Name of Sponsor/Company: Bristol-Myers Squibb Name of Finished Product: Abilify Name of Active Ingredient: aripiprazole Individual Study Table Referring to the Dossier (For National Authority Use Only) SYNOPSIS Clinical Study Report : Addendum 1 TITLE OF STUDY: A Multicenter, Randomized, Double-Blind Safety and Tolerability Study of Flexible doses of Aripiprazole and Olanzapine in the Treatment of Patients with Acute Schizophrenia (Week 52+ Double-Blind and Open-Label Phases) () INVESTIGATORS: The extension phase of this study, beyond Week 52 (abbreviated as Week 52+) was conducted by 20 primary investigators. STUDY CENTERS: There were 20 study centers involved in the Week 52+ Extension Phase (4 in Argentina, 1 in Brazil, 2 in Canada, and 13 in the United States) PUBLICATIONS: None STUDY PERIOD: Date first patient entered Week 52+ extension phase: 17-May-2001 Date last patient completed Week 52+ extension phase: 03-Apr-2003 CLINICAL PHASE: 3 OBJECTIVES: The objective of Addendum 1 to the clinical study report of 1-Dec-2004 was to evaluate the long-term safety and efficacy of aripiprazole versus olanzapine in patients who had been diagnosed at the start of the Acute Phase with schizophrenia, in acute relapse, and who responded to treatment in the Acute Phase, for the period of time from beyond Week 52 through Week 140 (Week 52+ Extension Phase). The database lock for Week 52+ took place on 9-Jul-2003. METHODOLOGY: This study was designed with a 12-Week Acute Phase followed by long-term Extension Phase dosing. The protocol was originally designed to evaluate data at Week 12; however, a protocol amendment revised the primary and secondary endpoints to Week 26 in order to capture long-term weight-gain data. There were 2 phases of treatment in this study: an Acute Phase (double-blind, flexible dosing through Week 12) and an Extension Phase (double-blind until the database lock of the first 52 weeks and open-label thereafter, flexible dosing beyond Week 12 through Week 140). Two previous and separate study reports were written: 1) for the period through Week 26, and 2) for the period beyond Week 26 through Week 52. This Addendum reports on the final period of time (from beyond Week 52 through Week 140), which will be referred to throughout this document as the Week 52+ Extension Phase. This addendum to the clinical study report presents efficacy (the CGI-S scale was the only efficacy measure collected in the Week 52+ Extension Phase) and safety data for the Extension Phase from Week 52 to Week 140. In this report, where baseline or change from baseline summaries are presented, baseline was defined as the time of the last available measurement prior to the start of double-blind dosing.
Changes to the protocol since the 52-week report include Amendments #7 through 9, which all involved the continuation of the study medication in the Week 52+ Extension Phase. A detailed reason for each amendment is presented in the following paragraphs. Protocol Amendment #7, dated 10-Apr-2002, modified the Extension Phase of the study to provide patients with open-label treatment after the database lock of the first 52 weeks data. Patients who still maintained an appropriate clinical response (at the discretion of the investigator) could receive open-label treatment in the same treatment arm until aripiprazole was available as a marketed product, or Dec-2002, whichever was sooner. Aripiprazole became a marketed product in the United States on 15-Nov-2002. Amendment #7 also ended data collection for Pharmacoeconomic Measures and Quality of Life Scales (Outcomes Research) after Week 52. All patients continued on double-blind study medication as they entered the Week 52+ Extension Phase. The reasons for patients not starting on open-label study medication were twofold: 1) the treatments could only be unblinded after the last patient who continued in the study completed 52 weeks, and 2) there was a delay in implementation of Protocol Amendment #7 during which the required local regulatory approval of the amendment at each site was obtained at each site. All patients continued on double-blind study medication as they entered the Week 52+ Extension Phase. During the double-blind portion, 13 patients discontinued the study for various reasons, of which 3 patients were lost to follow up. The length of time that patients were on double-blind treatment depended upon when patients were enrolled. From the first day of Week 52+, the longest duration of double-blind treatment was 380 days. After the database lock of the first 52 weeks data, Bristol-Myers Squibb notified investigators of each patient s treatment code, including the last dose the patient received according to the most recent Study Therapy Case Report Form page submitted to BMS. Following approval and implementation of Amendment #7, placebo supplies were discontinued and the remaining 34 patients continued on the same treatment they had received prior to Week 