Safety Study of Sertindole Versus Risperidone Under Normal Conditions of Use - Full Text View

Purpose

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.

Condition	Intervention	Phase
Schizophrenia	Drug: Sertindole Drug: Risperidone	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	Sertindole Versus Risperidone Safety Outcome Study: a Randomised, Partially-blinded, Parallel-group, Active-controlled, Post-marketing Study

Resource links provided by NLM:

Genetics Home Reference related topics: schizophrenia

MedlinePlus related topics: Schizophrenia

Drug Information available for: Risperidone

U.S. FDA Resources

Further study details as provided by H. Lundbeck A/S:

Primary Outcome Measures:

Number of Participants With All-cause Mortality [ 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 ] [ Designated as safety issue: Yes ]
The analysis was based on all deaths from the Whole Randomised Treatment (WRT)+30 days period and the Only Randomised Treatment (ORT) period, respectively
Second Primary Outcome: Number of Participants With Cardiac Events, Including Arrhythmias, Requiring Hospitalisation [ 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 ] [ Designated as safety issue: Yes ]
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 Outcome Measures:

Cause-specific Mortality: Number of Participants With Cardiac Deaths - ISC [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 Other Than Cardiac Deaths and Completed Suicides - ISC [ 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 ] [ Designated as safety issue: Yes ]
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 Cardiac Deaths - MedDRA [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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 [ 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 ] [ Designated as safety issue: Yes ]
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


Enrollment:	9809
Study Start Date:	July 2002
Study Completion Date:	February 2008
Primary Completion Date:	February 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Sertindole Normally in the range of 4 to 20 mg/day	Drug: Sertindole 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 Other Name: Serdolect
Active Comparator: Risperidone Normally in the range of 2 to 8 mg/day	Drug: Risperidone 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 Other Name: Risperdal

Arms

Assigned Interventions

Experimental: Sertindole

Normally in the range of 4 to 20 mg/day

Drug: Sertindole

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

Other Name: Serdolect

Active Comparator: Risperidone

Normally in the range of 2 to 8 mg/day

Drug: Risperidone

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

Other Name: Risperdal

Detailed Description:

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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00856583

Sponsors and Collaborators

H. Lundbeck A/S

Investigators


Study Director:	Email contact via H. Lundbeck A/S	LundbeckClinicalTrials@lundbeck.com

More Information

Publications:

Peuskens J, Tanghøj P, Mittoux A; Sertindole Cohort. The Sertindole Cohort Prospective (SCoP) study: rationale, design and methodology. Pharmacoepidemiol Drug Saf. 2008 May;17(5):425-33. doi: 10.1002/pds.1594.

Thomas SH, Drici MD, Hall GC, Crocq MA, Everitt B, Lader MH, Le Jeunne C, Naber D, Priori S, Sturkenboom M, Thibaut F, Peuskens J, Mittoux A, Tanghøj P, Toumi M, Moore ND, Mann RD. Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP). Acta Psychiatr Scand. 2010 Nov;122(5):345-55. doi: 10.1111/j.1600-0447.2010.01563.x.

Crocq MA, Naber D, Lader MH, Thibaut F, Drici M, Everitt B, Hall GC, Le Jeunne C, Mittoux A, Peuskens J, Priori S, Sturkenboom M, Thomas SH, Tanghøj P, Toumi M, Mann R, Moore ND. Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone. Eur Neuropsychopharmacol. 2010 Dec;20(12):829-38. doi: 10.1016/j.euroneuro.2010.09.001.

De Hert M, Mittoux A, He Y, Peuskens J. Metabolic parameters in the short- and long-term treatment of schizophrenia with sertindole or risperidone. Eur Arch Psychiatry Clin Neurosci. 2011 Jun;261(4):231-9. doi: 10.1007/s00406-010-0142-x. Epub 2010 Sep 5.

De Hert M, Mittoux A, He Y, Peuskens J. A head-to-head comparison of sertindole and risperidone on metabolic parameters. Schizophr Res. 2010 Nov;123(2-3):276-7. doi: 10.1016/j.schres.2010.07.030. Epub 2010 Aug 21.


Responsible Party:	H. Lundbeck A/S
ClinicalTrials.gov Identifier:	NCT00856583 History of Changes
Other Study ID Numbers:	99824 2004-000213-19
Study First Received:	March 5, 2009
Results First Received:	May 4, 2011
Last Updated:	August 18, 2011
Health Authority:	Austria: Agency for Health and Food Safety Belgium: Federal Agency for Medicinal Products and Health Products Bulgaria: Bulgarian Drug Agency Croatia: Agency for Medicinal Product and Medical Devices Czech Republic: State Institute for Drug Control Denmark: Danish Medicines Agency Estonia: The State Agency of Medicine Finland: Finnish Medicines Agency France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Greece: Ministry of Health and Welfare Hong Kong: Department of Health Hungary: National Institute of Pharmacy India: Drugs Controller General of India Italy: National Monitoring Centre for Clinical Trials - Ministry of Health Latvia: State Agency of Medicines Lithuania: State Medicine Control Agency - Ministry of Health Luxembourg: Ministère de la Santé Malaysia: Ministry of Health Netherlands: Medicines Evaluation Board (MEB) Norway: Norwegian Medicines Agency Philippines: Bureau of Food and Drugs Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Portugal: National Pharmacy and Medicines Institute Romania: National Medicines Agency Russia: FSI Scientific Center of Expertise of Medical Application Serbia and Montenegro: Agency for Drugs and Medicinal Devices Singapore: Clinical Trials & Epidemiology Research Unit (CTERU) Slovakia: State Institute for Drug Control South Korea: Korea Food and Drug Administration (KFDA) Spain: Spanish Agency of Medicines Sweden: Medical Products Agency Switzerland: Swissmedic Taiwan: National Bureau of Controlled Drugs Thailand: Food and Drug Administration Turkey: Ministry of Health Ukraine: Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:


Schizophrenia Schizophrenia Spectrum and Other Psychotic Disorders Mental Disorders Risperidone Sertindole Serotonin Antagonists Serotonin Agents Neurotransmitter Agents	Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Antipsychotic Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Dopamine Antagonists Dopamine Agents

ClinicalTrials.gov processed this record on September 28, 2016

Safety Study of Sertindole Versus Risperidone Under Normal Conditions of Use (SCoP)