Download Phase III, randomized, double-blind, placebo-controlled

Support Care Cancer (2014) 22:1233–1242
DOI 10.1007/s00520-013-2076-0
ORIGINAL ARTICLE
Phase III, randomized, double-blind, placebo-controlled
study of modafinil for fatigue in patients treated
with docetaxel-based chemotherapy
Elizabeth Hovey & Paul de Souza & Gavin Marx & Phillip Parente & Tal Rapke &
Andrew Hill & Antonino Bonaventura & Antony Michele & Paul Craft &
Ehtesham Abdi & Andrew Lloyd & on behalf of the MOTIF investigators
Received: 21 April 2013 / Accepted: 25 November 2013 / Published online: 17 December 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose Modafinil has been reported to benefit a subgroup of
patients suffering severe fatigue while undergoing chemotherapy. Docetaxel is associated with fatigue that may lead to premature therapy withdrawal. We investigated whether modafinil
could reduce fatigue during docetaxel chemotherapy.
Methods This multicenter, randomized, double-blind, placebocontrolled study evaluated the efficacy of modafinil in patients
with metastatic prostate or breast cancer undergoing docetaxel
chemotherapy (every 21 days; minimum dose 50 mg/m2). At
the start of their third or subsequent chemotherapy cycle,
patients with significant docetaxel-associated fatigue were randomized to receive concurrent modafinil 200 mg/day or placebo for 15 days (“treatment periods” (TP)). Docetaxel was
continued for up to four further cycles. Fatigue was evaluated
with the fatigue component of the MD Anderson Symptom
Inventory (MDASI). The primary endpoint was cumulative
MDASI area under the curve (AUC) during the first 7 days of
study medication during TP1 and TP2.
Results Evaluable data were available from 83 patients (65 with
prostate cancer). There was no statistically significant difference
between the two treatment arms for the primary endpoint
(MSADI AUC3–10 35.9 vs 39.6; 95 % confidence interval
−8.9, 1.4; P =0.15). Overall toxicity was comparable between
treatment groups; however, the incidence of grade ≤2 nausea
and vomiting was higher in the modafinil arm (45.4 vs 25 %).
Conclusions Assessing and managing chemotherapy-related
fatigue remains a major challenge. There was a lack of
Electronic supplementary material The online version of this article
(doi:10.1007/s00520-013-2076-0) contains supplementary material,
which is available to authorized users.
E. Hovey (*)
Department of Medical Oncology, Prince of Wales Hospital, High
Street, Randwick, New South Wales 2031, Australia
e-mail: [email protected]
A. Hill
Gold Coast Hospital, Southport, Queensland, Australia
E. Hovey : A. Lloyd
University of New South Wales, Sydney, New South Wales,
Australia
A. Bonaventura
ANZGOG, Newcastle, New South Wales, Australia
P. de Souza
University of Western Sydney, Penrith, New South Wales, Australia
A. Michele
Calvary Hospital, North Adelaide, South Australia, Australia
G. Marx
Sydney Haematology Oncology Clinics, Sydney, New South Wales,
Australia
P. Craft
The Canberra Hospital, Garran, Canberra, ACT, Australia
P. Parente
Box Hill Hospital, Box Hill, Victoria, Australia
E. Abdi
The Tweed Hospital, Tweed Heads, New South Wales, Australia
T. Rapke
Sanofi Australia Pty Ltd, Macquarie Park, New South Wales,
Australia
E. Abdi
Griffith University, Gold Coast, Queensland, Australia
1234
difference between the two arms in the planned primary
endpoint. However, there was a modest but consistent trend
towards improvement of docetaxel-related fatigue in those
treated with modafinil. Based on the study findings, modafinil
for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements. Larger, longer term,
randomized, controlled studies are required to clarify the exact
role of modafinil in the treatment of docetaxel-related fatigue.
Keywords Breast cancer . Docetaxel . Fatigue . Prostate
cancer . Modafinil . Chemotherapy
Introduction
Cancer-related fatigue occurs in around half of patients prior to the
start of cancer therapy, almost universally during cancer treatment,
and then as a long-term complication for months or years in up to
one third of patients during remission [1]. It is a complex, and
likely, heterogenous phenomenon which has potential contributions from associated psychological and behavioral factors, such
as sleep disturbance and depression, as well as putative biological
disturbances mediated by inflammation or changes in the hypothalamic–pituitary–adrenal (HPA) axis [2]. In particular, an
inflammation-induced reduction in central dopaminergic neurotransmission has been proposed as a unifying mechanism for
fatigue associated with acute infection, interferon administration,
and other disease states [3]. With specific reference to
chemotherapy-related fatigue, accumulating evidence supports a
link between chemotherapy and increased production of proinflammatory cytokines [2]. Other proposed mechanisms for
on-treatment fatigue include serotonin dysregulation, direct suppression of the HPA axis, and circadian rhythm disruption [4].
