Obesity
Conditions
Keywords
Obesity, Sibutramine
Brief summary
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
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.
Interventions
DRUGSibutramine hydrochloride
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.)
DRUGPlacebo
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.)
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | From randomization up to 6 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Experiencing a POE or a Revascularization Procedure | From randomization up to 6 years | 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. |
| Risk of Experiencing a Nonfatal MI Included in the POE | From randomization up to 6 years | For each subject, the first occurrence of a nonfatal MI included in the POE was evaluated using time-to-event analysis. |
| Risk of Death From Any Cause (All-cause Mortality) | From randomization up to 6 years | For each subject who died, the time to death was evaluated using time-to-event analysis. |
| Risk of Experiencing a Resuscitated Cardiac Arrest Included in the POE | From randomization up to 6 years | For each subject, the time to first occurrence of a resuscitated cardiac arrest included in the POE was evaluated using time-to-event analysis. |
| Risk of Experiencing Cardiovascular Death Included in the POE | From randomization up to 6 years | For each subject, the time to cardiovascular death included in the POE was evaluated using time-to-event analysis. |
| Risk of Experiencing a Nonfatal Stroke Included in the POE | From randomization up to 6 years | For each subject, the time to first occurrence of a nonfatal stroke included in the POE was evaluated using time-to-event analysis. |
Countries
United States
Participant flow
Pre-assignment details
Of the 10777 subjects enrolled into the study, 33 were not treated with Lead-in Period sibutramine. Of the 10744 subjects who took at least 1 dose of Lead-in Period sibutramine, 939 were not randomized. One of the remaining 9805 subjects was not dispensed randomized study drug and was not included in the intent-to-treat population (N = 9804).
Participants by arm
| Arm | Count |
|---|---|
| Randomized Sibutramine Subjects who completed the 6-week Lead-in Period and who were randomized and dispensed sibutramine during the Treatment Period and continued standard care for weight management. If sibutramine was prematurely discontinued, subjects continued standard care for weight management during the Follow-up Period. | 4,906 |
| Randomized Placebo Subjects who completed the 6-week Lead-in Period and who were randomized and dispensed placebo during the Treatment Period and continued standard care for weight management. If placebo was prematurely discontinued, subjects continued standard care for weight management during the Follow-up Period. | 4,898 |
| Total | 9,804 |
Baseline characteristics
| Characteristic | Randomized Sibutramine | Randomized Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1866 Participants | 1901 Participants | 3767 Participants |
| Age, Categorical Between 18 and 65 years | 3040 Participants | 2997 Participants | 6037 Participants |
| Age Continuous | 63.2 years STANDARD_DEVIATION 6.09 | 63.3 years STANDARD_DEVIATION 6.15 | 63.2 years STANDARD_DEVIATION 6.12 |
| Cardiovascular (CV) risk group status CV + DM | 2906 Participants | 2901 Participants | 5807 Participants |
| Cardiovascular (CV) risk group status CV only | 759 Participants | 793 Participants | 1552 Participants |
| Cardiovascular (CV) risk group status DM only | 1207 Participants | 1178 Participants | 2385 Participants |
| Cardiovascular (CV) risk group status Unknown CV risk group status | 34 Participants | 26 Participants | 60 Participants |
| Region of Enrollment Australia | 384 participants | 385 participants | 769 participants |
| Region of Enrollment Brazil | 233 participants | 234 participants | 467 participants |
| Region of Enrollment Europe | 4160 participants | 4150 participants | 8310 participants |
| Region of Enrollment Mexico | 129 participants | 129 participants | 258 participants |
| Sex: Female, Male Female | 2099 Participants | 2055 Participants | 4154 Participants |
| Sex: Female, Male Male | 2807 Participants | 2843 Participants | 5650 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 425 / 10,744 | 2,063 / 4,904 | 1,977 / 4,881 |
Outcome results
Primary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on intent-to-treat (ITT) population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized. Subjects were also categorized into 1 of 3 prespecified CV risk groups: diabetes mellitus (DM) only, CV only, and CV + DM.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomized Sibutramine | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 561 Participants |
| Randomized Placebo | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 490 Participants |
| DM Only Randomized to Sibutramine | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 79 Participants |
| DM Only Randomized to Placebo | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 77 Participants |
| CV Only Randomized to Sibutramine | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 77 Participants |
| CV Only Randomized to Placebo | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 66 Participants |
| CV + DM Randomized to Sibutramine | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 403 Participants |
| CV + DM Randomized to Placebo | Risk of Experiencing a Primary Outcome Event (POE) (i.e., Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, Resuscitated Cardiac Arrest, Cardiovascular [CV] Death) | Intent-to-treat population | 346 Participants |
Comparison: For the sample size calculation, a two-tailed alpha level of 0.05 was used along with power of 90%. The annual composite event rate in the placebo arm was assumed to be 7.0%. A sample of 3983 subjects in each of the 2 groups, corrected for a 30% noncompliance rate (15% in Year 1 and 6.3% in each year, Years 2 to 4), followed for at least 3 years was expected to have 90% power to detect a relative risk reduction of 15% with sibutramine relative to placebo.p-value: 0.01595% CI: [1.029, 1.311]Log Rank
Comparison: This analysis included only subjects with DM only in a comparison of sibutramine and placebo.p-value: 0.94895% CI: [0.738, 1.384]Log Rank
Comparison: This analysis included only subjects with CV only in a comparison of sibutramine and placebo.p-value: 0.14995% CI: [0.916, 1.776]Log Rank
Comparison: This analysis included only subjects with CV + DM in a comparison of sibutramine and placebo.p-value: 0.02295% CI: [1.024, 1.365]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Death From Any Cause (All-cause Mortality) | 418 Participants |
| Randomized Placebo | Risk of Death From Any Cause (All-cause Mortality) | 404 Participants |
p-value: 0.54395% CI: [0.91, 1.196]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Experiencing a Nonfatal MI Included in the POE | 200 Participants |
| Randomized Placebo | Risk of Experiencing a Nonfatal MI Included in the POE | 159 Participants |
p-value: 0.02295% CI: [1.036, 1.571]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Experiencing a Nonfatal Stroke Included in the POE | 127 Participants |
| Randomized Placebo | Risk of Experiencing a Nonfatal Stroke Included in the POE | 95 Participants |
p-value: 0.02595% CI: [1.038, 1.767]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Experiencing a POE or a Revascularization Procedure | 927 Participants |
| Randomized Placebo | Risk of Experiencing a POE or a Revascularization Procedure | 856 Participants |
p-value: 0.05195% CI: [0.999, 1.204]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Experiencing a Resuscitated Cardiac Arrest Included in the POE | 11 Participants |
| Randomized Placebo | Risk of Experiencing a Resuscitated Cardiac Arrest Included in the POE | 7 Participants |
p-value: 0.34395% CI: [0.613, 4.081]Log Rank
Secondary
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.
Time frame: From randomization up to 6 years
Population: Analysis based on ITT population, which consists of all randomized subjects dispensed randomized study drug and grouped according to the intervention to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Sibutramine | Risk of Experiencing Cardiovascular Death Included in the POE | 223 Participants |
| Randomized Placebo | Risk of Experiencing Cardiovascular Death Included in the POE | 229 Participants |
p-value: 0.89995% CI: [0.822, 1.188]Log Rank