Download HOVON 64 ITP Anti-CD20 treatment of relapsed or refractory

HOVON 64 ITP
Version: December 11, 2007
Anti-CD20 treatment of relapsed or refractory Immune Thrombocytopenic Purpura
(ITP) after first line corticosteroid treatment
A phase II study
PROTOCOL
Study Coordinators :
B.J. Biemond
H.R. Koene
G. Vreugdenhil
P.C.Huijgens
J.J. Zwaginga
Statistician
:
Y. van Norden
Data Manager
:
HOVON Data Center
Registration
:
HOVON Data Center
Erasmus MC – Daniel den Hoed
P.O. Box 5201
3008 AE ROTTERDAM
The Netherlands
tel.
+31.10.4391568
fax
+31.10.4391028
https://www.hdc.hovon.nl/top
EudraCT number
:
2004-002175-16
First version
:
March 2004
Final version
:
March 11, 2005
Date of activation
:
August 29, 2005
Approved
:
METC Academisch Medisch Centrum Amsterdam: June 9, 2005
Amendment 1
:
approved METC Academisch Medisch Centrum Amsterdam:
May 16 2006
Amendment 2
:
approved METC Academisch Medisch Centrum Amsterdam:
January 29, 2008
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HOVON 64 ITP
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Version: December 11, 2007
Scheme of study
ITP
Age 18 years or older
(splenectomy optional)
R
Arm A
375 mg/m 2
IV infusion
4 doses
rituximab
Arm B
Arm C
375 mg/m2
IV infusion
2 doses
rituximab
(d1, d8, d15, d22)
rituximab
(d1, d8)
Sustained
CR, GR or MR
Off protocol
750 mg/m 2
IV infusion
2 doses
(d1, d8)
Off protocol
No sustained response or NR
rituximab
375 mg/m2
IV infusion
2 doses
*
Off protocol
*:
rituximab (dose 3 and dose 4) will be administered immediately after initial
response is lost or at NR. Dose 4 will be given on day 8 from day dose 3 will be
administered.
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HOVON 64 ITP
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Version: December 11, 2007
Table of contents
1
Scheme of study ............................................................................................................................2
3
Synopsis ........................................................................................................................................5
4
Investigators and study administrative structure ...........................................................................6
4.1
5
Central
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
Laboratory analysis...................................................................................................... 6
Genetic polymorphism ................................................................................................. 6
Megakaryocyte culture studies ..................................................................................... 6
TPO measurement, anti-thrombocyte antibody detection, and antibody kinetic studies..... 7
Direct effects of rituximab on megakaryocytes ............................................................... 7
Sample collection ........................................................................................................ 7
Introduction....................................................................................................................................8
5.1
5.2
5.3
5.4
5.5
Idiopathic thrombocytopenic purpura (ITP) ................................................................................ 8
Standard treatment .................................................................................................................. 8
5.2.1 First line treatment ....................................................................................................... 8
5.2.2 Second line treatment .................................................................................................. 8
Post second line treatment ....................................................................................................... 9
Rationale of the study: ITP and rituximab .................................................................................. 9
National Registry of ITP patients............................................................................................... 9
6
Study objectives........................................................................................................................... 10
7
Study design ................................................................................................................................ 10
8
Study population .......................................................................................................................... 11
8.1
9
Eligibility for randomization..................................................................................................... 11
8.1.1 Inclusion criteria ........................................................................................................ 11
8.1.2 Exclusion criteria ....................................................................................................... 11
Treatment..................................................................................................................................... 12
9.1
9.2
9.3
Rituximab (anti-CD20) ........................................................................................................... 12
2
9.1.1 Conventional dose rituximab 375/m (arm A)............................................................... 12
2
9.1.2 Conventional dose rituximab 375 mg/m (arm B) ......................................................... 12
2
9.1.3 High-dose rituximab 750 mg/m (arm C)...................................................................... 12
Rituximab administration and precautions ............................................................................... 12
9.2.1 General considerations .............................................................................................. 12
9.2.2 Allowed premedication ............................................................................................... 13
9.2.3. Rituximab infusion dose rates ..................................................................................... 13
9.2.4 Infusion completion.................................................................................................... 13
Concomitant medication......................................................................................................... 13
10
End of protocol treatment ............................................................................................................ 14
11
Required clinical observations..................................................................................................... 15
11.1 Observations before randomization / at study entry.................................................................. 16
11.2 Observations during and following treatment ........................................................................... 16
12
Toxicities...................................................................................................................................... 16
13
Safety evaluations and adverse events reporting ........................................................................ 17
13.1 Definitions ............................................................................................................................. 17
13.2 Reporting of (serious) adverse events..................................................................................... 18
13.3 Processing of serious adverse event reports ........................................................................... 19
14
Endpoints..................................................................................................................................... 20
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Version: December 11, 2007
14.1 Primary endpoint ................................................................................................................... 20
14.2 Secondary endpoints ............................................................................................................. 20
15
Randomization ............................................................................................................................. 20
15.1 Randomization for rituximab treament ..................................................................................... 20
16
Forms and procedures for collecting data ................................................................................... 21
17
Statistical considerations............................................................................................................. 21
17.1
17.2
17.3
17.4
18
Patient numbers and power considerations ............................................................................. 21
Statistical analysis................................................................................................................. 22
Efficacy analysis.................................................................................................................... 22
Interim analysis ..................................................................................................................... 23
Ethics ........................................................................................................................................... 23
18.1 Independent ethics committee or institutional review board ...................................................... 23
18.2 Ethical conduct of the study.................................................................................................... 23
18.3 Patient information and consent ............................................................................................. 23
18.3.1 Biological studies ....................................................................................................... 23
19
Trial insurance ............................................................................................................................. 24
20
Publication policy......................................................................................................................... 24
21
Glossary of abbreviations............................................................................................................ 25
22
References ................................................................................................................................... 26
Appendices............................................................................................................................................ 27
A
B
C
D
E
F
Diagnostic criteria for ITP ....................................................................................................... 27
Response criteria .................................................................................................................. 28
Common Toxicity criteria........................................................................................................ 29
WHO performance status ....................................................................................................... 30
General rules for CRF handling .............................................................................................. 31
Sanquin sample scheme ........................................................................................................ 33
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HOVON 64 ITP
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Version: December 11, 2007
Synopsis
Study phase
Phase II
Study objective
The first objective of the current study is to investigate the
effectiveness of three different dosing schedules rituximab in
refractory or relapsed ITP patients, whether or not already
splenectomized. Because it is not clear whether rituximab is more
effective before or after splenectomy, patients will be stratified for
splenectomy. Non-splenectomized rituximab non-responders will be
advised to undergo splenectomy
Patient population
All ITP patients who have relapsed or refractory disease after first
line corticosteroid treatment whether or not splenectomized,
rituximab naive, age = 18 years, WHO performance status = 2.
Study design
The study is designed as a combined phase II, randomized
multicenter study. Patients will be stratified for splenectomy and
randomized after obtaining written informed consent between:
Arm A: conventional dose rituximab 375 mg/m 2, 4 weekly doses
Arm B: conventional dose rituximab 375 mg/m 2, 2 weekly doses (+ 2
weekly doses, dependent on response)
Arm C: high dose rituximab 750 mg/m 2, 2 weekly doses
Duration of treatment
2 to 10 weeks
Number of patients
150
Adverse events
Adverse events will be documented if observed, mentioned during
open questioning, or when spontaneously reported.
