A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

Abstract

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

• Authors: Christian Schmidt-Kraepelin, Sandra Feyerabend, Christina Engelke, Mathias Riesbeck, Eva Meisenzahl-Lechner, Wolfgang Gaebel, Pablo-Emilio Verde, Henrike Kolbe, Christoph U Correll, Stefan Leucht, Stephan Heres, Michael Kluge, Christian Makiol, Andrea Neff, Christina Lange, Susanne Englisch, Mathias Zink, Berthold Langguth, Timm Poeppl, Dirk Reske, Euphrosyne Gouzoulis-Mayfrank, Gerhard Gründer, Alkomiet Hasan, Anke Brockhaus-Dumke, Markus Jäger, Jessica Baumgärtner, Thomas Wobrock, Joachim Cordes
• Journal: European archives of psychiatry and clinical neuroscience (Eur Arch Psychiatry Clin Neurosci) Vol. 270 Issue 1 Pg. 83-94 (Feb 2020) ISSN: 1433-8491 [Electronic] Germany
• PMID: 31486890 (Publication Type: Clinical Trial Protocol, Journal Article)

Chemical References

• Amisulpride
• Antipsychotic Agents
• Olanzapine

Topics

• Adolescent
• Adult
• Aged
• Humans
• Middle Aged
• Young Adult
• Acute Disease
• Amisulpride (administration & dosage, adverse effects, pharmacology)
• Antipsychotic Agents (administration & dosage, adverse effects, pharmacology)
• Double-Blind Method
• Drug Therapy, Combination
• Multicenter Studies as Topic (methods)
• Olanzapine (administration & dosage, adverse effects, pharmacology)
• Randomized Controlled Trials as Topic (methods)
• Research Design
• Schizophrenia (drug therapy)