Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

Autor:	Schmidt-Kraepelin C; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Kaiserswerther Diakonie, Florence Nightingale Hospital, Department of Psychiatry and Psychotherapy, Düsseldorf, Germany. Electronic address: christian.schmidt-kraepelin@hhu.de., Feyerabend S; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Kaiserswerther Diakonie, Florence Nightingale Hospital, Department of Psychiatry and Psychotherapy, Düsseldorf, Germany., Engelke C; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Riesbeck M; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Meisenzahl-Lechner E; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Verde PE; Coordination Centre for Clinical Trials, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Correll CU; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Berlin, Germany., Kluge M; Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Leipzig, Germany., Makiol C; Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Leipzig, Germany., Neff A; LVR-Klinikum Langenfeld, Langenfeld, Germany., Lange C; LVR-Klinikum Langenfeld, Langenfeld, Germany., Englisch S; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Psychiatry and Psychotherapy, University Medical Centre Mainz, Mainz, Germany., Zink M; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; District Hospital Mittelfranken, Ansbach, Germany., Langguth B; Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany., Poeppl TB; Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany; Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany., Reske D; LVR-Klinikum Köln, Köln, Germany., Gouzoulis-Mayfrank E; LVR-Klinikum Köln, Köln, Germany., Gründer G; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany., Hasan A; Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, BKH Augsburg, Augsburg, Germany., Brockhaus-Dumke A; Department of Psychiatry and Psychotherapy 1 and 2, Rheinhessen-Fachklinik Alzey, Academic Hospital of the University of Mainz; Alzey, Germany., Jäger M; Department of Psychiatry II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany., Baumgärtner J; Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, BKH Augsburg, Augsburg, Germany., Leucht S; Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany., Cordes J; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Kaiserswerther Diakonie, Florence Nightingale Hospital, Department of Psychiatry and Psychotherapy, Düsseldorf, Germany.
Jazyk:	angličtina
Zdroj:	The lancet. Psychiatry [Lancet Psychiatry] 2022 Apr; Vol. 9 (4), pp. 291-306. Date of Electronic Publication: 2022 Mar 08.
DOI:	10.1016/S2215-0366(22)00032-3
Abstrakt:	Background: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. Methods: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. Findings: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). Interpretation: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. Funding: German Federal Ministry of Education and Research. Competing Interests: Declaration of interests CUC has been a consultant and advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen Pharmaceuticals, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Seqirus, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. MK received honoraria from Roche, Servier, and Tromssdorff and a travel grant from Janssen Cilag. MZ received scientific grants from the German Research Foundation and Servier; and speaker and travel grants from Otsuka, Lundbeck, Roche, Recordati, Ferrer and Trommsdorff. BL received honoraria and speaker's fees from ANM, AstraZeneca, Autifony Therapeutics, Desyncra, Lundbeck, Merz, MagVenture, Neurolite, Neuromod, Novartis, Pfizer, and Servier; research funding from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium für Bildung und Forschung, the American Tinnitus Association, AstraZeneca, and cerbomed; funding for equipment from MagVenture and Deymed Diagnostic; and travel and accommodation payments from Eli Lilly, Lundbeck, Servier, and Pfizer. TBP has served as a consultant for Rovi and received travel compensation from AstraZeneca and Pfizer. GG has served as a consultant for Allergan, Boehringer Ingelheim, Institute for Quality and Efficiency in Health Care, Janssen-Cilag, Lundbeck, Otsuka, Recordati, ROVI, Sage, and Takeda. He has served on the speakers' bureau of Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax. He is co-founder or shareholder, or both, of Mind and Brain Institute GmbH, Brainfoods GmbH, OVID Health Systems GmbH, and MIND Foundation gGmbH. AH was on the advisory board of Janssen-Cilag, Lunbeck, Roche, and Otsuka and has accepted paid speaking engagements for Janssen-Cilag, Lunbeck, and Otsuka. SL has received honoraria as a consultant or advisor, or for lectures, from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitshubishi. JC was a member of an advisory board of Roche; accepted travel or hospitality not related to a speaking engagement from Servier; received support for symposia from Inomed, Localite, Magventure, Roche, Mag & More, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel and Diamedic; and was involved in research and participated in studies funded by the German Research Foundation and the German Bundesministerium für Bildung und Forschung, Foundation European Group for Research In Schizophrenia, ACADIA Pharmaceuticals, Boehringer Ingelheim Pharma GmbH KG, Otsuka Pharmaceutical Europe, and EnVivo Pharmaceuticals. All other authors declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu