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OPTiMiSE study: Optimisation of Treatment and Management of Schizophrenia in Europe

Background

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. This disappointing fact may be attributable to three major issues: first, a considerable minority of patients still does not respond sufficiently to current treatments ; second, patients who do respond to medication often discontinue it and relapse ; finally, even patients who do respond well to treatment and do adhere to it, continue to suffer from substantial cognitive and functional deficits severely limiting their potential. In order to improve this unsatisfactory result, this project aims to optimize current treatments in schizophrenia and explore novel therapeutic options for schizophrenia through two clinical trials. The first trial comprises a medication intervention component, a psychosocial intervention component, a biological predictor component and an MRI component. The second clinical trial consists of a comparison in safety and effectiveness between cannabidiol, placebo and olanzapine. Overall, the project 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.

OPTiMiSE is conducted in various sites across Europe and Israel. The project is funded as a Seventh Framework Program of the European Union, dedicated to the funding of research and technological development in Europe. Sponsor and coordinator of the project is prof. dr. R.S. Kahn, based at the University Medical Center Utrecht, the Netherlands.

Trial 1 – Study design

The first trial is an intervention study consisting of a medication intervention component (partly randomized, controlled, double-blind) followed by a psychosocial intervention component (randomized, controlled). Neuroimaging and biomarker assessments take place at various time points during the medication intervention component.



The medication intervention component starts with 4 weeks of open label treatment with amisulpride. At the end of 4 weeks treatment, remission criteria are assessed. Patients not meeting remission criteria will be randomized to 6 weeks double blind treatment with either amisulpride or olanzapine. Through this design, it is tested whether it is preferred to continue treatment for another 6 weeks or whether a medication switch is indicated by an insufficient response after 4 weeks of treatment. In case patients do not meet remission criteria after 6 weeks of double blind treatment, clozapine is initiated for another 12 weeks, providing the opportunity to study the application of clozapine relatively early in the illness course. During the medication intervention component, extensive blood sampling takes place at baseline and at the end of each study phase (after 4, 10 and 22 weeks) to study of a broad array of biological markers (DNA, metabolomics, proteomics and immunological markers) in order to predict response.

In a limited number of participating sites, MRI assessments take place at baseline to study the nature and prevalence of ‘organic’ pathology, as well as the predictive value of MRI assessments regarding treatment response. In three centers, MRS (spectroscopy) assessments are performed to test predictive value of glutamatergic markers.

Subsequent to the medication intervention component, patients can take part in the psychosocial intervention component. Patients are randomized to either Treatment as Usual or a package of psychosocial interventions consisting of access to a psychoeducational website for patients and family members, 6 sessions of Motivational Interviewing and sms reminders for taking medication (content and frequency to be determined by the patient). Treatment allocation is blind for the study rater.

Trial 1 - Objectives

The objectives of the first trial are: 1. To test applicability of amisulpride as the first step in a treatment algorithm. 2. To test guideline recommendation that non-responders to an antipsychotic drug benefit from a switch to an antipsychotic with a different receptor binding profile. 3. To provide the acceptability and outcome data on the application of clozapine in non-responding patients within the first 10 weeks of their treatment initiation. 4. To test if an IT-enabled psychosocial intervention can improve treatment adherence and global functional outcome in symptomatically remitted first-episode schizophrenia patients. 5. To test whether glutamatergic markers predict response to first and second line treatments. 6. To test if a combination of pharmacogenetic, proteomics- and metabolomic markers can provide clinical valuable predictive value. 7. To define the nature and prevalence of ’organic’ pathology in patients presenting with a first episode schizophreniform psychosis. 8. To determine the extent to which MRI measures at first presentation predict the therapeutic response to subsequent antipsychotic treatment.

Trial 1 - Study population

500 first episode schizophrenia patients, aged 18-40 years, are included at multiple (20-24) sites in 14 countries. Patients can only be included if they have used less than 2 weeks of antipsychotic medication in the year prior to inclusion and/or 6 weeks lifetime.

Trial 1 – Participating centers

University Medical Center Utrecht, the Netherlands King’s College London, United Kingdom Institut National de la Santé et de la Reserche Médicale, France University of Manchester, United Kingdom Technische Universität München (TUM), Germany Innsbruck University Clinics, Austria Charles University, Czech Republic Psychiatric University Centre Glostrup, Denmark Martin-Luther-University of Halle-Wittenberg, Germany Sheba Medical Centre, Israel University of Naples SUN, Italy University of Medical Sciences Poznan, Poland Tangent Data, Romania Servicio Madrileño de Salud (SERMAS), Spain Clienia Schlössli AG, Switzerland The Helmholtz Center Munich, Germany Melbourne Neuropsychiatry Centre, Australia

Trial 1 - Timelines

First patient entered treatment in May 2011 at the Denmark site. It is expected that the last patient will be included in February 2015. Final study reports will be completed by February 2016.

Trial 2 - Study design

The second trial is an intervention study consisting of a four-week, multicenter, double-blinded, randomized trial investigating efficacy and safety of cannabidiol in acute, early stage schizophrenic patients. Patients are randomized in a 1:1:1 ratio to four-week treatment with cannabidiol, placebo and active control through olanzapine. Cannabidiol is one of at least 85 cannabinoids found in cannabis. It is a major constituent of the plant, second to THC, and represents up to 40% in its extracts. Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia. Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA. The second trial includes various questionnaires (PANSS as primary outcome), metabolic parameters, side effect assessments as well as (optional) MRI, fMRI, lumbar puncture and PET. The trial is coordinated by dr. F.M. Leweke, based at the Central Institute of Mental Health in Mannheim, Germany. A previous trial from this research group found a significant decrease in symptom severity after 2 and 4 weeks purified cannabidiol treatment in acute paranoid schizophrenia patients, similar to the effect of amisulpride. In addition, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.

Trial 2 - Objectives

The objectives of the second trial are: 1. To evaluate the efficacy of cannabidiol (ECP012A) in alleviating the positive, negative and general symptoms of schizophrenia compared to olanzapine and placebo. 2. To compare the impact of cannabidiol (ECP012A) on metabolic functioning in comparison to placebo and olanzapine. 3. To quantify the incidence of extrapyramidal unwanted effects following cannabidiol (ECP012A) treatment in comparison to placebo and olanzapine; 4. To explore the relationship between symptom severity and plasma levels of cannabidiol and/or endocannabinoids. 5. To collect samples for biobanking for independent assessment of exploratory biomarkers using multiple x-omics

Trial 2 - Study population

150 first episode schizophrenia patients, aged 18-65 years, are included at 6 sites in 3 countries. Patients can only be included if they have a minimal PANSS score (indicating symptom severity) of 75 and the first diagnosis of psychosis is not older than 3 years.

Trial 2 - Participation centers

Central Institute of Mental Health, Germany University of Heidelberg, Germany Ludwig-Maximilians University Munich, Germany Technische Universität München (TUM), Germany Psychiatric University Centre Glostrup, Denmark Martin-Luther-University of Halle-Wittenberg, Germany Tangent Data, Romania

Trial 2 - Timelines

First patient is expected to enter the study beginning of 2014. It is projected that the last patient will be included in July 2015. Final study reports will be completed by February 2016.

Additional information, including study progress for both trials, can be found at the study website and the Clinical Trials database.