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synopsis - Clinical Trials
Aripiprazole
BMS-337039/OPC-14597
CN138-001
Clinical Study Report
SYNOPSIS
Clinical Report Synopsis for Protocol CN138-001
TITLE OF STUDY: A Multicenter, Randomized, Double-blind, Placebo-controlled Study of Three Fixed
Doses of Aripiprazole in the Treatment of Patients with Acute Schizophrenia (Protocol CN138-001).
INVESTIGATORS AND STUDY CENTERS: Fifty-seven investigators participated in the conduct of
the study (53 in the United States and four in Canada). Investigator information is provided in Table 4.
PUBLICATIONS: None
STUDY PERIOD:
Date first patient enrolled: 03-Jan-2000
Date last patient completed: 09-Jan-2001
CLINICAL PHASE: III
OBJECTIVES:
Primary: The primary objective of this study was to compare the efficacy of three fixed doses of
aripiprazole with placebo in the treatment of acutely relapsed patients with a diagnosis of schizophrenia.
Secondary: The secondary objective of this study was to compare the safety of three fixed doses of
aripiprazole with placebo in the treatment of acutely relapsed patients with a diagnosis of schizophrenia.
METHODOLOGY: This study was a multicenter, randomized, double-blind, placebo-controlled trial
with four parallel groups of inpatients. After a minimum 2-day neuroleptic medication washout, patients
with a diagnosis of schizophrenia who were in acute relapse and who fulfilled all other entrance criteria
were randomized into the double-blind Acute Phase (6 weeks). Patients received blinded fixed doses of
10-mg, 15-mg, or 20-mg aripiprazole, or placebo. Patients unable to tolerate study medication were
discontinued from the study. Patients not responding by end of Week 3 (as indicated by a Clinical Global
Impression [CGI] Improvement Score of 4 [no improvement] to 7 [very much worse]) were discontinued
from blinded treatment and were offered the opportunity to receive open-label aripiprazole treatment
(20 mg with a dose decrease to 15 mg if needed based on tolerability) for Weeks 4, 5, and 6. Patients
remained hospitalized for the duration of the 6-week Acute Phase. Patients who discontinued due to lack of
response or adverse events (AEs) prior to the end of the study received up to 1 additional week of
hospitalization for stabilization.
To clarify terminology used in this report, the Acute Phase was defined as the first 6 weeks on treatment.
Patients could either receive double-blind treatment for the entire 6 weeks, or could discontinue
double-blind treatment at the end of Weeks 3, 4, or 5 and then continue through Week 6 on open-label
aripiprazole. Patients who received open-label aripiprazole were still considered to be in the Acute Phase.
The data obtained during the open-label Acute Phase was analyzed separately from the data obtained
during the double-blind Acute Phase.
At the conclusion of the 6-week Acute Phase, eligible patients (including patients who received open-label
treatment) were given the option of continuing into the double-blind Extension Phase for an additional
46 - 134 weeks. Upon entry into the Extension Phase, patients were randomized to a dose range group of
either 10 - 15 mg aripiprazole or 20 - 30 mg aripiprazole. The results of the Extension Phase will be
presented in a separate report after the completion of that phase.
NUMBER OF PATIENTS: Five hundred eight patients were enrolled in the study. Four hundred twenty
patients were randomized in the study; 326 (78%) of these patients were men and 94 (22%) of these
patients were women between 18 and 76 years of age. One hundred eight patients were randomized to the
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Aripiprazole
BMS-337039/OPC-14597
CN138-001
Clinical Study Report
placebo group, 106 were randomized to the aripiprazole 10-mg group, 106 were randomized to the
aripiprazole 15-mg group, and 100 were randomized to the aripiprazole 20-mg group. Four hundred fifteen
patients were included in the Safety Sample and 410 patients were included in the Efficacy Sample. One
hundred forty-two (34%) of the 420 randomized patients completed the study on double-blind treatment
without receiving open-label study medication.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Patients met the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia and were in acute relapse.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Aripiprazole
10-mg tablet, batch numbers 98B85A010D and 99C77A010A; aripiprazole 15-mg tablet, batch numbers
98B85A015B and 99H93A015B. Administered orally one tablet or two tablets QD as fixed doses of 10 mg,
15 mg, or 20 mg.
