Several randomized trials have been conducted to define the optimal dose fractionation schedule for
the palliation of painful bone metastases with external beam radiotherapy; however, it has been
observed that different conclusions may be reached depending on how endpoints are defined
[summarized in Chow 2002]. An international consensus on endpoint definitions has been established. One
of the most important contributions to future radiotherapy trials involving bone metastases was the
International Bone Metastases Consensus Working Party’s definition of response rates following
radiation treatment [Chow 2002]. They defined a complete response as a pain score of zero at the treated
site with no concomitant increase in analgesic intake (measured in daily oral morphine equivalent
doses, OMED). Partial response was defined as one of the following: pain reduction of two or more
points on a 0-10 scale at the treated site without increase in analgesic intake; or analgesic reduction of
25% or more from baseline without an increase in pain. Pain progression was defined as: an increase
in pain score of two or more points above baseline at the treated site with stable or increased analgesic
use; or an increase of 25% or more in daily oral morphine equivalent compared to baseline with stable
or increasing pain score.
2.3
Reported Experience of Pain Flare
Worsening of symptoms, including pain, has been observed following treatment with hormones in
patients with breast and prostate cancer. Such a phenomenon is termed ‘flare’ [Mortimer 2001; Bubley
2001] . In trials testing radiopharmaceuticals as palliative treatment of painful bone metastases, the
reported incidence of pain flare ranges from 7 to 44% [Turner 1989; Tian 1999; Turner 2001; Dafermou 2001].
Palliative radiotherapy has a proven record in the treatment of symptomatic bone metastases. Pain flare
is mentioned as a potential side-effect, but its properties and frequency are poorly documented [Wu
2003] . In addition, the use of different definitions of pain flare as well as different methods and timing
of assessment means that reports cannot be directly compared.
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There are several reports describing the incidence and qualities of radiation treatment-related pain
flare. In a pilot study in 1996, Kirkbride and Aslanidis administered 12 Gy in a single fraction to
patients with bone metastases and monitored short-term toxicity and pain relief at two weeks and one
month after treatment. An increase in pain immediately following treatment was observed in 5/16
(31%) patients [P. Kirkbride, personal communication, July 2006]. Foro et al conducted a randomized study
comparing the response rates of 8 Gy given as a single fraction treatment, 15 Gy given in three
fractions and 30 Gy given in ten fractions. Pain relief was evaluated according to a visual analog scale
(VAS) every three months for one year. A temporary increase in pain following treatment was reported
as a side effect in 15% of patients receiving a single dose [Foro 1998].
Roos et al began to evaluate ‘flare effect’ fifteen months after the initiation of a randomized trial
comparing a single 8 Gy fraction with 20 Gy given in five fractions for treatment of neuropathic pain
associated with bone metastases. Flare effect was defined as “a temporary increase in pain at the index
site within a week of commencing radiation treatment” and was graded on a three-point numerical
scale (1 = mild, 2 = moderate, 3 = severe increase in pain). The overall flare effect incidence was 10%
(20/194). There were two, five and seven patients in the single dose arm and two, two, and two in the
multi-fraction arm who experienced mild, moderate and severe flare effects respectively (p = 0.029
comparing trends versus grades). The flare rate was worse in the single fraction arm than in the
multiple fraction arm [Roos 2005].
Loblaw et al reported results of the Canadian Bone Metastases Trial, which compared a single fraction
of 8 Gy with 20 Gy in five fractions. They recorded pain scores using the Present Pain Intensity (PPI)
scale of the McGill-Melzack pain questionnaire along with an analgesic diary for seven days after
radiation. Pain flare was defined as a two-point increase in PPI with no decrease in analgesic score or a
50% increase in analgesic score with no decrease in PPI, on at least two consecutive days. Forty-four
patients completed the study. Fifteen of 44 (34%) patients experienced a pain flare that lasted a
median of three days. Ten of 23 (44%) and 5/21 (24%) patients who received 8 Gy and 20 Gy had a
pain flare, respectively (one-sided Z-test, p = 0.085).The authors concluded that pain flare is common
after palliative radiotherapy for bone metastases and that patients receiving single fraction radiotherapy
may be at higher risk [Loblaw 2007].
Led by Edward Chow, investigators have completed two pilot projects addressing pain flare. Pain flare
was defined a priori by using the definition of pain progression by the International Bone Metastases
Consensus Working Party [Chow 2002] (see section 2.2) and adding the proviso that pain score and
analgesic intake had to return to baseline levels prior to the end of the ten-day follow-up period to
distinguish pain flare from pain progression. Special parameters were used to define a pain flare in
those with baselines pain scores of 9 or 10. If the baseline pain was 9/10, a patient was considered to
have experienced pain flare if the follow-up pain score was 10/10 and was accompanied by a response
indicating that the current pain was worse than the baseline pain. If the baseline pain was 10, a patient
was considered to have experienced pain flare if the follow-up pain score was 10/10 and was
accompanied by a response indicating that the current pain was worse than the baseline pain.
In the first study by Chow’s group, performed at two centres, the radiation dose fractionation
schedules employed included single and multiple fractions [Chow 2005]. The median pain score before
treatment for all patients was 5 (range 0–10). The median analgesic intake (OMED) was 35 mg (range
0–3600). Pain flare was observed on Day 1 of treatment in 12/88 patients (14%; 95% confidence
interval 7–23%). For patients who received single fraction treatment, pain flare occurred in 14% of
patients on both Days 1 and 2, but then was reduced to less than 10% in the remaining study period.
For patients who received treatment in five daily fractions, the incidence of pain flare was 15% (95%
confidence interval 6–31%) on Day 1 but remained in the range of 10–20% during and immediately
after the treatment ended. Five patients received treatment in ten daily fractions and only one noticed a
pain flare on Day 3. The overall incidence of pain flare ranged from 2 to 16%.
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In a second study, completed at three centres, Hird et al also examined the incidence of pain flare
following a single fraction of 8 Gy or multiple fraction treatment (20 Gy in five fractions or 30 Gy in
ten fractions); participating centres were the Odette Cancer Centre, Princess Margaret Hospital and the
Tom Baker Cancer Centre [Hird 2009a]. The definition of pain flare was as outlined above. A total of
189 patients were enrolled with 111 patients providing complete data. Of these patients, 50 were male
and 61 were female with a median age of 62 years (range 40–89). Breast (38%), lung (23%) and
prostate (22%) were the most common primary cancer sites. The overall incidence of pain flare was
44/111 (40%). Seventy patients (63%) in this study were treated with a single fraction of 8 Gy. Of
these patients, there were 36 males and 34 females with a median age of 65 years (range 46-89). The
most common primary cancer sites were breast (34%), prostate (20%) and lung (15%) (unpublished
data). Twenty-seven of the 70 single fraction patients (39%) experienced pain flare during the ten-day
follow-up period [Hird 2009a]. The majority of patients who experienced pain flare did so between one
and five days after radiotherapy, as opposed to between six and ten days [25/27 (93%) vs. 2/27 (7%)
for single fraction patients (unpublished data)].
Hird et al also performed a qualitative evaluation of a subset of patients who had had pain flare as part
of the above study [Hird et al 2009c] . Thirteen patients (ten females and three males) with a median age
of 59 (range: 48-89) completed the interview process. The majority had breast (9/13) or prostate
cancer (2/13). Ten patients indicated some level of functional interference while experiencing pain
flare, with the majority of these indicating that it completely interfered with their daily activities. It
also resulted in negative mood and isolation from friends and family. To manage the increase in pain,
over three-quarters of the patients increased their analgesic intake; however, nine patients failed to
achieve adequate control of pain despite this increase. Some indicated that they were reluctant to take
additional pain medications due to the potential for side effects (e.g. constipation, dry mouth, fatigue).
Eleven of the thirteen patients explicitly stated that they would have preferred prevention of pain flare
as opposed to having it treated with additional analgesics.
In summary, if present, pain flare usually occurs during the first five days following palliative
radiotherapy with an incidence ranging from 14 – 40% depending on the definition and measurement
tool used. The impact on patients’ pain experience can be severe. Although patients can be instructed
to use breakthrough analgesics, preventive measures are preferred to avoid needless suffering, a
negative impact on QoL, potential toxicity from opioids and aversion to subsequent palliative
radiotherapy.
2.4
Dexamethasone for Pain Flare Prevention
Dexamethasone is a synthetic glucocorticoid used as an anti-inflammatory or immunosuppressive
agent. It has also been used as an adjuvant analgesic and a prophylactic medication for radiationrelated toxicities associated with the treatment of brain metastases (especially in patients with
intracerebral edema) and as an anti-emetic for patients receiving radiotherapy to the upper abdomen
[Kirkbride 2000] . These beneficial effects are at least in part attributed to its anti-inflammatory properties
and ability to modulate cytokine-related effects [Barnes 2006]. Known side effects include
hyperglycemia, insomnia, edema, infections, myopathy, and gastritis. The half-life of dexamethasone
is 36-54 hours [Solimando 2008].
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Cancer induced bone pain (CIBP) is a complex phenomenon mediated by the combined effects of
locally produced cytokines, local primary afferent nerve fibres and the central nervous system [Mantyh
2002; Joyce 2009] . Tumour metastasizing to bone causes activation of primary nerve afferents, a change
in osteoblast/osteoclast balance and the production of an inflammatory infiltrate [Mantyh 2002; Bussard
2008] . Macrophages, osteoblasts, osteoclasts, and tumour cells are all present at sites where cancer has
invaded the bone [Bussard 2008]. These cells can release numerous growth factors, cytokines,
chemokines, prostaglandins, and endothelins, which in turn cause stimulus of the sensory afferent and
sympathetic nerve fibers also present in bone [Goblirsch 2006; Luger 2005; Urch 2004]. Prostaglandins are
produced at the metastatic site by both cancer cells and responding immune cells (primarily
macrophages) invading the metastatic site [Mantyh 2002; Joyce 2009]. In animal models of CIBP,
inhibiting prostaglandin production by non-steroidal anti-inflammatory drugs (NSAIDs) has been
shown to reduce bone pain [Sabino 2002]. Other cytokines implicated in the initiation and maintenance
of the inflammatory process include nerve growth factor, tumour necrosis factor, and interleukins-1
and -6 [Luger 2005; Urch 2004]. The various growth factors released by cancer cells invading bone
promote osteoclast growth and activity, which is directly related to bone pain. Radiation of bone
metastases in an animal model of bone cancer has been shown to reduce tumour burden, osteolysis,
and pain [Goblirsch 2004]. That a similar mechanism may be in play in humans is supported by the
observation that, following radiation to sites of painful bone metastases, levels of urinary markers of
osteoclast activity were significantly lower in responders than non-responders [Hoskin 2000].
It is postulated that pain flare following external beam irradiation to painful bone metastases is
associated with an increased release of inflammatory mediators in predisposed individuals and that
dexamethasone can prevent or attenuate this, preventing the pain flare phenomenon. To test this,
Chow’s group conducted a pilot study to investigate the efficacy of a single 8 mg dose of
dexamethasone given at least one hour prior to radiotherapy to prevent pain flare in patients receiving
a single fraction 8 Gy treatment for bone metastases [Chow 2007]. The definition of pain flare used in
the group’s previous work [Chow 2005; Hird 2009a] was employed. Safety and tolerance of
dexamethasone were also assessed. Complete follow-up data were available for 33 of 45 enrolled
patients. There were 23 male and 10 female patients with a median age of 73 years and a median
Karnofsky Performance Status (KPS) of 80. The median total OMED at baseline was 18 mg/day. The
most common primary cancer sites were prostate and breast with the extremities, spine and pelvis as
the most common radiated sites. The baseline means of the worst, average and current pain scores
were 7.8, 5.2 and 4.0, respectively. No dexamethasone-related adverse events or functional
interference were reported. Eight of thirty-three patients (24%; 95% CI 10-39%) experienced pain
flare during the ten-day follow-up period. They were all male patients with a median age of 68 years.
The mean baseline worst pain score (± SD) was 6 (±2) versus 8 (±2) for those who did not experience
pain flare (p = 0.013). Two patients had a one-day pain flare on Day 3. Three patients had a one-day
pain flare on Day 7. Three other patients had a prolonged pain flare: one had a three-day pain flare on
Days 2-4; one had a three-day pain flare on Days 4-6; and the other had a six-day pain flare on Days 38. Since the half-life of dexamethasone is 36-54 hours, one would expect dexamethasone to have
maximum effect in the first two days following administration. Only one patient (3%) experienced
flare in the first two days of follow up. Three others had flare from Day 3 onwards. These three might
have benefited from repeated administration of dexamethasone.
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Following the above observations of potential efficacy of a single dose of dexamethasone, in a joint
effort involving the Odette Cancer Centre in Toronto, the Cross Cancer Centre in Edmonton and the
Mater Hospital in Australia, a phase II study was initiated to examine the optimal duration of
dexamethasone for prevention of pain flare following a single 8 Gy fraction of radiotherapy. Enrolled
patients took 8 mg of oral dexamethasone prior to RT (Day 0) and in the morning with breakfast daily
for three days following treatment (Days 1, 2, and 3) to minimize gastric irritation and insomnia (Hird,
2009b). Nine of 41 patients (22%) experienced eleven pain flares. The median day of flare initiation
was Day 5 and the median duration of pain flare was one day. Pain flares lasting a single day occurred
on Days 1, 2 and 4, while a three-day pain flare was experienced on Days 6 to 8. Five of nine patients
(56%) initiated their first pain flares on Day 5 (unpublished data). In total, 7/41 (17%) patients’ pain
flare began in the first five days after RT, while 2/41 (5%) had initiation of pain flare after Day 5. No
patients described dexamethasone-related adverse events. As patients were instructed to take the last
dose of dexamethasone on the morning of Day 3, the protective effect of dexamethasone likely lasted
to the morning of Day 5. This may explain why additional patients experienced flare starting after Day
5. As such, it is recommended that the dexamethasone treatment period be extended by one day to
prevent the flares initiated on Day 5.
% patients initiating pain flare
The following figure is a summary of the clinical data on the reduction in incidence of radiationinduced pain flare by dexamethasone.
25
20
No dex
1-day dex
4-day dex
15
10
5
0
1
2
3
4
5
6
7
8
9
10
Days (RT delivered on D0)
Dexamethasone is well-tolerated and is associated with a decrease in the incidence of pain flare. On
this basis, we propose this phase III randomized, double-blind study comparing dexamethasone and
placebo with the goal of reducing the incidence of pain flare in patients receiving a single fraction of 8
Gy.
2.5
Correlative Biology
The relationship between pain flare, inflammatory response and dexamethasone metabolism will be
investigated to better understand the mechanism of pain flare, and to develop a better way to manage
it. It is hypothesized that patients receiving dexamethasone who experience pain flare will have higher
levels of inflammatory cytokines, lower levels of parent drug in urine, and a genetic profile that
predisposes them to an increased rate of dexamethasone metabolism.
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2.5.1
Effects of Dexamethasone on Inflammatory Cytokines
As outlined above (section 2.4), inflammation resulting from changes in the balance between pro- and
anti-inflammatory cytokines is believed to be a major cause of CIBP. Dexamethasone has
demonstrated anti-inflammatory properties [Salerno 2006; Holte 2002] and reduces the incidence of pain
flare associated with palliative radiotherapy [Chow 2007; Hird 2009b]. The relative levels of inflammatory
cytokines may act as surrogate markers for the effects of dexamethasone.
Markers of inflammation are often measured in serum, but can also be measured in urine samples,
which is preferable for our patient population. This has been demonstrated in several studies using
ELISA assays [Sirera 2003; Erickson 2002]. For example, Sirera et al demonstrated no statistically
significant difference in levels of IL-6 and TNFα measured in serum and urine [Sirera 2003].
For this study, the levels of inflammatory mediators such as IL-1β, IL-6, and TNFα will be measured
in urine samples. Comparisons will be made between baseline and post-treatment samples after
extraction of the bone turnover markers pyridinoline and N-telopeptide (Ostex Seattle, WA) (see
section 2.5.3) and normalization relative to urinary creatinine concentration. Urinary calcium,
phosphate, and magnesium will also be measured for the purpose of normalization. The results of the
comparisons will be tested for correlation with the pain flare experience as documented in the clinical
portion of this study. Other markers of inflammation and/or pain modulation may be evaluated in the
future.
2.5.2
Dexamethasone Metabolism in Patients that Experience Pain Flare
Although prophylactic administration of dexamethasone may reduce the incidence of radiationinduced pain flare in patients with painful bone metastases [Chow 2007; Hird 2009b], not all patients
receiving dexamethasone are protected. We hypothesize that pain flare experienced in spite of
dexamethasone may be associated with rapid metabolism of dexamethasone. We will be evaluate this
hypothesis by examining levels of dexamethasone metabolites in urine as well as genetic
polymorphisms that may be associated with increased dexamethasone metabolism.
Dexamethasone has two 6-hydroxylation products, 6β-hydroxydexamethasone and 6αhydroxydexamethasone, which are obtained upon oxidation in an 85/15 ratio [Zurbonsen 2004; Puisset
2004] . Determining 6β-hydroxydexamethasone levels in urine by high performance liquid
