Obesity, Overweight
Conditions
Keywords
Body Weight, Bupropion, Cardiovascular Diseases, Diabetes Mellitus, Diabetes Mellitus, Type 2, Endocrine System Diseases, Glucose Metabolism Disorders, Heart Diseases, Metabolic Diseases, Narcotic Antagonists, Naltrexone, Nutrition Disorders, Obesity, Overnutrition, Overweight
Brief summary
The purpose of this study is to determine the effects of NB relative to placebo on major adverse cardiovascular events (MACE) such as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in overweight and obese subjects who are at a higher risk of having these events because they have diabetes and/or other cardiovascular risk factors.
Interventions
DRUGNB32
Naltrexone SR 32 mg/Bupropion SR 360 mg/day. Administered in addition to the weight management program.
DRUGPBO
Placebo. Administered in addition to the weight management program.
BEHAVIORALWeight Management Program
A comprehensive weight management program will be administered in addition to the subject's study medication assignment. The program includes internet counseling by an accredited health and fitness professional and a nutrition and exercise program with goal setting and educational and tracking tools.
Sponsors
Orexigen Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥50 years of age (women) or ≥45 years of age (men) 2. Body mass index (BMI) ≥27 kg/m2 and ≤50 kg/m2 3. Waist circumference ≥88 cm (women) or ≥102 cm (men) 4. At increased risk of adverse cardiovascular outcomes: * Cardiovascular disease (confirmed diagnosis or at high likelihood of cardiovascular disease) with at least one of the following: * History of documented myocardial infarction \>3 months prior to screening * History of coronary revascularization * History of carotid or peripheral revascularization * Angina with ischemic changes (resting ECG), ECG changes on a graded exercise test (GXT), or positive cardiac imaging study * Ankle brachial index \<0.9 (by simple palpation) within prior 2 years * ≥50% stenosis of a coronary, carotid, or lower extremity artery within prior 2 years AND/OR * Type 2 diabetes mellitus with at least 2 of the following: * Hypertension (controlled with or without pharmacotherapy at \<145/95 mm Hg) * Dyslipidemia requiring pharmacotherapy * Documented low HDL cholesterol (\<50 mg/dL in women or \<40 mg/dL in men) within prior 12 months * Current tobacco smoker
Exclusion criteria
1. Myocardial infarction within 3 months prior to screening 2. Angina pectoris Grade III or IV as per the Canadian Cardiovascular Society grading scheme 3. Clinical history of cerebrovascular disease (stroke) 4. History of tachyarrhythmia other than sinus tachycardia 5. Planned bariatric surgery, cardiac surgery, or coronary angioplasty 6. History of seizures (including febrile seizures), cranial trauma, or other conditions that predispose the subject to seizures 7. History of mania or current diagnosis of active psychosis, active bulimia or anorexia nervosa (binge eating disorder is not exclusionary) 8. Any condition with life expectancy anticipated to be less than 4 years (e.g., congestive heart failure NYHA Class 3 or 4)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Confirmed Occurrence of Major Adverse Cardiovascular Event (MACE) | Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up | The primary endpoint is the time from randomization to the first confirmed occurrence of any event within the primary MACE composite (defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Due to early termination of the study, pre-planned 50% interim analysis is considered the primary analysis for outcome measures. The pre-planned 50% interim analysis was conducted when 50% of the total planned MACE were observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke, or Nonfatal Unstable Angina Requiring Hospitalization | Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up | Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures. |
| Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death (Including Fatal Myocardial Infarction, Fatal Stroke) | Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up | Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures. |
| Percentage of Participants With a Confirmed Occurrence of Myocardial Infarction (Nonfatal or Fatal) | Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up | Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures. |
| Percentage of Participants With a Confirmed Occurrence of Stroke (Nonfatal or Fatal) | Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up | Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NB32 NB32: Naltrexone SR 32 mg/Bupropion SR 360 mg/day. Administered in addition to the weight management program.
Weight Management Program: A comprehensive weight management program will be administered in addition to the subject's study medication assignment. The program includes internet counseling by an accredited health and fitness professional and a nutrition and exercise program with goal setting and educational and tracking tools. | 4,455 |
| Placebo Administered in addition to the weight management program.