Planned start and end of
Start of recruitment: May 2005
recruitment
End of recruitment:
May 2008
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HOVON 64 ITP
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Version: December 11, 2007
Investigators and study administrative structure
Responsibility
Name
Affiliation/Address
Study Coordinators
B.J. Biemond
H.R. Koene
G. Vreugdenhil
Academic Medical Center, Amsterdam
St. Antonius Hospital, Nieuwegein
Maxima Medical Center, Veldhoven
J.J. Zwaginga
P.C. Huijgens
Academic Medical Center, Amsterdam
VU Medical Center, Amsterdam
M. Kappers
A. Brand
Erasmus MC, University Medical Center
Rotterdam
Leiden University Medical Center, Leiden
M. van Kraaij, V.M.J. Novotny
W. Vasmel
R. Fijnheer, E.J. Petersen
University Hospital Nijmegen
St. Lucas-Andreas Hospital, Amsterdam
Utrecht University Medical Center, Utrecht
M. Schipperus
J.Th.M de Wolf
G. Veth
Leyenburg Hospital, The Hague
University Hospital Groningen
St. Antonius Hospital, Nieuwegein
L. van Pampus
University Hospital Maastricht
Central Laboratory
analysis
M. de Haas, L. Porcelijn
Sanquin, Amsterdam
Statistician
Y. van Norden
HOVON Data Center, Rotterdam
Data Management
HOVON Data Center
HOVON Data Center, Rotterdam
Serious Adverse
Events (SAEs)
notification
HOVON Data Center
fax: +31 10 4391028
Writing Committee
4.1
Central Laboratory analysis
4.1.1
Genetic polymorphism
To investigate whether different genetic polymorphism’s for FcγRs are associated with response to
rituximab, DNA will be isolated to perform allele-specific PCR analysis. In recent studies 1, the
response to rituximab was found to be associated with a high-affinity isoform of FcγRIIIa. DNA will
be collected from the samples for thrombopoietin (TPO) and anti-thrombocyte antibodies (see
below). Analysis will be coordinated by dr. M. de Haas, Sanquin Research.
4.1.2
Megakaryocyte culture studies
Previous studies have shown that megakaryocytosis is suppressed in approximately 30% of ITP
patients 2. Increased megakaryocyte apoptosis might in part be responsible for this suppression3.
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Bone marrow aspirates will be collected from all patients and stored for megakaryocyte culture
studies. Analysis will be coordinated by dr. M. de Haas, Sanquin Research.
4.1.3
TPO measurement, anti-thrombocyte antibody detection, and antibody kinetic studies
Plasma levels of thrombopoietin (TPO) and anti-thrombocyte antibodies will be measured in all
patients according to regular procedure. Furthermore, for evaluation of the effects of rituximab on
anti-platelet antibody levels, serial tests will be performed during and after rituximab therapy. Blood
for antibody assays will be drawn weekly during the on treatment period and monthly thereafter to
study the kinetics and extent of the inhibitory effect of rituiximab on antibody production upto month
12.
4.1.4
Direct effects of rituximab on megakaryocytes
After rituximab treatment in ITP, three distinct response patterns are observed: a rapid increase of
the platelet counts within 1-2 weeks starting infusion, a delayed response 3-8 weeks after infusion
and third, an incomplete slow response. The mechanism of the fast response, similar to prednisolon,
is yet unravelled. It is unlikely that the anti-CD20 antibody directly affects macrophage function,
although indirect macrophage blocking by competition between antibody coated platelets and
antibody coated B cells for antibody-dependent-cellmediated-cytotoxicity (ADCC) may occur. Also
soluble CD20-anti-CD20 complexes may impair phagocytosis of platelets. Whether such effects can
take place in the bone marrow enhancing megakaryopoiesis is unknown.
Blood will be analysed to see whether quick and delayed recoveries after rituximab are
characterized by different effects on megakaryocyte formation.
Related questions might be:
1)
Is there a direct effect of ITP antibodies on megakaryocyte colony formation from bone marrow
(containing accessory cells) or on CD34 purified cells in liquid culture with TPO?
2)
Is there a direct effect of anti-CD-20 on megakaryocyte colony formation from bone marrow
(containing accessory cells) or on CD34 purified cells in liquid culture with TPO?
3)
Does patient plasma obtained at several intervals after rituximab improves megakaryopoiesis
compared to pre-rituximab plasma?
4)
If so, is this associated with a fast response to rituximab?
Analysis will be coordinated by Prof. Dr. A. Brand, Sanquin Bloodbank Soutwest, Leiden.
4.1.5
Sample collection
Samples for central analysis will only be collected after obtaining written informed consent. The
samples will be sent to Sanquin Research/CLB, Department of Experimental Immunohematology,
Laboratory of Thrombocyte-/Leucocyte Serology, Plesmanlaan 125, 1066 CX Amsterdam, to the
attention of HOVON 64 ITP. (May also be send with Sanquin Courier “CLB bode”)
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HOVON 64 ITP
Version: December 11, 2007
Volume, type, and schedule of blood samples (Appendix F):
•
30 ml of EDTA uncoagulated blood + 8 ml of coagulated blood: Prior to each rituximab
infusion,weekly during the on treatment period, and monthly during the follow up.
•
Additional 8 ml of coagulated blood:
o
Arm A: Prior to each rituximab infusion and at day 71..
o
Arm B (with respons): Prior to each rituximab infusion and also on day 15, 22 and 71.
o
Arm B (no response after 2nd gift or loss of response): Prior to each rituximab infusion
but in any case on day 15 and also on day 71.
o
Arm C: Prior to each rituximab infusion and also on day 15, 22 and 71.
For coordination (and questions) of the analyses please contact Sanquin (contact details see
above).
5
Introduction
5.1
Idiopathic thrombocytopenic purpura (ITP)
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a persisting
platelet count below 150 x 109/l due to antibody formation binding to platelet antigens causing their
premature destruction by the mononuclear phagocytic system, in particular in the spleen. ITP is a
diagnosis made by exclusion (see appendix A) and referred to as chronic if the thrombocytopenia
persists for more than six months.
5.2
Standard treatment
5.2.1
First line treatment
Based on the guidelines of the American Society of Hematology (ASH) 4,5 corticosteroid therapy is
appropriate as first line treatment in patients with platelet counts below 30 x 109/l, including
asymptomatic patients. First line treatment is also recommended in patients with platelet counts
between 30 x 109/l and 50 x 109/l who are symptomatic. The steroid regimens (such as prednisone
or dexamethasone) is mostly given in a pulsed fashion. Emergency therapy in case of severe
bleeding generally consists of intravenous immunoglobulin. Life-threatening bleeding should be
treated regardless of the platelet count.
5.2.2
Second line treatment
In case of insufficient or no response to steroids or early relapse, splenectomy is advised as second
line therapy. This approach accounts for a (partial or complete) response rate (RR) of 70-80%4,6-8.