chromatography (HPLC) has successfully measured dexamethasone metabolism [Zurbonsen 2004; Puisset
2004; Gentile 1996; McCune 2000; Rodchenkov 1988; English 1975; Minagawa 1986]. The urinary ratio of 6βhydroxydexamethasone/dexamethasone has been reported at 5.2 [Puisset 2004]. A one-compartment,
first-order elimination model can be applied to explain urinary dexamethasone concentration [Puisset
2004] . Correlations between the levels of urinary 6β-hydroxydexamethasone and the pain flare
experience will be investigated.
There is significant inter-individual variability in pharmacokinetic response to dexamethasone, some
of which may relate to an individual’s biological ability to clear dexamethasone [Zurbonsen 2004; Puisset
2004] . Understanding this may allow a balance between therapeutic effects of the drug and side effect
management, for example, by individual dosing. While in the previous work dexamethasone was welltolerated, the potential for side-effects exists. Optimal dosing based on individual characteristics might
increase quality of life for individuals taking this medication by decreasing side effects and
determining more effective dosing strategies [Hempen 2002; Weissman 1987].
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Inter-individual variability in dexamethasone clearance may be due in part to single nucleotide
polymorphisms (SNPs) of the main enzyme systems responsible for its degradation, specifically CYP
3A4 [Zurbonsen 2004; McCune 2000] or glucocorticoid receptors [Jewell 2007] . SNPs present in an
individual’s DNA may be related to that patient’s pain pathways and pain flare experience. SNPs will
be identified to explore the correlations between specific polymorphisms and the experience of pain
flare.
In order to obtain a DNA sample without the drawbacks of blood collection, salivary DNA will be
used. The Oragene•DNA Self-Collection Kit [Zurbonsen 2004] will be utilized for the collection,
preservation, transportation and purification of DNA from saliva. DNA collected with Oragene
technology has been shown to perform equivalent or better than blood extracted DNA in targeted
genotyping assays [Puisset 2004].
2.5.3
Pain Flare and Markers of Bone Turnover
Increased osteoclastic activity is a response to tumour cell invasion of bone. Pyridinoline and Ntelopeptide are markers of osteoclastic activity [Coleman 2002]. Lower baseline urinary concentrations of
pyridinoline correlate with a reduction in pain after treatment with palliative radiotherapy [Hoskin 2000].
High baseline concentrations of urinary N-telopeptide have been strongly associated with negative
outcomes, including skeletal-related events, in several cancers [Al Husaini 2009]. The relationship
between urinary levels of markers of bone turnover and pain flare will be explored.
2.6
Quality of Life
Both objective and subjective outcome measurements are relevant to the study of dexamethasone and
its impact on radiation-induced pain flare. Many previous clinical trials on bone metastases have
largely focused on the objective endpoints such as analgesic consumption, hypercalcaemia,
pathological fractures, spinal cord compression, and use of surgery and radiation. In this study,
patient-reported outcomes comprise the primary outcome (pain diary) and also health-related quality of
life (QOL) measures.
The World Health Organization describes health as ‘not merely the absence of disease or infirmity, but
a state of physical, mental and social well-being’ [World Health Organization 1948]. Quality of life
measurement is a subjective, multidimensional construct reflecting functional status, psychosocial
well-being, health perceptions, and disease- and treatment-related symptoms from the patient’s
perspective and is well-established as an important clinical outcome measure in clinical trials in
oncology [Gotay 2005; Lipscomb 2007]. Quality of life is an important consideration for patients when
making treatment decisions, and regulatory bodies, such as those in Canada, the UK, Australia,
Belgium, and many other countries, are giving increased importance to QOL as independent endpoints
in determining the cost-effectiveness of competing therapies.
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2.6.1
Assessment of Patient-Reported Outcomes
2.6.1.1 EORTC C15-PAL
The European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C15-PAL
questionnaire was developed by the EORTC QOL group in response to a need for low burden patientreported QOL outcomes suitable for a palliative setting [Groenvold 2006], which yields data compatible
with the original scales of the thirty-item EORTC questionnaire. By reduction of the number of
EORTC QLQ-C30-items, the authors addressed the issues that make it less suitable for use in
palliative care: length; and inappropriate or irrelevant content [Groenvold 2006]. Four functional scales
were shortened without reducing measurement precision. Important dimensions not covered by the
questionnaire were identified. The resulting fifteen-item EORTC QLQ-C15-PAL is a ‘core
questionnaire’ for palliative cancer patients which can be supplemented by additional items, modules
or questionnaires. The authors concluded that this new questionnaire “…has good content validity as a
‘core palliative care questionnaire’ assessing the symptoms and problems for which patients are
frequently treated.” In addition, due to the use of item response theory (IRT), the EORTC QLQ-C15PAL makes the extension of cancer clinical trials possible to patients receiving palliative care
[Groenvold 2006] . It has been expressed that the EORTC QLQ-C15-PAL will prove to be invaluable for
researchers conducting clinical trials with palliative cancer patients, and who would like to ease patient
burden while increasing successful follow-up duration [Echteld 2006] .
2.6.1.2 Bone Metastases Module (EORTC QLQ-BM22)
The Bone Metastases Module (EORTC QLQ-BM22) was developed according to the module
development guidelines of the EORTC Quality of Life Group to provide a comprehensive evaluation
of the benefits and possible side effects of interventions. Phase I to III development was recently
completed with over 600 patients from nine different countries undergoing a variety of bone
metastases specific treatments [Chow 2009]. It contains 22 items conceptualized into both symptom
scales (five painful sites and three pain characteristics) and functional scales (eight functional
interference and six psychosocial aspects). Phase IV testing is underway.
2.6.1.3 Dexamethasone Symptom Questionnaire (DSQ)
The DSQ was developed by Vardy, Tannock and colleagues [Vardy 2006] as a patient-reported outcome
tool designed to capture adverse events of dexamethasone in the setting of moderately-emetogenic
chemotherapy. It has been shown to have face and content validity and sensitivity, but has not been
widely validated. Patients and clinicians report that it is a simple yet comprehensive instrument with
two to three minute completion time [Vardy 2006]. The questionnaire comprises two constructs which
are scored by eleven individual items, each with a response option 1 to 4 on a Likert scale but scored 0
to 3. The main construct includes nine items that evaluate dexamethasone side effects: insomnia;
gastroesophageal reflux; agitation; increased appetite; weight gain; acne; hiccups; oral candida; and
depression on ceasing medication. Scores for this construct thus range from 0 to 27. In the validation
study, however, mean scores and variances on the total construct were not reported, but rather the
proportion of patients having zero, low or high (2-3) scores on each individual item were calculated
[Vardy 2006] . Two additional items which constitute the second construct evaluate the severity of
nausea and vomiting. The instrument is ideal for describing the patient-reported symptoms of
dexamethasone toxicity on this study. However, since all items/symptoms have other potential causes
(none are specific to dexamethasone), inferences will be required on a statistical basis between study
arms to properly interpret the descriptive data.
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Some modifications to the DSQ were required for use in this study. Only the items in the main
construct were included to assess dexamethasone toxicity while minimizing redundancy. In addition,
the final item asks if the patient experienced feelings of depression on stopping dexamethasone. Since
this is a blinded study, ‘dexamethasone’ was replaced with ‘study medication’ for this item. The time
frame of reference in the Vardy study was ‘during the week after chemotherapy’. As this is not
applicable to this study, the time frame was changed to ‘during the past week’ which is consistent with
items in the QLQ-C15-PAL and the QLQ-BM22.
2.6.2
QOL-Related Study Hypotheses and Proposed Analyses
2.6.2.1 Evaluation of the Benefits of Dexamethasone
The primary QoL question in this study addresses whether the use of dexamethasone improves
patients’ quality of life in the early phase of response to radiotherapy. Should dexamethasone
significantly reduce pain flare, this should be reflected in improved average quality life scores of
patients receiving dexamethasone compared to those not receiving dexamethasone. The main analysis
is, therefore, a between-group analysis by randomization assignment.
The primary endpoint will be evaluated using the EORTC QLQ-C15-PAL, specifically the physical
functioning domain, chosen as the functional scale most likely to reflect clinically meaningful
differences in QOL status related to the prevention of a pain flare. The null hypothesis is that there
will be no clinically or statistically significant difference between study arms with respect to QOL
change scores from baseline on the physical functioning domain. The alternative hypothesis is that
dexamethasone results in significant differences in mean change scores between arms. Since either
improved or deteriorated quality of life scores are possible, a two-sided approach is required. The
primary QOL analysis will involve comparing mean change scores (baseline to Day 10) between arms
using a repeated measures analysis and the standard NCIC CTG analysis [Osoba 2005].
For the purposes of this analysis, a between-arm difference in mean change scores of ten points or
more (on the 100 point scale) will be considered clinically significant. Note that in the phase II study,
standard deviations on the physical functioning subscale of the EORTC instrument were
approximately 20.0. Hence, the clinically significant difference of 10 points is also in keeping with an
effect size of 0.5, assuming similar pooled variance to that seen in the phase II study. Since the study
sample size required for the primary study outcome is sufficient to statistically detect an effect size of
0.4 (allowing for invaluable cases and missing data), the study will have sufficient power to detect the
difference of interest in the QOL primary outcome.
Secondary QOL analyses will involve comparing mean change scores in the remaining functional
scales, as well as relevant single items of the core questionnaire and the bone metastases module. A
clinical significance criterion of 10 points will be applied in these analyses as well. To address the
question of whether dexamethasone improves the efficacy of radiotherapy at Day 42, additional
secondary analyses will include comparing the proportion of patients improved at Day 42 on the
physical functioning domain, using the NCIC CTG Standard Analysis Approach, and defining
"improved status" as ten percentage points for each individual patient.
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2.6.2.2 Evaluation of Dexamethasone Toxicity
The benefits of dexamethasone may be outweighed by its adverse effects, which will be measured by the
main construct of the DSQ. For the purposes of this analysis, the nine-item dexamethasone toxicity
subscale will be used as validated by Vardy, Tannock and colleagues with the modifications noted in
section 2.6.1.3. The null hypothesis is that randomization arms will not differ in dexamethasone-related
symptoms, since many of these symptoms may be attributable to factors other than dexamethasone. The
alternative hypothesis is that dexamethasone causes detectable between-arm differences in mean scores
on this scale. Since the frame of reference for the questionnaire is "during the past week" this tool will
also be administered on Day 10 (given that this strategy is likely to reduce administrative complexity and,
therefore, reduce missing data). The expected mean scores and variance on the 9 item total symptom
scale are not known in this population. The analysis of this endpoint will be a comparison of the
proportion of patients on each item scoring 2 or 3 on the 3 point scale at Day 10 using conventional
analysis of proportions. As such, there is no formal proposed analysis to statistically compare the benefits
of dexamethasone to the observed risks. Both exercises will be descriptive (with statistical inference to
support any observed between-arm differences), thus allowing clinical interpretation of how to best weigh
the benefits against the risks of dexamethasone use in this setting.
2.6.2.3 Validation of the EORTC QLQ-BM22
This trial will contribute data that will test the reliability, clinical, and psychometric validity of the
EORTC QLQ-BM22 by including multi-trait scaling and other construct examinations, reliability
(internal consistency), correlation analyses with other instruments, clinical validity (i.e. known group
comparisons and sensitivity), and responsiveness to change over time in statistical analyses. A p < 0.05
will be considered as statistically significant, except where the alpha level for p value will be adjusted
for multiple comparisons.
Multi-trait scaling analysis will be employed to examine whether the individual items in the EORTC
QLQ-BM22 can be aggregated into hypothesized multi-item scales. Evidence of item convergent
validity is defined as correlation of 0.40 or greater between an item and its own scale (corrected for
overlap). Evidence of item discriminant validity will be based on a comparison of an item with its own
scales and with other scales. Scaling success for any item is defined as an item correlated significantly
higher with its own scales (corrected for overlap) than with another scale. Other construct examination
such as exploratory and confirmatory factor analyses will also be used to evaluate the structure of the
instrument.
Internal consistency for scales on the EORTC QLQ-BM22 will be examined. The internal consistency of
the multi-item questionnaire scales will be assessed by Cronbach's alpha coefficient [Cronbach 1951]. A
magnitude of > 0.70 is considered acceptable for group comparisons [Blazeby 2002; Blazeby 2004].
Three different approaches will be used to evaluate the validity of the questionnaire. First, correlations
among the various scales of the EORTC QLQ-BM22 and EORTC QLQ-C15-PAL will be examined
using Pearson's product moment correlation. We expect that those scales that are conceptually related
will correlate with one another (Pearson's r > 0.40). Conversely, those scales that are conceptually
unrelated are expected to exhibit lower correlations (Pearson's r < 0.40). Second, clinical validity will
be addressed by evaluating known group comparisons (sensitivity) to assess whether the questionnaire
scores can discriminate between subgroups including treatment modalities and clinical conditions such
as KPS, disease status and extent, and related bone metastases specific conditions (e.g. skeletal related
events). Group differences will be assessed using the Student's t-test/ANOVA or Wilcoxon rank sum
test/Kruskal Wallis test, depending on the distribution of the data and sample size of each group.
Correlation tests will be done for KPS.
To evaluate scale responsiveness over time, mixed effects regression model or generalized estimating
equations will be used to test for the significance of changes in QOL scores before and after treatment,
adjusting baseline clinical and socio-demographic variables.
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3.0
BACKGROUND THERAPEUTIC INFORMATION
3.1
Name and Chemical Information
Proper name:
Chemical name:
3.2
Dexamethasone, USP
(1) Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21trihydroxy-16-methyl-,(11β,16α)(2) 9-Fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione
Chemical Structure
Molecular formula:
Molecular weight:
3.3
C22H29FO5
392.47
Mechanism of Action
Dexamethasone is a synthetic glucocorticoid used as an anti-inflammatory or immunosuppressive
agent. It was approved by the FDA in 1958. At the molecular level, unbound glucocorticoids readily
cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding
induces a response by modifying transcription and ultimately protein synthesis to achieve the steroid’s
action.
3.4
Expected Toxic Effects
Because dexamethasone has been widely used for various indications for many years, its toxicity
profile is well known. Reported side effects include hyperglycemia, insomnia, osteoporosis, peripheral
edema, infections, proximal myopathy, mental disturbances, gastritis, peptic ulceration, Cushing’s
syndrome, and adrenal suppression, but these are rare when dexamethasone is used for short periods
only.
3.5
Pharmaceutical Data
Each tablet is oval, pale green and scored. Each active tablet contains 4 mg dexamethasone, corn
starch, FD & C Blue #1 Aluminum Lake 12%, D & C Yellow # 10 Aluminium Lake 17%, colloidal
silicon dioxide, sodium starch glycolate, microcrystalline cellulose, lactose and magnesium stearate.
The dexamethasone tablet will be over encapsulated using a DB capsule (Size A, opaque, grey in
color). The capsule will be backfilled with a 1:1 Microcrystalline Cellulose:Lactose 1:1 mix). Each
placebo DB capsule (Size B, opaque, grey in color) will be filled with the same powder used to
backfill the active dexamethasone capsule which is a 1:1 mixture of Microcrystalline
Cellulose:Lactose.
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Stability:
Expiry dates are provided on the product label.
Storage:
All investigational products must be kept in a secure place under appropriate storage conditions. The
capsules should be stored in the packs in which they are distributed until use. For further information,
please refer to the product label.
3.6
Administration
For this study, dexamethasone is administered orally at 8 mg daily at least one hour prior to palliative
radiotherapy to the painful bone metastasis (Day 0) and in the morning on Days 1 - 4 following
radiotherapy. Administration on days following radiotherapy should be done at approximately the
same time every day, preferably in the morning with food, to help prevent gastric irritation and
insomnia.
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4.0
TRIAL DESIGN
This is a multi-centre, randomized, double-blind placebo-controlled trial conducted by the NCIC
Clinical Trials Group. Dexamethasone or placebo will be given to patients prior to treatment on the
same day as single fraction 8 Gy palliative radiotherapy, and for the following four days.
4.1
Stratification
Patients will be stratified by:
• Baseline worst pain score on a 0-10 scale (2-4 vs. 5-6 vs. 7-10)
• Primary cancer site (breast vs. prostate vs. lung vs. other)
• Number of painful sites receiving radiation treatment (1 vs. 2)
• Centre
• Change of drug formulation
4.2
Randomization
Patients will be randomized to receive one of the following treatments to a planned sample size of 298:
Arm
Agent
Dose
Route
Duration
1
Dexamethasone
8 mg
PO
2
Placebo
NA
PO
Daily for 5 days (prior to
radiotherapy on Day 0, then on
Days 1 – 4 post radiotherapy)
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5.0
STUDY POPULATION
Cancer patients planned for palliative radiotherapy (a single fraction of 8 Gy) for bone metastases from
any non-hematologic primary cancer to no more than two sites.
5.1
Eligibility Criteria
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. Questions
about eligibility criteria should be addressed PRIOR to submitting randomization.
The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards
used to ensure that patients who enter this study are medically appropriate candidates for this therapy.
For the safety of the patients, as well as to ensure that the results of this study can be useful for making
treatment decisions regarding other patients with similar diseases, it is important that no exceptions be
made to these criteria for admission to the study.
Patients must fulfil all of the following criteria to be eligible for admission to the study:
5.1.1
Have a histologically or cytologically proven malignancy. All non-hematologic malignant tumours of
any histology are eligible.
5.1.2
Be 18 years of age or older at the time of randomization.
5.1.3
Have bone metastasis(es) corresponding to the clinically painful area(s) documented by radiological
imaging within six months prior to randomization.
5.1.4
Karnofsky Performance Status (KPS) must be ≥ 40 at the time of the baseline evaluation (within seven
days prior to randomization). As it is difficult to obtain complete data from inpatients on a daily basis,
they should not be randomized to this study.
5.1.5
Is planned to receive palliative radiotherapy to one or two bony metastasis(es) with the treatment given
as 8 Gy in a single fraction to all sites to be followed for the study. Although a maximum of two sites
can be treated and followed for the study, patients with more than two skeletal metastases are eligible.
At the time of delivery of study radiotherapy, only the site(s) being followed for the study may be
treated.
5.1.6
Is able to provide the worst pain score at the bony metastatic site(s) planned for palliative radiotherapy.
5.1.7
Has a baseline worst pain score ≥ 2 on a scale of 0-10 at all the bony metastatic site(s) planned for
palliative radiotherapy as part of this study within 7 days prior to randomization. If two painful sites
will be followed for the study, this requirement must be met on the same day for both sites.
5.1.8
Is able and willing to fill out the daily diary.
5.1.9
Is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaire in either
English or French. The baseline assessment must be completed within required timelines prior to
randomization. Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to
complete the questionnaires will not make the patient ineligible for the study. However, ability but
unwillingness to complete the questionnaires will make the patient ineligible.
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5.1.10 Patient consent must be obtained according to local Institutional and/or University Human
Experimentation Committee requirements. It will be the responsibility of the local participating
investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study
Coordinator that such clearance has been obtained, before the trial can commence in that centre.
Because of differing requirements, a standard consent form for the trial will not be provided but a
sample form is provided. A copy of the initial full board REB approval and approved consent form
must be sent to the central office. The patient must sign the consent form prior to randomization.
Please note that the consent form for this study must contain a statement which gives permission for
the NCIC CTG and monitoring agencies to review patient records (see Section 16.4 for further
details).
5.1.11 If being enrolled through a centre participating in the correlative science component of the study, is
willing and able to provide a pre- and post-treatment urine sample. Language pertaining to patient
consent for urine collection must be included in the consent form for the main study at these centres.
The patient must sign this consent form prior to collection of the first urine sample.
5.1.12 If being enrolled through a centre participating in the correlative science component of the study,
patient consent for the saliva collection component of the trial must be obtained in the same manner as
outlined in 5.1.10 for the main study consent. A sample Saliva Collection Informed Consent form is
provided. The patient must sign this consent form prior to collection of the saliva sample.
5.1.13 Must be accessible for treatment and follow-up. Investigators must be reasonably assured that the
patients randomized on this trial will be available for complete documentation of the treatment,
adverse events, and follow-up.
5.1.14 Protocol treatment is to begin within one week of patient randomization.
5.2
Ineligibility Criteria
Patients who fulfil any of the following criteria are not eligible for admission to the study:
5.2.1
Patients with hematologic malignancies (leukemia, Hodgkin’s or non-Hodgkin’s lymphoma or plasma
cell dyscrasia, including multiple myeloma) are ineligible as steroids constitute anti-cancer therapy for
these malignancies.
5.2.2
Concurrent use or use within previous seven days of any corticosteroid medication other than topical or
inhaled preparations. Patients with any type of cancer who are receiving steroids as a component of their
systemic therapy are ineligible. Patients requiring steroids for a co-existing medical problem are
ineligible. Patients who received a one- to three-day dose of steroids as an antiemetic for chemotherapy
treatment are eligible, as long as at least 72 hours have elapsed since the last dose of antiemetic therapy.
5.2.3
Medical contraindications to corticosteroids such as uncontrolled diabetes mellitus, uncontrolled
hypertension, active peptic ulcer or hypokalemia.
5.2.4
Uncorrected hypokalemia that is known to exist within 7 days prior to randomization. Patients with
previous hypokalemia that has been corrected are eligible. Hypokalemia is defined as a potassium
level < 3.0 mmol/L. Testing of electrolytes, including potassium level, is not a protocol requirement.
5.2.5
Random glucose level ≥ 13.9 mmol/L within 7 days prior to randomization. Testing of glucose within
7 days prior to randomization is a protocol requirement. Point of care testing with a glucometer is
permissible.
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5.2.6
Pathological fracture of the femora, tibiae, fibulae, humeri, radii or ulnae at the site(s) to be followed
for the study.
5.2.7
Radiological evidence of high-risk lesions for pathological fractures in the femora, tibiae, fibulae,
humeri, radii or ulnae at the site(s) to be followed for the study (lytic lesions > 3 cm or > 50% cortical
erosion of bone diameter).
5.2.8
Clinical or available radiologic evidence of spinal cord or cauda equina compression at the site(s) to be
followed for the study.
5.2.9
Plans to receive palliative radiotherapy to a site or sites other than the one(s) being followed for the
study during the ten-day period following study radiotherapy.
5.2.10 Planned orthopedic intervention, including kyphoplasty, vertebroplasty or cementoplasty, to any of the
site(s) to be followed for the study.
5.2.11 Prior palliative surgery to any of the site(s) to be followed for the study.
5.2.12 Inability, with available translator assistance, to record pain score and medication consumption in the
daily diary and to communicate this to study personnel.
5.2.13 Receipt of radiopharmaceutical treatment at any time.
5.2.14 Previous external beam radiotherapy (including hemibody radiotherapy) using a field that included the
site(s) to be followed for the study.
5.2.15 Inability to swallow or tolerate oral medications, e.g. due to intractable nausea and/or emesis.
5.2.16 Plans to receive cytotoxic chemotherapy or systemic steroids during the on-study period (day of study
radiotherapy and the subsequent ten days).
5.2.17 Plans to start or stop systemic therapy other than cytotoxic chemotherapy (e.g. hormonal therapy;
immunotherapy; bisphosphonates) during the on-study period (day of study radiotherapy and the
subsequent ten days). Patients who are already receiving these types of treatments are eligible as long
as no changes are planned during the study period.
5.2.18 Regular use of a non-steroidal anti-inflammatory drug (NSAID). Patients must not be taking NSAIDs
at randomization and their use during the on-study period (day of study radiotherapy and the
subsequent ten days) must not be required or expected. Patients who use daily low-dose ASA for antiplatelet therapy are eligible if ASA has been used for more than one month prior to the time of
randomization.
5.2.19 Plans for a change in analgesic regimen on the day of randomization.
5.2.20 Previous entry on the SC.23 study.
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6.0
PRE-TREATMENT EVALUATION
(See Appendix I)
Investigations
•
•
•
•
Baseline characteristics
Worst pain score
Contraindication to steroids
Review for clinical or existing radiological
evidence of pathological fracture (present or
impending) and spinal cord or cauda equina
compression at treatment site(s)
Karnofsky Performance Status
Documentation of cancer treatment received
during the 4 weeks prior to randomization
Within 7 days prior to
randomization
•
Random glucose (point of care testing with a
glucometer is permissible)
Within 7 days prior to
randomization
•
Radiological evidence of bone metastasis(es)
corresponding to the clinically painful area(s)
Within 6 months prior to
randomization
•
Patient diary, including pain scores and
analgesic intake
Concomitant medications
On day of study RT prior to
dex/placebo and radiotherapy
treatment
Urine specimen collection
On day of study RT prior to
dex/placebo and radiotherapy
treatment for patients randomized
at a centre participating in the
correlative science component of
the study
•
Saliva collection
Between randomization and
treatment for patients randomized
at a centre participating in the
correlative science component of
the study and who consented to the
optional saliva collection
•
Baseline adverse event evaluation (to
document residual adverse event from
previous therapy and baseline symptoms)
Within 7 days prior to
randomization
•
Quality of Life (EORTC QLQ-C15-PAL,
QLQ-BM22, and items from the
Dexamethasone Symptom Questionnaire)
Within 7 days prior to
randomization
History and Physical
Exam including:
•
•
Biochemistry
Radiology
Timing
•
•
Other Investigations
Adverse Events *
Quality of Life
*
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events
(CTCAE) (Appendix V).
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AMEND #1: 2013-DEC-19
7.0
ENTRY/RANDOMIZATION PROCEDURES
7.1
Entry Procedures
All randomizations will be done by the randomizing centre by means of the RAVE electronic data
capture system. RAVE will interact with Mango, NCIC CTG’s electronic patient allocation system, to
provide the patient’s treatment assignment.
Complete details regarding obtaining a password, accessing the system and carrying out
randomizations will be provided at the time of study activation.
If sites experience difficulties accessing the system and/or performing randomizations the SC.23 Study
Coordinator should be contacted (see last page of this protocol for contact details).
The following information will be required:
• Trial code (NCIC CTG SC.23)
• Treatment centre, NCIC CTG centre code and investigator
• Version of the informed consent that the patient signed
• Version of the Saliva Collection consent that the patient signed (if applicable)
• Patient's initials (may be coded)
• Confirmation of the requirements listed in section 5.0, including dates of essential tests and actual
laboratory values
• Stratification parameters
7.2
Stratification
Patients will be stratified by baseline worst pain score, primary cancer site, number of painful sites
being treated, change of drug formulation and randomizing centre.
7.3
Randomization
Randomization will be performed electronically by the electronic patient allocation system.
Note:
The validity of results of the trial depends on the authenticity of and the follow-up of all patients
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be withdrawn
prior to final analysis, except on withdrawal of patient consent.
All patients admitted to the trial will be followed by the coordinating centre. It is the responsibility of
the physician in charge to satisfy himself or herself that the patient is indeed eligible before requesting
randomization.
All randomized patients are to be followed until the final follow-up contact, which is to take place six
weeks (42 days) after study radiotherapy. The follow-up requirements for ineligible patients are the
same as for eligible patients.
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AMEND #1: 2013-DEC-19
8.0
TREATMENT PLAN
Although the NCIC Clinical Trials Group acts as the coordinating agency for the trial, the
responsibility for treatment of patients rests with the individual investigator.
Protocol treatment is to begin within one week of patient randomization.
8.1
Treatment Plan for the Prevention of Pain Flare Induced by Palliative Radiotherapy for Bony
Metastases
Patients will be randomized to one of the following arms:
Arm
1
2
8.1.1
Agent(s)
Dexamethasone
Placebo
Dose
Route
Timing
PO
Once daily
Two 4 mg capsules
Two placebo capsules
Schedule
Days 0, 1, 2, 3, and 4
(RT is given on Day 0)
Premedication
Patients planned for palliative radiotherapy over abdominal and/or pelvic areas are recommended to
receive ondansetron or other anti-emetic for prophylaxis of radiation-induced nausea and vomiting at
the discretion of the treating radiation oncologist. Premedication with a corticosteroid is not permitted.
8.1.2
Dexamethasone / Placebo Administration
For the first dose of dexamethasone / placebo, patients will be instructed to take two capsules of 4 mg
dexamethasone or placebo at least one hour before the scheduled start of study radiation treatment.
This is Day 0.
Patients will be asked to take two capsules of dexamethasone / placebo each day for the four
consecutive days following study radiotherapy (Days 1 – 4), preferably in the morning with breakfast.
If a patient forgets to take his/her capsules in the morning, they should be taken as soon as the patient
remembers. If the patient does not remember until the next day, a double dose should not be taken. If
the patient misses the dose that was supposed to be taken on Day 4 (i.e. the last dose of study
medication), it should not be taken on the morning of Day 5.
8.1.3
Blinding / Unblinding
Blinding is critical to the integrity of this clinical trial. In many cases, particularly when the emergency
is clearly not related to dexamethasone, the problem may be properly managed by assuming that the
subject is receiving active product without the need for unblinding. If there is a need to break the blind
this must first be discussed with the NCIC CTG as per Appendix IX. In addition, the NCIC CTG must
be notified as soon as possible of any emergency situation in which the drug code was broken. See List
of Contacts for details.
The desire to treat a patient with steroids is not an acceptable reason for unblinding. While the use of
steroids is not encouraged, this can be done if it is in the best interest of the patient. Patients who
experience a pain flare should manage the pain by increasing their intake of breakthrough analgesics
rather than initiating steroids. If steroids are initiated, their use must be noted as a concomitant
medication in the electronic data capture system.
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AMEND #1: 2013-DEC-19
8.1.4
Dose Adjustments
No dose or schedule adjustments to study medication will be made due to adverse events.
8.1.5
Duration of Therapy
Five days.
8.1.6
Discontinuation of Protocol Therapy Due to Adverse Events
Patients should be taken off protocol therapy if they experience any of the following adverse events
(graded according to the Common Terminology Criteria for Adverse Events (CTCAE); see
Appendix V) that are considered possibly, probably or definitely related to protocol therapy:
Adverse Event
Agitation
Anxiety
Psychosis
Hyperglycemia *
Any “hemorrhage” term within the
Gastrointestinal Disorders section of the CTCAE
Hypertension **
Any term within the Infections and Infestations
section of the CTCAE
* Random glucose
** Specifically uncontrolled hypertension
Minimum Grade
3
3
3
3
3
3
3
If the patient experiences any adverse event which, in the investigator’s opinion, makes it inadvisable
to continue protocol therapy, administration of study medication should be stopped.
8.1.7
Patient Compliance
Patients will be asked to record the approximate time and number of capsules taken in the Daily Diary
to facilitate compliance. The number of capsules the patient used each day will be collected on the
Telephone Contact Report and recorded in the Treatment Report.
As patients will be given only the number of capsules required to complete the study, it is expected
that the majority of patients will not have any leftover medication. Those that do will have to return
the partially used study medication blister packs to the randomizing centre via mail in pre-addressed
packages. The partially used kits must be returned to the pharmacy for the purpose of drug
accountability. Additional details are provided in Appendix III (Drug Supply, Distribution and
Control) and in the guidebook for pharmacists provided on the SC.23 web page.
8.2
Radiation Treatment Plan
Although the NCIC Clinical Trials Group acts as the coordinating agency for the trial, the
responsibility for treatment of patients rests with the individual investigator.
Protocol radiation therapy is to begin within one week of patient randomization.
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8.2.1
Dose and Fractionation
Each patient will receive 8 Gy in a single fraction to the area(s) to be followed for the study (the index
site(s)). Treatment can be given using Cobalt-60 or 4-20 MV photons. Orthovoltage or 5-20 MeV
electrons may be used for superficial sites such as the sternum, clavicle or ribs.
8.2.2
Treatment Volume
The volume(s) to be treated and the technique(s) used are left to the discretion of the treating radiation
oncologist with the following recommendations:
For metastases to the vertebral column, the treatment volume should include at least one vertebral
body above and below the painful vertebra(e) and the treatment length should not exceed 20 cm. The
minimum margin for long bone metastases should be 2 cm.
8.2.3
Dose Prescription and Treatment Verification
For spinal metastases, radiation dose should be prescribed to mid-vertebral body for single posterior
field; other sites should be prescribed to Dmax for single incident fields and mid-plane dose for opposed
fields.
Simulation films are required to document target localization; however these films should not be sent
to the NCIC CTG.
8.2.4
Analgesia Adjustments Following Radiation Treatment
Patients may be told that if pain improves following radiotherapy, the dose and/or interval of analgesia
may be reduced slowly. Titration of analgesia dosing may be continued by physicians involved or by
home care nurse familiar with the practice of analgesic adjustments.
8.2.5
Re-Irradiation Treatment
Re-irradiation may be delivered at the discretion of the treating radiation oncologist no sooner than
four weeks after study radiation therapy. If it will not adversely affect a patient’s pain management,
please consider postponing re-irradiation until after the final study contact at six weeks after study
radiation treatment. If re-irradiation is delivered, this will be recorded in RAVE and any response to
treatment will not be attributed to study radiotherapy.
8.3
Concomitant Therapy
8.3.1
Permitted


