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Research Proposal

Project Title: 
Safety of Risperidone and Paliperdone in schizophrenia and bipolar disorder diagnosed patients - a systematic review and meta-analysis
Scientific Abstract: 

Background: Risperidone and Paliperidone are two mainstay anti-psychotic drugs for treating schizophrenia and other mental health problems like bipolar disorder. However, among the research community, there is rising concerns about serious adverse events such as 'gynecomastia' and rare muscle related side-effects ‘extrapyramidal effects’.

Objective: As existing evidence about the safety of both drugs is based upon data from journal publications, which likely to lead to under reporting of harms. We aim to do a more robust meta-analysis using CSRs.

Study Design: We will carry out a robust and exhaustive systematic review including a large meta-analysis of RCTs to evaluate the safety of risperidone and paliperidone for use in patients with schizophrenia or bipolar disorder.

Participants: Participants of RCTs of risperidone or paliperidone irrespective of dose, age or gender and involving patient populations with schizophrenia and bipolar disorder.

Main Outcome Measures: Serious adverse events or adverse events and death related incidences. Patient safety narratives and listings will be used to assess causality.

Statistical Analysis: Relative risks, risk differences and their 95% confidence intervals will be calculated and combined in traditional pairwise meta-analysis. Sensitivity analysis will also be performed using Peto-OR, and more advance methods such as the beta-binomial model and Bayesian meta-analysis which are considered better for handling heterogeneity when the event rate is rare.

Please find attached PROSPERO protocol (CRD42019140556)

Brief Project Background and Statement of Project Significance: 

Risperidone and Paliperdone are mainstay treatment for people with schizophrenia and bipolar disorder. However, amongst the research community, there have been rising concerns about serious adverse events such as 'gynecomastia' and 'extrapyramidal effects' that have been linked with the use of Risperidone and Paliperdone. The current evidence on the safety of both drugs is based upon data from journal publications, which are susceptible to high levels of reporting bias and publication bias. Clinical study reports offer an untapped source of data and are far better suited to assess the safety profiles of pharmacological interventions. Therefore, to reach a level of precision and confidence about these serious adverse events and rare outcomes, a more robust meta-analysis using CSRs is required. We plan to achieve this goal by using the data from CSRs on Risperidone and Paliperdone trials available at YODA, and by making additional freedom of information requests at the European medicines agency (EMA).

Specific Aims of the Project: 

The aims of the project are to examine whether the antipsychotic drugs Risperidone and Paliperdone increase the risk of SAEs for patients suffering from schizophrenia and other mental health problems like bipolar disorder, and to determine whether treatment-related factors are associated with their occurrence.

Main hypothesis: There is an overall significant difference in serious adverse events in the Risperidone or Paliperdone group compared to placebo group.

The same hypothesis test will be used for all identified serious adverse events.

Subgroup analysis will include diagnostic subgroup, age (under 18s), gender, drug combination, dosage from the patient safety listings.

Please find attached PROSPERO protocol (CRD42019140556) for further information.

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

Study design: Systematic review and meta-analysis of RCTs.

Search strategy: We ran extensive searches in the electronic databases Cochrane Schizophrenia Groups Trials Register and CENTRAL, MEDLINE, EMBASE, BIOSIS, CINAHL, LILACS and PsycINFO. Additionally, we contacted all risperidone and paliperdone-marketing pharma companies for missing relevant data. The ‘’ and ‘’ will be searched to identify any potential unpublished trials. Medical Reviews at the Drugs@FDA and European Public Assessment Reports were checked for any further missing data. For trials that were not accessible via YODA, the CSRs were request via the EMA.

Inclusion criteria: Participants of randomised controlled trials of risperidone or paliperdone treated for schizophrenia and bipolar disorder.

Please find attached PROSPERO protocol (CRD42019140556) for further information.

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

The main outcome measure is the number(s) of serious adverse events in the treatment group and placebo group. The effect size measure will be the odd ratio, relative risk, risk difference and its 95% confidence intervals. We will calculate the number needed to treat to provide benefit/to induce harm, and its 95% CIs. All serious adverse events of interest will be assessed in the meta-analysis. In addition, rare adverse events will be analyzed in a sensitivity analysis involving more advanced methods including Peto-odds ratio, and more advanced methods like the beta-binomial model and Bayesian meta-analysis.