DURATION OF TREATMENT: Six weeks of double-blind treatment; and open-label treatment for
non-responders at Weeks 4, 5, and 6.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
Placebo tablet, batch numbers 98B85P000C and 99C77P000D. Administered orally one tablet or two
tablets QD.
CRITERIA FOR EVALUATION:
Efficacy: Efficacy rating scales completed during this study included the Positive and Negative Syndrome
Scale (PANSS), Clinical Global Impression (CGI) Improvement and Severity of Illness Scales, and
Montgomery Asberg Depression Rating Scale (MADRS). Response was defined as at least a 30% decrease
in the PANSS Total Score or a Score of 1 (very much improved) or 2 (much improved) on the
CGI Improvement Scale. The PANSS-derived Brief Psychiatric Rating Scale (BPRS) Score was calculated.
The primary efficacy measure was the PANSS Total Score; key secondary efficacy measures were the
PANSS-derived BPRS Core Score and the PANSS Negative Subscale Score.
Safety: Safety assessments included medical review of reports of AEs (including intercurrent illness), vital
sign measurements, electrocardiograms (ECGs), body weight, concomitant medications, and results of
physical examination and clinical laboratory tests. In addition, extrapyramidal symptoms (EPS) rating
scales completed during this study were the Simpson-Angus Scale (SAS), Abnormal Involuntary
Movement Scale (AIMS), and the Barnes Akathisia Rating Scale.
STATISTICAL METHODS: The primary efficacy outcome measure was the mean change from baseline
to Week 6 on the PANSS Total Score. The planned sample size of 400 evaluable patients (100 to each
treatment group) was estimated to yield 90% power to detect a difference of 12 in the change from baseline
to Week 6 in the PANSS Total Score between placebo and each of the three doses of aripiprazole. This
assumed a standard deviation of 23 and a two-sided t-test at the 0.0167 level adjusted for three comparisons
versus placebo. Two key secondary efficacy measures (mean change from baseline PANSS-derived BPRS
Core Score and mean change from baseline PANSS Negative Subscale Score) were prespecified. A
hierarchical testing procedure was applied to the primary and key secondary endpoints so as to maintain
this overall experiment-wise Type I error rate at 0.05.
The Safety Sample included those patients who received at least one dose of medication as indicated on the
dosing record. The Efficacy Sample included those patients in the Safety Sample who had at least one
postrandomization efficacy evaluation (i.e., evaluable patients). The Last Observation Carried Forward
(LOCF) data set was the primary data set; however, analyses on the Observed Cases (OC) data set were
also performed. The primary efficacy outcome measure (mean change from baseline to Week 6 in PANSS
Total score) was evaluated by analysis of covariance (ANCOVA), adjusting for baseline score and
controlling for study center. Categorical data, such as responder rates, were assessed by the
Cochran-Mantel-Haenszel (CMH) test controlling for study center. The Hochberg sequentially rejective
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Aripiprazole
BMS-337039/OPC-14597
CN138-001
Clinical Study Report
procedure was used for the primary efficacy outcome measure to adjust for the three multiple comparisons
of aripiprazole doses versus placebo. Analyses of the EPS scales, prolactin level, and body weight were
performed using ANCOVA.
EFFICACY RESULTS: The summary of efficacy results at endpoint is shown in the following table. All
three aripiprazole treatment groups showed statistically significantly greater improvement than placebo for
the PANSS Total Score, PANSS-derived BPRS Core Score, PANSS Negative and Positive Subscale
Scores, CGI Severity of Illness Score, and CGI Improvement Score. In the combined PANSS/CGI
responder analysis, the aripiprazole 10-mg and 20-mg groups were significantly superior to placebo. The
aripiprazole 20-mg group was statistically superior to placebo in the CGI responder analysis. In addition,
all aripiprazole groups were statistically significantly superior to placebo in the PANSS responder analysis.