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5.3
Version: December 11, 2007
Post second line treatment
After ruling out the presence of an accessory spleen, cases refractory to first and second line
treatment or relapses are generally treated on an individual basis with cytostatic and/or
immunosuppressive drugs. The optimal strategy for persistent ITP following splenectomy is
unknown. A recent literature study showed that azathioprine, cyclophosphamide and rituximab (antiCD20 monoclonal antibodies) had the most complete responses 9.
As stated above, 20-30% of cases do not respond to splenectomy4,6, and have persistent platelet
counts below 30 x 109/l. Apart from the unpredictable response to cytostatic/immunosuppressive
drugs, their use is associated with numerous (long-term) adverse events.
5.4
Rationale of the study: ITP and rituximab
Rituximab has been successfully used in the treatment of B-cell non-Hodgkin’s lymphoma. Several
recent studies have shown that addition of rituximab to standard lymphoma regimens improves
outcome of the disease. Since rituximab induces B-lymphocyte depletion, its effectiveness was
assessed in several auto-immune diseases. Several studies with refractory ITP patients have shown
responses to rituximab10-13. In a small clinical trial in 25 extensively treated refractory ITP patients, a
response rate of 30% was observed, lasting for more than one year, without serious adverse
events 10. Cooper et al11 observed a RR of 55% in 51 patients, lasting for at least 48 weeks. Of note,
durable responses were mainly seen in patients who achieved a complete remission and 94% of
responding patients had platelet increases within 8 weeks of the initial infusion. Cabrera et al.
reported similar results in 92 patients 14. Although these studies are promising, the definite role and
timing of rituximab in the treatment of ITP remains uncertain.
No dose-limiting toxicity was observed in phase I trials with rituximab15 and standard dosage in nonHodgkin’s lymphoma is currently 375 mg/m 2, once every week for 4 weeks. This dose induces a
complete B-lymphocyte depletion in most patients that lasts for approximately 9 months. Several
other dosing schedules have been studied, although not in a randomized controlled strategy. Doses
of up to 2250 mg/m 2 are not associated with additional toxicity16. It is possible that higher doses of
rituximab lead to stronger or longer lasting depletion of circulating and/or tissue B-lymphocytes.
5.5
National Registry of ITP patients
Although a common disorder, the incidence being approximately 5-7/10 5 in the USA4, large-scale
clinical trials concerning natural history and intervention are not available. In the Netherlands, ITP
patients are not registered, and therefore data with respect to incidence, prevalence and
effectiveness of second line therapy are not yet available.
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To enable insight in the incidence, a national registry for all ITP patients is managed via the website
www.medshare.nl (Chantal Rison). The national registry is not part of the clinical study. All ITP
patients will be asked for their consent separately to be registered.
6
Study objectives
♦ The main objective of the current study is to investigate the effectiveness of three different
dosing schedules rituximab in refractory or relapsed ITP patients, whether or not already
splenectomized.
♦ The stratification for splenectomy will be performed to reliably assess whether treatment of nonsplenectomized patients with rituximab results in avoidance of splenectomy after 1 year follow
up. Furthermore, the effects of rituximab treatment on megakaryopoiesis will be evaluated as
well as the effects of rituximab treatment on anti-platelet antibody levels.
7
Study design
The study is designed as a combined phase II, randomized multicenter study. Because it is not clear
whether rituximab is more effective before or after splenectomy, patients will be stratified for
splenectomy.
All patients will be randomized between:
Arm A:
conventional dose rituximab 375 mg/m 2, 4 weekly doses
Arm B:
conventional dose rituximab 375 mg/m 2, 2 weekly + 2 weekly doses, dependent on
response
Arm C:
high dose rituximab 750 mg/m 2, 2 weekly doses
Non-splenectomized rituximab non-responders will be advised to undergo splenectomy.
Details on treatment are given in section 9 of this protocol. Details on response criteria are given in
appendix B.
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HOVON 64 ITP
8
Study population
8.1
Eligibility for randomization
Version: December 11, 2007
All patients with ITP (fulfilling the diagnostic ITP criteria given in appendix A), who have refractory
disease or have relapsed after first line corticosteroid treatment, whether or not followed by
splenectomy, and who meet all criteria (inclusion and exclusion) will be randomized at the HOVON
Data Center before start of treatment with rituximab.
8.1.1
Inclusion criteria
♦ Age minimal 18 years
♦ Subjects with relapsed or refractory ITP (fulfilling the diagnostic criteria given in appendix A) and
platelet numbers <30 x 109/l
♦ Having completed first line treatment with corticosteroids
♦ Written informed consent
♦ WHO performance status = 2
8.1.2
Exclusion criteria
♦ The presence of an accessory spleen in splenectomized patients.
♦ Use of anticoagulants or chemotherapy or known other disorders and/or treatments influencing
the platelet number within 3 months of randomization date (tranexaminic acid (Cyklokapron®)
treatment is allowed).
♦ Pulsed or high dose corticosteroids, IVIG or splenectomy within 3 weeks prior to randomization.
Maintenance corticosteroid therapy is allowed.
♦ Prior therapy with rituximab.
♦ ITP treatments (other than corticosteroids, IVIG or splenectomy) within 3 months prior to
randomization (e.g. cyclosporine, vincristine). Stable treatment with non-immunosuppressive
medication (i.e. danazol, dapson, vitamin C) is permitted.
♦ Inadequate renal and liver function, i.e. creatinin or bilirubin >2.5 x the upper normal value
♦ Neutrophil count <1.5 x 109/l and hemoglobin level <6.2 mmol/l.
♦ Active bleeding (defined by grade 3 or 4 according to NCI CTCAE v3.0)
♦ Pregnant or lactating
♦ Systemic infections: active viral infections, including HIV
♦ Seriously immunocompromised patients
♦ Systemic autoimmune disorders (e.g. Systemic lupus erythematosus (SLE))
♦ Current malignant disease
♦ Any experimental therapy within 30 days prior to randomization.
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HOVON 64 ITP
9
Treatment
9.1
Rituximab (anti-CD20)
Version: December 11, 2007
Rituximab (375 or 750 mg/m 2) will be administered by intravenous infusion (see section 9.2
Rituximab administration and precautions). Day 1 is defined as the date on which the first dose is
administered. Only responding patients will be followed up for response duration according the
protocol follow up scheme (see section 11.3).
9.1.1
Conventional dose rituximab 375/m2 (arm A)
Patients will receive infusions of rituximab on day 1, day 8, day 15 and day 22 (4 doses in total).
Response will be assessed weekly until day 71 for all patients (responders as well as nonresponders).
9.1.2
Conventional dose rituximab 375 mg/m2 (arm B)
All patients will initially receive 2 doses of rituximab, one on day 1 and the other on day 8. Early
responders (CR, GR or MR), as assessed on day 15, who have a sustained or improved response
at day 43, will not receive dose 3 and 4, and go off protocol.
Patients who initially respond at day 15, but do not sustain this response until day 43, will receive
dose 3 and 4 with a weekly interval (dose 3 will be given immediately after the initial response is
lost). The day the 3rd dose will be given can be day 22 - day 43 (dose 4 will be given at day 29 - day
50)
Patients who show no response at day 15 will also receive dose 3 and 4 with a weekly interval (dose
3 will be given at day 22, dose 4 at day 29).
Response will be assessed weekly until day 71 for all patients (responders as well as nonresponders).