A variety of interventions to reduce cancer-related fatigue
have been examined in randomized, controlled clinical trials;
many of these studies have been summarized in systematic
reviews and meta-analyses [5–10]. However, management of
cancer-related fatigue remains unresolved, primarily because
of the lack of proven effective therapies.
Modafinil, a wakefulness-promoting agent, has demonstrated positive effects in other fatigue-related conditions
including narcolepsy, multiple sclerosis, and negative symptoms in schizophrenia [11–13]. Although its detailed mechanisms of action remain incompletely defined [14], it potentially can modify central dopaminergic pathways implicated
in cancer-related fatigue. Improvements in cancer-related
fatigue have been shown in a number of small, open-label
studies involving a variety of different tumor types in patients undergoing anticancer therapy [15, 16], or after the
completion of therapy [17–19]. In a large, randomized,
double-blind, placebo-controlled study, modafinil (200 mg)
did not significantly reduce cancer-related fatigue during
chemotherapy; however, post hoc analysis showed a
Support Care Cancer (2014) 22:1233–1242
statistically significant improvement in fatigue among patients with severe fatigue at baseline [20].
The use of docetaxel in the metastatic cancer setting is
commonly associated with fatigue as the predominant toxicity
that may lead to dose reductions or premature withdrawal
from therapy, compromising the potential for improved survival or improved quality of life. There are no known interactions between modafinil and docetaxel, but the combined
effects of the two agents have not been extensively studied.
To date, there have been no studies specifically assessing
the effect of modafinil in chemotherapy-related fatigue (as
opposed to “cancer-related fatigue”) and, in particular,
chemotherapy-related fatigue associated with the use of docetaxel in metastatic disease. This prospective, phase III, randomized, double-blind, placebo-controlled, parallel-group,
multicenter study examines the efficacy of modafinil
(200 mg/day) in reducing docetaxel-related fatigue during
chemotherapy for metastatic prostate or breast cancer.
Patients and methods
Study population
Patients with metastatic prostate or breast cancer undergoing outpatient docetaxel-based chemotherapy every
3 weeks at a minimum dose of 50 mg/m 2 who had already
received at least 2 cycles of docetaxel and were expected
to receive at least two further cycles were screened. They
were enrolled if they had a fatigue score ≥4/10 (measured
by the fatigue component of MD Anderson Symptom
Inventory (MDASI) [21]) during their previous chemotherapy cycle; ‘clinically significant’ fatigue as denoted
by a score ≥3 on the Somatic and Psychological Health
Report somatic subscale [22], worsening of fatigue after
the commencement of docetaxel chemotherapy, and a
hemoglobin level ≥10 g/dL within 2 weeks of study randomization. Ongoing steroid use was accepted as per the
individual center's standard practice. As established in the
TAX-327 study [23], a standard protocol for docetaxel in
metastatic prostate cancer includes daily prednisone or
prednisolone 5 mg twice a day, orally, as well as dexamethasone premedication (8 mg given 12, 3, and 1 h prior
to docetaxel dosing), but this was not mandated in our
study.
Exclusion criteria included docetaxel dose reduction to less
than 50 mg/m2 before cycle three, history of chronic fatigue,
uncontrolled hypertension, known hypersensitivity/
intolerance to modafinil or any of the excipients, pregnancy,
a psychological or social condition that did not permit treatment or medical follow-up and/or prohibited compliance with
the study protocol, or a serious concomitant illness that would
preclude participation in the study.
Support Care Cancer (2014) 22:1233–1242
Treatment protocol
Eligible patients were randomized 2:1 to modafinil or placebo
via a centralized treatment allocation procedure and stratified
according to tumor type (prostate or breast). All participants
and study staff were blinded to the treatment assignment. The
study was approved by the relevant institutional review boards
at each site, and written informed consent was obtained from
all patients prior to any study-specific procedure, as per the
Declaration of Helsinki.
Following randomization, patients were either assigned
200 mg modafinil (2×100 mg capsules) to be taken daily
before noon or corresponding placebo capsules, for a period
of 15 days during each 21-day docetaxel chemotherapy cycle
(Fig. 1). Compliance was assessed at each study visit by
counting the number of returned capsules and diary card
review. Within the study, a minimum of 2 cycles and a
maximum of 4 cycles of docetaxel-based chemotherapy were
administered; defined here as “treatment periods” (TP).
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measure in the calculation of AUC) while the score at day 10
measures the fatigue for the 24 h after the seventh dose of
study medication. The AUC was derived using the trapezoidal
rule and is expressed in the results as AUC3–10.
A number of secondary outcome measures were used to
assess the role of other factors known to influence or be
associated with prolonged fatigue and to determine whether
there were any confounders in the interpretation of the fatigue,
such as depression, sleep disturbance, exercise, cognition, and
mood states (see online resource 1 for further details).
Adverse event reporting was conducted via telephone for the
first 3 days of modafinil or placebo treatment during the first
cycle of chemotherapy and then subsequently at each study visit.
Study visits occurred every 3 weeks (coinciding with day 1 of
each TP) during which a physical examination, full blood count,
blood pressure, heart rate, and use of concomitant medications
were recorded. Discontinuation of docetaxel chemotherapy and
the number of chemotherapy cycles completed were also recorded. An end of study visit was conducted 3 weeks after the final
dose of docetaxel.
Outcome measures
Statistical analysis
Fatigue was measured using the single-item, 11-point fatigue
assessment scale from the MDASI [21], where zero denotes
“no fatigue” and 10 denotes fatigue “as bad as it can get.”
Patients recorded their MDASI fatigue score each morning
during each TP. The primary endpoint was defined as the area
under the curve (AUC) captured by a plot of the cumulative
daily MDASI fatigue score versus time during the first 7 days
of study medication treatment. The primary endpoint was
adjusted for treatment, cycle number, cancer type, and prior
number of docetaxel cycles completed. The MDASI score on
day 3 reflects fatigue for the 24 h prior to the first dose of study
medication in that chemotherapy cycle (providing a baseline
Fig. 1 Schematic showing study
medication schedule (given for
15 days during each 3-weekly
docetaxel chemotherapy cycle)
and timing and calculation of
MDASI fatigue score
The intent to treat (ITT) population was used to summarize the
baseline and demographic characteristics as well as the primary
and secondary endpoint measures of the study. The primary
endpoint was analyzed using a mixed model, specifically a
covariance pattern model [24], with SAS software (NC, USA),
where each subject contributed two AUC measures, one each for
TP1 and TP2. If only one cycle of chemotherapy was completed
during the study, the available single MDASI fatigue score AUC
was used. The unit of measurement for the AUC was “scoredays”. For example, if the average MDASI score was 6 for each
day of a 7-day period, then this equates to a cumulative score of
1236
42. Higher mean MDASI AUC3–10 scores equate to more fatigue. The a priori goal was to demonstrate a 10 % relative
difference in mean score-days between the two treatment groups.
A 10 % or greater relative difference was considered to be
reasonably meaningful. It had previously been suggested that in a
comparison of questionnaire-based data between two groups, an
absolute difference in outcome value that was equal to one half of
the standard deviation represented a clinically significant effect
size [25]. A difference of 10 % therefore equates to a difference
of 4.2 score days. For the purposes of the sample size calculation,
this was rounded to a difference of four score days.
Analyses of most secondary endpoints were undertaken
overall for two TPs, with additional analyses by tumor type
and treatment period to investigate possible interactions. These
analyses were then repeated for TP3 and TP4 where data were
available. Least squares mean (LSM) estimates were obtained
for each TP and each tumor type within each treatment group.
Statistical significance of the difference in these means was
determined via the F statistic from the mixed model analysis
of variance table, where H0: μ1= μ2 and HA: μ1 ≠ μ2.
Statistical significance was implied by a P value of <0.05.
An original sample size of 129 patients was calculated based
on a two-sided significance level of α=0.05, a power of 80 %, a
correlation of 0.75 between two consecutive intraindividual AUC
measurements, a difference of 4 between the mean AUC in the
modafinil group compared with the placebo group, a standard
deviation of 6.3 in AUC after accounting for the repeated measures nature of the data, and the 2:1 ratio of patients in each
treatment group. A blinded review was undertaken to assess the
validity of these assumptions, to re-estimate the sample size using
Fig. 2 CONSORT patient flow
diagram
Support Care Cancer (2014) 22:1233–1242
updated estimates of components of the sample size equation, and
to better account for the repeated measures' nature of the two
intraindividual MDASI fatigue score AUC estimates. A repeated
measures analysis of variance model (mixed model) was fitted to
the individual AUC estimates with a term for treatment cycle only
(no term for treatment was included in the model as the blind was
being maintained). The error mean square from this analysis was
then used as the estimated standard deviation for inclusion in
the sample size calculation. Based on these revised parameters,
it was estimated that a sample size of 77 patients (modafinil
arm: n =51; placebo arm: n =26) would provide 80 % power to
detect a difference of 4.0 between the mean AUC for each
treatment group. Allowing for a 5 % dropout rate during the
study, the planned sample size was revised to 82 patients
(modafinil arm: n =55; placebo arm: n =27).
