Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study

Abstract

Objective: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538).

Methods: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored.

Results: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups.

Conclusions: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Keywords: atypical antipsychotic; bipolar I disorder; bipolar depression; cariprazine; randomized controlled trial.

Conflict of interest statement

Drs Earley, Burgess, Rekeda, and Ms Khan are full‐time employees of Allergan. Dr Earley owns stock in Allergan and AstraZeneca. Drs Burgess, Rekeda, and Ms Khan own stock in Allergan. Dr Suppes in the past 36 months has reported grants from National Institute of Mental Health, Sunovion Pharmaceuticals, Elan Pharma International Limited, VA Cooperative Studies Program, Pathway Genomics, Stanley Medical Research Institute, National Institute of Health, Palo Alto Health Sciences, and National Institute on Drug Abuse; consulting fees from Sunovion and Allergan, Inc; honoraria from Medscape Education, Global Medical Education, and CMEology; and royalties from Jones and Bartlett, UpToDate, and Hogrefe Publishing. Dr Tohen has been a consultant or received honoraria from AstraZeneca, Abbott, Bristol‐Meyers Squibb, Eli Lily, GlaxoSmithKline, Johnson & Johnson, Alkermes, Otsuka, Roche, Lundbeck, Elan, Merck, Pamlab, Alexza, Forest, Sunovion, and Wyeth. Dr Calabrese has received funding from the Department of Defense, the Health Resources Services Administration, and NIMH; research support from Abbott, AstraZeneca, Bristol‐Myers Squibb, Cephalon, the Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, NARSAD, Repligen, the Stanley Medical Research Institute, Takeda, and Wyeth; served on advisory boards for Abbott, AstraZeneca, Bristol‐Myers Squibb, Cephalon, Dainippon Sumitomo, EPI Q, Forest Laboratories, the France Foundation, Gedeon Richter, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, Merck, Neurosearch, Ortho‐McNeil, Otsuka, Pfizer, Repligen, Schering‐Plough, Servier, Solvay, Supernus, Synosia, Takeda, and Wyeth; and provided CME lectures supported by AstraZeneca, Bristol‐Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson, Merck, Sanofi‐Aventis, Schering‐Plough, Pfizer, Solvay, and Wyeth.

© 2019 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.

Figures

Figure 1

CONSORT flow diagram for study patients. AE, adverse event; Incl/Excl criteria, patient did not meet inclusion/exclusion criteria; LOE, lack of efficacy; LTF, lost to follow‐up; NC, noncompliance with study drug; PV, protocol violation; WOC, withdrawal of consent

Figure 2

Mean change from baseline to Week 6 by visit in a) MADRS total score; b) CGI‐S score (LSM ± SE; ITT population, MMRM). Estimates derived from an MMRM with fixed factors (treatment group, pooled study center, and visit), baseline (a covariate), and interactions (treatment group by visit, baseline by visit). ITT population consists of randomized patients who had received ≥1 dose of double‐blind treatment and ≥1 postbaseline MADRS total score assessment. CGI‐S, Clinical Global Impressions ‐Severity; ITT, intent‐to‐treat; LS, least squares; LSM, least squares mean; MADRS, Montgomery‐Asberg Depression Rating Scale; MMRM, mixed‐effects model for repeated measures; SE, standard error

Figure 3

MADRS response, MADRS remission, and HAMD‐17 remission at Week 6 (ITT population, LOCF). The P‐value for a between‐treatment comparison at each visit is based on a logistic regression model, which included treatment group and the baseline MADRSa and HAMD‐17b total score value. The P‐value is from a Z‐test. LOCF was used for imputation. HAMD‐17, 17‐item Hamilton Depression Rating Scale; ITT, intent‐to‐treat; LOCF, last observation carried forward; MADRS, Montgomery‐Asberg Depression Rating Scale