Safety Study of Sertindole Versus Risperidone Under Normal Conditions of Use

H. Lundbeck A/S9,809 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

9,809

Conditions

Schizophrenia

Interventions

SertindoleDRUG

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

RisperidoneDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: 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

Secondary Outcomes

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.

Cause-specific Mortality: Number of Participants With Completed Suicides - ISC

Data from ClinicalTrials.gov

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Cause-specific Mortality: Number of Participants With Other Than Cardiac Deaths and Completed Suicides - ISC

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

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

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

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.

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

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

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