Results
Study population
The study was conducted from June 2009 to March 2011 in 25
centers throughout Australia. Eighty-eight patients from 23
centers (two centers opened but did not recruit) signed consent. Two withdrew prior to being screened for eligibility, and
two did not meet eligibility requirements; 84 patients were
therefore randomized to study treatment (Fig. 2).
Table 1 summarizes the baseline patient characteristics.
Depression was recorded in the medical history of 14 % of
patients in each treatment group. As expected, differences
Support Care Cancer (2014) 22:1233–1242
Table 1 Demographic and clinical characteristics at baseline
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Characteristic
Age, mean (SD), years
Commonly reported medications used prior to visit 1
Gonadotropin releasing hormone analogs
Anilides
Antiemetics
between patients with prostate (n =65) and breast cancer (n =
18) were observed; patients with prostate cancer were older
(mean 69.8±8.22 vs 56.5±11.79 years), had a longer time
since diagnosis (mean 6.2±4.51 vs 4.2±2.48 years), had
received fewer prior cycles of docetaxel chemotherapy (proportion who had received >2 prior cycles 44.5 vs 72.2 %), and
had lower MDASI scores (mean interference of symptoms
score 4.88±2.17 vs 5.40±1.83 and mean severity of symptoms scale score 3.76±1.60 vs 4.20±1.48).
Placebo arm (n =28)
n
n
%
66.4 (10.6)
Gender
Male
Race
Caucasian
Asian
Other
Disease characteristics at baseline
Time since cancer diagnosis, mean (SD), years
2–3 prior docetaxel chemotherapy cycles
4–8 prior docetaxel chemotherapy cycles
Docetaxel dose per cycle, mean (SD), mg/m2
Fatigue at baseline, mean (SD)
MDASI interference of symptoms score
MDASI severity of symptoms scale
Commonly used medicationsa
Bisphosphonates
Corticosteroids
Glucocorticoids
Proton pump inhibitors
a
Modafinil arm (n =55)
%
68.0 (10.7)
43
78.2
22
78.6
51
3
1
92.7
5.5
1.8
28
0
0
100
0
0
5.76 (4.34)
38
17
67.72 (9.49)
69
31
5.68 (4.05)
21
75
7
25
69.57 (9.29)
4.82 (2.17)
3.77 (1.76)
5.39 (1.92)
4.03 (1.13)
26
25
21
20
47
46
38
36
13
9
12
12
46
32
43
43
23
16
19
42
29
35
7
8
9
25
29
32
was cited as the reason for the dose reduction. In addition
to the docetaxel dose reduction, docetaxel dosing was
delayed on 24 occasions (15 in the modafinil arm and 9
in the placebo arm). Compliance with study medication
was higher in the placebo group than the modafinil group
for all TPs except for TP3 (modafinil vs placebo: 86 vs
93 %, 85 vs 92 %, 83 vs 82 %, and 96 vs 100 %, for
TPs 1–4, respectively).
Efficacy
Docetaxel dosing
Forty-seven percent of modafinil recipients (n =26) and 54 %
of placebo recipients (n =15) received 4 cycles of docetaxel
during the study. A further 21 % received 3 cycles (modafinil
10 (18.2 %) and placebo 7 (25 %)), 22 % received 2 cycles
(modafinil 13 (23.6 %) and placebo 5 (17.9 %)), and 8 %
received only 1 cycle (modafinil 6 (10.9 %) and placebo 1
(3.6 %)). The median cumulative docetaxel dose in the
modafinil arm was 225 mg/m2, compared with 240 mg/m2
in the placebo arm. Docetaxel dosing was reduced on 12
occasions in eight patients, in each case from the
modafinil arm. In three of the patients (two with breast
cancer and one with prostate cancer), febrile neutropenia
The primary endpoint of MDASI AUC3–10 during TP1 and
TP2 was not statistically different between the two treatment
arms (P =0.15; Table 2). A trend of greater treatment effect in
the modafinil arm during TP1 and TP2 was observed in both
the prostate and the breast cancer subgroups, although the
results were not statistically significant in either subgroup.
