Safety Study of Sertindole Versus Risperidone Under Normal Conditions of Use

Study Overview
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Brief Summary
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The purpose of the study is to determine whether there is an increased all-cause mortality in sertindole-treated patients in comparison to patients treated with a well-known antipsychotic (risperidone) when used under normal marketed conditions in the treatment of schizophrenia.

Detailed Description
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The Committee for Medicinal Products for Human Use (CHMP) requested a post-marketing study to ascertain that the favourable benefit-risk profile and low mortality rates seen in the clinical studies with sertindole would not be offset by higher mortality rates when sertindole was used under more normal conditions of use. It was recognised that, in a clinical trial setting, strict patient selection and monitoring could lead to higher compliance in patient management and thereby to a lower mortality rate. Study 99824 was therefore designed in collaboration with the CHMP as an open-label, randomised study with minimum study management that focused on mortality and general patient safety. The duration of the treatment period was not fixed. No efficacy measures were included.

Official Title
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Sertindole Versus Risperidone Safety Outcome Study: a Randomised, Partially-blinded, Parallel-group, Active-controlled, Post-marketing Study

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Sertindole
* Drug: Risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has signed the Informed Consent Form or, if he/she is not able to sign it (according to the ICH GCP guidelines and the Declaration of Helsinki), the patient's legal representative has signed the Informed Consent Form The patient has been diagnosed with schizophrenia Based on the patient's clinical status, new or change of antipsychotic treatment is indicated The patient is at least 18 years of age The patient meets the criteria set out in the national SPCs for sertindole and risperidone. For those countries in which sertindole was not marketed, the EU SPC applied Exclusion Criteria: The last treatment taken by the patient was sertindole or risperidone The patient has never previously received any antipsychotic drug therapy The patient has contraindications to treatment with either sertindole or risperidone In addition to sertindole/risperidone, treatment with another antipsychotic is indicated The patient is homeless The patient has previously been included in one of the two H. Lundbeck A/S post-marketing studies, 99823 or 99824 The patient is, in the opinion of the investigator, unlikely to comply with the study protocol or unsuitable for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sertindole<br>Normally in the range of 4 to 20 mg/day | Drug: Sertindole<br>* Sertindole was supplied as 4, 12, 16, and 20 mg tablets. The start and maintenance dosages as well as dose titration were set by the investigator, in accordance with the national Summary of Product Characteristics (SPC) for sertindole; in countries where sertindole was not marketed, the European Union (EU) SPC applied (all national and EU SPCs were essentially identical). Recommended dose range: 12 to 20 mg/day. The investigators were instructed to contact H. Lundbeck A/S if they deemed it necessary to increase the dose of sertindole to 24 mg/day, which was allowed in exceptional cases<br>* Other names: Serdolect;|
| Active Comparator: Risperidone<br>Normally in the range of 2 to 8 mg/day | Drug: Risperidone<br>* Risperidone was supplied as 1, 2, 3, and 4 mg tablets. The start and maintenance dosages as well as dose titration were set by the investigator, in accordance with the national SPC for risperidone. Recommended dose range: 2 to 8 mg/day<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All-cause Mortality | The analysis was based on all deaths from the Whole Randomised Treatment (WRT)+30 days period and the Only Randomised Treatment (ORT) period, respectively | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Second Primary Outcome: Number of Participants With Cardiac Events, Including Arrhythmias, Requiring Hospitalisation | Second primary endpoint: a serious adverse event where the patient was hospitalised and for which the Independent Safety Committee (ISC) classified the event as a cardiac event with documented arrhythmia. The analysis of this outcome was not performed due to low number of events. The presented analysis is a replacement analysis using all cardiac events, including arrhythmias, that required hospitalisation | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cause-specific Mortality: Number of Participants With Cardiac Deaths - ISC | The analysis was based on all deaths from the WRT+30 days period using the classification performed by the ISC. The ISC reviewed and classified those adverse events which resulted in death or hospitalisation or were possible suicide attempts and this review was blinded to exposure. The definition of cardiac death was intentionally wide; sudden or unexplained deaths were assumed to be cardiac if there was no non-cardiac explanation. To ensure consistent evaluation and classification, the ISC decided a priori to classify all instances of self harm as possible suicide. | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Cause-specific Mortality: Number of Participants With Completed Suicides - ISC | The analysis was based on all deaths from the WRT+30 days period using the classification performed by the ISC. The ISC reviewed and classified those adverse events which resulted in death or hospitalisation or were possible suicide attempts and this review was blinded to exposure. The definition of cardiac death was intentionally wide; sudden or unexplained deaths were assumed to be cardiac if there was no non-cardiac explanation. To ensure consistent evaluation and classification, the ISC decided a priori to classify all instances of self harm as possible suicide. | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Cause-specific Mortality: Number of Participants With Other Than Cardiac Deaths and Completed Suicides - ISC | The analysis was based on all deaths from the WRT+30 days period using the classification performed by the ISC. The ISC reviewed and classified those adverse events which resulted in death or hospitalisation or were possible suicide attempts and this review was blinded to exposure. The definition of cardiac death was intentionally wide; sudden or unexplained deaths were assumed to be cardiac if there was no non-cardiac explanation. To ensure consistent evaluation and classification, the ISC decided a priori to classify all instances of self harm as possible suicide. | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Cause-specific Mortality: Number of Participants With Cardiac Deaths - MedDRA | The analysis was based on all deaths from the WRT+30 days period using the classification based upon the Medical Dictionary for Regulatory Activities (MedDRA) terminology, that is, as reported by the investigator | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Cause-specific Mortality: Number of Participants With Completed Suicides - MedDRA | The analysis was based on all deaths from the WRT+30 days period using the classification based upon MedDRA terminology, that is, as reported by the investigator | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Cause-specific Mortality: Number of Participants With Other Than Cardiac Deaths and Completed Suicides - MedDRA | The analysis was based on all deaths from the WRT+30 days period using the classification based upon MedDRA terminology, that is, as reported by the investigator | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Number of Participants With Suicide Attempts (Fatal and Non-fatal) - ISC | The analysis was based on all suicides and suicide attempts from the WRT+30 days period using the classification performed by the ISC. The ISC reviewed and classified those adverse events which resulted in death or hospitalisation or were possible suicide attempts and this review was blinded to exposure. The definition of cardiac death was intentionally wide; sudden or unexplained deaths were assumed to be cardiac if there was no non-cardiac explanation. To ensure consistent evaluation and classification, the ISC decided a priori to classify all instances of self harm as possible suicide. | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Number of Participants With Suicide Attempts (Fatal and Non-fatal) - MedDRA | The analysis was based on all suicides and suicide attempts from the WRT+30 days period using the classification based upon MedDRA terminology, that is, as reported by the investigator | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Number of Participants With Hospitalisations, Excluding Hospitalisations Related to the Primary Psychiatric Disease | The analysis was based on time from start of study drug to first hospitalisation during the WRT+30 days period | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months | 
| Number of Participants With Discontinuation of Treatment for Any Reason Other Than Study Closure | The analysis was based on time from start of study drug until stop of study drug for any reason other than sponsor closure of the study | As study design allowed patients to continue study drug until the study was closed, many patients were followed for several years, with an overall median time period of approximately 14 months |