Summary of Efficacy Results at Endpoint, LOCF Data Set, Efficacy Sample
Treatment Group
Variable
Placebo
N = 107
Aripiprazole
10 mg
N = 103
Aripiprazole
15 mg
N = 103
Aripiprazole
20 mg
N = 97
92.63
92.90
92.42
91.91
(89.48, 95.78)
(89.72, 96.08)
(89.24, 95.60)
(88.63, 95.18)
-2.33
-15.04**
-11.73**
-14.44**
PRIMARY EFFICACY ENDPOINTS
PANSS Total Score
Mean Baseline
(95% CI)
Mean Change at Week 6
(95% CI)
(-6.96, 2.29)
(-19.71, -10.36) (-16.40, -7.05) (-19.25. -9.62)
KEY SECONDARY MEASURES
PANSS-Derived BPRS Core Score
Mean Baseline
(95% CI)
Mean Change at Week 6
(95% CI)
16.92
16.99
16.76
16.68
(16.37, 17.47)
(16.43, 17.54)
(16.21, 17.32)
(16.11, 17.25)
-1.37
-3.91**
-2.88*
-3.56**
(-2.25; -0.49)
(-4.80, -3.02)
(-3.77, -1.99)
(-4.48, -2.65)
23.16
23.83
23.54
23.59
(21.96, 24.36)
(22.61, 25.04)
(22.33, 24.76)
(22.34, 24.84)
0.08
-3.52**
-2.65**
-3.33**
(-1.20, 1.36)
(-4.82, -2.22)
(-3.94, -1.35)
(-4.67, -2.00)
PANSS Negative Subscale Score
Mean Baseline
(95% CI)
Mean Change at Week 6
(95% CI)
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Aripiprazole
BMS-337039/OPC-14597
CN138-001
Clinical Study Report
Summary of Efficacy Results at Endpoint, LOCF Data Set, Efficacy Sample
Treatment Group
Variable
Placebo
N = 107
Aripiprazole
10 mg
N = 103
Aripiprazole
15 mg
N = 103
Aripiprazole
20 mg
N = 97
24.47
24.53
24.38
24.20
(23.52, 25.42)
(23.56, 25.49)
(23.42, 25.34)
(23.21, 25.19)
-1.10
-4.98**
-3.81**
-4.51**
(-2.43, 0.23)
(-6.32, -3.64)
(-5.15, -2.47)
(-5.89, -3.13)
4.64
4.79
4.79
4.68
(4.50, 4.78)
(4.65, 4.93)
(4.65, 4.93)
(4.54, 4.83)
-0.18
-0.65**
-0.51*
-0.64**
(-0.39, 0.04)
(-0.87, -0.43)
(-0.73, -0.29)
(-0.86, -0.41)
4.00
3.33**
3.42**
3.31**
(0.16)
(0.15)
(0.16)
(0.16)
42 (41)*
36 (35)
(4.3)
(4.9)
(4.7)
25 (23)
35 (34)
32 (31)
(4.1)
(4.7)
(4.6)
OTHER SECONDARY MEASURES
PANSS Positive Subscale Score
Mean Baseline
(95% CI)
Mean Change at Week 6
(95% CI)
CGI Severity of Illness Score
Mean Baseline
(95% CI)
Mean Change at Week 6
(95% CI)
CGI Improvement Score
Mean at Week 6
(SE)
Responders N (%)
CGI or PANSS
(SE%)
CGI
b
(SE%)
a
⊥28 (26)
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44 (45)**
(5.1)
41 (42)**
(5.0)
Aripiprazole
BMS-337039/OPC-14597
CN138-001
Clinical Study Report
Summary of Efficacy Results at Endpoint, LOCF Data Set, Efficacy Sample
Treatment Group
Variable
Placebo
N = 107
Aripiprazole
10 mg
N = 103
c
14 (13)
31 (30)**
(SE%)
(3.3)
PANSS
(4.5)
Aripiprazole
15 mg
N = 103
Aripiprazole
20 mg
N = 97
26 (25)*
25 (26)*
(4.3)
(4.4)
Protocol CN138-001
* (0.01 < p ≤ 0.05) compared with placebo.