When the MDASI AUC3–10 for all four TPs were combined (Table 2), the difference between the modafinil and
placebo arms was not statistically significant (P =0.12).
However, a statistically significant difference in favor of
modafinil during TP2 (difference=−6.4, P =0.03) and TP4
(difference=−8.4, P =0.03; Table 2) was noted, suggesting
a delayed effect for modafinil. There was a trend in favor
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Support Care Cancer (2014) 22:1233–1242
Table 2 Least squares means from repeated measurements analysis of MDASI AUC3–10 scores for first two TPs (primary endpoint) and individual TPs
Least squares meana
Primary end point: TP 1 and 2
Group
All patients, all TPs
TP 1 (n: modafinil 55; placebo 28)
TP 2 (n: modafinil 47; placebo 26)
TP 3 (n: modafinil 33; placebo 22)
TP 4 (n: modafinil 26; placebo 13)
Difference (modafinil–placebo)
P value
Modafinil (n =55)
Placebo (n =28)
35.9 [32.4, 39.3]
39.6 [35.1, 44.1]
−3.7 [−8.9, 1.4]
0.15
35.0
38.0
33.7
33.7
33.8
39.2
39.4
40.1
37.1
42.2
−4.2 [−9.5, 1.1]
−1.4 [−7.0, 4.2]
−6.4 [−12.1, −0.6]
−3.3 [−9.9, 3.2]
−8.4 [−15.7, −1.0]
0.12
0.62
0.03
0.32
0.03
Lower scores are better; negative differences indicate a better outcome for patients in the modafinil arm. A total of 152 subject cycles were included in the
analysis, of which 10 involved some form of data imputation
TP treatment period (95 % confidence intervals are displayed in brackets)
a
Model fitted and least squares mean estimates obtained using SAS PROC MIXED model: MDASI fatigue score AUC=Teatment group+Cancer type (breast
or prostate)+Number of prior cycles of docetaxel+TP (1, 2, 3, or 4). Subject ID is a random effect, with subjects contributing up to four repeated measures
of the modafinil arm in TP3, although this did not reach
any significance (difference=−3.3, P =0.32).
Repeating the primary efficacy analysis on the area
under the MDASI fatigue score–time curve for days 3–
18 (AUC3–18) failed to demonstrate any significant differences between the two groups. However, as for AUC3–10,
there was a trend for modafinil recipients to have slightly
less fatigue than placebo recipients, particularly during
Fig. 3 Daily MDASI fatigue scores for each of the four treatment periods
TP2 and TP4. In addition, the trend over time for the
modafinil group showed a drop in MDASI score between
TP1 and TP2 that was sustained out to TP4.
The patterns of change in MDASI throughout each TP
were qualitatively different in the modafinil arms as compared
to the placebo arms (Fig. 3). A decrease in MDASI scores was
observed in both treatment arms over days 3–10 when averaged across the first two TPs, 0.14 per day in the modafinil
Support Care Cancer (2014) 22:1233–1242
1239
arm and 0.22 in the placebo arm. The difference in the rate of
change (0.08) indicated that the decrease in MDASI was
slightly higher in the placebo arm of the study, but this was
not statistically significant (P =0.27). The effect of modafinil
on MDASI was experienced from day 1 of treatment, which
therefore showed a less pronounced slope in the trend over
time. Increasing MDASI fatigue scores to day 5 or 6 were
reported in the placebo group after docetaxel chemotherapy
before improving, showing a slightly more pronounced decrease in this trend over time. The rate of decrease in daily
MDASI fatigue scores was greater in TP1 versus TP2 and in
TP3 versus TP4, irrespective of treatment arm. The placebo
arm showed the largest rate of decrease in both TPs, although
results were not statistically significant for either TP (TP1
treatment effect=0.13, P =0.14; TP2 treatment effect=0.03,
P =0.70).
The time taken to reach maximum MDASI fatigue score
was longer in the modafinil arm (6.0 days) than in the placebo
arm (4.6 days; difference=1.4 days, P =0.02). While there
was no significant difference between groups for any of the
other secondary endpoints, responses in the modafinil arm
were consistently better and less variable than those in the
placebo group.
associated with modafinil use. Compared to the placebo
group, a larger proportion of the modafinil group experienced
any adverse event or a grade 3 or 4 adverse event (Table 3).
Eleven of the 21 grade 3 or 4 adverse events were possibly
related to docetaxel: one was possibly related to modafinil and
nine to neither treatment. The most common treatment emergent adverse events reported in both treatment groups were
diarrhea, nausea, and vomiting. Almost double the percentage
of patients in the modafinil arm experienced nausea and
vomiting (45.4 %) compared to the placebo group (25 %).
