A Multicenter, Double-Blind Randomized, Comparative Study of Aripiprazole and Olanzapine in the Treatment of Patients with Acute Schizophrenia

OBJECTIVES: The objective of Addendum 1 to the clinical study report of 21-Jan-2005 was to present data from the extension phase beyond Week 52 through to Week 140 (52+ Week Treatment Phase). The database lock for the entire study took place on 05-Dec-2003. PRIMARY: The co-primary objectives of this study were to compare the efficacy of aripiprazole versus olanzapine as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score, and to compare the safety and tolerability of aripiprazole versus olanzapine as evidenced by significant (≥ 7%) weight gain during treatment. SECONDARY: The secondary objectives of this study were to compare the efficacy profiles of aripiprazole versus olanzapine based upon the results of efficacy scales (PANSS, Clinical Global Impression [CGI], and Montgomery-Asberg Depression Rating Scale [MADRS]), and to compare the safety and tolerability of aripiprazole versus olanzapine, and the response rate and discontinuation rate in patients having received aripiprazole versus olanzapine (responders were patients with a CGI Improvement [CGI-I] Score of very much or much improved, or with a decrease in PANSS Total Score of at least 30% from baseline). PHARMACOECONOMICS AND OUTCOMES RESEARCH: The objectives of pharmacoeconomics and outcomes research were to compare quality-of-life scores, overall health care resource utilization, and functional outcomes measures between treatment groups. Data from the pharmacoeconomics and outcomes research study will be reported in a separate report. METHODOLOGY: EXTENSION PHASE: Study CN138003 was initially designed as a 6-week Acute Phase and a 46-week Extension Phase study, for a total duration of 52 weeks. The Extension Phase, starting after the 6 week Acute Phase, was double-blind until all data collected through Week 52 was locked. These results are reported in the Clinical Study Report for the Acute Phase and Extension Phases up to Week 52. Protocol Amendment 4 dated 18-Jun-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 continued in the study on their assigned treatment and dose until the drug was available as a marketed product or March 2003, whichever was sooner. After the database lock for Week 52 data (June 2002), Bristol-Myers Squibb notified investigators of each patient’s treatment code, including the patient’s last dose received according to the most recent Study Therapy Case Report Form page submitted to BMS. Until the local regulatory approval of this amendment, although investigators were unblinded to treatment code, patients continued to receive study therapy packaged as double-blind therapy. At the time of local regulatory approval of this amendment (no later than January 2003), patients who still maintained an appropriate clinical response (at the discretion of the investigator) received open-label treatment in the same treatment arm until aripiprazole was available as a marketed product, or March 2003, whichever was sooner. The same medications were prohibited during the Acute and the Extension Phases. Protocol Amendments 5 and 6 extended the Extension Phase until 31-Aug-2003. 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: A total of 302 patients completed Week 52; 33 of those patients did not continue beyond Week 52. Of the 269 patients continuing beyond Week 52, 76 patients discontinued prematurely. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Patients were required to meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for acute schizophrenia and be in acute relapse. Patients must have had a previous response to a neuroleptic treatment other than clozapine. In order to be initially randomized into the study, patients had to have a PANSS Total Score ≥ 60 and a score of ≥ 4 on 2 or more on the following PANSS items: delusions, hallucinatory behavior, conceptual disorganization, suspiciousness. Patients had to have a CGI-I Score of 1 to 3 or a reduction of at least 20% on the PANSS Total Score at the Week 6 visit in order to continue into the extended treatment period. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Aripiprazole 5-mg tablets, 1 tablet daily, administered orally, batch numbers 99J84A005A and 00A75A005A; 10-mg tablets, 1 tablet daily, administered orally, batch numbers 98B85A010E, 99C77A010B, and 00F85A010; and 15-mg tablets, 1 tablet daily, administered orally, batch numbers 99H93A015B, 99H93A015A, and 99L77A015. DURATION OF TREATMENT: The total duration of treatment was up to 140 weeks (6 weeks initial Acute Phase treatment plus extended treatment up to 134 weeks). Patients could remain in extended treatment until approximately August 2003. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Olanzapine 5-mg capsules, 2, 3, or 4 capsules daily, administered orally, batch numbers M00007 and M00026; Zyprexa 5-mg tablet (open-label) 2, 3, or 4 tablets daily, administered orally, batch number A018116; placebo tablets, 1, 2 or 3 tablets daily, administered orally, batch numbers 98B85P000C, 98B85P000D, 99K77P000A, and 99K77P000B; placebo capsules, 2, 3, or 4 capsules daily, administered orally, batch numbers 99F081, 00F090, 00F091, 00F092, and 00F093. CRITERIA FOR EVALUATION: EFFICACY: The only efficacy assessment in the Week 52+ Treatment Phase was the CGI Severity of Illness Score. SAFETY: Safety assessments included the following: • the number of patients showing significant weight gain (a ≥ 7% change from baseline 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), extrapyramidal symptom (EPS)-related AEs, anticholinergic medications for potential treatment of EPS, central nervous system (CNS) medications, and concomitant medications • the number and incidence of potentially clinically relevant changes or events in vital signs, electrocardiograms (ECGs), and laboratory measurements • the change from baseline to Weeks 76, 100, and 140 in serum prolactin, fasting glucose, glycosylated hemoglobin, and fasting lipids (low-density [LDL]-cholesterol and high density [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 was defined as for the 52-weeks report, ie, prior to start of double-blind dosing. During the Week 52+ Treatment 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+ Treatment Phase, ie, covering both the Week 52+ Double-Blind Phase and Week 52+ Open-Label Phase. Patient disposition was summarized separately for the Week 52+ Double-Blind Phase and for the Week 52+ Open-Label Phase as well as for both phases combined. Data listings including the data beyond Week 52 have been presented with the 52-week report. The CGI-S scale was the only efficacy measure collected in the Week 52+ Treatment Phase. No statistical treatment comparisons were prepared for the Week 52+ clinical study report. Where 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 pre-treatment characteristics. All analyses used the observed cases (OC) data set because of the high attrition rate in the initial 52-week phase. 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 they were randomized to. EFFICACY RESULTS: Assessments took place at Weeks 76, 100, and 140. In general, the mean changes from baseline in CGI Severity Score were similar across both treatment groups at all 3 timepoints; however, the Week 140 results should be interpreted with care due to the small numbers of patients observed at that timepoint. SAFETY RESULTS: A total of 302 patients completed Week 52, and 33 of those patients did not continue beyond Week 52. Of the 269 patients continuing beyond Week 52, 76 (28.3%) patients discontinued prematurely. The most frequent reason for premature discontinuation was the patients’ withdrawal of consent (17 olanzapine patients; 9 aripiprazole patients), followed by the occurrence of AEs (11 olanzapine patients; 7 aripiprazole patients). Lack of efficacy accounted for the discontinuation of 3 (2.1%) patients in the olanzapine group and 1 (0.8%) patient in the aripiprazole group. The 2 treatment groups were largely balanced regarding demographic characteristics, with the exception of their weight. The patients in the aripiprazole group were slightly heavier (74.3 kg was the average weight in the olanzapine group, while 77.8 kg was the average weight in the aripiprazole group - a difference of 3.5 kg). This was reflected in the mean BMI, which was 25.59 and 26.64 in the olanzapine and aripiprazole groups, respectively. The end of baseline ratings were similar for the 2 treatment groups in PANSS Total Score, PANSS Positive Score, PANSS Negative Score, PANSS-Derived Brief Psychiatric Rating Scale (BPRS) Core Score, and CGI Severity of Illness Score. A greater number of patients in the aripiprazole treatment group took anticholinergic drugs for EPS than did the patients randomized to olanzapine. Otherwise the 2 treatment groups were similar in respect to CNS concomitant medication use and concomitant medication usage in general. A similar proportion of patients in both groups reported AEs: 52% of patients in the olanzapine group and 55% in the aripiprazole group. The percentage of patients in both treatment groups reporting SAEs was comparable: 10% in the olanzapine