** (p ≤ 0.01) compared with placebo.
Note: The results of all analyses are model based; however, the presentation of results for treatment groups
is not model based for CGI Improvement Score or % Responders.
a
b
c
CGI or PANSS Responders = patients with CGI Improvement Score of 1 (very much improved) or
2 (much improved) or a ≥ 30 % decrease in PANSS Total Score.
CGI Responders = patients with CGI Improvement Score of 1 (very much improved) or 2 (much
improved).
PANSS Responders = patients with a ≥ 30% decrease in PANSS Total Score.
SAFETY RESULTS:
Three hundred sixty (87%) of the 415 patients in the Safety Sample reported at least one AE during the
study: 86 (80%) of the 107 patients in the placebo group, 90 (86%) of the 105 patients in the aripiprazole
10-mg group, 96 (91%) of the 105 patients in the aripiprazole 15-mg group, and 88 (90%) of the 98 patients
in the aripiprazole 20-mg group. The most frequently occurring AEs (≥ 10% incidence and a greater
incidence than the placebo group) for any of the aripiprazole groups were headache, insomnia, nausea,
anxiety, dyspepsia, vomiting, lightheadedness, constipation, somnolence, pain extremity, diarrhea, and
akathisia. Of these, the only AE that occurred at a rate at least twice that of placebo across all of the
aripiprazole dose groups was vomiting.
No deaths were reported during the Acute Phase of this study. Twenty-five patients reported a serious
adverse event (SAE) during the study or within 30 days of discontinuing from the Acute Phase (excluding
those SAEs occurring during the Extension Phase). The number of patients reporting an SAE was
comparable among all aripiprazole dose groups and the placebo group. Of the 25 patients who reported an
SAE, eight were in the placebo group, three were in the aripiprazole 10-mg group, ten were in the
aripiprazole 15-mg group, and four were in the aripiprazole 20-mg group. No pregnancies were reported in
the study.
The discontinuation rate due to an AE was comparable among all aripiprazole dose groups and the placebo
group. Twenty-five (6%) of the 420 patients in the Randomized Sample discontinued from double-blind
treatment because of an AE. Six (6%) of 108 in the placebo group, 11 (10%) of 106 in the aripiprazole
10-mg group, three (3%) of 106 in the aripiprazole 15-mg group, and five (5%) of 100 in the aripiprazole
20-mg group discontinued double-blind treatment because of an AE.
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BMS-337039/OPC-14597
CN138-001
Clinical Study Report
Of the specific EPS-related AEs, only akathisia was reported at a frequency of ≥ 10% and twice the rate of
placebo and only for the 10-mg aripiprazole treatment group (11%). However, the incidence of akathisia
for the aripiprazole 15-mg and aripiprazole 20-mg treatment groups (6% and 5%, respectively) was
comparable to that for placebo (4%). Furthermore, the results of the analyses of the SAS, AIMS, and
Barnes Global Clinical Assessment of Akathisia at endpoint and the highest on-treatment values as shown
in the following table demonstrate a general equivalence among the aripiprazole treatment groups and the
placebo group with respect to the impact of treatment on EPS ratings. Statistically significant worsening
among the aripiprazole treatment groups and placebo was seen only in the 15-mg aripiprazole group for the
Barnes Global Clinical Assessment of Akathisia Score mean change at endpoint. This difference, however,
was not seen in the aripiprazole 10-mg or aripiprazole 20-mg dose groups. Furthermore, there was a
statistically significant improvement on the AIMS Total Score mean change at endpoint for both the 10-mg
and 20-mg aripiprazole treatment groups.
