Optimization of Treatment and Management of Schizophrenia in Europe

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is optimising current treatments in schizophrenia and explore novel therapeutic options for schizophrenia. The study intends to both address basic, but so far unanswered, questions in the treatment of schizophrenia and develop new interventions. It is expected that the project will lead to evidence that is directly applicable to treatment guidelines, and will identify potential mechanisms for new drug development.

Detailed Description
-----------------
Despite nearly fifty years of pharmacological and psychosocial research, the overall prognosis of schizophrenia has improved only marginally. While the efficacy of most antipsychotic medication is generally uncontested, their overall functional impact has been modest. In order to improve this unsatisfactory result, this study aims to optimize current treatments in schizophrenia and explore novel therapeutic options for schizophrenia. The study comprises a medication intervention component, a psychosocial intervention component, a biological predictor component and an MRI component. MRI assessments are performed at baseline, and used to determine whether potential organic causes for psychotic symptoms are present, and to test prospective value of these assessments for subsequent treatment response. MRI assessments of healthy volunteers will be included to test for deviations in patients' assessments; these volunteers will not participate in any other protocol procedure. The medication intervention component comprises a first 4-week phase of amisulpride treatment. Non-responders will subsequently be randomised to a 6-week double blind phase on either amisulpride or olanzapine. Patients who classify as non-responders at the end of this phase, a 12-week open label treatment with clozapine is initiated. Patients who classify as a responder in phase I, II or III, are drop outs or who are non-responders at the end of phase III flow to the psychosocial intervention component of the study. During this part, several interventions are tested, aimed to increase treatment compliance and keep patients on the medication to which they've responded well. Through the biological predictor component, it is determined whether glutamatergic markers predict response to first and second line treatments, and if an empirical combination of pharmacogenetic, proteomics- and metabolomic markers can provide clinical valuable predictive value.

Official Title
-----------------
Optimization of Treatment and Management of Schizophrenia in Europe

Conditions
-----------------
Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder

Intervention / Treatment
-----------------
* Drug: Amisulpride open label
* Drug: 6-week amisulpride double blind treatment
* Drug: 6-week olanzapine double blind treatment
* Drug: 12-week clozapine open-label treatment
* Behavioral: Psychosocial intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of schizophrenia as defined by DSM-IV-R as determined by the M.I.N.I.plus Age 18 or older. The first psychosis occurred at least one year and no more than 7 years ago.* If patients are using an antipsychotic drug, a medication switch is currently under consideration. Capable of providing written informed consent. Exclusion Criteria: Intolerance / hypersensitivity to one of the drugs (including active substances, metabolites and excipients) in this study including oral risperidone, paliperidone and aripiprazole and/or hypersensitivity to risperidone. Pregnancy or lactation. Patients who are currently using clozapine. Patients who do not fully comprehend the purpose or are not competent to make a rational decision whether or not to participate. Patients with a documented history of non-response and/or intolerance to any of the study medications and/or a documented history of non-response to a treatment with one of the study drugs of at least 6 weeks within the registered dose range. Forensic patients. Patients who have been treated with an investigational drug within 30 days prior to screening. Simultaneous participation in another intervention study (neither medication or psychosocial intervention).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Phase I: 1 arm 'amisulpride open label'<br>For 4 weeks, all patients will be treated with amisulpride open label. | Drug: Amisulpride open label<br>* 4-week open label amisulpride treatment<br>|
| Active Comparator: Phase II: 'amisulpride double blind'<br>Patients who do not meet remission criteria during phase I (4 weeks open label amisulpride), flow to phase II where they are randomised to 1 of 2 6-week double blind treatment arms, one of which is 'amisulpride double blind' | Drug: 6-week amisulpride double blind treatment<br>* 6-week amisulpride double blind treatment<br>|
| Active Comparator: Phase II 'olanzapine double blind'<br>Patients who do not meet remission criteria during phase I (4 weeks open label amisulpride), flow to phase II where they are randomised to 1 of 2 6-week double blind treatment arms, one of which is 'olanzapine double blind' | Drug: 6-week olanzapine double blind treatment<br>* 6-week olanzapine double blind treatment<br>|
| Other: Phase III: 1 arm 'clozapine open label'<br>Patients who do not meet remission criteria during phase II (6-week double blind amisulpride vs olanzapine), flow to phase III, where only 1 arm is available: 'clozapine open label' | Drug: 12-week clozapine open-label treatment<br>* 12-week clozapine open-label treatment<br>|
| Experimental: Psychosocial intervention<br>Patients who meet remission criteria during any of the phases of the medication component, patients who drop out of the medication component and patients who did not meet remission criteria at the end of the medication component, will flow to the psychosocial intervention component, where they are randomised to 1 of 2 arms, one of which is the 'Psychosocial Intervention' arm. | Behavioral: Psychosocial intervention<br>* Psychosocial intervention<br>|
| No Intervention: Psychosocial Intervention phase: 'TAU'<br>Patients who meet remission criteria during any of the phases of the medication component, patients who drop out of the medication component and patients who did not meet remission criteria at the end of the medication component, will flow to the psychosocial intervention component, where they are randomised to 1 of 2 arms, one of which is the 'Treatment as usual' arm. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PANSS | Study consists of multiple components, each with their own objectives. For this (medication) component: number of patients in remission, based on PANSS scores (criteria of Andreasen et al.; 2005) after 4 weeks open label amisulpride, after 6 weeks double blind amisulpride or olanzapine and after 12 weeks of open label clozapine. | Jan 2016 | 
| Sellwood rating scale | Psychosocial intervention component, objective A: drug adherence rates as a function of (standardized self report and) Sellwood rating scales after 12 and 52 weeks. | Jan 2016 | 
| Biological profile | Biological predictors component, objective A: drug response (remission vs non-remission) as a function of biological profile, after 4 weeks, 10 weeks and 22 weeks (after each medication phase). | jan 2016 | 
| MRS measures | Biological predictors component, objective B: using MRS scans, differences between responders and non-responders in regional glutamate levels a) at baseline and b) between baseline and after one month of treatment with amisulpiride. | jan 2016 | 
| SOFAS global functioning | Psychosocial intervention component, objective B: drug adherence rates as a function of standardized global functioning (SOFAS score after 1 year) following psychosocial intervention vs treatment as usual. | jan 2016 | 
| MRI assessments | MRI component objective: the percentage of first episode patients that show radiological abnormalities suggestive of neurological disorders which may explain the occurrence of psychotic symptoms - measurement at baseline only. | jan 2016 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause treatment discontinuation | The different components of the study have their own secondary objectives: Medication component has multiple secondary objectives, most important one is all-cause treatment discontinuation after 4 weeks, 10 weeks and 22 weeks. Number and reason for premature discontinuations (treatment discontinuation) of the amisulpride and the olanzapine group will be compared (after 10 weeks). | jan 2016 | 
| All cause discontinuation | Psychosocial intervention component has multiple secondary objectives, most important one is all-cause treatment discontinuation between treatment groups after 12 and 52 weeks. | jan 2016 | 
| Biological markers | Biological predictors component has multiple secondary objectives, most important one is the ability of biological markers to predict response to antipsychotic and treatment tolerability in schizophrenia, after 4, 10 and 22 weeks. | jan 2016 | 
| MRI assessments | The ability of MRI to predict response to antipsychotic treatment in schizophrenia, after 4, 10 and 22 weeks. | jan 2016 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Schizophrenia, Schizophreniform disorder, Schizoaffective disorder, Imaging, Prognosis, Treatment guidelines, Pharmacogenetics