9.1.3
High-dose rituximab 750 mg/m2 (arm C)
Patients will receive high dose rituximab (750 mg/m 2) on day 1 and day 8 (see section 9.2 Rituximab
administration and precautions).
Patients in the high dose arm will all (responders as well as the non-responders) be evaluated
weekly for response until day 71 (week 10) before going off study.
9.2
Rituximab administration and precautions
9.2.1
General considerations
Antibody infusions may be given to patients in an outpatient setting or following hospital admission
as an inpatient. A peripheral intravenous (IV) line will be established. Vital signs (blood pressure,
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pulse, respiration, body temperature) should be monitored every 15 minutes x 4 or until stable and
then hourly until the IV line is discontinued and until stable.
9.2.2
Allowed premedication
Premedication with paracetamol and/or antihistaminics (e.g clemastine) is allowed.
9.2.3. Rituximab infusion dose rates
The initial dose rate should be 50 mg/hr for the first hour. Patients may experience transient fever
and rigors with infusion of rituximab. When these adverse events (AE’s) are noted, antibody infusion
should be temporarily discontinued, the patient should be observed and severity of the AE’s should
be evaluated and if necessary treated according to best available local practices and procedures.
Following observation, if the patient’s symptoms improve, the infusion should be continued, initially,
at 1/2 the previous rate (see table below).
Decrease dose rate to ½ if one or more of the following is applicable:
Fever
Rigors
Mucosal congestion or edema
Drop in Systolic BP
> 38.5 °C
mild / moderate
mild / moderate
> 30 mm Hg
If after one hour of infusion at ½ dose rate no AE’s are observed, the dose rate may be escalated in
30 minutes intervals with increment steps of 50 mg/hr, to a maximum of dose rate of 400 mg/hr.
Following the antibody infusion, the IV line should be kept open for other medication.
If no AE’s occured with the previous infusion, the infusion rate at the start of following infusions can
be 100 mg/hr and as no further AE’s are observed the infusion rate can be increased with 30
minutes intervals with increment steps of 50 mg/hr to a maximum of 400 mg/hr.
Rituximab may also be infused with a rate according to local standards of the hospital but should
always be in accordance with the maxima as stated in the product information.
9.2.4
Infusion completion
If there are no complications, the IV line may be removed after one hour of observation. If
complications occur during infusion, the patient should be observed for two hours after the
completion of the infusion.
9.3
Concomitant medication
All patients are forbidden to use any of the following medications while participating in the study:
♦ any immunosuppressive medication,
♦ other investigational drugs;
♦ any treatment which influences the platelet number;
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♦ anticoagulant therapy;
♦ chemotherapy;
♦ any treatment e.g. pulsed or high dose corticosteroids or IVIG
Provided that dosage is unchanged during the study the following concomitant medication is
allowed:
♦ maintenance corticosteroids;
♦ tranexaminic acid (Cyklokapron);
♦ non-immunosuppressive medication (e.g. danazol, vitamin C, dapsone)
10
End of protocol treatment
Reasons for going off protocol treatment are:
1. Need for emergency therapy, i.e. hemorrhage/bleeding defined by grade 3 or 4 according to NCI
CTCAE v3.0, indication for IVIG treatment.
2. Thrombosis
3. Intercurrent death
4. Opportunistic infection
5. Non-compliance of the patient
6. Pregnancy
7. Major protocol violation
8. Normal completion of protocol treatment
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HOVON 64 ITP
11
Version: December 11, 2007
Required clinical observations
See table and section 11.1 and 11.2.
At entry
During treatment
Follow up
until day 71
For responding
patients until
relapse/week 52
Pre-rituximab
After rituximab
4 weekly
weekly
Medical History
X
X
X
X
Physical examination
X
X
X
X
Hemorrhage/bleeding
X
X
X
X
Hematology
X
X
X
X
Fragmentocytes
X
X
X
X
Blood coagulation
X
X
X
X
B-lymphocyte quantification
X
X
Blood chemistry
X
X
Serology
X
Pregnancy test
X
Anti dsDNA antibodies
Bone marrow aspirate
X
1
X
(megakaryocyte culture
study) (Sanquin)
TPO 1 (Sanquin)
X
Anti-thrombocyte antibodies
X
X
X
X
X
X3
X
detection and antibody
kinetic studies 1 (Sanquin)
Blood megakaryocyte culture
studies
1, 2
(Sanquin)
Additional tests
o.i.
o.i.:
on indication
1:
for details concerning volume and type of sample see paragraph 4.1 and Sanquin sample
scheme (Appendix F)
2:
arm B responders and arm C also samples on day 15 and 22. Arm B non-responders also
samples on day 15 and day of 3rd and 4th rituximab gift
3:
after rituximab gifts only one sample collection at day 71
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HOVON 64 ITP
11.1
Version: December 11, 2007
Observations before randomization / at study entry
♦ Medical history (including concomitant medication)
♦ Physical examination (standard examination including vital signs, exclusion of pseudo
thrombocytopenia and other causes of thrombocytopenia, and in patients who underwent
splenectomy, the presence of an accessory spleen should be analyzed)
♦ Hemorrhage/bleeding status (purpura/petechia, epistaxis, oral bleeding, menorrhagia, bruising,
intracranial bleeds)
♦ Hematology: complete blood count (including platelets) and WBC differential
♦ Fragmentocytes (schistocytes)
♦ Blood coagulation: PT, aPTT
♦ B-lymphocyte quantification (CD19)
♦ Blood chemistry: electrolytes, renal and liver function tests (creatinine, BUN, ASAT, ALAT, AP, ?GT, LDH, bilirubin)
♦ Serology: HBV, HCV, HIV, CMV, EBV
♦ Pregnancy test
♦ Anti double-stranded (ds)DNA antibodies
♦ Fc?R genotyping (Sanquin, Amsterdam: see section 4.1.1)
♦ Bone marrow aspirate (local and Sanquin, Amsterdam: see section 4.1.2)
♦ Thrombopoietin (TPO) level (Sanquin, Amsterdam: see section 4.1.3)
♦ Anti-thrombocyte auto-antibodies and antibody kinetics (Sanquin, Amsterdam: see section 4.1.3)
♦
Blood megakaryocyte culture studies (Sanquin, Amsterdam: see section 4.1.4)
♦ Additional investigations on indication, according to ASH guidelines (see appendix A)
11.2
Observations during and following treatment
Weekly platelet counts should be performed during treatment and patients should be evaluated at
least every 4 weeks for clinical response, bleeding and adverse events. During rituximab infusion
vital signs (blood pressure, respiration rate, pulse, and body temperature) will be recorded.
12
Toxicities
Fever is common during or after infusion of rituximab. Anaphylactic reactions occur in a low
frequency. Treatment required during such an event should be available prior to each infusion.
(All toxicities will be scored according to the NCI Common Terminology for Adverse Events, version
3.0 (appendix C)).
Page 16 of 36
HOVON 64 ITP
Version: December 11, 2007
13
Safety evaluations and adverse events reporting
13.1
Definitions
Adverse event (AE)
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study subject
during protocol treatment. An AE does not necessarily have a causal relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medicinal (investigational)
product, whether or not related to the medicinal (investigational) product.