EPS Rating Scales: Mean Change from Baseline, LOCF Data Set, Safety Sample
Placebo
Aripiprazole
10 mg
Aripiprazole
15 mg
Aripiprazole
20 mg
(N = 107)
(N = 104)
(N = 102)
(N = 96)
Mean change at endpoint
-0.20
-0.80
0.01
-0.41
Mean change to highest value
1.17
0.44
1.44
0.89
(N = 104)
(N = 101)
(N = 97)
(N = 92)
Mean change at endpoint
0.14
-0.69*
-0.45
-0.66*
Mean change to highest value
0.37
-0.33
-0.10
-0.36
(N = 107)
(N = 104)
(N = 102)
(N = 96)
Mean change at endpoint
-0.25
-0.07
0.06*
-0.13
Mean change to highest value
0.26
0.44
0.48
0.34
Variable
SAS Total Score
a
AIMS Total Score
Barnes Akathisia Scale
Protocol CN138-001
* P ≤ 0.0167, Bonferroni correction for multiple comparisons.
a
First seven items.
All treatment groups showed a decrease in prolactin levels from baseline to endpoint. All aripiprazole
treatment groups showed a statistically significant greater decrease relative to the placebo treatment group.
Adverse events potentially related to cardiovascular etiology showed no clinically important findings with
the exception of a 16% incidence of lightheadedness in the aripiprazole 20-mg group compared with 6% in
the placebo group, 9% in the aripiprazole 10-mg group, and 8% in the aripiprazole 15-mg group. AE
reports of lightheadedness were rarely accompanied by orthostatic vital sign changes.
Vital signs, in general, showed no differences among the aripiprazole treatment groups and placebo, with
the exception of standing heart rate, which showed an increased incidence of increased heart rate for all
aripiprazole treatment groups. The incidence was 3% for the placebo group, 7% for the aripiprazole 10-mg
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BMS-337039/OPC-14597
CN138-001
Clinical Study Report
group, 10% for the aripiprazole 15-mg group, and 6% for the aripiprazole 20-mg group. These increases in
heart rate were not accompanied, however, by clinically important changes in blood pressure. No patients
discontinued from the study due to vital sign abnormalities.
ECGs for four patients showed an increase in QTc when the Bazett’s correction factor was utilized. Two of
these patients were in the aripiprazole 15-mg treatment group, one patient was in the aripiprazole 20-mg
treatment group, and one patient was in the placebo group but was receiving open-label aripiprazole at the
time of the ECG. Three of these patients also experienced an increase in heart rate at the time the ECG was
taken, relative to their baseline heart rate. The QTc for these three patients was normalized when the
correction factor utilized by the Neuropharmacology Division of the FDA was applied. None of these
patients reported a cardiac-related AE.
There were no statistically significant differences in the mean change from baseline in weight at endpoint
between any aripiprazole treatment groups and the placebo treatment group. There also were no statistically
significant differences between any aripiprazole treatment group and the placebo group for the mean
change to highest weight gain at any time. There were no significant differences in the percentage of
patients showing significant weight gain at endpoint between any aripiprazole treatment group and the
placebo group, nor were there any significant differences in the analysis of patients showing a significant
weight gain at any time between any aripiprazole treatment groups and placebo.
CONCLUSIONS:
•
All three fixed doses of aripiprazole were shown to be effective in the treatment of patients with
schizophrenia in acute relapse based on the predefined primary and key secondary endpoints of the
PANSS Total Score, PANSS-derived BPRS Core Score, and PANSS Negative Subscale Score.
•
Aripiprazole was demonstrated to be safe and well tolerated across all dose groups. The rates of SAEs
and discontinuations for AEs were comparable among all aripiprazole treatment groups and placebo.
•
The analysis of EPS rating scales, related AEs, and treatment with medication for EPS showed that
aripiprazole treatment was associated with a comparable EPS profile relative to placebo.
•
Analysis of prolactin levels showed statistically significant decreases for all aripiprazole treatment
groups compared with placebo.
•
There were no clinically important cardiac risks identified for aripiprazole.
•
Analysis of patient weight showed no statistically significant differences for aripiprazole versus
placebo.
DATE OF REPORT: 27-Jul-2001
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