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2016-0880

Research Proposal

Project Title: 
Incidence of death and other SAEs related to second generation antipsychotic or placebo treatment in RCTs - a systematic review and meta-analysis
Scientific Abstract: 

Background: Antipsychotic drugs are the mainstay for the treatment of schizophrenia, but are also very important and widely used therapeutic options for the treatment of several other psychiatric diseases and disorders. In the community of patients, professionals and scientists it is currently a highly discussed topic, if their application is associated with a decreased or increased risk of serious adverse events including death. Up to date analysis are based on observational studies with inherent methodological problems.
Study Design: We are working on a systematic review including a large meta-analysis of randomized controlled trials to evaluate and differentiate the risk of death and other serious adverse events related to antipsychotic drug treatment or no treatment of mental dsorders.
Participants: Participants of randomized placebo-controlled trials of second generation antipsychotic drugs irrespective of indication, age or gender.
Main Outcome Measures: incidence rates of serious adverse events including death.
Statistical Analysis: Odds ratios and their 95% confidence intervals will be calculated and combined in pairwise meta-analysis.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Brief Project Background and Statement of Project Significance: 

Antipsychotic drugs are the mainstay for the treatment of schizophrenia, but are also very important and widely used therapeutic options for the treatment of several other psychiatric diseases and disorders. In the community of patients, professionals and scientists it is currently a highly discussed topic, if their application is associated with a decreased or increased risk of serious adverse events including death.
Up to date analysis are based on observational studies with inherent methodological problems.
To reach a high level of precision and confidence about these rare but very important outcomes, analyses on the basis of randomized populations and high number of participants are required. We are planning to achieve this goal by conducting by a big size meta-analyses of RCT comparing SGAs as a groups to placebo over all indications.

Please find attached our successfull application for a grant from the German ministry of education and research (BMBF) for further details concerning the relevance of our project and references to prior work.

Specific Aims of the Project: 

The aims of this project are to examine whether antipsychotic drugs increase the risk for death and other serious adverse events, to further evaluate the differential incidence of specific serious adverse events in pharmacologically treated (SGA-drug-group) and non treated (placebo-group) patients suffering from mental disorders and to find out which patient or treatment related factor are associated with their occurence.

Main hypothesis (two sided ): There is an overall significant difference in mortality and incidence of serious adverse events in antipsychotic drug trials between the verum and the placebo group.

The same two sided hypothesis will be used for all identified specific serious adverse events.

Subgroup analysis will incude antipsychotic drug used, diagnostic subgroup, age, gender, drug combination, dosage.
We expect the state of treatment (active antipsychotic treatment or placebo) to be the main predictor.
Other potential predictors that will be adressed in subgroup analysis are specific antipsychotic drug, diagnostic subgroup, age, gender, combination of drugs, dosage.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

What is the purpose of the analysis being proposed? Please select all that apply.: 
New research question to examine treatment safety
Confirm or validate previously conducted research on treatment safety
Summary-level data meta-analysis
Summary-level data meta-analysis pooling data from YODA Project with other additional data sources
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 

Systematic review and meta-analysis:

Search strategy: We ran electronic searches in the databases MEDLINE, EMBASE, Cochrane Central Register of Randomised Trials (CENTRAL), BIOSIS, CINAHL, Dissertation Abstracts, LILACS, PSYNDEX, PsycINFO). Additionally we contacted all SGA-marketing pharma companies for missing relevant data.

inclusion criteria: Participants of randomized placebo-controlled clinical trials of second generation antipsychotic drugs irrespective of underlying mental disease, age or gender.

Included SGAs are amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone and zotepine. First generation antipsychotics will only be evaluated if they are used as additional active comparator.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Main Outcome Measure and how it will be categorized/defined for your study: 

The main outcome measure is the incidence of serious adverse events in the drug group and the placebo group.
The effect size measure will be the odds ratio (OR) and its 95% confidence intervals (CIs). We will calculate the number needed to treat to provide benefit /to induce harm, and its 95% confidence intervals (CIs). Analyses will be carried out in accordance to the ‘intention-to-treat’ principal when possible (‘once randomized always analyze’). As all outcomes of interest (serious adverse events) are rare we will assume for those who have been lost to follow-up that they will not have had the outcome (unless it occurred before dropping out), because other strategies would overestimate the risk because the outcomes are rare.

If data is available, we will calculate incidence rates per mean time in study to control for different periods of observation in the drug and the placebo group.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: 

We expect the state of treatment (active antipsychotic treatment or placebo) to be the main predictor.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: 

Other potential predictors that will be adressed in subgroup analysis are specific antipsychotic drug, diagnostic subgroup, age, gender, combination of drugs, dosage.

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Statistical Analysis Plan: 

Pairwise meta-analyses within a Bayesian framework will be used to estimate the summary comparative effect sizes. All outcomes will be dichotomous and be primarily analysed as odds ratios, supplemented by NNT/NNH. Special statistical attention in terms of data synthesis and heterogeneity assessment will be paid to the fact that events will be rare. Predefined subgroups analyses will address: diagnostic subgroup, age, gender, antipsychotic drug used, antipsychotic combinations, dose. Publication bias will be examined with funnel-plot methods, recommendations will be made with GRADE.
The following sensitivity analyses of the primary outcome are planned a priori: a) random-effects instead of fixed effects model, b) exclusion of open RCTs, c) exclusion of studies that used doses higher than in the official labels (“off-label doses”).

Please find attached our successfull application to the German ministry of education and research (BMBF) and the PROSPERO protocol for further information.

Narrative Summary: 

Antipsychotic drugs are the mainstay for the treatment of schizophrenia, but are also very important and widely used therapeutic options for the treatment of several other psychiatric diseases and disorders. In the community of patients, professionals and scientists it is currently a highly discussed topic, if their application is associated with a decreased or increased risk of serious side effects including death.
Since these serious outcomes are fortunately rare, this can only be answered by analyses including high numbers of patients. We are tackling this issue therefore by a big size meta-analysis comparing antipsychotic drugs as a group to placebo in RCTs over all indications.

Project Timeline: 

Start of project: 09/2015
First contact of data holders: 11/2015
Actual state of the project: identification of included RCTs from literature search and data extraction.

It is planned to finish data extraction and to start data analysis by 07/2016
First data presentations and publications are planned for the following month.

According to the framework of our grant, there is a deadline for data presentation in 03/2017.

Dissemination Plan: 

We will produce a very large review with approximately 50000 participants. The research question is a priority for patients with schizophrenia and it is important for many other psychiatric patient groups for which antipsychotics have indications or are used “off-label”. Therefore, it is likely that we will be able to publish the results in a general medicine journal with high visibility such as the BMJ or the Lancet in which other reviews of our group have already been published [29, 30, 31, 32]. It can be expected that our findings will be rapidly implemented in national and international treatment guidelines. For example, Stefan Leucht is a member of the group producing the schizophrenia and depression guidelines of the German national psychiatric association (DGPPN) and of the British Association of Psychopharmacology, and he is leading the schizophrenia guideline group of the Collegium Internationale Psychopharmacologicum (CINP).
For references and further information please find attached our successfull application for a grant from the german ministry of education.

Bibliography: 

For references and further information please find attached our successfull application for a grant from the german ministry of education.

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