A Long Term Study of Sibutramine and the Role of Obesity Management in Relation to Cardiovascular Disease in Overweight and Obese Patients

Study Overview
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Brief Summary
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The purpose of the study was to determine the long-term effect of sibutramine treatment on cardiovascular outcomes in overweight and obese patients at risk of a cardiovascular event.

Detailed Description
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The study consisted of 4 periods: 1) a Screening Period of approximately 2 weeks; 2) a 6-week Lead-in Period, during which subjects received single-blind sibutramine and country-specific standard of care for weight management. Subjects who discontinued study drug treatment during the Lead-in Period were not randomized and did not participate in the double-blind Treatment Period or the Follow-up Period; 3) a double-blind Treatment Period in which subjects were randomized to 1 of the 2 treatment groups and were followed until the study ended; and 4) a double-blind Follow-up Period, during which randomized subjects who discontinued study drug were followed until the study ended. The Randomization Phase consisted of the double-blind Treatment Period and the double-blind Follow-up Period. Subjects received country-specific standard of care for weight management during the Randomization Phase. An independent events adjudication committee evaluated all potential cardiovascular outcome events and confirmed the outcome events and time of onset to be included in the statistical analyses.

Official Title
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Sibutramine Cardiovascular Morbidity/Mortality Outcomes Study in Overweight or Obese Subjects at Risk of a Cardiovascular Event

Conditions
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Obesity

Intervention / Treatment
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* Drug: Sibutramine hydrochloride
* Drug: Placebo
* Drug: Sibutramine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's body mass index (BMI) was >= 27 kg/m(2) and <= 45 kg/m(2) or their BMI was >= 25 kg/m(2) and < 27 kg/m(2) with waist circumference of >= 102 cm in males or >= 88 cm in females. Medical history positive for: Preexisting cardiovascular disease (i.e., coronary artery disease, cerebrovascular disease, or peripheral arterial occlusive disease) and/or Type 2 diabetes mellitus with at least 1 other risk factor (i.e., dyslipidemia, controlled hypertension, current smoker, or diabetic nephropathy with evidence of microalbuminuria) Exclusion Criteria: History of recent myocardial infarction. Heart failure symptoms greater than New York Heart Association Functional Class II. Hemodynamically significant valvular or left ventricular (LV) tract obstruction. Subjects without a pacemaker and with any of the following: Sinus bradycardia (< 50 bpm) Sick sinus syndrome Atrioventricular block of more than 1st degree Mean sitting systolic blood pressure (SBP) > 160 mmHg. Mean sitting diastolic blood pressure (DBP) > 100 mmHg. Mean sitting heart rate (HR) > 100 bpm. Syncopal episodes presumed to be due to uncontrolled life-threatening arrhythmias. Planned cardiac surgery or coronary angioplasty within 6 months of screening. History of recent non-hemorrhagic stroke or transient ischemic attack (TIA), history of hemorrhagic stroke. Hyperthyroidism. Known chronic liver disease or endstage renal disease. Severe, symptomatic benign prostatic hyperplasia which may require surgery. Known pheochromocytoma, history of narrow angle glaucoma, Gilles de la Tourette syndrome, history of seizures, history of bariatric or abdominal obesity surgery (excluding liposuction). Concomitant use of monoamine oxidase inhibitors or drugs that increase levels of serotonin in the brain. Treated hypertension stabilized for less than 3 months. Inability to perform regular physical activity.

Ages Eligible for Study
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Minimum Age: 55 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sibutramine<br>Subjects were randomized to receive sibutramine 10 mg once daily (QD) during the Treatment Period after a 6-week Lead-in Period | Drug: Sibutramine hydrochloride<br>* One 10 mg tablet QD plus country-specific standard care for weight management. (During the Treatment Period, the dose could have been titrated up to 15 mg at the investigator's discretion.)<br>* Other names: Reductil;|
| Placebo Comparator: Placebo<br>Subjects were randomized to receive placebo QD during the Treatment Period after a 6-week Lead-in Period | Drug: Placebo<br>* 1 tablet QD plus country-specific standard care for weight management (During the Treatment Period, the dose could have been titrated up to 15 mg at the investigator's discretion.)<br>|
| Experimental: Lead-in sibutramine<br>All subjects received 10 mg sibutramine QD during a 6-week Lead-in Period | Drug: Sibutramine hydrochloride<br>* 10 mg tablet QD during the 6-week Lead-in Period plus country-specific standard care for weight management<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | For each subject, POE status (with/without an event) and time to first occurrence of a POE using time-to-event analysis were evaluated. All POE confirmed by an independent adjudication committee were included in the analysis. | From randomization up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk of Death From Any Cause (All-cause Mortality) | For each subject who died, the time to death was evaluated using time-to-event analysis. | From randomization up to 6 years | 
| Risk of Experiencing a POE or a Revascularization Procedure | This outcome includes nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, CV death (including events such as fatal MI and fatal stroke), and any of the following revascularization procedures: percutaneous transluminal coronary angioplasty, coronary artery bypass graft, coronary artery stent placement, cardiac transplant, peripheral vascular bypass or angioplasty, and carotid endarterectomy. For each subject, the POE or revascularization status (yes/no) and time to first occurrence of an event using time-to-event analysis were evaluated. | From randomization up to 6 years | 
| Risk of Experiencing a Nonfatal MI Included in the POE | For each subject, the first occurrence of a nonfatal MI included in the POE was evaluated using time-to-event analysis. | From randomization up to 6 years | 
| Risk of Experiencing a Nonfatal Stroke Included in the POE | For each subject, the time to first occurrence of a nonfatal stroke included in the POE was evaluated using time-to-event analysis. | From randomization up to 6 years | 
| Risk of Experiencing a Resuscitated Cardiac Arrest Included in the POE | For each subject, the time to first occurrence of a resuscitated cardiac arrest included in the POE was evaluated using time-to-event analysis. | From randomization up to 6 years | 
| Risk of Experiencing Cardiovascular Death Included in the POE | For each subject, the time to cardiovascular death included in the POE was evaluated using time-to-event analysis. | From randomization up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Sibutramine