52, but now as open-label treatment. Protocol Amendment #8 continued the Extension Phase of the study in Canada, Brazil and Argentina, enabling patients responding to aripiprazole or olanzapine treatment to remain on their currently assigned treatment, and collecting safety data until aripiprazole was commercially available for marketing in those countries, an expanded access protocol/roll-over study was available, or Mar-2003, whichever was sooner. Aripiprazole became a marketed product in Brazil on 11-Apr-2003 and it has not been approved in Canada and Argentina. Protocol Amendment #9 enabled patients in Argentina to continue past Week 52 until aripiprazole was commercially available for marketing in that country, an expanded access protocol/roll-over study was available, or 31-Aug-2003, whichever date was sooner. Aripiprazole has not been approved in Argentina. Dosing for the Extension Phase was flexible within the assigned dose range. Patients unable to tolerate the lowest dose within the assigned dose range were discontinued from the study. NUMBER OF PATIENTS: Of the 47 patients who continued beyond Week 52, 18 discontinued due to study termination, 19 discontinued prematurely, and 10 completed the Week 52+ Extension Phase. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Upon study entry, patients were required to meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia and were in acute relapse. Upon entry into Extension Phase dosing, patients had a CGI-I Score of 1-3 or a 20% decrease from baseline in PANSS Total Score. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Aripiprazole was supplied in 5-mg, 10-mg, and 15-mg tablets. Doses consisted of a 15-mg dose (one 15-mg aripiprazole tablet), a 20-mg dose (one 15-mg aripiprazole tablet and one 5-mg aripiprazole tablet) or a 30-mg dose (one 15-mg aripiprazole tablet, one 5-mg aripiprazole tablet, and one 10-mg aripiprazole tablet) administered orally QD. Batch numbers were 99J84A005C, 98J82A005, 00A75A005A (5 mg), 98B85A010E, 99C77A010A, 00F85A010, 2B57248 (10 mg), and 98B85A015D, 99H93A015B, 00F90A0151,
00F90A015A (15 mg). Following implementation of Amendment #7, and the database lock of the data up to and including Week 52, study supplies were unblinded and placebo supplies were discontinued. DURATION OF TREATMENT: The total duration of treatment was up to 140 weeks. Patients could remain in extended treatment until aripiprazole was available as a marketed product, or Dec-2002, whichever was sooner. In Canada and Brazil patients could remain in extended treatment until aripiprazole was commercially available for marketing in those countries, an expanded access protocol/roll-over study was available, or Mar-2003, whichever was sooner. And in Argentina, treatment was possible until aripiprazole was commercially available for marketing in that country, an expanded access protocol/rollover study was available, or 31-Aug-2003, whichever date was sooner. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Olanzapine was supplied in 5-mg capsules. Doses consisted of an olanzapine 10-mg dose (two 5-mg olanzapine capsules), a 15-mg dose (three 5-mg olanzapine capsules), or a 20-mg dose (four 5-mg olanzapine capsules), administered orally QD. Patients who received active aripiprazole also received placebo capsules that were identical in size and appearance to olanzapine capsules as follows: 15-mg aripiprazole dose (2 placebo capsules), 20-mg aripiprazole dose (3 placebo capsules), 30-mg aripiprazole dose (4 placebo capsules). Patients who received active olanzapine also received placebo tablets that were identical in size and appearance to aripiprazole tablets: 10-mg olanzapine dose (1 placebo tablet), 15-mg olanzapine dose (2 placebo tablets), 20-mg olanzapine dose (3 placebo tablets), Batch numbers for olanzapine (5 mg) were 99F079, 05005.01, 05302.01, and 05606.01; for aripiprazole placebo were 98J82P000A, 99C77P000D, 99C77P000A, 99K77P000B, and 00F82P000; and for olanzapine placebo were 99F081 and 99F082. Following implementation of Amendment #7, study supplies were unblinded and placebo supplies were discontinued. At that time, commercial olanzapine was used and was obtained locally by each study site. CRITERIA FOR EVALUATION: Efficacy: The only efficacy assessment was the CGI Severity of Illness Score. Safety: Safety assessments included the following: the number of patients showing significant weight gain (a 7% increase in weight) the change and percentage change in weight from baseline to Weeks 76, 100, and 140 the number and incidence of adverse events (AEs), discontinuations due to AEs, serious adverse events (SAEs), EPS-related AEs, anticholinergic medications for potential treatment of EPS, and central nervous system (CNS) medications the number and incidence of potentially clinically relevant changes or events in vital signs, ECGs, and laboratory measurements the change from baseline to Weeks 76, 100, and 140 in serum