Adverse reaction (AR)
Adverse reactions (AR) are those AEs of which a reasonable causal relationship to any dose
administered of the investigational medicinal product and the event is suspected.
Serious adverse event (SAE)
A serious adverse event is defined as any untoward medical occurrence that at any dose results in:
•
death
•
a life-threatening event (i.e. the patient was at immediate risk of death at the time the
reaction was observed)
•
hospitalization or prolongation of hospitalization
•
significant / persistent disability
•
a congenital anomaly / birth defect
•
any other medically important condition (i.e. important adverse reactions that are not
immediately life threatening or do not result in death or hospitalization but may jeopardize the
patient or may require intervention to prevent one of the other outcomes listed above)
Note that ANY death, whether due to side effects of the treatment or due to progressive disease or
due to other causes is considered as a serious adverse event.
Unexpected SAE
Unexpected Serious Adverse Events are those SAE’s of which the nature or severity is not
consistent with information in the relevant source documents. For a medicinal product not yet
approved for marketing in a country, a company’s Investigator’s Brochure will serve as a source
document in that country.
Suspected unexpected serious adverse reaction (SUSAR)
All suspected ARs which occur in the trial and that are both unexpected and serious.
Page 17 of 36
HOVON 64 ITP
Version: December 11, 2007
Protocol treatment period
The protocol treatment period is defined as the period from the first study-related procedure until 30
days following the last dose of protocol treatment or until the start of another systemic anti-cancer
treatment off protocol, if earlier.
13.2
Reporting of (serious) adverse events
Adverse event
AEs will be reported on the CRF. All adverse events of Grade 2 or higher, with the exception of
progression of disease, occurring during the protocol treatment period will be reported. Adverse
events occurring after that period should also be reported if considered related to protocol treatment.
SAE and Unexpected serious adverse event
All SAEs occurring during the protocol treatment period must be reported to the HOVON Data
Center by fax within 24 hours of the initial observation of the event, except hospitalizations for:
•
a standard procedure for protocol therapy administration. Hospitalization or prolonged
hospitalization for a complication of therapy administration will be reported as a Serious Adverse
Event.
•
the administration of blood or platelet transfusion. Hospitalization or prolonged hospitalization for
a complication of such transfusion remains a reportable serious adverse event.
•
a procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy,
sampling for laboratory tests, bone marrow sampling). Hospitalization or prolonged
hospitalization for a complication of such procedures remains a reportable serious adverse
event.
•
prolonged hospitalization for technical, practical, or social reasons, in absence of an adverse
event.
•
a procedure that is planned (i.e., planned prior to starting of treatment on study; must be
documented in the CRF). Prolonged hospitalization for a complication considered to be at least
possibly related to the protocol treatment remains a reportable serious adverse event.
All details should be documented on the Serious Adverse Event and Death Report. In
circumstances where it is not possible to submit a complete report an initial report may be made
giving only the mandatory information. Initial reports must be followed-up by a complete report within
a further 2 working days and sent to the HOVON Data Center. All SAE Reports must be dated and
signed by the responsible investigator or one of his/her authorized staff members.
Page 18 of 36
HOVON 64 ITP
Version: December 11, 2007
At any time after the protocol treatment period, Serious Adverse Events that are considered to be at
least suspected to be related to protocol treatment must also be reported to the HOVON Data
Center using the same procedure, within 24 hours after the SAE was known to the investigator.
The investigator will decide whether the serious adverse event is related to the treatment (i.e.
unrelated, unlikely, possible, probable, definitely and not assessable) and the decision will be
recorded on the serious adverse event form. The assessment of causality is made by the
investigator using the following:
RELATIONSHIP
DESCRIPTION
UNRELATED
There is no evidence of any causal relationship to the protocol treatment (also
include pre-existing conditions)
UNLIKELY
There is little evidence to suggest there is a causal relationship (e.g. the event did
not occur within a reasonable time after administration of the trial medication).
There is another reasonable explanation for the event (e.g. the patient’s clinical
condition, other concomitant treatments).
POSSIBLE
There is some evidence to suggest a causal relationship (e.g. because the event
occurs within a reasonable time after administration of the trial medication).
However, the influence of other factors may have contributed to the event (e.g. the
patient’s clinical condition, other concomitant treatments).
PROBABLE
There is evidence to suggest a causal relationship and the influence of other factors
is unlikely.
DEFINITELY
There is clear evidence to suggest a causal relationship and other possible
contributing factors can be ruled out.
NOT
There is insufficient or incomplete evidence to make a clinical judgement of the
ASSESSABLE
causal relationship.
13.3
Processing of serious adverse event reports
The HOVON Data Center will forward all reports within 24 hours of receipt to the study coordinator,
Roche Netherlands, and the study central data manager. The report of an SAE will be the signal for
the central datamanager to ask the investigator or the responsible local datamanager to complete
and send as soon as possible all relevant CRF’s for the involved patient with details of treatment
and outcome.
Page 19 of 36
HOVON 64 ITP
14
Endpoints
14.1
Primary endpoint
Version: December 11, 2007
The response (CR/GR/MR/NR) to treatment.
14.2
Secondary endpoints
♦ Need for emergency treatment (platelet count <10 or hemorrhagic diathesis,
hemorrhage/bleeding defined by grade 3 or 4 according to NCI CTCAE v3.0)
♦ Time to treatment failure/relapse
♦ Level of megakaryopoiesis
♦ Level of anti-platelet antibody production
15
Randomization
15.1
Randomization for rituximab treament
After obtaining written informed consent for the treatment according to this protocol each patient will
be randomized at the HOVON Data Center of the Erasmus MC, Daniel den Hoed clinic by phone
call: +31.10.4391568 or fax +31.10.4391028 Monday through Friday, from 09:00 to 17:00 or
(preferably) via the Internet via TOP (Trial Online Process; https://www.hdc.hovon.nl/top). A logon to
TOP can be requested at the HOVON Data Center for participants.
The following information will be requested at registration:
1. Protocol number
2. Institution name
3. Name of caller/responsible investigator
4. Patient’s initials or code
5. Sex
6. Date of birth
7. Patient’s hospital record number
8. WHO performance status
9. Date of ITP diagnosis
10. Eligibility criteria
All eligibility criteria will be checked with a checklist. Each patient will be given a unique patient study
number.
Page 20 of 36
HOVON 64 ITP
16
Version: December 11, 2007
Forms and procedures for collecting data
Data will be collected on Case Report Forms (CRF) to document eligibility, safety and efficacy
parameters, compliance to treatment schedules and parameters necessary to evaluate the study
endpoints. Data collected on the CRF are derived from the protocol and will include at least:
♦ inclusion and exclusion criteria
♦ baseline status of patient including medical history and stage of disease
♦ timing and dosage of protocol treatment
♦ adverse events
♦ parameters for response evaluation
♦ any other parameters necessary to evaluate the study endpoints
♦ survival status of patient
♦ reason for end of protocol treatment
The CRF will be completed on site by the local investigator or an authorized staff member. General
rules for CRF handling are mentioned in more detail in appendix E. Each page must be dated and
signed by the local investigator upon completion. All CRF entries must be based on source
documents. The CRF and study specific written instructions for completing the CRF will be provided
by the HOVON Data Center.