8.3.2
Any opioid analgesic
Any co- or adjuvant analgesic, with the exception of any systemic steroid
Not Permitted


Any systemic steroid
Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA; aspirin) are not
permitted due to the increased risk of GI bleed. Low dose ASA for anti-platelet therapy may be
continued if it has been used for more than one month at the time of randomization.
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9.0
EVALUATION DURING AND AFTER PROTOCOL TREATMENT
All patients entered on study must be evaluated according to the schedule outlined in Appendix I with
documentation submitted according to the schedule in Appendix IV.
9.1
Evaluation During and After Protocol Treatment
Investigations
Timing
•
•
Daily Patient Diary /
Telephone Contact Report
•
Day 42 follow-up telephone
interview / Telephone Contact •
Report
•
Pain score and
analgesic consumption
Concomitant
medications
•
•
Adverse Events*
•
Other investigations
•
•
Quality of Life
Pill compliance
•
Collected on Telephone
Contact Report at each study
telephone contact
•
•
*
•
Day 42
Day 2, Day 4, Day 7 and Day 10 (with
leeway for weekends)
Day 42
Patients must be monitored
for adverse events at each
•
study telephone contact with
details recorded on Telephone •
Contact Report
Day 2, Day 4, Day 7 and Day 10 (with
leeway for weekends)
Day 42
Spinal cord or cauda equina
compression
Pathological fractures
•
Day 10 and Day 42; no study-specific
radiologic investigations required
•
Day 10 and Day 42
•
Patient records information daily for 10
days following radiotherapy
CRA collects on Telephone Contact
Report on Day 2, Day 4, Day 7 and Day
10 (with leeway for weekends)
Quality of Life questionnaire
(EORTC QLQ-C15-PAL,
QLQ-BM22 and items from
the Dexamethasone Symptom
Questionnaire)
Daily Patient Diary /
Telephone Contact Report
•
•
Translational research
Patient records information daily for 10
days following radiotherapy
CRA collects on Telephone Contact
Report on Day 2, Day 4, Day 7 and Day
10 (with leeway for weekends)
Urine collection
Morning of Day 4 after radiotherapy for
patients randomized at a centre
participating in the correlative science
component of the study
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse
Events (CTCAE) (Appendix V).
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9.2
Format of Patient Evaluations
9.2.1
Daily Patient Diary and Electronic Data Capture
A diary in paper form will be given to the patient prior to dexamethasone / placebo administration and
radiation treatment. This will be used to obtain the patient’s worst pain score(s) (using Question 3 of
the Brief Pain Inventory – Short From, including reference to the sites(s) of treatment) and opioid
analgesic use for the 24 hours prior to treatment. The CRA must enter this information into the NCIC
CTG RAVE system for electronic data capture in the Baseline Report.
The patient will complete the rest of the diary over the next 10 days. This will be used to obtain the
patient’s worst pain score(s) and opioid analgesic use for each day.
9.2.2
CRA Telephone Contacts With Patient
All telephone contacts and attempts to contact the patient must be documented using the Telephone
Contact Report. For monitoring purposes, this form will act as source documentation for telephone
contacts with patients.
During these telephone contacts, the CRA will obtain the patient’s pain score and opioid analgesic use
(as recorded by the patient in the daily diary with clarification if necessary) for each of the days since
the last contact. This information will be entered into the NCIC CTG RAVE system. In addition, any
adverse events and the use of concomitant medications will be recorded and reported in RAVE.
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On-Study Period
The on-study period is defined as the time between the first dose of study medication and end of the
tenth day following the first dose of study medication.
During the on-study period, the CRA is to contact the patient by telephone on Days 2, 4, 7 and 10 with
leeway for weekends and patient unavailability. A table with guidelines for contact scheduling is
provided below.
Day of RT
(Day 0)
Actual Day 2
Actual Day 4
Actual Day 7
Actual Day 10
Day 2 contact
Day 4 contact
Day 7 contact
Day 10 contact
Wednesday
Friday
Subsequent Monday
Subsequent Thursday
Wednesday
Friday *
Subsequent Monday **
Subsequent Thursday ♦
Thursday
Saturday
Subsequent Tuesday
Subsequent Friday
Thursday
Friday *
Subsequent Tuesday **
Subsequent Friday ♦
Friday
Sunday
Subsequent Wednesday
Subsequent Saturday
Friday
Subsequent
Monday *
Subsequent
Wednesday ** ♦
Second subsequent
Monday
Saturday
Subsequent Monday
Subsequent Thursday
Subsequent Sunday
Friday
Subsequent
Monday *
Subsequent Thursday ** ♦
Second subsequent
Monday
Sunday
Subsequent Tuesday
Subsequent Friday
Second subsequent
Monday
Subsequent
Monday
Subsequent
Tuesday *
Subsequent Friday **
Second subsequent
Monday ♦
Monday
Tuesday
Wednesday
Thursday
Friday
*
**
♦
Remind patients participating in the urine collection component of the study to collect a sample on Day 4.
Obtain date of urine collection from appropriate patients and record in RAVE.
Remind patient to complete Day 10 Quality of Life questionnaire and to return the questionnaires to the
randomizing site by mail.
During the Day 4 contact, the CRA should remind patients participating in the urine collection
component of the study to collect a urine sample if they have not already done so on that day. During
the Day 7 contact, the CRA should confirm that the sample was collected and shipped to the
randomizing centre for storage and record the date(s) of collection and shipping.
The patient should be reminded to complete the Day 10 Quality of Life questionnaire on the
appropriate day as outlined above. The patient should be given a paper copy of this questionnaire prior
to the expected completion date and should be instructed to mail the completed questionnaire back to
the randomizing centre. If it is preferable to the patient, or s/he is not able to return the questionnaire
by mail, the CRA can contact the patient on the appropriate day and administer the questionnaire by
telephone. Please see Appendix VII for more details.
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9.2.3
Follow-Up Contact at Day 42 After Radiotherapy
At Day 42 after a patient’s radiotherapy treatment, the CRA should contact the patient by telephone to
obtain the patient’s pain score(s) and opioid medication intake information, as well as other
information such as the experience of any adverse events and the use of any concomitant medications.
This information must be documented on a Telephone Contact Report and will be recorded in the
NCIC CTG RAVE system. In addition, the patient should be reminded to complete the Quality of Life
questionnaire (given or mailed to patient prior to expected completion date) and mail it back to the
randomizing centre. If it is preferable to the patient, or s/he is not able to return the questionnaire by
mail, the CRA can administer the questionnaire by telephone.
9.3
Minimum Data to Collect
At a minimum, the patient’s worst pain score(s), the comparison of the current worst pain to the
baseline worst pain, and complete opioid analgesic consumption should be obtained. This includes the
exact amount of breakthrough analgesia the patient used. As pain flare is a transient phenomenon, it is
imperative that this information is obtained for each of the ten daily assessments after radiotherapy. If
information is missing for even one day, it is likely that it will not be possible to accurately assess
whether or not the patient experienced pain flare.
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10.0
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS
10.1
Evaluability
10.1.1 Evaluable for Adverse Events
All patients will be evaluable for adverse event evaluation from the time of their first treatment with
dexamethasone / placebo.
10.1.2 Evaluable for Pain Flare
All patients who have received at least a single 8 Gy dose of palliative radiotherapy and provide
complete worst pain score information for at least one site of radiation treatment and opioid analgesic
intake information at baseline and for each day during the on-study period will be considered
evaluable for pain flare. The definition of pain flare is outlined below.
10.1.3 Evaluable for Response to Radiotherapy
All patients who have received at least a single 8 Gy dose of palliative radiotherapy and provide
complete worst pain score information for at least one site of radiation treatment and opioid analgesic
intake information at baseline and at the Day 42 follow up contact will be considered evaluable for
response to radiotherapy. Patients will have their response classified according to the definitions set
out below.
10.1.4 Evaluable for Quality of Life Assessment
All patients who have completed a baseline quality of life questionnaire (EORTC QLQ-C15-PAL +
QLQ-BM22 + items from the Dexamethasone Symptom Questionnaire) and at least one follow-up
questionnaire (Day 10 or Day 42) are evaluable for quality of life as assessed by the instrument(s)
completed.
10.2
Definitions of Pain Flare, Response and Progression
10.2.1 Definition of Pain Flare
Patients must meet both criterion a) and b) listed below at a particular treated site to be considered to
have experienced pain flare.
a) Changes in Pain Score and/or Analgesic Intake
Pain flare is defined a priori as a minimum of a two-point increase in worst pain score on a scale
of 0-10 (wording taken from Question 3 of the Brief Pain Inventory - Short Form [Cleeland 1994])
for the treated site compared to the 24-hour worst pain score recorded on the day of treatment
(Day 0) prior to receiving study medication with no decrease in analgesic intake, or a 25% or more
increase in analgesic intake (employing daily oral morphine equivalence) compared to the
analgesic intake in the 24 hours prior to receiving study medication with no decrease in worst pain
score. If the worst pain score recorded prior to treatment on Day 0 is 9, the criteria for pain flare
are met if the follow-up worst pain score is 10 accompanied by the response that the
corresponding worst pain is worse than the worst pain recorded prior to treatment on Day 0 with
no decrease in analgesic intake. If the worst pain score recorded prior to treatment on Day 0 is 10,
the criteria for pain flare are met if the follow-up worst pain score is 10 accompanied by the
response that the corresponding worst pain is worse than the worst pain recorded prior to
treatment on Day 0, again with no decrease in analgesic intake.
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For patients who are not using opioid analgesics in the 24 hours prior to receiving study
medication (daily oral morphine equivalence = 0), consumption of any opioid analgesic without a
reduction in worst pain score relative to the worst pain score recorded prior to treatment on Day 0
will meet this criterion for pain flare.
b) Return to Baseline
To distinguish pain flare from progression of pain, the worst pain score and analgesic intake must
return to levels that are the same as or less than those recorded prior to treatment on Day 0 to be
considered a pain flare. This must occur within the eleven-day on-study period.
10.2.2 Definition of Pain Response
Response to radiotherapy is based on the International Bone Metastases Consensus Endpoint
definitions.
Complete response is defined as a worst pain score of zero (0) at the bony metastatic site with no
concomitant increase in analgesic intake (stable or reduced oral morphine equivalent dosage
(OMED)).
Partial response is defined as any of the following:
i.
Reduction in worst pain score of two or more at the bony metastatic site on a 0–10 scale without
analgesic increase.
ii. Analgesic reduction of 25% or more from baseline without an increase in worst pain score with
reference to baseline.
iii. For patients who were using opioid analgesics at the baseline assessment, a daily oral morphine
equivalence of zero (0) without an increase in worst pain score relative to the baseline worst pain
score.
10.2.3 Definition of Pain Progression
Pain progression is based on the International Bone Metastases Consensus Endpoint definition.
Pain progression is defined as any of the following:
i.
An increase in worst pain score of two or more points above baseline at the treated site without
reduction of analgesic use.
ii. An increase of 25% or more in daily oral morphine equivalent compared with baseline, without
reduction in worst pain score.
iii. For patients who were not using opioid analgesics at the baseline assessment (daily oral morphine
equivalence = 0), consumption of any opioid analgesic without a reduction in worst pain score
relative to the baseline worst pain score.
Stable pain (SD) is assigned to the remaining evaluable patients.
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10.3
Evaluation of Response-Related Endpoints
10.3.1 Incidence of Pain Flare
Patients will be considered to have pain flare if they meet the criteria for pain flare outlined above. For
the primary endpoint, pain flare incidence will be assessed on a per patient basis. As a patient can
receive radiation treatment at one or two painful sites as part of this study, a secondary analysis will be
done to determine the incidence of pain flare per treated site.
If an individual patient experiences more than one pain flare in the eleven-day on-study period, only
the first episode of pain flare will be considered for the primary endpoint.
If the pain flare starts during Days 0 - 5, but does not return to baseline until the Day 6 - 10 time
period, the flare will be assigned to the both the Day 0 - 5 and Day 6 - 10 time periods for the
appropriate secondary endpoints.
Patients who experience increased worst pain scores and/or analgesic intake as outlined above in the
definition of pain flare, but who do not have their pain scores and/or analgesic intake return to baseline
levels by Day 10 after radiotherapy are considered to have progressive pain.
10.3.2 Response to Radiation Treatment
The response to radiation treatment will be determined using the overall response rate (complete
response and partial response) at Day 42 after radiation therapy. Any response observed for patients
who have received re-irradiation treatment to the index site(s) prior to the Day 42 assessment will be
attributed to the re-irradiation treatment, not the study treatment.
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11.0
SERIOUS ADVERSE EVENT REPORTING
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy of
the CTCAE can be downloaded from the CTEP web site:
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse events
must be recorded on case report forms. In addition, all “reportable” serious adverse events are subject
to expedited reporting using the SAE portion of the NCIC CTG electronic data capture system being
used for this trial. The term ‘reportable SAE’ is used in the definitions which follow to describe those
SAEs which are subject to expedited reporting to NCIC CTG.
11.1
Definition of a Reportable Serious Adverse Event

All serious adverse events which are unexpected and related to protocol treatment must be
reported in an expedited manner (see Section 11.2 for reporting instructions). These include
events occurring during the treatment period (until 30 days after last protocol treatment
administration) and at any time afterwards.

Unexpected adverse events are those which are not consistent in either nature or severity with
information contained in the product monograph.

Adverse events considered related to protocol treatment are those for which a relationship to the
protocol agent cannot reasonably be ruled out.

A serious adverse event (SAE) is any adverse event that at any dose:
–
results in death
–
is life-threatening
–
requires inpatient hospitalization or prolongation of existing hospitalization (excluding
hospital admissions for study drug administration, transfusional support, scheduled elective
surgery and admissions for palliative or terminal care)
–
results in persistent or significant disability or incapacity
–
is a congenital anomaly/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited reporting is
appropriate in other situations such as important medical events that may not be immediately lifethreatening or result in death or hospitalization but may jeopardize the patient or may require
intervention to prevent one of the events listed above.
11.2
Serious Adverse Event Reporting Instructions
All reportable serious adverse events must be reported using the web-based Electronic Data Capture
(EDC) system being used for this trial. For details about accessing the EDC system and completing the
online SAE report form, please refer to the NCIC CTG Generic Data Management Guidebook for
EDC Studies posted on the SC.23 section of the NCIC CTG website (www.ctg.queensu.ca).
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Within 24 hours:
Complete preliminary Serious Adverse Event Report and submit to NCIC CTG
via EDC system.
Within 10 days:
Update Serious Adverse Event Report as much as possible and submit report to
NCIC CTG via EDC system.
EDC Web Application Interruption:
In the rare event that internet connectivity to the RAVE EDC system is disrupted, please print and
complete a paper copy of the SAE Report available from the trial specific website.
Fax the paper SAE report to:
Carolyn Wilson, Study Coordinator
NCIC Clinical Trials Group
Fax: 613-533-2941
Please use the same timelines for submission as for direct EDC reporting.
Once internet connectivity is restored, the information that was faxed to NCIC CTG on the paper SAE
report must be entered by the site into the EDC SAE web application.
Local Internet Interruption:
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report
from the trial website, please phone the SC.23 trial team (613-533-6430) to obtain a copy of the SAE
Report by fax. Once completed, the report must be faxed back to NCIC CTG as indicated above. Once
internet connectivity is restored, the information that was faxed to NCIC CTG on the paper SAE
Report must also be entered by the site into the EDC SAE web application.
In cases of prolonged internet interruptions, please contact the NCIC CTG Safety Desk for further
instructions (613-533-6430).
11.3
NCIC CTG Responsibility for Reporting Serious Adverse Events to Health Canada (Office of Clinical
Trials)
The NCIC CTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials)
for those events which meet regulatory requirements for expedited reporting, i.e. events which are
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or for
which a causal relationship with protocol treatment cannot be ruled out).
11.4
Reporting Safety Reports to Local Research Ethics Boards
NCIC CTG will notify all Investigators of all Safety Reports (Serious Adverse Events (SAEs) from
this trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory
authorities in Canada as reported to the NCIC CTG. This includes all serious events that are
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. Investigators must
notify their Research Ethics Boards (REBs) and file the report with their product monograph. The date
of REB Submission for SAEs and SUs will need to be entered into the NCIC CTG trial SC.23 webbased safety monitoring utility and documentation of REB submission must be retained in the study
binder on site.
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For this purpose, the REB submission template letter provided by NCIC CTG should be used. Please
note:

this letter must be either printed on institutional letterhead or contain the centre identification/REB
name;

the date of REB submission must be provided;

this form must be signed by one of the approved participants (according to the participants list) for
this trial.
The submission of these events to your ethics board should be done as soon as possible (we suggest
within 30 days). REB submissions greater than 90 days from the date of notification will be regarded
as delinquent and a major deficiency will be assigned.
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12.0
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING
12.1
Criteria for Discontinuing Protocol Treatment
Patients may stop protocol treatment in the following instances:
 Intercurrent illness which would, in the judgment of the investigator, affect assessment of clinical
status to a significant degree, and require discontinuation of protocol therapy.
 Unacceptable toxicity as defined in Section 8.0.
 Disease progression as identified and defined by investigator opinion.
 Request by the patient.
 Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the
investigation schedule and continue follow-up, even if patients discontinue protocol treatment
prematurely and/or no longer attend the participating institution.
12.2
Therapy After Protocol Treatment is Stopped
Therapy after protocol treatment is at the discretion of the investigator.
12.3
Follow-Up Off Protocol Treatment
Patients will be contacted six weeks after study radiotherapy to obtain their pain score and opioid
medication intake information. In addition, the adverse event experience and concomitant medication
use should be recorded. The patient should also complete the Quality of Life questionnaire.
After this contact, it is no longer necessary to follow patients (e.g. for survival).
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13.0
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION
There is no central radiology, radiotherapy or pathology review for this trial.
13.1
Specimen Collection
Tumour blocks will not be collected or banked as part of this trial.
Participation in the correlative science component of this study may be limited to centres that are
expected to enroll significant proportions of patients on the trial. Collection of urine samples for
correlative studies is mandatory for participation on the study for patients at these designated sites;
however, collection of the saliva sample is not. Patients who wish to contribute samples must have
completed the informed consent process for specimen collection prior to sample donation.
Additional details on collection of saliva and urine samples can be found in the Correlative Studies
Manual (posted on the SC.23 web page).
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AMEND #1: 2013-DEC-19
14.0
STATISTICAL CONSIDERATIONS
14.1
Clinical Study of Pain Flare Incidence
14.1.1 Objectives and Design
The primary objective is to compare the effectiveness of prophylactic dexamethasone vs. placebo in
reducing the incidence of radiation-induced pain flare. The secondary objectives include examining
the toxicity of dexamethasone, comparing the quality of life of patients in the two treatment groups,
and studying the relationship between pain flare and the response to radiotherapy at six weeks
following the completion of radiation treatment.
The study is designed as a superiority study. The null hypothesis for the primary endpoint is that the
incidence of pain flare with placebo is equal to or lower than the incidence with dexamethasone. The
alternative hypothesis is that the incidence is higher with placebo than with dexamethasone. Patients
will be randomized with equal probability to each of the dexamethasone arm and the placebo arm and
will be stratified according to baseline worst pain score, primary cancer site, number of painful sites
receiving radiation treatment, change of drug formulation and centre.
14.1.2 Primary Endpoint and Analysis
The primary endpoint is the per-patient incidence of radiation-induced pain flare that occurs from the
time of radiotherapy to ten days after the completion of radiation treatment. Pain flare is defined in
section 10.2.1. The analysis of the primary outcome will be based on the intent-to-treat principle and
will include all randomized patients, regardless of whether radiation therapy is given, given as per
protocol or whether there has been fidelity to treatment allocation. Patients that are inevaluable for the
primary endpoint due to missing data will be considered to have experienced pain flare for the intentto-treat analysis of the primary endpoint. Multiple sensitivity analyses will also be performed to further
evaluate the results: (i) complete case analysis that treats missing data as a separate inevaluable
category; (ii) an analysis that assumes patients with missing data do not have pain flare; (iii) extreme
case analysis favouring placebo that assigns patients with missing data with and without pain flare in
the dexamethasone arm and placebo arm, respectively; (iv) imputation analysis that assigns different
portions of the missing data to be either pain flare or no pain flare. In addition, an analysis of the
incidence of pain flare per painful site treated will be performed. A secondary “as treated” sensitivity
analysis will be performed to include only eligible patients who have received protocol-stated radiation
therapy.
A Chi-square analysis will be applied to the pain flare incidence rates between the two arms and the
lower 95% confidence bound of the rate difference between the two arms will be evaluated. The
method of Mantel-Hanzeal Chi-square will be used for the stratified analysis (stratify by baseline worst
pain score, primary cancer site, number of painful sites receiving radiation treatment, change of drug
formulation. A pre-planned subset analysis will be conducted for patients randomized prior to change
of drug formulation. Subset analysis for patients randomized after change of drug formulation will not
be conducted due to small sample size).
14.1.3 Sample Size and Duration of Study
Based on pilot work [Chow 2007; Hird 2009a; Hird 2009b], it is hypothesized that the incidence of pain
flare with radiation treatment will be reduced from 35% to 15% with dexamethasone for the primary
endpoint. Assuming a 15% attrition and inevaluable rate, we expect the incidences of pain flare for the
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intent-to-treat analysis to change to 44.75% and 27.75% for the placebo and dexamethasone arms,
respectively. Using two proportions power analysis with Fleiss continuity correction for phase III
clinical trials [Fleiss 1980] with one-sided alpha = 0.05 and beta = 0.1 (i.e. power = 0.9), a sample size
of 149 patients are required in each arm (298 total patients) after taking into account one planned
interim analysis (see section 14.1.5 for details). Assuming that 210 patients will be randomized prior
to change of drug formula, the power will be reduced to 78% for the pre-planned subset analysis.
Assuming an accrual rate of ten patients per month, the estimated duration of the study is 2.5 years.
14.1.4 Safety Monitoring
Adverse events will be monitored on an ongoing basis by the central office and their frequencies
reported annually at investigators' meetings.
14.1.5 Interim Analysis
For the randomized clinical study, one interim analysis will be planned when 149 patients can be
assessed for the primary end point, to allow early stop of the trial if the results are extreme. Based on
the Lan-DeMets error spending function utilizing a power family with power 3, which approximates
the O’Brien-Fleming boundaries [Jennison 2000], the stopping boundary for the interim analysis will be
p ≤ 0.006 for superiority and p > 0.575 for futility . The final analysis will be conducted at an alpha
level of 0.0486 to maintain the overall one-sided alpha of 0.05. At the time of the interim analysis, if
the pain flare incidence for the placebo group is obviously different from the pre-estimated 35% or the
inevaluable rate is obviously different from 15%, an adjustment of sample size may be necessary.
14.2
Cytokine Changes
14.2.1 Objectives and Design
The primary objective is to determine if pain flare is mediated by changes in the balance between proand anti-inflammatory cytokines. The secondary objective is to determine if prophylaxis of pain flare
by dexamethasone is mediated by its modulation of cytokine levels.
The levels of markers of inflammation such as IL-1, IL-6 and TNFα will be measured in urine before
and after treatment. The associations between pain flare incidence, changes in cytokine levels and
dexamethasone treatment will be investigated.
14.2.2 Endpoints and Analysis
The primary endpoints of this correlative study are the changes in inflammatory cytokine levels (IL-1,
IL-6 and TNF-α) before and after treatment.
Analysis of variance procedures will be used to analyze the differences in inflammatory cytokine level
changes between patients with and without pain flare in the first ten days after radiotherapy, with
stratification for treatment (dexamethasone and placebo). Changes in the levels of these inflammation
markers will be correlated to dexamethasone treatment using linear regression models. The differential
benefit of dexamethasone treatment on pain flare for patients with different changes of cytokine levels
will be investigated through logistic regression models with interaction between treatment and
cytokine level changes.
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14.2.3 Sample Size
Based on a clinical pain flare incidence rate of 35% in patients receiving palliative RT for painful bone
metastases, a sample size was calculated. Assuming that the TNFα level in the urine samples has a
mean value of 3.9 pg/mL with standard error of the mean (SEM) of 1.3pg/mL (based on 30 patients)
for pain flare patients and SEM of 0.3pg/mL (based on 30 patients) for patients without pain flare
[Sirera 2003], to detect a 50% change in the TNFα level with a two-sided alpha = 0.05 and 80%
power, a sample size of 169 patients (59 patients with pain flare and 110 patients without pain flare) is
required. Assuming a 15% attrition and inevaluability rate, we will need to enroll 198 patients in total
for this translational study.
The sample size will be re-evaluated when data is available from pilot studies examining TNFα levels
in patients treated with dexamethasone as part of previous studies.
14.3
Markers of Bone Turnover
Changes in the levels of markers of bone turnover have been correlated with pain response to external
beam palliative radiotherapy [Hoskin 2000]. The association between baseline levels of pyridinoline and
N-telopeptide and pain flare will be investigated in an exploratory analysis.
14.4
Analysis of Single Nucleotide Polymorphisms (SNPs) in DNA Obtained from Saliva Specimens
Genetic variation may be a cause of the observed inter-individual variability in rates of dexamethasone
metabolism. In this exploratory analysis, associations between single nucleotide polymorphisms,
dexamethasone metabolism by patients and pain flare will be investigated.
14.5
Quality of Life Analysis
In the primary QOL analysis, the mean score changes (baseline to Day 10) between arms will be
compared using a repeated measures analysis and the standard NCIC CTG QOL data analysis. If all
298 patients will participate in the QOL study, we will have 90% power to detect an effect size of 0.41
or higher at a two-sided significant level of 0.05, assuming that 15% of cases are inevaluable or have
missing data.
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15.0
PUBLICATION POLICY
15.1
Authorship of Papers, Meeting Abstracts, Etc.
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to
publish the trial under a group title, or with naming of individual authors. If the latter approach is
taken, the following rules will apply:




The first author will generally be the chair of the study.
A limited number of the members of the NCIC Clinical Trials Group may be credited as authors
depending upon their level of involvement in the study.
Additional authors, up to a maximum of 15, will be those who have made the most significant
contribution to the overall success of the study. This contribution will be assessed, in part but not
entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the study
chair.
In the event of a separate paper dealing with the quality of life outcomes, the first author will
generally be the Quality of Life Coordinator on the trial committee.
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made:
"A study coordinated by the NCIC Clinical Trials Group. Participating
investigators included: (a list of the individuals who have contributed
patients and their institutions)."
15.2
Responsibility for Publication
It will be the responsibility of the study chair to write up the results of the study within a reasonable
time of its completion. If after a period of six months following the analysis of study results the draft is
not substantially complete, the central office reserves the right to make other arrangements to ensure
timely publication.
15.3
Submission of Material for Presentation or Publication
Material may not be submitted for presentation or publication without prior review by the NCIC CTG
Physician Coordinator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair.
Individual participating centres may not present outcome results from their own centres separately.
Supporting groups and agencies will be acknowledged.
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16.0
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES
16.1
Institution Eligibility for Participation
Selected NCIC CTG member centres and international single-study centres will be chosen to
participate in this study. Criteria for inclusion include participation in pilot studies, demonstrated
accrual to previous NCIC CTG palliative radiotherapy trials, projected accrual contributions of a
minimum of 20 patients to the current study, and demonstration of data quality (where available).
The NCIC CTG will submit a completed Health Canada Clinical Trial Site Information Form via fax
to Health Canada for each participating Canadian centre prior to local activation.
16.2
Investigator Qualifications
For all investigators (principal investigators and co-investigators) the following documentation must
be on file with the NCIC CTG:
 Current curriculum vitae, updated and submitted within two years at the time of randomization.
 Documentation indicating completion of training in the protection of human research participants
(e.g. NCI U.S. Completion Certificate).
 Completion of the required NCIC CTG GCP training modules.
For the principal investigator only:
 A Health Canada Qualified Investigator Undertaking Form must be completed and signed by the
principal investigator of the study at participating Canadian centres and received by the NCIC
CTG central office before that centre can be locally activated.
16.3
REB (Research Ethics Board) Approval for Protocols
Each participating centre will have on file with the NCIC CTG central office, as part of its
membership / agreement documents, a description of its ethics review process and composition of its
REB.
REB Composition
Membership of an REB approving this protocol must be consistent with Canadian regulatory
requirements, summarized as follows:
 at least 5 members;
 majority of members are Canadian citizens or permanent residents;
 includes 2 members whose primary expertise and experience are in a scientific discipline with
broad experience in the methods and areas of research to be approved (1 of these is from a
medical discipline);
 includes 1 member knowledgeable in ethics;
 includes 1 member knowledgeable in Canadian laws relevant to the biomedical research to be
approved;
 includes 1 member whose primary experience and expertise are in a non-scientific discipline;
 includes 1 member who is from the community or is a representative of an organization interested
in the areas of research to be approved and who is not affiliated with the NCIC CTG or the centre
where the clinical trial is to be conducted.
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A Health Canada REB Attestation Form must be completed and signed by the REB representative.
Alternatively, an attestation to the following may be included in the signed local ethics approval
document:
 The membership of the Research Ethics Board complies with the membership requirements for
Research Ethics Boards defined in Division 5 of the Food and Drug Regulations;
 The Research Ethics Board carries out its functions in a manner consistent with Good Clinical
Practice; and
 The Research Ethics Board has reviewed and approved the clinical trial protocol and informed
consent for the trial which is to be conducted by the qualified investigator named at the specified
clinical trial site. This approval and the views of this Research Ethics Board have been
documented in writing.
This documentation must be received by the NCIC CTG central office before the centre can be locally
activated.
Initial Approval
Member centres wishing to participate in a trial are required to obtain full board local ethics approval
of the protocol and consent form (see below) by the appropriate REB.
Annual Re-Approvals
Annual re-approval must continue until NCIC CTG informs you that it is no longer required.
Amendments/Administrative Updates
All amendments or administrative updates to the protocol must undergo review by local REBs.
Amendments/administrative updates will be circulated to all participating sites in a standard format
with clear instructions regarding REB review. If full board approval of an amendment is required it
will be specified.
Amendments will be reviewed and approved by Health Canada prior to central implementation of the
amendment, and by REBs prior to local implementation, EXCEPT when the amendment eliminates an
immediate hazard to clinical trial subjects. Amendments will be distributed with Health Canada REB
attestation forms which must be completed. For each amendment NCIC CTG will collect
documentation of REB approval, a completed REB attestation form, and the date the amendment is
locally activated.
REB Refusals
If an REB refuses to approve this protocol (or an amendment/administrative update to this protocol)
the NCIC CTG must be notified immediately of the date of refusal and the reason(s) for the refusal.
Notification will then be made to Health Canada.
Serious Adverse Events, Safety Updates, Investigator Brochure Updates and Product Monograph
Updates
During the course of the study serious adverse events, safety updates, investigator brochure updates or
product monographs may be sent to you for reporting to your REB. The date of REB submission for
these documents will need to be entered into the NCIC CTG trial SC.23 web based safety monitoring
utility and documentation of REB submission must be retained in the study files on site.
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16.4
Informed Consent
Informed Consent Document
The REB of an institution must approve the consent form document which will be used at that centre
prior to its local activation; changes to the consent form in the course of the study will also require
REB approval.
It is essential that the consent form contain a clear statement which gives permission for 1) information
to be sent to and 2) source medical records to be reviewed by the NCIC CTG and other agencies as
necessary. The consent form must include all ICH-GCP consent elements. In addition, the consent
form should include all elements required by NCIC CTG policy, and centres receiving funding from
NCEHR, SSHRC and/or CIHR should include elements from the Tri Council Policy Statement
(TCPS).
Informed consent forms that do not contain all ICH-GCP required elements will require an amendment
and will lead to the delay of local activation. A complete list of the elements required by regulations,
guidelines and NCIC CTG policy can be found by accessing the NCIC CTG website at
http://www.ctg.queensu.ca/private/ethics/consent_RE_Checklists.html.
Consent Process/Patient Eligibility
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically
incapacitated such as comatose patients) are not to be recruited into the study. Patients competent but
physically unable to sign the consent form may have the document signed by their nearest relative or
legal guardian. Each patient will be provided with a full explanation of the study before consent is
requested.
16.5
Retention of Patient Records and Study Files
ICH Good Clinical Practice guidelines apply to NCIC CTG studies. It is the responsibility of NCIC
CTG to inform the investigator/institution as to when trial related records no longer need to be
retained. The investigator/institution should take measures to prevent accidental or premature
destruction of these documents.
NCIC CTG will notify all the trial investigators/institutions and all the regulatory authorities if clinical
development of an investigational product discontinues or when trial related records no longer need to
be retained.
16.6
Centre Performance Monitoring
This study is eligible for inclusion in the Centre Performance Index (CPI). Forms are to be submitted
according to the schedule in the protocol. There are minimum standards for performance.
Because of the intensiveness of data collection required to evaluate the primary endpoint for this study,
patient inevaluability will also be monitored on an ongoing basis as part of central monitoring, as well
as the reasons for inevaluability. In particular, the patient inevaluability rate at each centre will be
determined after the accrual of the first ten patients. This will be compared to the expected
inevaluability rate for the trial and the inevaluability rate at other centres. If data from a centre is not of
appropriate quality to permit evaluation of a significant proportion of randomized patients and/or is
out of line with data quality at other centres, the information will be reviewed by the trial committee
and an action may be required.
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16.7
On-Site Monitoring/Auditing
NCIC CTG site monitoring/auditing will be conducted at participating centres in the course of the
study as part of the overall quality assurance program. The monitors/auditors will require access to
patient medical records to verify the data, as well as essential documents, standard operating
procedures (including electronic information), ethics documentation and pharmacy documentation (as
applicable).
As this trial is conducted under a CTA with Health Canada, your site may be subject to an inspection
by the Health Canada Inspectorate.
16.8
Case Report Forms
A list of forms to be submitted, as well as expectation dates, is found in Appendix IV.

The Eligibility Checklist (EC) must be completed to randomize the patient.

The Site Irradiation Report (SI) must be completed before any other post-randomization folders
and must reflect the painful site(s) treated for the study if different than what was planned and
noted on the Eligibility Checklist.

The Baseline Report (BL) collects pre-randomization information as well as some information
about Day 0 (the day of study radiotherapy).

All telephone contacts (and contact attempts) with the patient must be documented using the
Telephone Contact Report (TCR) paper form. This will become source documentation for
monitoring of the trial. The patient will report the information recorded in his/her diary to the
CRA during each telephone contact. The CRA will record this information on the TCR during the
telephone contact, then enter it in the RAVE electronic data capture system. The pain and opioid
information must be entered into the Telephone Follow-Up Report (TF) after each telephone
contact, but other information related to the on-study period (e.g. adverse event and concomitant
medication information) will be entered into the Treatment Report (TR) at the end of the on-study
period (ten days after study radiotherapy).

The Day 42 contact with the patient must also be documented on a Telephone Contact Report
form. This information is entered into the RAVE EDC system in the Follow-Up Report.

A Death Report is only required if the patient dies before the Day 42 follow-up contact.
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17.0
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Minagawa K, Kasuya Y, Baba S, et al. Identification and quantification of 6β-hydroxydexamethasone as a major
urinary metabolite of dexamethasone in man. Steroids 1986; 47:175.
Mortimer JE, Dehdashti F, Siegel BA, et al. Metabolic flare: indicator of hormone responsiveness in advanced
breast cancer. J Clin Oncol 2001; 19:2797.
Osoba D, Bejak A, Brundage M, et al. Analysis and interpretation of health-related quality-of-life data from clinical
trials: basic approach of The National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 2005; 41:280.
Puisset F, Chatelut E, Dalenc F, et al. Dexamethasone as a probe for docetaxel clearance. Cancer Chemother
Pharmacol 2004; 54:265.
Rodchenkov GM, Uralets VP, Semenov VA, et al. Analysis of dexamethasone, triamcinolone, and their metabolites
in human urine by microcolumn liquid and capillary gas chromatography mass spectrometry. HRC CC J High
Resolut Chromatogr Chromatogr Commun 1988; 11:283.
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Roos DE, Turner SL, O’Brien PC, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy
for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother
Oncol 2005; 75:54.
Sabino MA, Ghilardi JR, Jongen JL, et al. Simultaneous reduction in cancer pain, bone destruction and tumor
growth by selective inhibition of cyclooxygenase-2. Cancer Res 2002; 62:7343.
Salerno A, Hermann R. Efficacy and safety of steroid use for postoperative pain relief: Update and review of the
medical literature. J Bone Joint Surg Am 2006; 88:1361.
Sirera R, Salvador A, Roldan I, et al. Quantification of proinflammatory cytokines in the urine of congestive heart
failure patients. Its relationship with plasma levels. European J of Heart Fail 2003; 5:27.
Solimando DA. Drug Information Handbook for Oncology, 7th ed. Hudson: Lexi-Comp 2008; 331.
Tian JH, Zhang JM, Hou QT, et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur
J Nucl Med 1999; 26:2.
Turner JH, Claringbold PG, Hetherington EL, et al. A phase I study of samarium-153
ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases. J Clin Oncol 1989;
7:1926.
Turner SL, Gruenewald S, Spry N, et al. Less pain does equal better quality of life following strontium-89 therapy
for metastatic prostate cancer. Br J Cancer 2001; 84:297.
Vardy J, Chiew KS, Galica J et al. Side effects associated with the use of dexamethasone for prophylaxis of
delayed emesis after moderately emetogenic chemotherapy. Br J Cancer 2006; 94:1011.
Weissman DE, Dufer D, Vogel V, et al. Corticosteriod toxicity in neuro-oncology patients. J Neur Enter 1987;
5:125.
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Documents 1948.
Wu J, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of
painful bone metastases. Int J Radiat Oncol Biol Phys 2003; 55:594.
Urch C. The pathophysiology of cancer-induced bone pain: Current understanding. Pall Med 2004; 18:267.
Zurbonsen K, Bressolle F, Solassol I, et al. Simultaneous determination of dexamethasone and 6βhydroxydexamethasome in urine using solid-phase extraction and liquid chromatography: applications to in vivo
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804:421.
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APPENDIX I - PATIENT EVALUATION FLOW SHEET
Required Investigations
Prerandomization *
Daily for
10 days
Day 0 after RT
Day 2
after
RT **
Day 4
after
RT **
Day 7
after
RT **
Day 10
after
RT **
Day 42
after RT
X+
X+
X+
X+
X ++
X
X
X
X
X
Physical
Baseline characteristics
X
Contraindications to steroids
X
Karnofsky Performance
Status
X
Biochemistry
Random glucose
X
Radiology
Any radiological evidence of
bone metastases
corresponding to the
clinically painful area ♦
X♦
Other Investigations
Daily patient diary, including
pain score and analgesic
intake
X ♦♦
X
X ♦♦
Concomitant medications
X
Pathological fractures
X
X
X
Spinal cord compression
X
X
X
X
X
X
X
Urine specimen (participating
centres only)
X
Saliva specimen
(participating patients only)
X†
X
Adverse Events
AE assessment
X
X
X
X
Quality of Life
Quality of Life questionnaire
*
**
♦
♦♦
+
++
†
X
Within 7 days prior to randomization, unless otherwise noted.
See section 9.2.2 for schedule when contact day is on a weekend.
Radiological evidence within 6 months prior to randomization must be available.
Information is to be recorded in the NCIC CTG SC.23 RAVE system in the Baseline Report.
During telephone contact, CRA will obtain complete pain score(s) and medication information from patient (as recorded in Daily
Diary with prompting for completeness if necessary). This information will be recorded in the NCIC CTG SC.23 RAVE system in
the Telephone Follow-up Report.
Information is to be recorded in the NCIC CTG SC.23 RAVE system in the Follow-Up Report.
May be obtained any time between randomization and first administration of dex / placebo.
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be multiples of 10.
ECOG (Zubrod)
Score
0
1
2
3
4
*
Description
Fully active, able to carry on all
pre-disease performance
without restriction.
Restricted in physically
strenuous activity but
ambulatory and able to carry
out work of a light or sedentary
nature, e.g. light housework,
office work.
Ambulatory and capable of all
selfcare but unable to carry out
any work activities. Up and
about more than 50% of waking
hours.
Capable of only limited
selfcare; confined to bed or
chair more than 50% of waking
hours.
Completely disabled. Cannot
carry on any selfcare. Totally
confined to bed or chair.
Karnofsky
Score
Description
Lansky*
Score
Description
100
Normal, no complaints, no
evidence of disease.
100
Fully active, normal.
90
Able to carry on normal activity;
minor signs or symptoms of
disease.
90
Minor restrictions in physically
strenuous activity.
80
Normal activity with effort; some
signs or symptoms of disease.
80
Active, but tires more quickly.
70
Cares for self, unable to carry on
normal activity or do active work.
70
Both greater restriction of and
less time spent in play activity.
60
Requires occasional assistance, but
is able to care for most of his/her
needs.
60
Up and around, but minimal
active play; keeps busy with
quieter activities.
50
Requires considerable assistance
and frequent medical care.
50
Gets dressed, but lies around
much of the day; no active play;
able to participate in all quiet
play and activities.
40
Disabled, requires special care and
assistance.
40
Mostly in bed; participates in
quiet activities.
30
Severely disabled, hospitalization
indicated. Death not imminent.
30
In bed; needs assistance even for
quiet play.
20
Very sick, hospitalization
indicated. Death not imminent.
20
Often sleeping; play entirely
limited to very passive activities.
10
Moribund, fatal processes
progressing rapidly.
10
No play; does not get out of bed.
The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.
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AMEND #1: 2013-DEC-19
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL
General
Dexamethasone and placebo was originally supplied by Valeant Canada, but as of January 2014 will be
supplied by Sunnybrook Pharmacy Manufacturing. The study medication will be packaged into kits by Bay
Area Research Logistics (BARL). Each individual kit will contain enough dexamethasone or placebo capsules
for the entire treatment of a single patient.
Investigational product (dexamethasone / placebo) must be stored in a secure area according to local policies
and regulations and under the storage conditions provided on the product label.
Distribution
Initial supply
When a centre is locally activated, NCIC CTG will notify BARL to send a shipment of drug kits to the centre.
A unique kit number will identify each kit. Upon receipt of the shipment by the centre, the shipment number
must be logged in the NCIC CTG Mango web-based randomization and drug distribution system before any
kits can be assigned to patients. Please see the Pharmacy Guidebook for details. The approximate time between
shipment request and arrival at the centre is 48 hours.
Resupply
Shipment of additional kits will be based on accrual to the trial and will be coordinated through Mango. Please
see the Pharmacy Guidebook for details. Upon receipt of each resupply shipment at the centre, the shipment
number must be logged into Mango before any drug kits can be assigned to patients.
Study medication will generally be shipped in batches tailored to accrual at each site. If you are anticipating an
increase in enrollment, please contact the SC.23 Study Coordinator to ensure that you will have enough kits on
site. The approximate time between shipment request and arrival at the centre is 48 hours.
Damaged supplies
If any damage to kits has occurred in transit or at the centre, please contact the SC.23 Study Coordinator as
soon as possible to arrange shipping of replacement kits.
Labeling and Dispensing to Patient
When a patient has been successfully randomized, the confirmation of randomization letter will contain the kit
assignment for that particular patient. The NCIC CTG SC.23 patient serial number and initials must be
recorded on the label prior to giving the kit to the patient.
Patients who use all study medication are not required to return the empty packaging to the randomizing centre.
Patients who have any capsules remaining will be instructed to mail the capsules and associated packaging
back to the centre. This leftover medication must be returned to the pharmacy for drug destruction following
documentation.
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Drug Accountability
It is the responsibility of the investigator to ensure that the study medication is only dispensed to study subjects
by authorized personnel and according to local policies and regulations. It is the responsibility of the
investigator to ensure that a current record of investigational product disposition is maintained at each study
site where investigational product is inventoried and disposed.
NCIC CTG will provide forms to facilitate inventory control including a master inventory log to record all drug
received and a patient-specific drug accountability log showing the amount, strength and kit number of
investigational product dispensed to each patient and returned at the end of each patient’s participation in the
study. The patient-specific drug accountability log is required even though it is expected that each patient will
only receive a single kit during his or her participation on the study. Copies of completed logs (both master
inventory and patient-specific) will be requested by NCIC CTG at the end of the trial for final reconciliation.
Drug Destruction
Patient returns and expired drug should be destroyed on site as per local Standard Operating Procedures and
documented on the drug accountability log. Instructions on handling unused drug will be provided by the
NCIC CTG at trial closure. Final drug reconciliation will be coordinated by NCIC CTG following trial closure.
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AMEND #1: 2013-DEC-19
APPENDIX IV - DOCUMENTATION FOR STUDY
Follow-up is required for patients from the time of randomization and will apply to all patients. See section
16.8 for additional information.
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except Quality of
Life. For details of accessing the EDC system and completing the online Case Report Forms please refer to the
NCIC CTG EDC Generic Data Management Guidebook posted on the SC.23 area of the NCIC CTG web-site
(www.ctg.queensu.ca).
Electronic CRFs:
Electronic Folder
To Be Completed
Electronically1
Aim Of Folder
Supporting Documentation
and Patient Questionnaires
to be sent by MAIL2
 Consent form for main

