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. 2019 May 1;16(5-6):15-21.

Olanzapine Plus Samidorphan in Subjects with Schizophrenia and Comorbid Alcohol Use Disorder: Rationale and Design for a Phase II, Double-blind, Randomized Study

Leslie Citrome  1   2   3   4 , Stephanie S O'Malley  1   2   3   4 , David McDonnell  1   2   3   4 , Ying Jiang  1   2   3   4 , Adam C Simmons  1   2   3   4 , Mark P Berry  1   2   3   4 , Lauren E Dipetrillo  1   2   3   4
Affiliations

Olanzapine Plus Samidorphan in Subjects with Schizophrenia and Comorbid Alcohol Use Disorder: Rationale and Design for a Phase II, Double-blind, Randomized Study

Leslie Citrome et al. Innov Clin Neurosci. .

Abstract

Background: Alcohol use disorder (AUD) is a common comorbidity in patients with schizophrenia. Although pharmacological options for the management of each disease exist separately, there is no agent approved for both. Moreover, studies conducted in this patient population, who face practical and social challenges as a consequence of being diagnosed with schizophrenia and comorbid AUD, are limited. Methods: We describe the design of a Phase II, double-blind, randomized trial to evaluate adult outpatients with schizophrenia and comorbid AUD receiving a combination of olanzapine plus samidorphan (OLZ+SAM; ALKS 3831), a novel entity currently under development for the treatment of schizophrenia. The combination drug formulation of OLZ+SAM is intended to provide the antipsychotic efficacy of OLZ while mitigating the weight gain and concomitant metabolic abnormalities commonly associated with OLZ alone. In considering this patient population, the novel primary efficacy endpoint is the time from randomization to the first event of exacerbation of disease symptoms (EEDS) based on the occurrence of any of eight prespecified events related to worsening of disease symptoms and/or AUD, as confirmed by a blinded independent adjudication committee. The rate and number of EEDS, improvement in drinking level, and the safety and tolerability of OLZ in combination with SAM will also be assessed. Discussion: A limited number of studies have been conducted in patients with schizophrenia and AUD, and the need for further research in this difficult-to-study population is well documented. This study is, to our knowledge, the largest and longest trial with a randomized, double-blind, active-controlled design. In addition to providing evidence for the development of OLZ+SAM (ALKS 3831) as a therapeutic option, the study aims to provide insights into the clinical management of subjects with schizophrenia and comorbid AUD. Trial registration: Clinical trials NCT02161718, registered May 2014; EudraCT Number: 2014-001211-39.

Keywords: ALKS 3831; Schizophrenia; alcohol use disorder; olanzapine; samidorphan.

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Conflict of interest statement

FUNDING: This study was sponsored by Alkermes, Inc., Waltham, Massachusetts, who participated in the design of the study. Funding for editorial support was provided by Alkermes, Inc., Waltham, Massachusetts. DISCLOSURES: Dr. Citrome was the chair of the independent event adjudication committee for this study and received payment from Alkermes for this role. He also served as consultant and/or advisor to or has received honoraria from Acadia, Alexza, Allergan, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Intra-Cellular Therapeutics, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Neurocrine, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, Valeant, and Vanda; has stocks in (small number of shares of common stock) Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer (purchased >10 years ago); and received royalties from Wiley (Editor in Chief, International Journal of Clinical Practice), UpToDate (reviewer), and Springer Healthcare (book). Dr. O’Malley reports being a consultant or an advisory board member for Alkermes, Amygdala, Cerecor, Mitsubishi Tanabe, Opiant; a member of the American Society of Clinical Pharmacology Alcohol Clinical Trials Initiative supported by Amygdala, Ethypharm, Lilly, Lundbeck, Otsuka, Pfizer, Arbor Pharmaceuticals, and Indivior. Dr. McDonnell is an employee of Alkermes Pharma Ireland Limited. Drs. Jiang, Simmons, Berry and DiPetrillo are employees of Alkermes, Inc.

Figures

FIGURE 1.
FIGURE 1.
Study design. *Drinking days will be measured by the TLFB method, with at least 2 of these drinking days meeting criteria for a heavy drinking day (≥4 drinks in a day for women and ≥5 drinks in a day for men). †Dose adjustments will be permitted in the first 3 weeks of the open-label lead-in period. ‡Subjects will complete a study visit every two weeks and the double-blind treatment period will last for a minimum of 36 weeks and a maximum of 60 weeks (the double-blind period will be stopped when the last randomized subject completes their 36-week visit). OLZ: olanzapine; PBO: placebo; SAM: samidorphan 10mg; TLFB: Timeline Follow-Back.
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