Copies of the CRF will be kept on site. The original CRF pages must be sent to the HOVON Data
Center at the requested timepoints. How and when to send in forms is described in detail in the CRF
header and the CRF instructions.
17
Statistical considerations
17.1
Patient numbers and power considerations
This randomized phase II trial follows an optimal two-stage design, as described in Simon17 (1989).
Note: the objective of this randomized phase II trial is to evaluate, on an individual basis, whether
the treatments are worth further study, and NOT to compare the two treatments. The sample size
calculation is based on the percentage of patients reaching CR (complete response), GR (Good
Response), or MR (Moderate Response), in each treatment arm. A percentage less than 30% is
considered uninteresting (H0 : p ≤ 0.30), and a percentage greater than 50% as desirable (H1: p ≥
0.50). A percentage greater than 50% has been shown to be feasible11. The probability of accepting
a treatment as worth further study, while in fact it is not (i.e., H0 is true), is limited to 10% (α = 0.10).
The probability of rejecting a treatment for further study, while in fact it is (i.e., H1 is true), is limited to
Page 21 of 36
HOVON 64 ITP
Version: December 11, 2007
10% (β = 0.10). These characteristics imply a sample size of 138 patients in total, 46 patients per
arm (details of the sample size calculation can be found in Simon17). In addition, a drop-out rate of
8% is taken into account. This results in a sample size of 150 patients in total, 50 per arm. No
information on the incidence of ITP in the Netherlands is available (hence the registration). The
incidence in the USA is 5 per 100000 citizens 4. Taking this as a guideline, 150 patients are to be
accrued in three years, accounting for a possible lower incidence in the Netherlands.
17.2
Statistical analysis
All main analyses will be done in accordance with the intention-to-treat principle.
17.3
Efficacy analysis
With respect to the main endpoint:
♦ A binomial probability test, for each arm separately, will be used to evaluate whether the
treatment is worth further study, i.e., differs significantly from 30%. A 90% confidence interval for
the percentage in each arm will be presented. If, in multiple arms, the percentage of patients
reaching GR or MR exceeds the 30% significantly, the treatment with the highest percentage is
considered the most promising (in line with Simon, Wittes and Ellenberg18). This formalizes the
decision procedure.
With respect to the secondary endpoints:
♦ The time to treatment failure will be analyzed using an actuarial Kaplan-Meier estimate.
Treatment failure is applicable if on of the following is true:
♦
NR after 2 or 4 doses Rituximab,
♦
death on treatment,
♦
emergency treatment given,
♦
or relapse.
♦ The need for emergency treatment will be analyzed through tabulation.
♦ For each arm, the ratio of patients who – after inclusion – underwent splenectomy and the
patient who entered the study with spleen will be estimated.
♦ The effects of rituximab on megakaryopoiesis and anti-platelet antibody levels will be estimated
by regression analysis.
All analyses of secondary endpoints are exploratory. Hence, no conclusions will be drawn from
them.
Page 22 of 36
HOVON 64 ITP
17.4
Version: December 11, 2007
Interim analysis
An interim analysis for each arm will be done when response data of the first 22 patients are
available in the arm. In line with Simon17 a treatment will be excluded from further study (and no
longer persued in this trial) if 7 or less patients attained a response (CR, GR or MR). This stopping
criterion implies a probability of early termination of a treatment, when indeed H0 is true, of 67%. No
conclusions with respect to the acceptance of a treatment for further study will be drawn at interim
analysis.
If, in a particular arm, 22 patients have been included and their response data are not available, no
further patients will be included in this arm if, at that time, less than eight responses have been
reported. Otherwise, inclusion of patients in the particular arm may proceed.
18
Ethics
18.1
Independent ethics committee or institutional review board
The study protocol and any amendment that is not solely of an administrative nature will have to be
approved by an Independent Ethics Committee or Institutional Review Board.
18.2
Ethical conduct of the study
The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki
and the ICH-GCP Guidelines. The local investigator is responsible for ensuring that the study will be
conducted in accordance with the protocol, the ethical principles of the Declaration of Helsinki,
current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory requirements.
18.3
Patient information and consent
Written informed consent of patients is required before treatment randomization (and before
registration at the national registry).
18.3.1 Biological studies
Registration of patients will be used to set up possibilities for local and nation wide research into the
pathophysiology of ITP. Bone marrow and DNA will be collected and stored at Sanquin, Amsterdam.
Any research question will be evaluated by the writing committee and, if necessary, incorporated in
the protocol after approval of the Ethics Committee.
Page 23 of 36
HOVON 64 ITP
19
Version: December 11, 2007
Trial insurance
The HOVON insurance program covers all patients from participating centers in the Netherlands
according to Dutch law (WMO). The WMO insurance statement can be viewed on the HOVON Web
site www.hovon.nl.
Individual participating centers from outside the Netherlands have to inform the HOVON about the
national laws regarding the risk insurance of patients participating in a study. If necessary HOVON
will extend the insurance to cover these patients.
Intergroup studies.
The HOVON insurance program does not cover the risk insurance of patients from centers
participating within another cooperative group taking part in an intergroup study. The other
participating groups will cover the insurance of patients registered/randomized through their offices.
20
Publication policy
The final publication of the trial results will be written by the study coordinator(s) on the basis of the
statistical analysis performed at the HOVON Data Center. A draft manuscript will be submitted to the
Data Center and all co-authors (and the sponsor, where applicable) for review. After revision by the
Data Center, the other co-authors (and the sponsor), the manuscript will be sent to a peer reviewed
scientific journal.
Authors of the manuscript will include the study coordinator(s), the lead investigators of the major
groups (in case of intergroup studies), investigators who have included more than 5% of the
evaluable patients in the study (by order of inclusion), the statistician(s) and the HOVON data
manager in charge of the study, and others who have made significant scientific contributions.
Any publication, abstract or presentation based on patients included in this study must be approved
by the study coordinator(s). This is applicable to any individual patient who is treated with rituximab.
Page 24 of 36
HOVON 64 ITP
21
Version: December 11, 2007
Glossary of abbreviations
ADCC
AE
aPPT
ASH
BP
BSA
BUN
CKTO
cMETC
CMV
CR
CRF
CTCAE
ds
EBV
EurdraCT
Fc?R
GR
HBV
HCV
HIV
HOVON
HSV
ITP
IV
IVIG
MR
NCI
NR
PCP
PR
PPT
RR
SAE
TOP
TPO
antibody-dependent-cellmediated-cytotoxicity
adverse event
activated partial prothrombine time
American Society of Hematology
blood pressure
body surface area
blood urea nitrogen
‘Commissie voor Klinisch Toegepast Onderzoek’
‘centrale Medisch Ethische Toetsings Commissie’
cytomegalovirus
complete response
case report form
common toxicity criteria for adverse events
double-stranded
Epstein Barr virus
European drug regulatory affairs Clinical Trials
IgG-Fc Receptor
good response
hepatitis B virus
hepatitis C virus
human immunodeficiency virus
Dutch-Belgian Hematology-Oncology Cooperative Group
herpes simplex virus
immune thrombocytopenic purpura
intravenous
intravenous immune globulin
moderate response
National Cancer Institute
no response
pneumocystis carinii pneumonia
partial response
partial prothrombine time
response rate
serious adverse event
Trial Online Process
thrombopoietin
Page 25 of 36
HOVON 64 ITP
22
Version: December 11, 2007
References
1. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic
activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor
FcgammaRIIIa gene. Blood. 2002; Feb 1;99(3):754-8)
2. Louwes H, Zeinali Lathori OA, Vellenga E, de Wolf JT. Platelet kinetic studies in patients with
idiopathic thrombocytopenic purpura. Am J Med 1999;106:430-4
3. Houwerzijl EJ, et al. Ultrastructural study shows morphologic features of apoptosis and paraapoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood
2004;103:500-6
4. George JN, Woolf SH, Raskob GE. Idiopathic thrombocytopenic purpura: a guideline for
diagnosis and management of children and adults. American Society of Hematology. Ann Med.
1998;30:38-44.
5. Diagnosis and Treatment of Idiopathic Thrombocytopenic Purpura: Recommendations of the
American Society of Hematology. Ann Intern Med. 1997;126:319-326.
6. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in
adults, children and in pregnancy. Br J Haematol. 2003;120:574-596.
7. Portielje JEA, Westendorp RGJ, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults
with idiopathic thrombocytopenic purpura. Blood. 2001;97:2549-2554.
8. Cines DB, Blanchette VS. Medical progress: Immune thrombocytopenic purpura. New England
Journal of Medicine. 2002;346:995-1008.
9. Vesely SK, Perdue JJ, Rizvi MA, Terrell DR, George JN. Management of Adult Patients with
Persistent Idiopathic Thrombocytopenic Purpura Following Splenectomy: A Systematic Review.
Ann Intern Med. 2004;140:112-120.
10. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody
treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98:952-957.
11. Cooper N, Stasi R, Feuerstein M, Bussel JB et al. The efficacy and safety of B-cell depletion with
anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J
Haematol 2004;125(2):232-9.
12. Giagounidis AA, Anhuf J, Schneider P et al. Treatment of relapsed idiopathic thrombocytopenic
purpura with the anti-CD20 monoclonal antibody Rituximab: a pilot study. Eur J Haematol.
2002;69:95-100.
13. Riksen NP, Keuning JJ, Vreugdenhil G. Rituximab in the treatment of relapsing idiopathic
thrombocytopenic purpura. Neth J Med. 2003;61:262-265.
14. Cabrera JF, Penalver FJ, Millan I, Jimenez-Yuste V, Almagro M, Alvarez-Larran A, Rodriquez L.
Mabthera (rituximab) in the treatment of 92 patients with refractory immune thrombocytopenic
purpura. ASH 2004 abstract number 2074
15. Maloney DG, Liles TM, Czerwinski DK et al. Phase I clinical trial using escalating single-dose
infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent Bcell lymphoma. Blood. 1994;84:2457-2466.
16. Keating M, O'Brien S. High-dose Rituximab therapy in chronic lymphocytic leukemia. Semin
Oncol. 2000;27:86-90.
17. Simon, R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials.
1989;10:1-10.
18. Simon, R, Wittes, RE, Ellenberg, SS. Randomized Phase II Trials. Cancer Treatment Reports.
69;1375-1381.
Page 26 of 36
APPENDIX A
HOVON 64 ITP
Version: December 11, 2007
Appendices
A
Diagnostic criteria for ITP
The diagnosis of ITP is made according to the guidelines of the American Society of
Hematology4,5:
1. Isolated thrombocytopenia (low platelet count with an otherwise normal complete blood count
and blood smear).
2. Exclusion of pseudothrombocytopenia (EDTA artifact)
3. Absence of:
♦
other autoimmune diseases
♦
disseminated intravascular coagulation
♦
drug-induced thrombocytopenia
♦
HIV infection
♦
lymphoproliferative disorders
♦
myelodysplasia
♦
agammaglobulinemia
♦
alloimmune, congenital or hereditary thrombocytopenia
History, including use of drugs, physical examination, blood count and peripheral blood film should
be performed in every case, aiming at the detection of alternative causes of thrombocytopenia.
Page 27 of 36
APPENDIX B
HOVON 64 ITP
B
Version: December 11, 2007
Response criteria
All responses should last for at least 4 weeks.
a. Complete response (CR): Platelet count =150 x 109/l
b. Good response (GR): platelet count = 50 x 109 /l
c. Moderate response (MR): platelet count over = 30 x 109/l AND at least double of baseline count
d. No response (NR)
♦ Platelet count below 30 x 109/l
♦ Platelet count = 30 x 109 /l AND not double of baseline count
Relapse: platelets below 30 x 109 /l after an initial (confirmed) response (CR, GR, or MR).
(The response criteria are in line with Kojouri et al. Blood 2004;104:2623-2634 and Vesely et al.
Ann Intern Med 2004;140:112-120)
Page 28 of 36
APPENDIX C
HOVON 64 ITP
C
Version: December 11, 2007
Common Toxicity criteria
The grading of toxicities and adverse events will be done using the NCI Common Terminology
Criteria for Adverse Events, CTCAE version 3.0, published December 12, 2003. A complete
document (72 pages) may be downloaded from the following sites:
http://ctep.info.nih.gov/reporting/ctc.html
http://www.hovon.nl (under Studies > Documents)
Page 29 of 36
APPENDIX D
HOVON 64 ITP
D
Version: December 11, 2007
WHO performance status
0.
fully active, able to carry out all normal activity with normal activity
1.
Restricted in physically strenuous activity, but ambulatory and able to carry out light or
sedentary work
2.
Ambulatory and capable of all self-care but unable to carry out any work, up and about more
than 50% of time
3.
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4.
Completely disabled; cannot carry out any self-care, totally confined to bed and chair
5.
Dead
Page 30 of 36
APPENDIX E
HOVON 64 ITP
E
Version: December 11, 2007
General rules for CRF handling
Patient namecode
Use a three-letter code, preferably the first letter of the patient’s first name and the first two letters of his/her
last name. If the patient is a married woman, use the first two letters of her maiden name. Use the same
namecode on all forms, as an extra means of identification besides patient study number.
Date format
The date format is dd/mm/yyyy (day, month, year).
CRF data entry
Please adhere to the following rules:
Data reported on the CRF, that are derived from source documents, should be consistent with the source
documents or the discrepancies should be explained.
Write clearly and legible.
Use a blue or black pen (no pencil).
All entries must be in English.
Avoid abbreviations and symbols if possible.
Make corrections by crossing out the incorrect answer once (do not obscure the original entry) and writing
the new answer next to it, dated, initialled, and explained (if necessary). Do not use correction tape or fluid.
Fill out lab values in the units that are requested on the form if possible; if another unit is used make sure this
is clear by crossing out the printed unit and adding the type of unit used.
With a few exceptions, never leave any item blank. If something is ‘not done ‘, ‘unknown’, etc., make a
comment (“ND”, “UK”, etc.), so it is obvious the item is not just forgotten to be filled out. If there is an item
asking if a certain test was done and the answer is ‘no’, you may leave the subsequent questions about the
test results open. If there is no reason to specify an answer, you may leave the specification blank. Other
exceptions are described for each form in the instructions on the previous pages.