Patient Enrolment To document the patient’s eligibility
Folder
characteristics
Baseline Report
Site Irradiation
Report
At the time of randomization
study 3
Saliva Collection
Informed Consent form
(only for patients from
centres participating in
correlative studies
component of trial)3
To collect information at the time of
randomization.
Within 6 weeks after
randomization
 QoL
To collect the actual site(s) that received
study palliative radiotherapy
Within 2 weeks after treatment
and before any information is
entered in any other folders
(except for the Eligibility
Checklist, which is completed
prior to randomization)
 NA
Within 2 weeks after each
telephone contact
 NA
To collect the daily worst pain score and
Telephone Followopioid intake obtained at each telephone
Up Report
contact with patient
Treatment Report
To collect information on protocol
treatment
Within 2 weeks after the end of
the reporting period
 QoL
End of Treatment
Report
To collect information at the completion
of protocol therapy
At the time protocol treatment is
permanently discontinued
 NA
Correlative Studies To document the collection and shipment Within 2 weeks after final urine
Report
of samples for correlative studies
sample collection
 NA
Follow-Up Report
To collect follow-up information at Day
42 after radiotherapy
Within 8 weeks of the follow-up
contact
 QoL
Death Report
To collect information at the time of the
patient’s death if the patient dies before
the Day 42 follow-up contact
Within 8 weeks after the
patient’s death
 Autopsy report, if done.
SAE Report
Within 24 hours of becoming
To document Serious Adverse Events (as
aware of event (updated report
defined in Section 11)
due within 10 days)
 All documentation
relevant to event
1 All supporting documentation and patient questionnaires must also be submitted within the timeframes listed.
2 Supporting documents and patient questionnaires should be mailed as soon as possible after the folder they refer to has been completed electronically.
3 For Canadian centres, it is acceptable to submit only the signature page(s) of the main consent and only the checkbox page(s)/signature page(s) of
the optional consent (if applicable), provided that the version date of the consent form is indicated.
Please see the following page for information on paper CRFs and questionnaires.
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Paper CRFs and Questionnaires:
Form
To be Completed
Due in Central Office
Supporting
Documentation
Required
Quality of Life questionnaire
 Within 7 days prior to
(EORTC QLQ-C15-PAL,
randomization
QLQ-BM22 and items from
 At Day 10 after RT
the Dexamethasone
 At Day 42 after RT
Symptom Questionnaire)
 Within 6 weeks of
randomization
 Within 2 weeks of the end of
the on-study period
 Within 8 weeks of the followup contact
NA
Daily Diary
 Day 0 pre-treatment
information must be
completed with the
patient prior to
receiving first dex /
placebo treatment and
radiotherapy
 Remaining Day 0
information and Day 1
– 10 information must
be completed by the
patient on the
corresponding day
Not required. The patient will be
asked to return the diary to the
centre by mail.
NA
Telephone Contact Report
 At each telephone
contact (and attempt)
with patient
Not required. This document will
be treated as source
documentation when trial is
monitored.
NA
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APPENDIX V -
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas should
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from
the CTEP web site
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
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APPENDIX VI – CORRELATIVE STUDIES AND SAMPLE COLLECTION INSTRUCTIONS
Two sets of samples will be collected for correlative studies, urine and saliva. This section outlines some of the
investigations that will be done using these samples and provides instructions on how to collect, store and ship
them.
Only selected centres will participate in the correlative science component of the trial.
Once each participating centre has obtained local REB approval for SC.23 and is activated, urine and saliva
sample collection kits will be sent to the centre. Please contact the SC.23 Study Coordinator or Clinical Trials
Assistant at the NCIC Clinical Trials Group when more collection kits are required. Please do so at least ten
days before your current stock of kits will be used up to allow time for additional kits to reach your site.
Urine Samples
A urine sample will be collected at the clinic on Day 0 prior to dexamethasone / placebo treatment and
palliative radiotherapy using one of the kits provided. The sample will be aliquoted, frozen and stored at the
randomizing centre.
The patient will be provided with another urine collection kit to collect a second urine sample on the fourth day
after radiotherapy. This will allow the patient to collect the sample without having to come in to the clinic. The
sample will be couriered to the randomizing centre, where it will be aliquoted, frozen and stored. During the
course of the study, batches of frozen samples will be sent to the NCIC CTG Tumour/Tissue Bank where they
will be stored until analysis.
Saliva Samples
A saliva sample will be collected at the clinic after randomization but prior to dexamethasone / placebo
treatment and palliative radiotherapy using the kit provided. Samples will be stored at the randomizing centre
after collection. During the course of the study, batches of saliva samples will be sent to the NCIC CTG
Tumour/Tissue Bank where they will be stored until analysis.
Please see the Correlative Studies Manual for detailed instructions for sample collection and storage
and kit ordering information. This is available on the SC.23 webpage.
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APPENDIX VII - QUALITY OF LIFE ASSESSMENT
Introduction
The assumption that control of symptoms will automatically improve quality of life is probably true but hasn't
yet been tested, especially in determining how certain symptoms may or may not affect quality of life. Current
literature reveals interesting things; two in particular are:
 additional and useful information may be obtained from quality of life measurements
 a growing consensus that the goal of medical care today for most patients is the preservation of function
and well-being in everyday life.
We have reached the stage where the collection of information about psychological distress, social disruption,
emotional trauma and painful side-effects is not only necessary but a routine component in many protocols.
Quality of life data can be used in a variety of ways:
• to try to achieve the best possible outcome for patients
• to evaluate the extent of change in the quality of life of an individual or group across time
• to evaluate new treatments and technologies
• to support approval of new drug applications
• to try to provide the best value for health care dollars
• to compare costs and benefits of various financial and organizational aspects of health care services
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be
based on a combination of quality of life, survival, response, and adverse event data.
Quality of Life for SC.23
The Quality of Life questionnaire will have three components:
• The EORTC QLQ-C15-PAL is a shortened version of the widely-used EORTC QLQ-C30. It represents a
core questionnaire for palliative patients.
• The EORTC QLQ-BM22 module assesses quality of life issues relevant to patients with bone metastases. It
follows the QLQ-C15-PAL.
• A series of single items from the modified Dexamethasone Symptom Questionnaire is intended to cover the
most likely effects of adverse events experienced by patients receiving dexamethasone. It follows the QLQBM22 module.
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as a
guide for the administration of the Quality of Life questionnaire.
1. Preamble
Quality of life data are collected for research purposes, and will usually not be used for the patient’s
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must be
completed by the patient only, without translation, coaching or suggestions as to the "correct" answer by
relatives or health care personnel.
The scheduled times to obtain the questionnaires are as follows:
• pre-randomization (baseline)
• at the end of the on-study period
• at the follow-up contact
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The information provided by the patient in the completed questionnaire is confidential and should not be
discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient.
If a particular question has not been answered, please document the reason(s) in the appropriate space on
the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) on the
appropriate case report forms.
2. Pre-Treatment Assessment
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of
treatment on different areas of the patient's life, e.g. psychological distress, social disruption, side-effects,
et cetera.
The CRA should collect the questionnaire as soon as it has been completed, check to see that each
question has been answered and gently remind the patient to answer any inadvertently omitted questions. If
a patient states that s/he prefers not to answer some questions and gives a reason(s), the reason(s) should be
noted on the questionnaire. If a specific reason is not given, this also should be noted on the questionnaire.
If it is preferable to the patient, the CRA can administer the questionnaire in an interview format.
3. Assessment at Day 10
The quality of life questionnaire should be given or mailed to the patient before the expected date of
completion. The patient should be informed of the expected date of completion and should be instructed to
mail the completed questionnaires back to the randomizing centre. During the Day 7 telephone contact (see
the table in section 9.2.2), the patient should be reminded that the quality of life questionnaire is to be
completed on Day 10. If it is preferable to the patient, or s/he is not able to return questionnaires by mail,
the CRA can administer the questionnaire by telephone during the Day 10 follow-up contact.
4. Assessment at Day 42
The quality of life questionnaire should be given or mailed to the patient before the expected date of
completion. The patient should be informed of the expected date of completion and should be instructed to
mail the completed questionnaires back to the randomizing centre. During the Day 42 follow-up contact,
the patient should be reminded to complete and submit the quality of life questionnaire if he or she has not
already done so. If it is preferable to the patient, or s/he is not able to return questionnaires by mail, the
CRA can administer the questionnaire by telephone during the Day 42 follow-up contact.
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell.
In that case, you may express sympathy that things are below par, but state that this is exactly the
information we require if we are to understand more about how quality of life is affected. You
may also remind them that it takes only a few minutes to complete.
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!
5. Waiving the Quality of Life Component
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he is
not literate in either English or French (or other languages that the questionnaire may be available in). In
other words, if the assistance of a translator is required to comprehend the questions and reply, the
questionnaires should not be completed. Translation of the questions is not acceptable. This should be
noted at the time of randomization and on the web eligibility checklist.
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6. Unwillingness to Complete Quality of Life Questionnaire
If a patient speaks and reads English or French (or other languages that the questionnaires may be available
in), but does not wish to complete the questionnaires then s/he is NOT eligible and should NOT be put on
study.
7. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or French)
An eligible patient may be willing but physically unable to complete the questionnaires, because of
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire
should be read to them and the answers recorded by a health care professional (e.g. preferably the clinical
research associate assigned to the trial, but another clinic nurse, a doctor or social worker who is familiar
with the instructions for administering the questionnaires would be acceptable). If the patient is completing
the questionnaire at home, and a telephone interview by the clinical research associate is not possible, then
a spouse or friend may read the questions to the patient and record the answers. However, this method
should be a last resort, and the spouse or friend should be instructed to not coach or suggest answers to the
patient. Whichever method is used, it should be recorded on the questionnaire.
If these special arrangements are not possible or feasible, then the patient would not be required to
complete the questionnaires, and this should be reported on the appropriate case report form.
The SC.23 Quality of Life questionnaire is available at the end of this document and from the SC.23 web
page.
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APPENDIX VIII – DAILY PATIENT DIARY
Two versions of the Daily Patient Diary are available. One is for patients being irradiated to a single site for the
study; the other is for patients being irradiated to two painful sites.
The success of this study is dependent on patients filling in their diaries completely and accurately. This is
because the endpoint of the study combines the pain information and analgesic consumption recorded in the
diary. Education of the patient by the CRA or study nurse will greatly facilitate proper diary completion. If the
patient does not record all the relevant information in the diary, the CRA or study nurse must obtain the
missing information during the telephone contacts with the patient.
Guidelines for the CRA or study nurse to assist and educate the patient in proper completion of the diary are
provided on the SC.23 website. Certain portions of the diary must be pre-filled prior to giving it to the patient.
The CRA or study nurse should work with the patient to complete the first two sections of the diary to explain
what is required and how information should be recorded.
Each version of the diary is available the end of this document, and from the SC.23 website as an e-fillable
form. This allows some of the information to be included in the diary before the printing the document. This is
done to avoid having to record repeated information multiple times. For example, the information about the
patient’s pain medication only needs to be entered in the first table. The e-fillable form will repeat the same
information in each medication table in the diary so the CRA or study nurse does not have to manually record
the same information in each table. If it is preferred, a blank diary can be printed and all information can be
listed manually.
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AMEND #1: 2013-DEC-19
APPENDIX IX – BLINDING / UNBLINDING
Emergency Unblinding
Dexamethasone and matching placebo are identical in appearance, as are the packages in which they are
provided. Blinding is critical to the integrity of this clinical trial. However, in the event of a medical emergency
in an individual subject, in which knowledge of the randomization assignment is critical to the subject's
management, the blind for that subject may be broken by the treating physician. Before breaking the blind of
an individual subject's blinded treatment, the investigator should have determined that the information is
necessary, i.e. that it will alter the subject's immediate management. In many cases, particularly when the
emergency is clearly not related to dexamethasone, the problem may be properly managed by assuming that the
subject is receiving active product without the need for unblinding.
If a patient is unblinded, they are considered to be off dexamethasone/placebo treatment. The need to break the
blind must first be discussed and approved by the NCIC CTG. For any treatment code unblinding, the reason
and parties involved must be documented in the patient’s medical record. Treatment identification information
should be kept confidential. The NCIC CTG must be notified as soon as possible of any emergency situation in
which the drug code was broken (see List of Contacts for details).
The desire to treat a patient with steroids is not an acceptable reason for unblinding. While the use of steroids is
not encouraged, this can be done if it is in the best interest of the patient. Patients who experience a pain flare
should manage the pain by increasing their intake of breakthrough analgesics rather than initiating steroids. If
steroids are initiated, their use must be noted as a concomitant medication in the electronic data capture system.
Please note: Requests to unblind for information only or to permit participation in other clinical trials will not
be considered until the trial has been unblinded and reported.
Unblinding Procedure:
To unblind the treatment for a patient you must contact NCIC CTG and receive the approval from an NCIC
CTG physician whenever possible.
8am-4pm (EST): Please send an email to the study coordinator including the trial code, patient identification,
patient initials, last treatment kit (if applicable) and the reason for the unblinding request. This email will be
forwarded to the Senior Investigator for approval. When approval is obtained, authorized personnel at NCIC
CTG will unblind the patient and send the unblinding information via email to the investigator who requested
the unblinding.
(4pm-8am EST) and statutory holidays: Please phone the following number as appropriate:
North America calls:
877-617-2810 Toll Free
International calls:
613-541-3280
You will be required to provide basic information regarding the trial code, patient identification, last treatment
kit (if applicable) and the reason for the unblinding request as well as contact information of the caller (and the
Investigator/treating physician to whom the information is to be relayed if different from the caller). The
unblinding information will be conveyed to the Investigator by phone and may also be followed with a
confirmation email or fax.
CONFIDENTIAL
61
CONFIDENTIAL
PROTOCOL DATE: 2010-SEP-24
NCIC CTG TRIAL: SC.23
AMEND #1: 2013-DEC-19
LIST OF CONTACTS
Contact
ADMINISTRATIVE QUERIES
Tammy McQuade
Clinical Trials Assistant
NCIC CTG
Email:
[email protected]
STUDY SUPPLIES
Forms, Protocols
Available on NCIC CTG Website:
http://www.ctg.queensu.ca
under: Clinical Trials
PRIMARY CONTACTS FOR
GENERAL PROTOCOLRELATED QUERIES
(including eligibility questions
and protocol management)
STUDY CO-CHAIRS
Carolyn Wilson
Study Coordinator
NCIC CTG
Email:
[email protected]
Dr. Edward Chow
Study Chair
Email:
[email protected]
and
Dr. Alysa Fairchild
Study Co-Chair
Email:
[email protected]
SERIOUS ADVERSE EVENT
REPORTING
See protocol Section 11.0 for
details of reportable events.
DRUG SUPPLY QUESTIONS
See Appendix III for full details.
Tammy McQuade
Clinical Trials Assistant
CORRELATIVE STUDIES
SAMPLE COLLECTION KIT
ORDERING
Tammy McQuade
Clinical Trials Assistant
or
Carolyn Wilson
Study Coordinator
REQUESTS FOR
UNBLINDING
Fax #
613-533-6430
613-533-2941
416-480-4998
416-480-6002
780-432-8516
780-432-8380
613-533-6430
613-533-2941
or:
Dr. Ralph Meyer
Physician Coordinator
NCIC CTG
Email:
[email protected]
Carolyn Wilson
Study Coordinator
NCIC CTG
or
Dr. Ralph Meyer
Physician Coordinator
NCIC CTG
See Correlative Studies Manual
for full details
Tel. #
NCIC CTG
Carolyn Wilson
or
Dr. Ralph Meyer
613-533-6980
North America calls:
Toll Free
After hours:
International calls:
CONFIDENTIAL
62
877-617-2810
613-541-3280
CONFIDENTIAL
PROTOCOL DATE: 2010-SEP-24
NCIC CTG TRIAL: SC.23
LIST OF PATIENT REPORTED OUTCOMES
Quality of Life
Daily Patient Diary – One Site
Daily Patient Diary – Two Sites
CONFIDENTIAL
63
CONFIDENTIAL
Quality of Life Questionnaire – ENGLISH
NCIC CTG Trial: SC.23
This page to be completed by the Clinical Research Associate
Patient Information
NCIC CTG Patient Serial No: ___________
Hospital No.:__________________
Patient Initials: ____ ____ ____
(if permitted by REB)
Institution: ___________________________________________
(first-middle-last)
Investigator: ______________________________
Scheduled time to obtain quality of life assessment: please check ()
 Prior to randomization
 Day 10
 Day 42 contact
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________
Where was questionnaire completed:  home
 clinic
 another centre
Comments: ____________________________________________________________________________________
_____________________________________________________________________________________________
Date Completed: __ __ __ __ - __ __ __ - __ __
yyyy
mmm
dd
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION.
NCIC CTG use only
Logged: _______
______ - ____ - ____
Study Coord: _______
______ - ____ - ____
Res Assoc: _______
______ - ____ - ____
Data Ent’d:
_________
Verif:
_________
(2010-SEP-24)
This box to be completed by the clinical research associate:
Pt. Serial #: _____________ Pt. Initials: ___ ___ ___
European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire (C15-PAL)
We are interested in some things about you and your health. Please answer all of the questions yourself by
circling the number that best applies to you. There are no “right” or “wrong” answers. The information that you
provide will remain strictly confidential.
Not
At All
A
Little
Quite
a Bit
Very
Much
1.
Do you have any trouble taking a short walk outside of
the house?
1
2
3
4
2.
Do you need to stay in a bed or a chair during the day?
1
2
3
4
3.
Do you need help with eating, dressing, washing
yourself or using the toilet?
1
2
3
4
Not
At All
A
Little
Quite
a Bit
Very
Much
During the past week:
4.
Were you short of breath?
1
2
3
4
5.
Have you had pain?
1
2
3
4
6.
Have you had trouble sleeping?
1
2
3
4
7.
Have you felt weak?
1
2
3
4
8.
Have you lacked appetite?
1
2
3
4
9.
Have you felt nauseated?
1
2
3
4
1
2
3
4
10. Have you been constipated?
NCIC CTG Trial SC.23
EORTC QLQ-C15 PAL
Page 1 of 5
Please go on to the next page
This box to be completed by the clinical research associate:
Pt. Serial #: _____________ Pt. Initials: ___ ___ ___
Not
At All
A
Little
Quite
a Bit
Very
Much
11. Were you tired?
1
2
3
4
12. Did pain interfere with your daily activities?
1
2
3
4
13. Did you feel tense?
1
2
3
4
14. Did you feel depressed?
1
2
3
4
During the past week:
For the following question please circle the number between 1 and 7 that best applies to you.
15. How would you rate your overall quality of life during the past week?
1
Very Poor
NCIC CTG Trial SC.23
EORTC QLQ-C15 PAL
2
3
4
Page 2 of 5
5
6
7
Excellent
Please go on to the next page
This box to be completed by the clinical research associate:
Pt. Serial #: _____________ Pt. Initials: ___ ___ ___
Bone Metastases Module (BM22)
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to
which you have experienced these symptoms or problems during the past week. Please answer by circling the
number that best applies to you.
During the past week have you had pain in any of the
following parts of your body?
Not
At All
A
Little
Quite
a Bit
Very
Much
16. in your back?
1
2
3
4
17. in your leg(s) or hip(s)?
1
2
3
4
18. in your arm(s) or shoulder(s)?
1
2
3
4
19. in your chest or rib(s)?
1
2
3
4
20. in your buttock(s)?
1
2
3
4
Not
At All
A
Little
Quite
a Bit
Very
Much
21. Have you had constant pain?
1
2
3
4
22. Have you had intermittent pain?
1
2
3
4
23. Have you had pain not relieved by pain medications?
1
2
3
4
24. Have you had pain while lying down?
1
2
3
4
25. Have you had pain while sitting?
1
2
3
4
During the past week:
NCIC CTG Trial SC.23. EORTC QLQ-BM22
Page 3 of 5
Please go on to the next page
This box to be completed by the clinical research associate:
Pt. Serial #: _____________ Pt. Initials: ___ ___ ___
Not
At All
A
Little
Quite
a Bit
Very
Much
26. Have you had pain when trying to stand up?
1
2
3
4
27. Have you had pain while walking?
1
2
3
4
28. Have you had pain with activities such as bending or
climbing stairs?
1
2
3
4
29. Have you had pain with strenuous activities (e.g.
exercise, lifting)?
1
2
3
4
30. Has pain interfered with your sleeping at night?
1
2
3
4
31. Have you had to modify your daily activities because of
your illness?
1
2
3
4
32. Have you felt isolated from those close to you (e.g.
family, friends)?
1
2
3
4
33. Have you worried about loss of mobility because of your
illness?
1
2
3
4
34. Have you worried about becoming dependant on others
because of your illness?
1
2
3
4
35. Have you worried about your health in the future?
1
2
3
4
36. Have you felt hopeful your pain will get better?
1
2
3
4
37. Have you felt positive about your health?
1
2
3
4
During the past week:
NCIC CTG Trial SC.23. EORTC QLQ-BM22
Page 4 of 5
Please go on to the next page
This box to be completed by the clinical research associate:
Pt. Serial #: _____________ Pt. Initials: ___ ___ ___
Dexamethasone Symptom Questionnaire (DSQ)
Not
At All
A
Little
Quite
a Bit
Very
Much
38. Did you have indigestion/heartburn/reflux or discomfort
in the upper abdomen?
1
2
3
4
39. Did you have trouble getting to sleep?
1
2
3
4
40. Have you had increased appetite?
1
2
3
4
41. Have you had hiccups?
1
2
3
4
42. Have you gained weight?
1
2
3
4
43. Have you felt agitated/nervous?
1
2
3
4
44. Have you had a rash/acne on your face?
1
2
3
4
45. Have you had thrush/yeast infection in your mouth?
1
2
3
4
46. Did you experience feelings of depression on stopping
your study medication?
1
2
3
4
During the past week:
 Check () here if this question is not applicable
(pre-treatment questionnaire)
Please check to make sure you have answered all the questions.
Please fill in your initials to indicate that you have completed this questionnaire: ______________
Today's date (Year, Month, Day): ________________________________
Thank You.
NCIC CTG Trial SC.23. DSQ
Page 5 of 5
NCIC CTG Trial SC.23
A PHASE III DOUBLE-BLIND STUDY OF DEXAMETHASONE VERSUS PLACEBO IN THE PROPHYLAXIS OF
RADIATION-INDUCED PAIN FLARE FOLLOWING PALLIATIVE RADIOTHERAPY FOR BONE METASTASES
Patient Initials:
_____________
First – Middle - Last
Patient Serial #:
___________________
Institution:
_______________________________________
Investigator:
_______________________________________
DAILY PATIENT DIARY – ONE RADIOTHERAPY SITE
To Whom It May Concern:
The above patient is in a clinical study. In the event of a medical emergency, please telephone one
of the individuals listed below:
1. _______________________________________________
(Name)
______________________
(Number)
2. _______________________________________________
(Name)
______________________
(Number)
To the Patient:
If you have any questions about your study medication or your diary, please telephone the study
nurse or CRA listed below.
__________________________________________________
(Name)
______________________
(Number)
Hours of Availability:
______________________________________________________________________________
INFORMATION AND INSTRUCTIONS FOR THE PATIENT
Thank you for participating in this research study.
This document is a diary that you will use to record your pain every day and the
medication you take to treat it. The next 7 pages contain instructions to help you fill
in the diary with all the information we need for the study.
You are being asked to fill in the diary:
•
before you take your first dose of study medication and receive your
radiotherapy treatment (Section 1),
•
after you receive your radiotherapy treatment, but on the same day (Section 2),
and
•
for the 10 days after you receive radiotherapy (Section 3).
When you receive the diary, the clinical research associate (CRA) or study nurse will
have already filled in certain parts:
•
the date and day of the week for each day you will need to fill in the diary,
•
the painful site receiving radiation treatment, and
•
the names and doses of the medications you regularly take to treat your pain.
For each day you fill in the diary, you will be asked to give us three types of
information:
•
your pain,
•
how much medication you have taken to treat your pain, and
•
the number of study pills you have taken and what time you took them.
In addition, there will be space for you to write down any symptoms you have and
any medications you have taken for reasons other than pain control.
The CRA or study nurse will contact you by telephone every few days while you are
filling out the diary so you can tell him or her about your pain, your pain medication
and how you are taking your study medication. He or she will also ask you about any
symptoms you have and any other medications you have been taking.
If you have any questions, please ask the CRA or study nurse to help you.
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 1 of 31
INSTRUCTIONS FOR THE PATIENT
Your Pain
We will ask you about your pain in all sections of the diary.
To tell us about your pain, you will be provided with a list of numbers and asked to rate your pain
by choosing one number from 0 (no pain) to 10 (pain as bad as you can imagine) that
best describes your pain in the last 24 hours.
This is what that question looks like:
Please rate your pain by circling the one number that best describes your pain at its WORST
in your ________________________ in the last 24 hours:
0
1
No pain
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
Some correct and incorrect sample answers are shown below:
0
1
2
3
4
5
6
7
8
9
10