Longer-term outcomes will be assessed in a sensitivity analysis with the trials that had greater length of follow-up. Incidence rates will be calculated if the mean times are available.

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

The state of the treatment (risperidone, paliperdone or placebo) will be the main predictor.

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 addressed in the subgroup analysis include diagnostic subgroup (schizophrenia/bipolar), age (younger children or adolescents), gender, risperidone vs. paliperdone, combination of other drugs and dosage.

Statistical Analysis Plan: 

Because of the novelty and size of clinical study reports (including appendices listing data) we subdivided the extraction, appraisal, and analysis of the data into a two stage exercise. We included trials meeting our inclusion criteria (that is, had an appropriate study design) in stage 1. Trials not meeting our inclusion criteria (for example, open label studies) were not included in stage 1. In stage 1 we assessed the reliability and completeness of the identified trial data. This allowed us to identify missing important text or data. To aid us in determining completeness of the relevant parts of clinical study reports we constructed an extraction form based on the CONSORT-harms statement checklist and expert opinion from the research team.

We decided to only include data in stage 2 of the review (full analysis following standard Cochrane methods) if they satisfied the following three criteria:
1. Completeness: clinical study reports include identifiable CONSORT harms statement specified methods to enable replication of the study. Identifiable CONSORT harms statement specified results (safety results in the core report, tables of adverse and serious adverse events, appendices with serious adverse event narratives (E3 sections 12.3.1, 12.3.2 & 14.3.3) and individual participant safety listings (E3 section 16.2.7) and CRFs for SAEs and withdrawals for AEs (E3 Section 16.3.1)) should be available. A comparison table checklist will be used to support this decision.
2. Internal consistency: all parts (for example, denominators) of the same clinical study reports or unpublished reports are consistent.
3. External consistency: consistency of data as reported in regulatory documents, other versions of the same clinical study reports or unpublished reports, and other references, established by cross-checking.

The analysis will become clearer after stage 1 when we have assessed the state of the reports. An initial plan is outlined below:

Adverse events and Serious adverse events will be assessed by pooling the relative risk (RR) across trials. Effect estimates will be pooled across trials using Mantel-Haenszel fixed or random-effect meta-analysis dependent upon the number of studies reporting the outcome of interest. If there are less than five trials reporting the outcome, then we will use the fixed-effect approach as recommended in the Cochrane handbook. Initial sensitivity analysis was also performed pooling the relative difference instead of RR for rare events (Bradburn et al 2007, Sweating et al 2002). However, because adverse events are likely to be sparse, we will include the peto-odds ratio approach as this has been found to be more effective method for analysing rare event outcomes. We will also calculate the number needed to treat to provide benefit/to induce harm, and its 95% CIs.

Heterogeneity was assessed visually in the forest plots and the I² statistics will be compared between the CSR-based and the journal publication-based analyses to determine the magnitude of heterogeneity. I² values greater than 50% we interpreted as considerable levels of heterogeneity. Publication bias will be examined with funnel-plots (trim-and-fill), and the Cochrane risk of bias and GRADE assessment tool will be used to assess the quality of the studies.

Narrative Summary: 

Risperidone and Paliperdone are antipsychotic-drugs approved for the treatment of schizophrenia in adults and adolescents, and for the short-term treatment of manic or mixed episodes of bipolar disorder. However, over the last decade there have been a rising number of cases of hormonal imbalances leading to breast tissue development and infertility in boys and girls. To date, meta-analysis of both drugs in schizophrenic patients have solely been based on published RCTs, involving adults, and analyzed using standard methods of meta-analysis. We propose a more robust assessment of the safety of both drugs, using more innovative methodologies involving Clinical Study Reports (CSRs).

Project Timeline: 

Start of project: 05/2019
First contact of data holders: 06/2019
Actual state of project: Identification of included RCTs from literature search and reported SAEs.

It is planned, that the data extraction and statistical analysis will start by 04/2020

Conference presentations and publication drafts are planned for the preceding months.

Dissemination Plan: 

We are performing a very large systematic review involving over 60,000 participants with a robust meta-analysis incorporating CSRs, narratives, patient safety listings and CRFs. The research question is a priory for patients with schizophrenia and bipolar indications and is in line with recent NIHR health technology assessment funding calls to research the safety of anti-psychotic interventions. Therefore, we anticipate that we would look to publish our results in a leading medical journal such as the BMJ or the Lancet in which collaborators with this study have already published. Furthermore, we expect our findings would be translated and implemented into national and international treatment guidelines and through policy involvement with mental health (with specific focus on schizophrenia and bipolar disorder).