If a form consists of more than one page and it can relate to more than one treatment phase or date (like a
Follow Up form or Treatment Evaluation form), the treatment phase or date (‘index’ item) is repeated on
page 2 and following pages. This way the correct pages of each form stay together. So don’t forget to fill out
this item on every page of the form.
Always send in all pages of a form, even if all items on a page are ‘not done’ or ‘not applicable’. In that case,
draw a line through the page and mark it with “ND”, “NAP”, initialled and dated. If applicable, do fill out the
repeated ‘index’ item on all pages.
For items with a label attached to it (like 0=no, 1=yes), make sure you only write down the corresponding
number for the correct answer (so not ‘Y’ for yes). If the answer is ‘other’, always specify.
Only use “specify” fields to give a relevant specification of the item it refers to. Do not use it for additional
comments on the item.
Additional comments to any item on a form should be entered in the “Comments” lines on that form. Specify
the item number the comment refers to.
Page 31 of 36
APPENDIX E
HOVON 64 ITP
Version: December 11, 2007
If it is not possible to enter important relevant comments on the “Comments” line of the form, use the
General Comments form. Specify the form and item number the comment refers to, including the index
(treatment cycle, date of evaluation, etc.) of the form.
Do not add additional entries or remarks in the margins of the form.
Only use the “Comments” lines or General Comments form for important relevant information that is not
otherwise available from the data on the CRF.
Sending of CRFs
All forms have to be sent to:
HOVON Data Center, Erasmus MC – Daniel den Hoed, P.O. Box 5201, 3008 AE ROTTERDAM, The
Netherlands.
Send in the original CRF’s, completed, dated, named and signed by the local investigator or the person who
has been authorised by the investigator to be responsible for the quality of the data on his/her behalf.
Keep a copy of all CRF’s.
Corrections afterwards can be made as follows:
On top of your copy of the CRF’s write “revised”. Write the corrections on this copy and initialize and date the
form. Make a copy for your own files and send the revised CRF pages to the HDC
Page 32 of 36
APPENDIX F
HOVON 64 ITP
F
Version: December 11, 2007
Sanquin sample scheme
Arm A
HOVON 64 ITP
Patient study number ...…
Patient name code ………..
ARM A
DAY
Determine at hospital
(see p15 of protocol)
Inclusion
pre Ritux*
Max 3 wks before start
d1
Hemat+Fragm+Coagulation
pre Ritux*
d8
pre Ritux*
pre Ritux*
7 ml
Bone Marrow
X
X
X
X
X
X
Hemat+Fragm+Coagulation
X
X
X
d15
Hemat+Fragm+Coagulation
X
X
X
d22
Hemat+Fragm+Coagulation
X
X
X
d29
X
X
d36
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d43
Hemat+Fragm+Coagulation
X
X
d50
Hemat+Fragm+Coagulation
X
X
d57
X
X
d64
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d71
Hemat+Fragm+Coagulation
X
X
m3 (= d90) untill m12
Hemat+Fragm+Coagulation
B-cell+Chemistry
X (10 samples)
X (10 samples)
22
22
TOTAL samples…..
X
Samples to send to Sanquin Amsterdam
30 ml
8 ml
8 ml
EDTA blood
coagulated blood coagulated blood
1
* pre Rituximab max 4 hrs before gift
Page 33 of 36
X
6
APPENDIX F
HOVON 64 ITP
Version: December 11, 2007
Arm B (responders)
HOVON 64 ITP
Patient study number ...…
Patient name code ………..
ARM B:response
DAY
Determine at hospital
(see p15 of protocol)
Inclusion
pre Ritux*
Max 3 wks before start
d1
Hemat+Fragm+Coagulation
pre Ritux*
d8
7 ml
Bone Marrow
X
X
X
X
X
X
Hemat+Fragm+Coagulation
X
X
X
d15
Hemat+Fragm+Coagulation
X
X
X
d22
Hemat+Fragm+Coagulation
X
X
X
d29
X
X
d36
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d43
Hemat+Fragm+Coagulation
X
X
d50
Hemat+Fragm+Coagulation
X
X
d57
X
X
d64
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d71
Hemat+Fragm+Coagulation
X
X
m3 (= d90) untill m12
Hemat+Fragm+Coagulation
B-cell+Chemistry
X (10 samples)
X (10 samples)
22
22
TOTAL samples…..
X
Samples to send to Sanquin Amsterdam
30 ml
8 ml
8 ml
EDTA blood
coagulated blood coagulated blood
1
* pre Rituximab max 4 hrs before gift
Page 34 of 36
X
6
APPENDIX F
HOVON 64 ITP
Version: December 11, 2007
Arm B (non-responders or loss of response)
HOVON 64 ITP
Patient study number ...…
Patient name code ………..
ARM B:
no response on day 15 or loss
of response before day 43
DAY
Determine at hospital
(see p15 of protocol)
Inclusion
pre Ritux*
max 3 wk voor start
d1
Hemat+Fragm+Coagulation
X
X
X
X
X
X
pre Ritux*
d8
Hemat+Fragm+Coagulation
X
X
X
d15
Hemat+Fragm+Coagulation
X
X
X
pre Ritux* (day 22 to day 43)
d22
Hemat+Fragm+Coagulation
X
X
X or pre Ritux
pre Ritux* (day 29 to day 50)
d29
X
X
X or pre Ritux
d36
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d43
Hemat+Fragm+Coagulation
X
X
d50
Hemat+Fragm+Coagulation
X
X
d57
X
X
d64
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d71
Hemat+Fragm+Coagulation
X
X
m3 (= d90) untill m12
Hemat+Fragm+Coagulation
B-cell+Chemistry
X (10 samples)
X (10 samples)
22
22
7 ml
Bone Marrow
X
TOTAL samples…..
1
* pre Rituximab max 4 hrs before gift
Page 35 of 36
Samples to send to Sanquin Amsterdam
30 ml
8 ml
8 ml
EDTA blood
coagulated blood coagulated blood
X
7
APPENDIX F
HOVON 64 ITP
Version: December 11, 2007
Arm C
HOVON 64 ITP
Patient study number ...…
Patient name code ………..
ARM C
DAY
Determine at hospital
(see p15 of protocol)
Inclusion
pre Ritux*
Max 3 wks before start
d1
Hemat+Fragm+Coagulation
pre Ritux*
d8
7 ml
Bone Marrow
8 ml
coagulated blood
X
X
X
X
X
X
Hemat+Fragm+Coagulation
X
X
X
d15
Hemat+Fragm+Coagulation
X
X
X
d22
Hemat+Fragm+Coagulation
X
X
X
d29
X
X
d36
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d43
Hemat+Fragm+Coagulation
X
X
d50
Hemat+Fragm+Coagulation
X
X
d57
X
X
d64
Hemat+Fragm+Coagulation
B-cell+ Chemistry
Hemat+Fragm+Coagulation
X
X
d71
Hemat+Fragm+Coagulation
X
X
m3 (= d90) untill m12
Hemat+Fragm+Coagulation
B-cell+Chemistry
X (10 samples)
X (10 samples)
22
22
TOTAL samples…..
X
Samples to send to Sanquin Amsterdam
30 ml
8 ml
EDTA blood
coagulated blood
1
* pre Rituximab max 4 hrs before gift
Page 36 of 36
X
6