group and 12 % in the aripiprazole group. The most frequently reported SAE in both groups was reaction schizophrenic (3% in the olanzapine group and 2% in the aripiprazole group). One patient in the aripiprazole group died due to heart failure. The event was judged by the investigator to be not likely related to study drug. The incidence of AEs leading to study discontinuation was 7% in the olanzapine group and 5% in the aripiprazole group. There were very few potentially clinically significant abnormal laboratory values in the study related to hepatic or renal function in either treatment group. The number and percentage of patients with potentially clinically significant prolactin values was lower in the aripiprazole group compared with the olanzapine group. Laboratory values related to cardiovascular risk were more favorable in the aripiprazole treatment group than in those patients treated with olanzapine. Increased HDL-cholesterol values, reduced total cholesterol, LDL-cholesterol values, and triglyceride values were reported for the aripiprazole group at the Week 76 and Week 100 timepoints. By the Week 140 timepoint, the number of study participants was so reduced as to make interpretation difficult. Analyses were also performed to determine the number of patients who had normal HDL and LDL cholesterol values up to Week 52, and then subsequently had abnormal values beyond Week 52 (Week 52+ Treatment Phase). For HDL cholesterol, 39 olanzapinetreated patients had a normal HDL value at the 52-week assessment and 9 (22%) of those patients then had at least 1 abnormal HDL level during the Week 52+ Treatment Phase. There were 37 aripiprazole-treated patients with a normal HDL at the 52-week assessment and 8 (16%) with a subsequent abnormal value during the Week 52+ Treatment Phase. For LDL cholesterol, 30 olanzapine-treated patients had a normal LDL value at the 52-week assessment and 6 (20%) of those patients then had at least 1 abnormal HDL level during the Week 52+ Treatment Phase. There were 24 aripiprazole-treated patients with a normal HDL value at the 52-week assessment and 3 (13%) with a subsequent abnormal value during the Week 52+ Treatment Phase. Mean changes from baseline in fasting glucose values showed greater decreases in the aripiprazole group at the Week 76 and Week 100 timepoints than in the olanzapine group. Mean changes from baseline in the AIMS Total Score were -0.34 and -0.33 in the olanzapine group and -0.57 and -0.61 in the aripiprazole group at Week 76 and Week 100, respectively. Weight gain in general was greater in those patients treated in the olanzapine group. The incidence of significant weight gain (significant gain was defined as an increase in weight of at least 7% from baseline) was higher in the olanzapine treatment group. The mean change from baseline in BMI showed greater increases from baseline in the olanzapine treatment group than in the aripiprazole group. Hip and waist circumference increased in the olanzapine treatment group, while the aripiprazole group reported decreases in those measurements. There were no clinically meaningful differences between the groups in regard to vital signs and ECGs. CONCLUSIONS: The results of the Week 52+ Treatment Phase demonstrated that aripiprazole at the doses administered was well-tolerated, safe, and produced results in CGI-S scores similar to those obtained in the olanzapine group. In addition, aripiprazole produced more favorable results in the lipid profile and in measurements of weight stability than those obtained with olanzapine. Results supporting these conclusions included the following: • CGI-S score results for the Week 52+ study extension were similar in the 2 treatment groups • The proportion of AEs, SAEs, and EPS-related AEs were similar in the 2 treatment groups • There was 1 death during the study in the aripiprazole treatment group; this was judged by the investigator to be not likely related to study drug • The improvements in total cholesterol, LDL-cholesterol, triglycerides, and prolactin levels noted in the aripiprazole group during the first 52 weeks of the study were sustained through the Week 52+ study extension • Weight gain in general and significant weight gain in particular was greater in the olanzapine treatment group compared with the aripiprazole group • Waist and hip circumference increased in the olanzapine group, whereas those measurements decreased in the aripiprazole treatment group • Vital sign and electrocardiogram (ECG) findings in both groups continued to be comparable • No new safety signals emerged during the Week 52+ study extension