Weight Management Program: A comprehensive weight management program will be administered in addition to the subject's study medication assignment. The program includes internet counseling by an accredited health and fitness professional and a nutrition and exercise program with goal setting and educational and tracking tools. | 4,450 |
| Total | 8,905 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized but not dispensed study med | 1 | 4 |
Baseline characteristics
| Characteristic | NB32 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1482 Participants | 1397 Participants | 2879 Participants |
| Age, Categorical Between 18 and 65 years | 2973 Participants | 3053 Participants | 6026 Participants |
| Age, Continuous | 61.1 years STANDARD_DEVIATION 7.27 | 60.9 years STANDARD_DEVIATION 7.38 | 61.0 years STANDARD_DEVIATION 7.33 |
| Baseline Antidepressant Medication Use | 1042 Participants | 1015 Participants | 2057 Participants |
| Body Mass Index (BMI) | 37.2 kg/m^2 STANDARD_DEVIATION 5.26 | 37.4 kg/m^2 STANDARD_DEVIATION 5.44 | 37.3 kg/m^2 STANDARD_DEVIATION 5.35 |
| Cardiovascular (CV) risk group CV disease without T2DM (type 2 diabetes mellitus) | 670 Participants | 646 Participants | 1316 Participants |
| Cardiovascular (CV) risk group CV disease with T2DM | 745 Participants | 801 Participants | 1546 Participants |
| Cardiovascular (CV) risk group T2DM without CV disease | 3039 Participants | 3002 Participants | 6041 Participants |
| Dyslipidemia No | 355 Participants | 380 Participants | 735 Participants |
| Dyslipidemia Yes | 4100 Participants | 4070 Participants | 8170 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 279 Participants | 291 Participants | 570 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4174 Participants | 4156 Participants | 8330 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| History of Depression No | 3424 Participants | 3455 Participants | 6879 Participants |
| History of Depression Yes | 1031 Participants | 995 Participants | 2026 Participants |
| Hypertension No | 293 Participants | 333 Participants | 626 Participants |
| Hypertension Yes | 4162 Participants | 4117 Participants | 8279 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 20 Participants | 31 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 27 Participants | 46 Participants |
| Race (NIH/OMB) Black or African American | 656 Participants | 648 Participants | 1304 Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 25 Participants | 51 Participants | 76 Participants |
| Race (NIH/OMB) White | 3738 Participants | 3698 Participants | 7436 Participants |
| Region of Enrollment United States | 4455 Participants | 4450 Participants | 8905 Participants |
| Sex: Female, Male Female | 2437 Participants | 2419 Participants | 4856 Participants |
| Sex: Female, Male Male | 2018 Participants | 2031 Participants | 4049 Participants |
| Weight | 105.6 kilogram STANDARD_DEVIATION 19.09 | 106.3 kilogram STANDARD_DEVIATION 19.18 | 106.0 kilogram STANDARD_DEVIATION 19.14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,157 / 4,455 | 282 / 4,450 |
| serious Total, serious adverse events | 463 / 4,455 | 386 / 4,450 |
Outcome results
Primary
Percentage of Participants With a Confirmed Occurrence of Major Adverse Cardiovascular Event (MACE)
The primary endpoint is the time from randomization to the first confirmed occurrence of any event within the primary MACE composite (defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Due to early termination of the study, pre-planned 50% interim analysis is considered the primary analysis for outcome measures. The pre-planned 50% interim analysis was conducted when 50% of the total planned MACE were observed.
Time frame: Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up
Population: Intent-to-treat (ITT) population is defined as subjects who undergo randomization into the Treatment Period (TP) and are dispensed study medication. Treatment refers to the treatment assigned during TP randomization rather than the actual treatment received. ITT population is the primary analysis population for the primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NB32 | Percentage of Participants With a Confirmed Occurrence of Major Adverse Cardiovascular Event (MACE) | 90 Participants |
| Placebo | Percentage of Participants With a Confirmed Occurrence of Major Adverse Cardiovascular Event (MACE) | 102 Participants |
99.7% CI: [0.57, 1.34]
Secondary
Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death (Including Fatal Myocardial Infarction, Fatal Stroke)
Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures.
Time frame: Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up
Population: Intent-to-treat (ITT) population is defined as subjects who undergo randomization into the Treatment Period (TP) and are dispensed study medication. Treatment refers to the treatment assigned during TP randomization rather than the actual treatment received. ITT population is the primary analysis population for the primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NB32 | Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death (Including Fatal Myocardial Infarction, Fatal Stroke) | 17 Participants |
| Placebo | Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death (Including Fatal Myocardial Infarction, Fatal Stroke) | 34 Participants |
99.7% CI: [0.21, 1.19]
Secondary
Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke, or Nonfatal Unstable Angina Requiring Hospitalization
Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures.
Time frame: Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up
Population: Intent-to-treat (ITT) population is defined as subjects who undergo randomization into the Treatment Period (TP) and are dispensed study medication. Treatment refers to the treatment assigned during TP randomization rather than the actual treatment received. ITT population is the primary analysis population for the primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NB32 | Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke, or Nonfatal Unstable Angina Requiring Hospitalization | 133 Participants |
| Placebo | Percentage of Participants With a Confirmed Occurrence of Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke, or Nonfatal Unstable Angina Requiring Hospitalization | 142 Participants |
99.7% CI: [0.66, 1.33]
Secondary
Percentage of Participants With a Confirmed Occurrence of Myocardial Infarction (Nonfatal or Fatal)
Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures.
Time frame: Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up
Population: Intent-to-treat (ITT) population is defined as subjects who undergo randomization into the Treatment Period (TP) and are dispensed study medication. Treatment refers to the treatment assigned during TP randomization rather than the actual treatment received. ITT population is the primary analysis population for the primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NB32 | Percentage of Participants With a Confirmed Occurrence of Myocardial Infarction (Nonfatal or Fatal) | 55 Participants |
| Placebo | Percentage of Participants With a Confirmed Occurrence of Myocardial Infarction (Nonfatal or Fatal) | 57 Participants |
99.7% CI: [0.55, 1.67]
Secondary
Percentage of Participants With a Confirmed Occurrence of Stroke (Nonfatal or Fatal)
Due to early termination of the study, the pre-planned 50% interim analysis is considered the primary analysis for outcome measures.
Time frame: Confirmed occurrence of event between Day 1 (randomization) and up to a maximum of 4 years of follow-up
Population: Intent-to-treat (ITT) population is defined as subjects who undergo randomization into the Treatment Period (TP) and are dispensed study medication. Treatment refers to the treatment assigned during TP randomization rather than the actual treatment received. ITT population is the primary analysis population for the primary and secondary endpoints.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NB32 | Percentage of Participants With a Confirmed Occurrence of Stroke (Nonfatal or Fatal) | 22 Participants |
| Placebo | Percentage of Participants With a Confirmed Occurrence of Stroke (Nonfatal or Fatal) | 21 Participants |
99.7% CI: [0.43, 2.55]