All but one of these events were classed as grade 1/2 and were
mild in nature. The single episode of grade 3 vomiting in one
modafinil-treated patient was not deemed to be related to the
study drug. The rate of discontinuation due to an adverse
event was comparable between the two treatment groups
(modafinil arm =8 (14.3 %), placebo arm =4 (14.3 %)).
Eight patients withdrew from the study because of adverse
events, six of whom had adverse events that were considered
possibly related to modafinil (insomnia, agitation, headache,
severe fatigue). There were three deaths during the study; all
were in the placebo arm (3=prostate cancer), and none were
considered to be related to either docetaxel or modafinil.
Safety
Discussion
Toxicity profiles were largely consistent with docetaxel-based
chemotherapy and with previously reported adverse events
Prior studies have shown that modafinil may improve cancerrelated fatigue [15–20]. The results of our study did not
Table 3 Summary of treatment
emergent adverse events (TEAE)
Placebo (n =28)
Patients with any TEAE (including SAEs)
Hematological
Anemia
Febrile neutropenia
Neutropenia
Pancytopenia
Non-hematological
Health deterioration
Injection site pain
Abdominal pain
Constipation
Diarrhea
Nausea/vomiting
Fatigue
Pain
Headache
Infections
Insomnia
Pulmonary embolism
Modafinil (n =55)
All grades
Grade ≥3
All grades
Grade ≥3
24 (85.7 %)
5 (17.9 %)
51 (92.7 %)
16 (29.1 %)
2 (7.1 %)
0 (0.0 %)
1 (3.6 %)
0 (0.0
0 (0.0
0 (0.0
1 (3.6
%)
%)
%)
%)
2 (3.6 %)
1 (1.8 %)
0 (0.0 %)
2 (3.6
3 (5.5
1 (1.8
0 (0.0
%)
%)
%)
%)
1 (3.6 %)
2 (7.1 %)
0 (0.0 %)
4 (14.3 %)
1 (3.6
0 (0.0
0 (0.0
0 (0.0
%)
%)
%)
%)
0 (0.0 %)
0 (0.0 %)
6 (10.9 %)
3 (5.5 %)
0 (0.0
1 (1.8
0 (0.0
0 (0.0
%)
%)
%)
%)
7 (25.0 %)
7 (25.0 %)
1 (3.6 %)
2 (7.1 %)
1 (3.6 %)
6 (21.4 %)
1 (3.6 %)
0 (0.0 %)
0 (0.0
0 (0.0
0 (0.0
2 (7.1
0 (0.0
1 (3.6
0 (0.0
0 (0.0
%)
%)
%)
%)
%)
%)
%)
%)
10 (18.2 %)
25 (45.4 %)
9 (16.4 %)
10(18.2 %)
5 (9.1 %)
2 (3.6 %)
11 (20 %)
1 (1.8 %)
0 (0.0
1 (1.8
1 (1.8
2 (3.6
2 (3.6
2 (3.6
1 (1.8
1 (1.8
%)
%)
%)
%)
%)
%)
%)
%)
1240
demonstrate a statistically significant improvement in our primary endpoint. However, they are suggestive of a potential beneficial effect of modafinil. We demonstrated a 9.3 % reduction in
MDASI score between the modafinil arm and the placebo arm,
which closely approached our predefined clinically meaningful
benefit of 10 % and a trend towards modafinil reducing fatigue
was seen. Further post hoc analyses suggested that the overall
difference was diluted by lack of a difference in TP1, whereas a
significant difference was found in TP2—potentially indicating a
delay in the therapeutic effect of modafinil.
Similar findings of a delayed effect on fatigue improvement
have been reported with the use of American ginseng, which
showed significant reductions in cancer-related fatigue at week 8
but not week 4 [26]. In our study, patients on placebo receiving
docetaxel for 4 cycles reported a similar level of fatigue across all
four TPs, whereas patients on modafinil had improved levels of
fatigue at the commencement of TP2, which were then sustained
over subsequent periods.
This study had several limitations. Dexamethasone
premedication (per standard protocols) was used to reduce
allergic reactions and nausea during and/or subsequent to the
chemotherapy infusion. We therefore withheld modafinil for
3 days before and after chemotherapy to reduce the influence
of dexamethasone premedication on the potential for
modafinil to modify fatigue. However, dexamethasone itself
may have reduced fatigue levels at the start of each cycle, thus
artificially distorting our efficacy results. A study of prolonged
use of dexamethasone (4 mg twice daily for 14 days) has
shown significant improvements in fatigue and quality of life
in patients with advanced cancer [27].