prolactin, fasting glucose, glycosylated hemoglobin, and fasting lipids (LDL and HDL cholesterol, total cholesterol, and triglycerides) the change from baseline to Weeks 76, 100, and 140 for body mass index (BMI), standing and supine blood pressures, and hip and waist circumference the change from baseline to Weeks 76, 100, and 140 for Abnormal Involuntary Movement Scale (AIMS) STATISTICAL METHODS: Baseline in this report is defined as the last available measurement prior to the start of Acute Phase double-blind dosing. During the Week 52+ Extension Phase, patients may have terminated double-blind treatment, but continued on open-label treatment. AEs and concomitant medications were summarized separately for both the Week 52+ Double-Blind Phase as well as for the Week 52+ Open-Label Phase. In addition, these data were summarized for the entire Week 52+ Extension Phase, ie, covering both the Week 52+ Double-Blind Phase
and Week 52+ Open-Label Phase. Patient disposition was summarized for both phases separately and combined in the Randomized Sample. The CGI-S scale was the only efficacy measure collected in the Week 52+ Extension Phase. No treatment comparisons were prepared for the Week 52+ clinical study report. When key data were summarized, summary statistics comprised (for discrete data) the frequency and percentage, or, for continuous data, the mean, standard error of the mean, median, minimum, and maximum. All summaries were carried out by treatment group. In addition to the summaries by treatment group, summaries across treatment groups were provided for patient disposition and pretreatment characteristics. All analyses used the OC data set and patients were assigned to treatment groups according to the treatment they received rather than the treatment to which they were randomized, these not being necessarily the same. Only for baseline summaries were patients included in the treatment group to which they were randomized. All analyses were carried out using SAS, version 8. EFFICACY RESULTS: Assessments took place at Weeks 76, 100, and 140. In general, the mean changes from baseline in CGI Severity Score were similar in magnitude and showed slight decreases in both treatment groups at Weeks 76 and 100; however, results should be interpreted with care due to the small numbers of patients observed. In the Acute Phase of this study, approximately 160 patients per treatment group were treated and the Week 52+ Extension Phase has only 29 olanzapine patients and 18 aripiprazole patients. The Week 140 CGI-S results are only available for 2 patients, both in the olanzapine group. SAFETY RESULTS: A total of 52 patients completed Week 52, and 5 of those patients did not continue beyond Week 52. Of the 47 patients continuing beyond Week 52, 37 patients discontinued before completing the Extension Phase. The most frequent reasons for discontinuation were other known cause (10 in each treatment group, of whom 9 in each group discontinued due to study termination) and adverse event (AE) (6 patients in the olanzapine group and 1 patient in the aripiprazole group). The 2 treatment groups were largely balanced regarding demographic characteristics, except for differences in age and weight. The end of baseline PANSS scores (including all assessment areas) and CGI-S ratings were similar for the 2 treatment groups. The 2 treatment groups were also similar with respect to anticholinergic drugs taken for EPS usage. A greater percentage of patients in the aripiprazole treatment group (83%) took concomitant CNS medication than in the olanzapine treatment group (59%). Eighty-one percent of patients in the olanzapine group and 72% in the aripiprazole group reported an AE during the Week 52+ double-blind and open-label phases combined. The percentage of patients in the olanzapine treatment group reporting SAEs was slightly higher than in the aripiprazole group: 26% in the olanzapine group and 17% in the aripiprazole group. Two patients died following their participation in the Week 52+ Extension Phase (> 30 days after the last dose of study medication), 1 in each treatment group. The incidence of AEs leading to study discontinuation was slightly higher in the olanzapine treatment group. There were no to very few potentially clinically significant laboratory abnormal values in studies related to hepatic or renal function in either treatment group. The percentage of patients with potentially clinically significant laboratory abnormalities in prolactin values was substantially lower in the aripiprazole group compared with those in the olanzapine group (46.2% and 21.4%, respectively). Cholesterol values were also of importance: substantially fewer patients in the aripiprazole group compared with the olanzapine group had abnormal values in HDL-cholesterol (50.0% and 73.3%, respectively). For LDL cholesterol, 30.0% of patients had an abnormal value in the aripiprazole group compared with 53.3% in the olanzapine group.