• References related to risperidone and pailiperdone with the indications of interest:

1. Komossa, K., et al., Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev, 2011(1): p. Cd006626.
2. Leucht, S., et al., Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet. 373(9657): p. 31-41.
3. Alvir , J.M.J., et al., Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States. New England Journal of Medicine, 1993. 329(3): p. 162-167.
4. Edwards, J.G., Risperidone for schizophrenia. BMJ, 1994. 308(6940): p. 1311-1312.
5. Bishop, J.R. and M.N. Pavuluri, Review of risperidone for the treatment of pediatric and adolescent bipolar disorder and schizophrenia. Neuropsychiatr Dis Treat, 2008. 4(1): p. 55-68.
6. Picchioni, M.M. and R.M. Murray, Schizophrenia. BMJ, 2007. 335(7610): p. 91-95.
7. Anderson, I.M., P.M. Haddad, and J. Scott, Bipolar disorder. BMJ, 2012. 345.
8. Samara, M.T., et al., Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis. JAMA Psychiatry, 2016. 73(3): p. 199-210.
9. Leucht, S., et al., Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet, 2009. 373(9657): p. 31-41.
10. Kay, S.R., A. Fiszbein, and L.A. Opler, The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull, 1987. 13(2): p. 261-76.
11. Woods, S.W., et al., Effects of Development on Olanzapine-Associated Adverse Events. Journal of the American Academy of Child & Adolescent Psychiatry, 2002. 41(12): p. 1439-1446.
12. Stanniland, C. and D. Taylor, Tolerability of atypical antipsychotics. Drug Saf, 2000. 22(3): p. 195-214.
13. Drugwatch. Risperdal: Schizophrenia, Bipolar ADHD Drug uses & side effects. Last accessed 20th October 2016. Available at:
14. Wang, B., et al., Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis. PLoS ONE, 2016. 11(3): p. e0152195.
15. Gilbody, S.M., et al., Risperidone versus other atypical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev, 2000(3): p. Cd002306.
16. Hughes, S., D. Cohen, and R. Jaggi, Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study. BMJ Open, 2014. 4(7).
17. Carpenter , W.T.J. and R.W. Buchanan Schizophrenia. New England Journal of Medicine, 1994. 330(10): p. 681-690.

• Methodological references when using clinical study reports:

1. Jones M, Jefferson T, Doshi P, Hodkinson A et al. When to include clinical study reports and regulatory documents in systematic reviews. BMJ Evidence-Based Medicine 2018; 23:210-217.
2. Hodkinson A, Jefferson T, Doshi P, Heneghan C. The use of clinical study reports to enhance the quality of systematic reviews: A survey of systematic review authors. Systematic Reviews (2018) 7:117
3. Hodkinson A, Gamble C, Tudur Smith C. Reporting of harms outcomes: A comparison of journal publications with unpublished clinical study reports of orlistat trials. Trials 2016 17;207.
4. Rodgers Mark A, Brown Jennifer V E, Heirs Morag K, Higgins Julian P T, Mannion Richard J, Simmonds Mark C et al. Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion BMJ 2013; 346 :f3981
5. Jefferson T, Doshi P, Hodkinson A, et al. (2018). Interim guidance on the inclusion of clinical study reports and other regulatory documents in Cochrane Reviews – Interim report. Cochrane methods innovation fund 2. Available:
6. Jefferson Tom, Jones Mark, Doshi Peter, Spencer Elizabeth A, Onakpoya Igho, Heneghan Carl J et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments BMJ 2014; 348 :g2545
7. Doshi P, Jefferson T.Clinical study reports ofrandomised controlled trials:an exploratory review ofpreviously confidential industryreports.BMJOpen2013;3:e002496. doi:10.1136/bmjopen-2012-002496
8. Eyding Dirk, Lelgemann Monika, Grouven Ulrich, Härter Martin, Kromp Mandy, Kaiser Thomas et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ 2010; 341 :c4737
9. Maund Emma, Tendal Britta, Hróbjartsson Asbjørn, Jørgensen Karsten Juhl, Lundh Andreas, Schroll Jeppe et al. Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial

Supplementary Material: 

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