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

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.

SUBMITTER: Citrome L

PROVIDER: S-EPMC6659992 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Citrome Leslie L O'Malley Stephanie S SS McDonnell David D Jiang Ying Y Simmons Adam C AC Berry Mark P MP Dipetrillo Lauren E LE

Innovations in clinical neuroscience 20190501 5-6

<b>Background:</b> 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. <b>Methods:</b> We describe the design of a Phase II, double-blind, randomized trial to eval ...[more]

PMID: 31440397

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Project description:IntroductionSchizophrenia is a complex medical illness characterized by hallucinations, delusions, and cognitive issues. Olanzapine, a second-generation antipsychotic widely prescribed for schizophrenia has proven to be efficacious, however, its use is associated with major adverse effects such as weight gain, metabolic syndrome and diabetes mellitus. Recently, FDA approved a combination dose of olanzapine and samidorphan (OLZ/SAM) to mitigate the adverse outcomes associated with olanzapine use for the treatment of Schizophrenia.ObjectivesThe approval of olanzapine/samidorphan combination by FDA in treatment of schizophrenia and bipolar I disorder has been a milestone. This article summarizes the clinical trials reporting the clinical efficacy and adverse effects of olanzapine/samidorphan combination along with their bias assessment.MethodsPubmed, science direct, Ovid SP and Google Scholar were comprehensively searched for data collection. Clinical trials reporting the efficacy and adverse outcomes of the OLZ/SAM regimen were included in the review and the Cochrane risk of bias assessment tool (RoB 2.0, version 2019) was used to assess the risk of bias in each study.ResultsFive trials employed the use of Positive and Negative Syndrome Scales (PANSS) and Clinical Global Impression-Severity (CGI-S) scale to assess the efficacy of OLZ/SAM. Overall, OLZ/SAM showed a significant reduction in PANSS total scores and CGI-S scores and might be a viable option for long-term treatment. The safety of combined therapy is assessed by trials considering the factors of ECG parameters, suicidal events, and movement disorders. Major adverse events included nervous system disorders, changes in blood chemistry, and metabolic or nutritional disorders, with worsening of adverse outcomes observed in a total of nineteen cases in six studies.ConclusionThe FDA-approved drug recombination of OLZ/SAM for the treatment of schizophrenia revealed efficacious outcomes and was generally well tolerated by patients partaking in various trials. The potential of samidorphan in mimicking the efficacy of olanzapine while mitigating olanzapine-induced weight gain makes it a promising regimen for improving symptoms and health outcomes in schizophrenic patients.

Project description:IntroductionHead-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia.MethodsThe study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram.ResultsOlanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05).DiscussionThe results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Project description:BackgroundIn patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic.MethodsData were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥ 30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥ 40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders.ResultsEarly response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8.ConclusionsAmong acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics.Clinical trials registryF1D-MC-HGJZ: Comparison of Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia http://clinicaltrials.gov/ct2/show/NCT00088478?term=olanzapine+depot&rank=3Registry identifier - NCT00088478.

Dataset Information

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

Publications

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

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