Comparison of Antipsychotic Combination Treatment of Olanzapine and Amisulpride to Monotherapy (COMBINE)

A Randomized Double-blind Controlled Trial to Assess the Benefits of Olanzapine and Amisulpride Combination Treatment in Acutely Ill Schizophrenia Patients. - COMBINE

A study to examine whether an antipsychotic combination treatment of olanzapine and amisulpride is more effective than olanzapine and amisulpride alone.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Amisulpride; Drug: Olanzapine and Amisulpride; Drug: Olanzapine

Detailed Description

Polypharmacy in antipsychotic therapy is an important issue when treating patients with schizophrenia. It is not well confirmed that a combination of two antipsychotic drugs lead to therapeutic benefit in contrast to monotherapy. However there is a highly frequent practice of combining atypical non-clozapine treatment that could be due to potential benefits when seeking alternatives to a high rate of non-response in acute phase. Therefore there is a need for further trials of sufficient power to address efficacy and safety issues of this regimen. Combining two selected atypical drugs in a complementary way may minimize side-effects and enhance efficacy. In order to specify these advantages it is intend to examine approaches to combination treatment: Amisulpride and olanzapine show complementing receptor binding profiles and have shown to have efficacy and good tolerability when administered in combination in retrospective studies. The object of this trial is to study whether acutely ill patients with combination of amisulpride and olanzapine are more frequently in symptomatic remission after 8 weeks than those with olanzapine or amisulpride monotherapy.

• Study Type: Interventional
• Enrollment (Actual): 328
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • RWTH Aachen
  • Alzey, Germany, 55232
    • Rheinhessen Fachklinik Alzey
  • Andernach, Germany, 56626
    • Rhein-Mosel-Fachklinik Andernach
  • Augsburg, Germany, 89156
    • Bezirkskliniken Schwaben, Bezirkskrankenhaus Augsburg
  • Berlin, Germany, 10117
    • Charite-Universitatsmedizin Berlin
  • Dortmund, Germany, 44281
    • LWL-Klinik Dortmund
  • Düsseldorf, Germany, 40629
    • LVR-Klinikum Düsseldorf
  • Groß-Umstadt, Germany, 64823
    • Zentrum für Seelische Gesundheit Kreiskliniken Darmstadt-Dieburg Standort: Groß-Umstadt
  • Göttingen, Germany, 37075
    • Universitätsmedizin Göttingen
  • Günzburg, Germany, 89312
    • Klinik für Psychiatrie, Psychotherapie und Psychosomatik am Bezirkskrankehaus Günzburg
  • Hannover, Germany, 30625
    • Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie Medizinische Hochschule Hannover (MHH)
  • Heidelberg, Germany, 69115
    • Universitätsklinikum Heidelberg
  • Köln, Germany, 51109
    • LVR-Klinikum Köln
  • Langenfeld, Germany, 40764
    • LVR-Klinik Langenfeld
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig, Klinik und Poliklinik für Psychiatrie und Psychotherapie
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz Klinik für Psychiatrie und Psychotherapie
  • Mannheim, Germany, 68159
    • Zentralinstitut für seelische Gesundheit
  • München, Germany, 80336
    • LMU Munchen
  • München, Germany, 81675
    • TU München
  • Regensburg, Germany, 93053
    • Bezirksklinikum Regensburg, Klinik für Psychiatrie und Psychotherapie
  • Würzburg, Germany, 97080
    • Universitätsklinikum Würzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with schizophrenia and schizoaffective disorder according to International Classification of Diseases (ICD-10);
• age 18-65;
• Positive and Negative Symptom Scale Total-Score ≥ 70 and two items of the positive symptom subscale ≥4.
• voluntary treatment after written informed consent
• legal capacity
• exclusion of pregnancy by laboratory test (Beta HCG)

Exclusion Criteria:

• participation in other interventional studies with drugs or medical devices
• first episode patients
• physical disease that might have effects on the conduct or evaluation of the trial
• contraindications to medication according to experts information
• oversensitivity to active substance or other component of the drugs used
• known clozapine resistance
• suicidal ideation
• pregnancy or lactation
• which of pregnancy or absence save contraception
• dependency to sponsor or investigator
• institutionalization through judicial or regulatory order
• oversensitivity to placebo (mannite/aerosil)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Olanzapine or Placebo	Drug: Amisulpride; 200-800 mg milligram(s)per day for 16 weeks; Other Names: Amisulprid Hexal; Drug: Olanzapine and Amisulpride; Zyprexa: Coated tablet 5-20 mg milligram(s) per day for 16 weeks Amisulpride: Coated tablet 200-800 mg milligram(s)per day for 16 weeks; Other Names: Zyprexa, Amisuprid Hexal
Active Comparator: Amisulpride or Placebo	Drug: Olanzapine and Amisulpride; Zyprexa: Coated tablet 5-20 mg milligram(s) per day for 16 weeks Amisulpride: Coated tablet 200-800 mg milligram(s)per day for 16 weeks; Other Names: Zyprexa, Amisuprid Hexal; Drug: Olanzapine; Coated tablet 5-20 mg milligram(s) per day for 16 weeks; Other Names: Zyprexa
Active Comparator: Olanzapine and Amisulpride	Drug: Amisulpride; 200-800 mg milligram(s)per day for 16 weeks; Other Names: Amisulprid Hexal; Drug: Olanzapine; Coated tablet 5-20 mg milligram(s) per day for 16 weeks; Other Names: Zyprexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic improvement of schizophrenia after 8 weeks of treatment in comparison to time of inclusion of patient measured py Positive and Negative Symptom Scale (PANSS)	Whether there is a symptomatic improvement of schizophrenia after 8 weeks of treatment in comparison to time of inclusion of patient measured py Positive and Negative Symptom Scale (PANSS)	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic improvement of schizophrenia after 16 weeks of treatment in comparison to time of inclusion of patient measured py PANSS total score reduction	To study whether a combination treatment of olanzapine and amisulpride show a PANSS total score reduction from baseline to week 16.	16 weeks.
Symptomatic improvement of schizophrenia from baseline to week 2 up to week 16 measured by PANSS total score reduction.	Whether a combination treatment of olanzapine and amisulpride show a PANSS total score reduction from baseline to every 2 weeks up to week 16.	Every 2 weeks up to week 16.
PANSS total score reduction from baseline to week 2 as a predictor of the change after 8 weeks	Whether a change of PANSS total score reduction from baseline to week 2 is a predictor of the change after 8 weeks	8 weeks
Serious adverse drug reactions	Frequency and severity of serious adverse drug reactions	16 weeks
Change of clinical condition measured by Clinical Global Impression Scale (CGI scale)	Whether there is a change of clinical condition measured by Clinical Global Impression Scale (CGI scale)	every 2 weeks from baseline up to week 16
Change of the subjective well-being measured by Subjective Wellbeing under Neuroleptics Scale (SWN-K)	Whether there is a change of the subjective well-being measured by Subjective Wellbeing under Neuroleptics Scale(SWN-K)	between week 0, 8, 16

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Investigators: Principal Investigator: Christian Schmidt-Kraepelin, Dr., Heinrich-Heine University, Duesseldorf

Publications and helpful links

General Publications

• Schmidt-Kraepelin C, Feyerabend S, Engelke C, Riesbeck M, Meisenzahl-Lechner E, Verde PE, Correll CU, Kluge M, Makiol C, Neff A, Lange C, Englisch S, Zink M, Langguth B, Poeppl TB, Reske D, Gouzoulis-Mayfrank E, Gründer G, Hasan A, Brockhaus-Dumke A, Jäger M, Baumgärtner J, Leucht S, Cordes J; COMBINE Study Group. Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial. Lancet Psychiatry. 2022 Apr;9(4):291-306. doi: 10.1016/S2215-0366(22)00032-3. Epub 2022 Mar 8.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2012
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: May 23, 2012
• First Submitted That Met QC Criteria: May 29, 2012
• First Posted (Estimate): May 31, 2012

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 15, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: schizophrenia; olanzapine; polypharmacy; amisulpride
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Olanzapine; Amisulpride
• Other Study ID Numbers: COMBINE