We found that MDASI scores were highest on days 6–10 of
each TP, indicating that fatigue was most common at this point
in time, presumably when the effects of dexamethasone
premedication had waned. Thus, the temporal trends observed
during modafinil treatment are of interest, including a longer
time to maximal fatigue, and less fluctuation in the level of
fatigue (see Fig 3), potentially suggesting that modafinil may
be working most effectively at a time when patients are
maximally fatigued. During docetaxel chemotherapy for prostate cancer, prednisone 5 mg PO BID is likely to have been coadministered on a regular basis. Consequently, ongoing
steroid-induced insomnia may have countered the potential
benefit of modafinil and confounded interpretation of the data.
The modafinil dose (200 mg/day) used is comparable to that
used in other studies evaluating modafinil for fatigue. Unlike
other studies, in order to avoid any potential drug–drug interaction, docetaxel and modafinil were not administered on the same
days. While we believe the 200 mg/day dose was adequate, the
6-day no-drug phase in each chemotherapy cycle may have
impacted the results.
A potential explanation for the lack of statistically significant
benefit for modafinil in our study is the inclusion of patients with
only moderate fatigue at baseline. Previously, the benefit of
Support Care Cancer (2014) 22:1233–1242
modafinil has been most significant in alleviating severe fatigue
[20]. The average self-reported fatigue was overestimated in this
population. The baseline score for MDASI severity of symptoms
scale was only 3.77 in the modafinil arm and 4.03 in the placebo
arm. Considering that a screening fatigue score of at least 4 was
required to be eligible for the study, this implies that there were
inconsistencies with the screening tool. Baseline data collection
was timed to capture the worst score in the previous 24 h, which
was at the beginning of a cycle when fatigue is likely to have
improved and is also at a time when patients were taking
dexamethaonse premedication. Better selection for patients with
severe fatigue would have been achieved if baseline data have
been collected at days 10–15 in the previous chemotherapy cycle
when fatigue would have been at its worst.
Errors in our original assumptions may also have contributed
to the lack of statistically significant benefit. At the time of study
design, very little was known about the distribution of MDASI
fatigue scores in the population under study, and therefore, the
likely outcomes/treatment effect size had to be estimated. Given
the screening criterion of “Fatigue≥4 on the MDASI fatigue
assessment scale during the previous docetaxel chemotherapy
cycle,” it was deemed reasonable to expect a mean daily MDASI
fatigue score of “6” among recruited patients undergoing chemotherapy. Hence, there was the assumption of an AUC of 42
score-days (score of 6 multiplied by 7 days) for patients in the
placebo group. A standard deviation of eight score-days,
representing nearly one fifth of the mean value, was also considered to be conservatively reasonable. Although there were minimal data regarding what constitutes a clinically meaningful
change in MDASI fatigue score, a 10 % or greater relative
difference was considered to be conservatively reasonable based
on available publications [25].
Docetaxel dose reductions and study withdrawals were
higher in the modafinil arm. This may have contributed to
reduced chemotherapy dose intensity and therefore “insufficient fatigue” in the experimental arm with a subsequent
impact on the primary endpoint analysis. In our study, the
incidence of nausea and vomiting was higher in the modafinil
arm (45.4 vs 25 % in the placebo arm). Nausea and vomiting
are both very common in patients with advanced cancer.
Although clinical trials in other settings have reported the
incidence of nausea to be more common with modafinil than
with placebo (11 vs 3 %), in post-marketing surveillance based
on spontaneous reporting, nausea and vomiting are found to be
rare (1/10,000<1/1,000). A higher incidence of these adverse
effects has not previously been reported in the modafinil arm of
studies evaluating this treatment for cancer-related fatigue.
These findings are likely attributable to chance.
Despite the placebo-controlled design employed in our study,
our ability to show a statistically significant difference was likely
influenced by the relatively small sample size, especially given
that fatigue is a subjective symptom known to be susceptible to a
large placebo effect [28]. Negative results have recently been
Support Care Cancer (2014) 22:1233–1242
reported in a well-powered study evaluating modafinil for lung
cancer-related fatigue [29]. Results for fatigue were similar in
both study arms, leading the authors to conclude that there is a
large placebo effect. Commentary about these results have led to
the suggestion that psychostimulants may improve fatigue secondary to improving mood and/or depressive symptoms. We
evaluated anxiety and depression using the Hospital Anxiety
and Depression scale at baseline and study end (data not shown)
but found no difference between treatment groups and no consistent evidence of improvement. It is plausible that the tools used
to measure fatigue lack sufficient specificity to determine the true
mechanism of modafinil's effect. Further research in this area is
warranted. Although the 13 MDASI core symptoms have been
validated in patients with cancer as reflecting symptomatology of
sufficient severity to interfere with activities of daily living [21,
30], we chose only the single-item fatigue measure (question 2)
from the MDASI to determine the severity of fatigue for the
primary endpoint assessment. This single item measure has not
been validated for use in isolation. While this single-item fatigue
measure is designed to measure cancer-related fatigue, it is
limited by its ability to measure only the severity of the fatigue.
Despite a potential susceptibility to bias, single-question assessment tools are commonly used when assessing cancer-related
fatigue [30].
Modafinil was well tolerated in our study. There are no
known interactions between modafinil and docetaxel, but the
combined effects of the two agents have not been extensively
studied. Any potential for interactions was moderated by ensuring that both drugs were not administered on the same day.
Unlike chemotherapy in the adjuvant setting, the use of
chemotherapy in metastatic disease is, to a large extent, palliative; thus, the aim of treatment is to improve patient wellbeing and quality of life while minimizing unwanted adverse
effects such as fatigue. This study was designed to enroll
patients at the start of their third, fourth, or fifth cycle of
docetaxel chemotherapy because fatigue is cumulative, and
most patients report higher levels of fatigue after several
cycles of chemotherapy. Our study population enrolled significantly more patients with prostate than breast cancer; this
seems due primarily to investigator and site selection, and
diminished patient availability (several alternative agents are
now commonly used in metastatic breast cancer).
To conclude, despite not demonstrating a conclusive difference in the two treatment arms for the primary endpoint, this
study has shown a consistent trend towards improvement of
docetaxel-related fatigue with modafinil. However, nausea and
vomiting were a potential complication of modafinil therapy.
To the best of our knowledge, it is the first phase III study
specifically assessing a pharmacological approach in the setting of chemotherapy-related fatigue. Assessing and managing chemotherapy-related fatigue remains a major challenge.
Larger, well-designed studies are needed to better understand
the biological basis of docetaxel-related fatigue and to define
1241
the role of modafinil as a pharmacological intervention for the
treatment of docetaxel-related fatigue.
Acknowledgments We thank the patients and their families who took
part in this study. We greatly appreciate the contributions of the clinicians
and their staff from the hospitals from around Australia that were involved
in this study, although not all were able to recruit patients. NSW: Prince of
Wales Hospital, Bankstown - Lidcombe Hospital, Southern Medical Day
Care, Sydney Haematology & Oncology Clinical Trials Unit, St George
Hospital, St Vincent's Hospital, Coffs Harbour Base Hospital, Armidale
Hospital, Tamworth Hospital, Lingard Private Hospital, The Tweed Hospital, Southern Highlands Cancer Centre, Manning Rural Referral Hospital; ACT: The Canberra Hospital; VIC: Box Hill Hospital, Monash
Medical Centre, Frankston Hospital, Frankston Private Hospital, John
Fawkner Private Hospital, Ballarat Oncology & Haematology Services;
TAS: Launceston General Hospital; SA: Royal Adelaide Hospital, The
Queen Elizabeth Hospital, Calvary Hospital North Adelaide and QLD:
Gold Coast Hospital.
Funding and financial disclosures This work has been carried out
with financial support from Sanofi Australia Pty Ltd. The sponsor was
involved in the design and conduct of the study, provided logistical
support during the trial, funded statistical and editorial assistance, and
reviewed the final draft before submission. The study Steering Committee
(EJH, PLDeS, GMM, and AL) designed the trial protocol and contributed
to the design of the statistical analysis plan. This study is registered at
ClinicalTrials.gov, NCT00917748. Statistical analyses were performed
externally (Caro-Anne Badcock, Statistical Revelations Pty Ltd). The
decision to submit the report for publication was made by the Steering
Committee, who drafted then finalized the report with the help of a
medical writer (Hazel Palmer, Scius Solutions Pty Ltd). The sponsor
funded statistical and editorial assistance and reviewed the final draft
before submission.
Conflict of interest Phillip Parente is currently conducting research
sponsored by Sanofi Australia. Tal Rapke is an employee of Sanofi
Australia Pty Ltd. Elizabeth Hovey, Gavin Marx, Paul deSouza, and
Phillip Parente have each sat on an advisory board for Sanofi
oncology products. All remaining authors have declared no conflict
of interest.
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