synopsis - Clinical Trials
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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 Approved v4.0 930000317 1.0 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 Approved v4.0 930000317 1.0 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) Approved v4.0 930000317 1.0 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 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) Approved v4.0 930000317 1.0 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. Approved v4.0 930000317 1.0 Aripiprazole 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 Approved v4.0 930000317 1.0 Aripiprazole 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 Approved v4.0 930000317 1.0