Laboratory values related to cardiovascular risk were more favorable in the aripiprazole treatment group than in patients treated with olanzapine: increased HDL values and reduced total cholesterol and LDL values were reported for the aripiprazole group at the Week 100 timepoint. By the Week 140 timepoint, the number of study participants was too small for interpretation. Mean changes from baseline in fasting glucose values showed a small increase in both treatment groups at Week 76 and at Week 100; a decrease from baseline was observed in the olanzapine group while an increase in the aripiprazole group was noted. A potentially clinically significant glycosolated hemoglobin A1c value was identified for 5 (19.2%) patients in the olanzapine group and 5 (35.7%) patients in the aripiprazole group during the Week 52+ Extension Phase. Mean change from baseline in the AIMS Total Score was similarly decreased in treatment groups at Week 76 and nominally lower in the aripiprazole group than in the olanzapine group at Week 100. Weight gain is a common reason for treatment noncompliance with the use of antipsychotics. In addition, weight gain is associated with serious physical illnesses, such as coronary heart disease, ischemic stroke, hypertension, diabetes mellitus, joint and locomotor disorders, and the metabolic syndrome, as well as psychological distress. Weight gain in general was greater in patients treated with olanzapine group (57.7%) than in the aripiprazole treatment group (37.5%). At Weeks 76 and 100, significant weight (an increase in weight of at least 7% from baseline) gain occurred more frequently in the olanzapine treatment group compared with the aripiprazole treatment group (56.5% versus 25.0% and 64.7% versus 30.0%, respectively). Increases in BMI followed a similar trend, with slightly greater mean increases in the olanzapine group. Treatment differences in favor of aripiprazole in mean change from baseline at Weeks 76 and 100 were observed of 1.3 to 1.8 kg/m 2, respectively. Hip and waist circumference increased slightly from baseline in both treatment groups. There were no clinically meaningful differences between the groups in regard to vital signs. Potentially clinically significant ECG abnormalities were present only in the olanzapine treatment group: 2 patients had a QT c abnormality (defined as a QT c [Bazett s correction] of at least 450 msec with at least a 10% increase from baseline) and 1 had a premature ventricular beat. CONCLUSIONS: Although sample sizes for the Week 52+ Extension Phase were very small (< 15% of the total number of treated patients in this study), the results are consistent with the assertion that aripiprazole, at the doses administered, is efficacious and well tolerated for patients who have been stable for 1 year on medication. In addition, aripiprazole produced more favorable results in measurements of weight stability than those observed with olanzapine. Results supporting these overall conclusions included the following: CGI S score results for the Week 52+ study extension were similar in magnitude and showed slight decreases in both treatment groups at Weeks 76 and 100. The proportion of AEs, SAEs, and EPS-related AEs were similar between treatment groups. Many of the same AEs that were most prevalent up to and including Week 52 were reported in the 52+ Week Extension Phase, but usually at a smaller frequency. There were 2 deaths: 1 aripiprazole-treated patient died 1 day after the last dose of study medication and 1 olanzapine-treated patient died > 30 days after the last dose of study medication; both events were judged by the investigator to be unrelated to study drug. No trends in mean change from baseline were noted for the aripiprazole group during Week 52+ double-blind and open-label phases in total cholesterol, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol. Mean triglycerides increased somewhat from baseline at both Weeks 76 and 100 and prolactin levels showed a large mean decrease at both these weeks in the aripiprazole group. Mean weight change was greater and significant weight gain was more prevalent in the olanzapine treatment group compared with the aripiprazole group at Weeks 76 and 100.
Waist circumference increased more from baseline in the olanzapine group and hip circumference increased slightly from baseline in both treatment groups at Weeks 76 and 100. The olanzapine group had slightly more potentially clinically significant vital sign abnormalities than the aripiprazole group, but no overall trends were seen in either group. Potentially clinically significant ECG findings were seen only in the olanzapine treatment group. No new safety trends emerged during the Week 52+ Extension Phase. DATE OF REPORT: 22-Dec-2005