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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

  • Christian Schmidt-KraepelinEmail author
  • 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
Original Paper
  • 63 Downloads

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.

Keywords

Schizophrenia Antipsychotics Combination Amisulpride Olanzapine Polypharmacy 

Notes

Acknowledgements

This study is funded by the German Federal Ministry of Education and Research (BMBF 01KG1102).

Funding

This trial is funded by the German Federal Ministry of Education and Research (BMBF 01KG1102) and registered at clinicaltrials.gov (NCT01609153) and in the German Clinical Trials Register (DRKS00003603). EudraCT-No. is 2011-002463-20.

Compliance with ethical standards

Conflict of interest

C Schmidt-Kraepelin, S. Feyerabend, C. Engelke, M. Riesbeck, E. Meisenzahl-Lechner, P. E. Verde, S. Heres, H. Kolbe, C. Makiol, A. Neff, C. Lange, T. Poeppl, D. Reske, E. Gouzoulis-Mayfrank, A. Brockhaus-Dumke, M. Jäger, J. Baumgärtner have no conflicts of interests to declare. W. Gaebel is a member of the Faculty of the Lundbeck International Neuroscience Foundation, Denmark. C. U. Correll has been a consultant and/or advisor to or has received honoraria from: Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Rovi, Servier, Sunovion, Supernus, Takeda, and Teva. 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. S. Leucht has received honoraria for consulting or lectures from LB Pharma, Lundbeck, Otsuka, TEVA, LTS Lohmann, Geodon Richter, Recordati, Boehringer Ingelheim, Sandoz, Janssen, Lilly, SanofiAventis, Servier and Sunovion in the last 3 years. M. Kluge has received honoraria from Roche, Servier, and Tromssdorff. S. Englisch received travel expenses and consultant fees from Janssen-Cilag, Lundbeck, Otsuka Pharma, and Servier. M. Zink received scientific grants from the German Research Foundation, and Servier; speaker and travel grants were provided from Otsuka, Servier, Lundbeck, Roche, Ferrer, and Trommsdorff. B. Langguth received honoraria and speakers’ 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. G. Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Eli Lilly (Indianapolis, Ind, USA), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Janssen Cilag, Neuraxpharm (Langenfeld, Germany), Lundbeck, Otsuka, Recordati, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Mind and Brain Institute GmbH (Zornheim, Germany) and Brainfoods GmbH (Zornheim, Germany). A. Hasan has been in the advisory board of Janssen-Cilag, Lunbeck, Roche and Otsuka and has accepted paid speaking engagements for Janssen-Cilag, Lunbeck and Otsuka. T. Wobrock was a member of the Advisory Board of Janssen Cilag and Otsuka/Lundbeck and has accepted paid speaking engagements for Alpine Biomed, AstraZeneca, Bristol Myers Squibb, Eli Lilly, I3G, Glaxo-Smith-Kline, Janssen Cilag, Novartis, Lundbeck, Otsuka, Roche, Sanofi-Aventis and Pfizer. He has received a research grant from AstraZeneca, Cerbomed, I3G and AOK (health insurance company). In addition he received research support from The German Research Funding Organisation (DFG) and the Federal Ministry of Education and Research (BMBF). J. Cordes was a member of an advisory board of Roche, accepted travel or hospitality not related to a speaking engagement from Servier, support for symposia from Inomed, Localite, Magventure, Roche, Mag and More, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel and Diamedic, research and study participation funded by the German Research Foundation and the German Bundesministerium für Bildung und Forschung, Foundation European Group for Research In Schizophrenia, ACADIA Pharmaceuticals Inc., Boehringer Ingelheim Pharma GmbH and Co. KG, Otsuka Pharmaceutical Europe Ltd. and EnVivo Pharmaceuticals.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christian Schmidt-Kraepelin
    • 1
    Email author
  • Sandra Feyerabend
    • 1
  • Christina Engelke
    • 1
  • Mathias Riesbeck
    • 1
  • Eva Meisenzahl-Lechner
    • 1
  • Wolfgang Gaebel
    • 1
  • Pablo-Emilio Verde
    • 2
  • Henrike Kolbe
    • 2
  • Christoph U. Correll
    • 3
    • 4
    • 5
  • Stefan Leucht
    • 6
  • Stephan Heres
    • 6
    • 7
  • Michael Kluge
    • 8
  • Christian Makiol
    • 8
  • Andrea Neff
    • 9
  • Christina Lange
    • 9
  • Susanne Englisch
    • 10
    • 11
  • Mathias Zink
    • 10
    • 11
  • Berthold Langguth
    • 12
  • Timm Poeppl
    • 12
    • 13
  • Dirk Reske
    • 14
  • Euphrosyne Gouzoulis-Mayfrank
    • 14
  • Gerhard Gründer
    • 10
    • 13
  • Alkomiet Hasan
    • 15
  • Anke Brockhaus-Dumke
    • 16
  • Markus Jäger
    • 17
  • Jessica Baumgärtner
    • 18
  • Thomas Wobrock
    • 19
    • 20
  • Joachim Cordes
    • 1
    • 21
  1. 1.Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Clinic DüsseldorfHeinrich-Heine-University DuesseldorfDuesseldorfGermany
  2. 2.Coordination Center for Clinical Trials, Medical FacultyHeinrich-Heine-UniversityDuesseldorfGermany
  3. 3.Department of Psychiatry and Molecular MedicineDonald and Barbara Zucker School of Medicine at Hofstra/NorthwellHempsteadUSA
  4. 4.Northwell HealthThe Zucker Hillside Hospital, Psychiatry ResearchGlen OaksUSA
  5. 5.Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and PsychotherapyCharité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  6. 6.Department of Psychiatry and PsychotherapyTechnische Universität MünchenMunichGermany
  7. 7.kbo-Isar-Amper-Klinikum München-OstMunichGermany
  8. 8.Department of Psychiatry and PsychotherapyUniversity Hospital LeipzigLeipzigGermany
  9. 9.LVR-Klinikum LangenfeldLangenfeldGermany
  10. 10.Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental HealthUniversity of HeidelbergMannheimGermany
  11. 11.Department of Psychiatry and PsychotherapyUniversity Medical Center MainzMainzGermany
  12. 12.Department of Psychiatry and PsychotherapyUniversity of RegensburgRegensburgGermany
  13. 13.Department of Psychiatry, Psychotherapy and PsychosomaticsRWTH Aachen UniversityAachenGermany
  14. 14.LVR-Klinikum KölnCologneGermany
  15. 15.Department of Psychiatry and PsychotherapyKlinikum der Universität München, Ludwig-Maximilians-UniversityMunichGermany
  16. 16.Department of Psychiatry and Psychotherapy 1 und 2, Rheinhessen-Fachklinik AlzeyAcademic Hospital of the University of MainzAlzeyGermany
  17. 17.Department of Psychiatry II, Bezirkskrankenhaus GünzburgUlm UniversityGünzburgGermany
  18. 18.Department of Psychiatry, Psychotherapy and Psychosomatics, Bezirkskrankenhaus AugsburgUniversity AugsburgAugsburgGermany
  19. 19.Department of Psychiatry and PsychotherapyCounty Hospitals Darmstadt-DieburgGroß-UmstadtGermany
  20. 20.Department of Psychiatry and PsychotherapyGeorg-August-University GöttingenGöttingenGermany
  21. 21.Department of Psychiatry and Psychotherapy, Kaiserswerther DiakonieFlorence Nightingale HospitalDüsseldorfGermany

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