Incorrect: 0
1
2
3
4
5
6
7
8
9
10

Incorrect: 0
1
2
3
4
5
6
7
8
9
10

Correct:
Later on in the study, as well as knowing how you rate your pain, we also want to know how it
compares to the pain you experienced before receiving your radiotherapy treatment. For this
question, you will be asked to place an “X” in the box that best matches your answer. Please mark
only one box to answer this question.
This is what that question looks like:
How does the pain in your ________________________ during the last 24 hours compare to the
pain you experienced there before your radiation treatment?
My pain in the last 24
hours was WORSE than

before my radiation
treatment
My pain in the last 24
hours was the SAME as

before my radiation
treatment
My pain in the last 24
hours was BETTER than

before my radiation
treatment
A sample of a correct response is shown below:
My pain in the last 24
hours was WORSE than

before my radiation
treatment
My pain in the last 24
hours was the SAME as
 before my radiation
treatment
My pain in the last 24
hours was BETTER than

before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 2 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Your Study Medication
Before you receive your radiation treatment, you will take your first dose of study pills. You are
also scheduled to take 2 study pills every day for the first four days after your radiation treatment.
You will be asked to record how many study pills you take and what time you take them by
answering some questions in your diary.
This is what the questions about the number of pills look like:
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took by
marking the correct answer:
 0 pills
 1 pill
 3 pills or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
This is what the question about the time you took your study pills looks like:
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
If you are unsure about how to answer these questions, please ask the CRA or study nurse for more
information.
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 3 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Your Pain Medication
To tell us how much pain medication you take each day, you will be asked to fill in a table. In most
cases, the CRA or study nurse will have already filled in some information about the medications
you usually take for pain. For example, if you use 10 mg tablets of Medication A and 2 mg tablets
of Medication B, the table will look like this:
Name of medication
Strength of each How is medication
unit of medication*
taken? **
Medication A
10 mg
By mouth
Medication B
2 mg
By mouth

Number of units taken 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Your pain medication information will be recorded in three different sections in the diary.
•
Section 1 will be completed before you receive your first dose of study medication and your
radiation treatment. We will ask you to remember how much pain medication you used in
the previous 24 hours. The CRA or study nurse will work with you to record this
information.
•
Section 2 will be completed after you receive your radiation treatment but on the same day.
We will ask you to remember how much pain medication you have taken since waking up
this morning. The CRA or study nurse will work with you to record this information. Also in
this section, we will ask you to write down every time you take a medication for pain as you
go on through the day.
•
Section 3 will be completed every day for the 10 days after your radiation treatment. The
CRA or study nurse will telephone you every few days to collect this information.
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 4 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Here are some examples of how to fill in the medication table:
Ex. 1: Your doctor has prescribed 10 milligram (mg) tablets of Medication A for your pain and told
you to take one tablet in the morning and one at night. Your doctor has also prescribed 2 mg
tablets of Medication B and told you to take one tablet as needed when you have extra pain
(also called breakthrough pain), up to four times a day. In the last 24 hours, you took both of
the 10 mg Medication A tablets and three of the 2 mg Medication B tablets.
This is the correct way to fill in the table:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication A
10 mg
By mouth
2

Medication B
2 mg
By mouth
3

e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
This is an incorrect way to fill in the table:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication A
10 mg
By mouth
2

Medication B
2 mg
By mouth
1 as needed

e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
This is incorrect because it does not tell us exactly how much of Medication B you took before
filling in the table. We need to know this to be able to get complete results for the study.
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 5 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Here are some examples of how to record your medication if you use formats other than
tablets:
Ex. 2: You use a patch on your skin that delivers 25 micrograms (mcg) of Medication C every
hour. You change this patch every three days.
Name of medication
Medication C
*
Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
25 mcg / h
Patch
1 every 3 days

A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
Ex. 3: Some pain medications are available in liquid or syrup form. Your doctor has prescribed 2
mg/mL Medication D to you. You can take 1 to 3 millilitres (mL) of this liquid when you
have pain, up to six times a day. Today, you took 2 mL of Medication D just before lunch, 1
mL in the middle of the afternoon, and 3 mL just before going to bed (for a total of 6 mL).
Name of medication
Medication D
*
Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
2 mg / mL
By mouth
2+1+3=6

A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
Here is an example of how to fill in the medication table for the day you receive your study
medication and radiation treatment (Day 0):
Ex. 4a: Your doctor has prescribed 5 mg tablets of Medication E for your pain and told you to take
one tablet in the morning and one at night. Your doctor has also prescribed 1 mg tablets of
Medication F and told you to take one or two tablets as needed when you have extra
(breakthrough) pain, up to six times a day. Before coming to the clinic, you took one tablet
of Medication E with your breakfast. While at the clinic, you received your first study pills,
and then went for your radiation treatment. Now you are ready to fill in your diary with the
medications you have taken so far today.
Here is what the table will look like after you mark down that you took one tablet of Medication E:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
Medication F
1 mg
By mouth
1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Example continues on the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 6 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Ex. 4b: After lunch, you experience some extra (breakthrough) pain, so you take two 1 mg tablets
of Medication F and list them in the table in your diary.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1
Medication F
1 mg
By mouth
2
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Ex. 4c: In the afternoon, you are still experiencing some extra pain, so you take another 1 mg
Medication F tablet and record it in your diary.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1
Medication F
1 mg
By mouth
2+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Ex. 4d: After dinner, you take your evening tablet of 5 mg Medication E and list it in the table.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1+1
Medication F
1 mg
By mouth
2+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Example continues on the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 7 of 31
INSTRUCTIONS FOR THE PATIENT CONTINUED
Ex. 4e: You go to bed early, but some extra (breakthrough) pain wakes you up in the middle of the
night, so you take one of your 1 mg Medication F tablets. You record this in the table, then
go back to bed and sleep soundly for the rest of the night.
Here is what the table looks like now:
Name of medication

Dose or strength of
How is medication
each unit of
Number of units taken 
taken? **
medication*
Medication E
5 mg
By mouth
1+1
Medication F
1 mg
By mouth
2+1+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
When you wake up in the morning, you are ready to start recording your pain medication for Day 1.
When the CRA or study nurse telephones you and asks how much medication you took to relieve
your pain on Day 0, you will tell him/her that you took:
•
1 + 1 = 2 tablets of Medication E
•
2 + 1 + 1 = 4 tablets of Medication F
Now you are ready to fill out your diary.
If you have any questions or need help, please contact the CRA or study nurse
(contact information provided on the cover page).
Thank you for valuable contribution to this research study
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 8 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0
SECTION 1 - BASELINE INFORMATION (YESTERDAY)
CRA / Study Nurse to complete below, in advance:
Day 0 is :
Day of week:
________________
_________________________
Please complete this page of the study diary before taking your study medication
and receiving your radiation treatment.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please write down the number of units of each medication you have taken
in the last 24 hours. If you did not use any of a particular medication in the last 24 hours,
please note this by writing “zero” (0) in the corresponding column.
If you took other medications to treat your pain that are not included in the table, please
write them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
If you have any questions about how to complete this table, please ask the CRA or study nurse.
Please go to the next page after taking your study medication
and receiving your radiation treatment.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 9 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0 (continued)
SECTION 2 - MEDICATION INTAKE FOR TODAY
Please complete this section after taking your study medication
and receiving your radiation treatment.
3.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 10 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0 (continued)
MEDICATION INTAKE FOR TODAY (continued)
5.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today. You may have
already recorded some of this medication use in the table on an earlier page. That’s OK –
please list it again.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
This completes Day 0.
Please fill in the information for Day 1 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 11 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
SECTION 3 – ON-STUDY INFORMATION
DAY 1
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 1 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 12 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 1 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each
How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 1.
Please fill in the information for Day 2 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 13 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 2
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 2 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 14 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 2 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 2.
Please fill in the information for Day 3 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 15 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 3
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 3 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 16 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 3 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you have taken for pain since getting up this morning by
writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications you take for
pain by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 3.
Please fill in the information for Day 4 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 17 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 4
PAIN SCORE AND MEDICATION INTAKE
This should be the day you take the last of your study pills.
CRA / Study Nurse to complete below, in advance:
Day 4 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 18 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 4 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you have taken for pain since getting up this morning by
writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications you take for
pain by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each
unit of
medication*
How is medication
Number of units taken 
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 4.
Please fill in the information for Day 5 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 19 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 5
PAIN SCORE AND MEDICATION INTAKE
This should be the first day you do not have any study pills left to take.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 5 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 20 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 5 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 5.
Please fill in the information for Day 6 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 21 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 6
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 6 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 22 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 6 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 6.
Please fill in the information for Day 7 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 23 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 7
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 7 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 24 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 7 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 7.
Please fill in the information for Day 8 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 25 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 8
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 8 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 26 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 8 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 8.
Please fill in the information for Day 9 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 27 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 9
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 9 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 28 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 9 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 9.
Please fill in the information for Day 10 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 29 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 10
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 10 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
2
3
4
5
6
7
8
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
3.
9
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pill
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle
Please go to the next page.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 30 of 31
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 10 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you take
for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
You have now completed the study diary.
The CRA or study nurse will call you in the near future to obtain
the final set of information from your diary.
Thank you for your valuable contribution to this research study.
SC.23 – Daily Patient Diary – One Radiotherapy Site (2010-SEP-24)
Page 31 of 31
NCIC CTG Trial SC.23
A PHASE III DOUBLE-BLIND STUDY OF DEXAMETHASONE VERSUS PLACEBO IN THE PROPHYLAXIS OF
RADIATION-INDUCED PAIN FLARE FOLLOWING PALLIATIVE RADIOTHERAPY FOR BONE METASTASES
Patient Initials:
_____________
First – Middle - Last
Patient Serial #:
___________________
Institution:
_______________________________________
Investigator:
_______________________________________
DAILY PATIENT DIARY – TWO RADIOTHERAPY SITES
To Whom It May Concern:
The above patient is in a clinical study. In the event of a medical emergency, please telephone one
of the individuals listed below:
1. _______________________________________________
(Name)
______________________
(Number)
2. _______________________________________________
(Name)
______________________
(Number)
To the Patient:
If you have any questions about your study medication or your diary, please telephone the study
nurse or CRA listed below.
__________________________________________________
(Name)
______________________
(Number)
Hours of Availability:
_______________________________________________________________________________
INFORMATION AND INSTRUCTIONS FOR THE PATIENT
Thank you for participating in this research study.
This document is a diary that you will use to record your pain every day and the
medication you take to treat it. The next 7 pages contain instructions to help you fill
in the diary with all the information we need for the study.
You are being asked to fill in the diary:
before you take your first dose of study medication and receive your
radiotherapy treatment (Section 1),
• after you receive your radiotherapy treatment, but on the same day (Section
2), and
• for the 10 days after you receive radiotherapy (Section 3).
•
When you receive the diary, the clinical research associate (CRA) or study nurse will
have already filled in certain parts:
•
•
•
the date and day of the week for each day you will need to fill in the diary,
the painful sites receiving radiation treatment, and
the names and doses of the medications you regularly take to treat your
pain.
For each day you fill in the diary, you will be asked to give us three types of
information:
•
•
•
your pain at each radiation treatment site,
how much medication you have taken to treat your pain, and
the number of study pills you have taken and what time you took them.
In addition, there will be space for you to write down any symptoms you have and
any medications you have taken for reasons other than pain control.
The CRA or study nurse will contact you by telephone every few days while you are
filling out the diary so you can tell him or her about your pain, your pain medication
and how you are taking your study medication. He or she will also ask you about any
symptoms you have and any other medications you have been taking.
If you have any questions, please ask the CRA or study nurse to help you.
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 1 of 41
INSTRUCTIONS FOR THE PATIENT
Your Pain
We will ask you about your pain in all sections of the diary.
To tell us about your pain, you will be provided with a list of numbers and asked to rate your pain at
each site of radiation treatment by choosing one number from 0 (no pain) to 10 (pain as bad
as you can imagine) that best describes your pain in the last 24 hours. Since you will be treated
to two painful sites, you will be asked the question twice, once for each site.
This is what that question looks like for one of your painful sites:
Please rate your pain by circling the one number that best describes your pain at its WORST
in your ________________________ in the last 24 hours:
0
1
No pain
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
Some correct and incorrect sample answers are shown below:
0
1
2
3
4
5
6
7
8
9
10

Incorrect: 0
1
2
3
4
5
6
7
8
9
10

Incorrect: 0
1
2
3
4
5
6
7
8
9
10

Correct:
Later on in the study, as well as knowing how you rate your pain, we also want to know how it
compares to the pain you experienced before receiving your radiotherapy treatment. For this
question, you will be asked to place an “X” in the box that best matches your answer. Please mark
only one box to answer this question.
This is what that question looks like for one of your painful sites:
How does the pain in your ________________________ during the last 24 hours compare to the
pain you experienced there before your radiation treatment?
My pain in the last 24
hours was WORSE than

before my radiation
treatment
My pain in the last 24
hours was the SAME as

before my radiation
treatment
My pain in the last 24
hours was BETTER than

before my radiation
treatment
A sample of a correct response is shown below:
My pain in the last 24
hours was WORSE than

before my radiation
treatment
My pain in the last 24
hours was the SAME as
 before my radiation
treatment
My pain in the last 24
hours was BETTER than

before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 2 of 41
INSTRUCTIONS FOR THE PATIENT
Your Study Medication
Before you receive your radiation treatment, you will take your first dose of study pills. You are
also scheduled to take 2 study pills every day for the first four days after your radiation treatment.
You will be asked to record how many study pills you take and what time you take them by
answering some questions in your diary.
This is what the questions about the number of pills look like:
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took by
marking the correct answer:
 0 pills
 1 pill
 3 pills or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
This is what the question about the time you took your study pills looks like:
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
If you are unsure about how to answer these questions, please ask the CRA or study nurse for more
information.
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 3 of 41
INSTRUCTIONS FOR THE PATIENT
Your Pain Medication
To tell us how much pain medication you take each day, you will be asked to fill in a table. In most
cases, the CRA or study nurse will have already filled in some information about the medications
you usually take for pain. For example, if you use 10 mg tablets of Medication A and 2 mg tablets
of Medication B, the table will look like this:
Name of medication
Strength of each How is medication
unit of medication*
taken? **
Medication A
10 mg
By mouth
Medication B
2 mg
By mouth

Number of units taken 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Your pain medication information will be recorded in three different sections in the diary.
•
Section 1 will be completed before you receive your first dose of study medication and your
radiation treatment. We will ask you to remember how much pain medication you used in
the previous 24 hours. The CRA or study nurse will work with you to record this
information.
•
Section 2 will be completed after you receive your radiation treatment but on the same day.
We will ask you to remember how much pain medication you have taken since waking up
this morning. The CRA or study nurse will work with you to record this information. Also in
this section, we will ask you to write down every time you take a medication for pain as you
go on through the day.
•
Section 3 will be completed every day for the 10 days after your radiation treatment. The
CRA or study nurse will telephone you every few days to collect this information.
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 4 of 41
INSTRUCTIONS FOR THE PATIENT
Here are some examples of how to fill in the medication table:
Ex. 1: Your doctor has prescribed 10 milligram (mg) tablets of Medication A for your pain and told
you to take one tablet in the morning and one at night. Your doctor has also prescribed 2 mg
tablets of Medication B and told you to take one tablet as needed when you have extra pain
(also called breakthrough pain), up to four times a day. In the last 24 hours, you took both of
the 10 mg Medication A tablets and three of the 2 mg Medication B tablets.
This is the correct way to fill in the table:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication A
10 mg
By mouth
2

Medication B
2 mg
By mouth
3

e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
This is an incorrect way to fill in the table:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication A
10 mg
By mouth
2

Medication B
2 mg
By mouth
1 as needed

e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
This is incorrect because it does not tell us exactly how much of Medication B you took before
filling in the table. We need to know this to be able to get complete results for the study.
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 5 of 41
INSTRUCTIONS FOR THE PATIENT
Here are some examples of how to record your medication if you use formats other than
tablets:
Ex. 2: You use a patch on your skin that delivers 25 micrograms (mcg) of Medication C every
hour. You change this patch every three days.
Name of medication
Medication C
*
Strength of each How is medication
unit of medication*
taken?
25 mcg / h
Number of units taken
Patch
1 every 3 days

A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
Ex. 3: Some pain medications are available in liquid or syrup form. Your doctor has prescribed 2
mg/mL Medication D to you. You can take 1 to 3 millilitres (mL) of this liquid when you
have pain, up to six times a day. Today, you took 2 mL of Medication D just before lunch, 1
mL in the middle of the afternoon, and 3 mL just before going to bed (for a total of 6 mL).
Name of medication
Medication D
*
Strength of each How is medication
unit of medication*
taken?
2 mg / mL
By mouth
Number of units taken
2+1+3=6

A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
Here is an example of how to fill in the medication table for the day you receive your study
medication and radiation treatment (Day 0):
Ex. 4a: Your doctor has prescribed 5 mg tablets of Medication E for your pain and told you to take
one tablet in the morning and one at night. Your doctor has also prescribed 1 mg tablets of
Medication F and told you to take one or two tablets as needed when you have extra
(breakthrough) pain, up to six times a day. Before coming to the clinic, you took one tablet
of Medication E with your breakfast. While at the clinic, you received your first study
pills, and then went for your radiation treatment. Now you are ready to fill in your diary
with the medications you have taken so far today.
Here is what the table will look like after you mark down that you took one tablet of Medication E:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
Medication F
1 mg
By mouth
1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Example continues on the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 6 of 41
INSTRUCTIONS FOR THE PATIENT
Ex. 4b: After lunch, you experience some extra (breakthrough) pain, so you take two 1 mg tablets
of Medication F and list them in the table in your diary.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1
Medication F
1 mg
By mouth
2
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Ex. 4c: In the afternoon, you are still experiencing some extra pain, so you take another 1 mg
Medication F tablet and record it in your diary.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1
Medication F
1 mg
By mouth
2+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Ex. 4d: After dinner, you take your evening tablet of 5 mg Medication E and list it in the table.
Here is what the table looks like now:
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
Medication E
5 mg
By mouth
1+1
Medication F
1 mg
By mouth
2+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
Example continues on the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 7 of 41
INSTRUCTIONS FOR THE PATIENT
Ex. 4e: You go to bed early, but some extra (breakthrough) pain wakes you up in the middle of the
night, so you take one of your 1 mg Medication F tablets. You record this in the table, then
go back to bed and sleep soundly for the rest of the night.
Here is what the table looks like now:
Name of medication

Dose or strength of
How is medication
each unit of
Number of units taken 
taken? **
medication*
Medication E
5 mg
By mouth
1+1
Medication F
1 mg
By mouth
2+1+1
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
When you wake up in the morning, you are ready to start recording your pain medication for
Day 1.
When the CRA or study nurse telephones you and asks how much medication you took to
relieve your pain on Day 0, you will tell him/her that you took:
• 1 + 1 = 2 tablets of Medication E
• 2 + 1 + 1 = 4 tablets of Medication F
Now you are ready to fill out your diary.
If you have any questions or need help, please contact the CRA or study nurse
(contact information provided on the cover page).
Thank you for valuable contribution to this research study.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 8 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0
SECTION 1 - BASELINE INFORMATION (YESTERDAY)
CRA / Study Nurse to complete below, in advance:
Day 0 is :
Day of week:
________________
_________________________
Please complete this page of the study diary before taking your study medication
and receiving your radiation treatment.
1.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2.
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
3.
2
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please write down the number of units of each medication you have taken
in the last 24 hours. If you did not use any of a particular medication in the last 24 hours,
please note this by writing “zero” (0) in the corresponding column.
If you took other medications to treat your pain that are not included in the table, please
write them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
If you have any questions about how to complete this table, please ask the CRA or study nurse.
Please go to the next page after taking your study medication and receiving your
radiation treatment.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 9 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0 (continued)
SECTION 2 - MEDICATION INTAKE FOR TODAY
Please complete this section after taking your study medication and receiving
your radiation treatment.
4.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
5.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 10 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 0 (continued)
MEDICATION INTAKE FOR TODAY (continued)
6.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today. You may have
already recorded some of this medication use in the table on an earlier page. That’s OK –
please list it again.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
7.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
8.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
This completes Day 0.
Please fill in the information for Day 1 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 11 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
SECTION 3 – ON-STUDY INFORMATION
DAY 1
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 1 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 12 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 1 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 13 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 1 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each
How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 1.
Please fill in the information for Day 2 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 14 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 2
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 2 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 15 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 2 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 16 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 2 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
In the following table, the CRA or study nurse has listed all the medications you usually take
to treat your pain. Please record all the medications you have taken for pain since getting up
this morning by writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications for pain you
take by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you do not use any of a particular medication today, please note this by writing “zero” (0)
in the corresponding column at the end of the day.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 2.
Please fill in the information for Day 3 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 17 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 3
PAIN SCORE AND MEDICATION INTAKE
CRA / Study Nurse to complete below, in advance:
Day 3 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 18 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 3 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 19 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 3 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you have taken for pain since getting up this morning by
writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications you take for
pain by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 3.
Please fill in the information for Day 4 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 20 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 4
PAIN SCORE AND MEDICATION INTAKE
This should be the day you take the last of your study pills.
CRA / Study Nurse to complete below, in advance:
Day 4 is :
Day of week:
________________
_________________________
Please take two study pills with breakfast this morning and then complete this
section of the diary.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 21 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 4 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Did you take two study pills today?
 Yes
 No
If, in error, you took a different number of study pills, please tell us how many you took
by marking the correct answer:
 0 pills
 1 pill
 3 or more pills; please specify _______
Please also tell us why you took more or fewer study pills:
__________________________________________________________________________
4.
Please tell us the approximate time you took your study pills today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 22 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 4 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you have taken for pain since getting up this morning by
writing in the number of units you have taken so far today.
As you go on through the day, please continue to record all the medications you take for
pain by writing in the number of units beside the appropriate medication. Please make sure
you record all of the pain medication you take, including the medication you take for
breakthrough pain, and any medication you take for pain that wakes you up while sleeping
at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each
unit of
medication*
How is medication
Number of units taken 
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 4.
Please fill in the information for Day 5 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 23 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 5
PAIN SCORE AND MEDICATION INTAKE
This should be the first day you do not have any study pills left to take.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 5 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 24 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 5 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 25 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 5 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 5.
Please fill in the information for Day 6 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 26 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 6
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 6 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 27 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 6 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 28 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 6 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 6.
Please fill in the information for Day 7 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 29 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 7
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 7 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 30 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 7 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 31 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 7 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 7.
Please fill in the information for Day 8 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 32 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 8
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 8 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 33 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 8 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 34 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 8 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 8.
Please fill in the information for Day 9 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 35 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 9
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 9 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 36 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 9 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle)
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 37 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 9 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
This completes Day 9.
Please fill in the information for Day 10 tomorrow
(starting on the next page).
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 38 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 10
PAIN SCORE AND MEDICATION INTAKE
You should not have any study pills to take today.
If you do have any study pills left, please do not take them.
CRA / Study Nurse to complete below, in advance:
Day 10 is :
Day of week:
________________
_________________________
Please complete this section of the diary in the morning after breakfast.
1a.
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
1b.
2
3
4
5
6
7
8
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please rate your pain by circling the one number that best describes your pain at its
WORST in your ________________________ in the last 24 hours:
0
1
No pain
2b.
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
2a.
9
2
3
4
5
6
7
8
9
10
Pain as bad as
you can imagine
How does the pain in your ________________________ during the last 24 hours
compare to the pain you experienced there before your radiation treatment?
My pain in the last 24
My pain in the last 24
hours was WORSE than
hours was the SAME


before my radiation
as before my radiation
treatment
treatment
My pain in the last 24
hours was BETTER

than before my radiation
treatment
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 39 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 10 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
3.
Please confirm you did not take any study pills today.
 Correct; I DID NOT take any
study pills today
 No, I DID take study pills today
If, in error, you did take study pills today, please tell us how many you took by marking
the correct answer:
 1 pills
 2 pills
 3 or more pills; please specify _______
Please also tell us why you took study pills today:
__________________________________________________________________________
4.
If you DID take study pills, please tell us the approximate time you took them today:
____________________ am / pm (please circle
Please go to the next page.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 40 of 41
DAILY DIARY – PATIENT TO COMPLETE
Patient Initials: _______
Patient Serial #:_______________
DAY 10 (continued)
PAIN SCORE AND MEDICATION INTAKE (continued)
5.
Please record all the medications you take for pain today, including what you have already
taken since getting up this morning. Please make sure you record all the medication you
take for breakthrough pain, and any medication you take for pain that wakes you up while
sleeping at night.
If you took other medications to treat your pain that are not included in the list, please write
them in the table and fill in all the columns.
Name of medication

Strength of each How is medication
Number of units taken 
unit of medication*
taken? **
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units.
*
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch.
**
For example, medications can be taken by mouth, rectally, or in patch form.
6.
If you wish, you can write down any other medications you have taken today here:
__________________________________________________________________________
__________________________________________________________________________
7.
If you wish, you can write down any symptoms you are having here:
__________________________________________________________________________
__________________________________________________________________________
You have now completed the study diary.
The CRA or study nurse will call you in the near future to obtain the
final set of information from your diary.
Thank you for your valuable contribution to this research study.
SC.23 – Daily Patient Diary – Two Radiotherapy Sites (2010-SEP-24)
Page 41 of 41