Effect of Naltrexone Hydrochloride ER and Bupropion Hydrochloride ER Combination (Contrave®/Mysimba®) on Major Adverse Cardiovascular Events (MACE)

Study Overview
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Brief Summary
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A randomized, double-blinded, placebo controlled study intended to capture cardiovascular outcomes during real-world use of naltrexone/bupropion (NB).

Detailed Description
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This multi-center, prospective, randomized, pragmatic, double-blinded study has been designed to capture CV outcomes during the real-world use of NB after initial randomization. The aim of the study is to assess whether patients receiving treatment with NB are at an elevated risk of experiencing MACE compared with patients receiving placebo. Both patient groups will also be counselled to lose weight via a reduced-calorie diet and increased physical activity.

Official Title
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Phase IV Pragmatic Randomized Controlled Study to Assess the Effect of Naltrexone Hydrochloride Extended Release (ER) and Bupropion Hydrochloride ER Combination (Contrave®/Mysimba®) on the Occurrence of Major Adverse Cardiovascular Events

Conditions
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Obesity

Intervention / Treatment
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* Drug: Naltrexone-Bupropion (NB) Combination
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age ≥18 years at screening Able to understand the key components of the study, as described in the written informed consent document, and willing and able to provide written informed consent BMI ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of at least 1 weight-related comorbidity (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia) At increased risk of adverse cardiovascular outcomes: In the opinion of the investigator, has a high likelihood of cardiovascular disease with at least 1 of the following: History of documented MI >90 days prior to screening History of coronary revascularization (ie, coronary artery bypass graft surgery, stent placement, percutaneous transluminal coronary angioplasty, or laser atherectomy) >90 days prior to screening History of carotid or peripheral revascularization (ie, carotid endarterectomy, lower extremity atherosclerotic disease atherectomy, repair of abdominal aorta aneurysm, femoral or popliteal bypass) >90 days prior to screening Angina with ischemic changes (resting echocardiogram (ECHO), 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 or Type 2 diabetes mellitus with at least 2 of the following: Hypertension (controlled with or without pharmacotherapy at <145/95 mmHg) Dyslipidemia requiring pharmacotherapy Documented low HDL cholesterol (<50 mg/dL in women or <40 mg/dL in men) within the prior 12 months Current tobacco smoker Patients who have completed a 2-week washout period of the prohibited concomitant medication(s) at screening Exclusion Criteria: Using prescription medications, other than Contrave/Mysimba, or surgical or medical device interventions for weight loss History of MI or stroke within 90 days prior to screening Uncontrolled hypertension, defined as systolic BP ≥160 mmHg and/or >100 mmHg diastolic BP on the average of 3 seated BP measurements after the patient has been at rest for at least 5 minutes Confirmed end-stage renal disease (ie, a degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate [<15 mL/minute/1.73 m2] and other manifestations including increased serum creatinine), severe hepatic impairment (Child-Pugh score 10 to 15 [Class C]), or hemodynamic instability, including patients with severe heart failure (New York Heart Association Class IV) Seizure disorders or history of seizures Use of other bupropion-containing products (including but not limited to Wellbutrin, Wellbutrin SR, Wellbutrin XL, and Aplenzin) Active anorexia nervosa or bulimia Chronic opioid or opiate agonist (eg, methadone) or partial agonists (eg, buprenorphine) use, or acute opioid withdrawal or has a positive urine drug result for opioids at screening Undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs Concomitant administration of MAOIs. This also includes use of reversible MAOIs, such as linezolid or intravenous methylene blue. At least 14 days should elapse between discontinuation of MAOIs and initiation of treatment with Contrave/Mysimba. Known allergy to bupropion, naltrexone, or any other component of Contrave/Mysimba Pregnant or nursing Known life-threatening arrythmias, including Brugada syndrome

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Naltrexone/Bupropion (NB)<br>Patients will be randomly assigned to NB (naltrexone 8 mg and bupropion 90 mg) extended-release oral tablet. | Drug: Naltrexone-Bupropion (NB) Combination<br>* A total daily dosage of two NB 8 mg/90 mg tablets twice daily (32 mg/360 mg) is reached at the start of Week 4.<br>|
| Placebo Comparator: Placebo<br>Patients will be randomly assigned to placebo. | Drug: Placebo<br>* A total daily dosage of two placebo tablets twice daily (in an identical, non-medicine containing tablet) is reached at the start of Week 4.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Cardiovascular Death | Occurrence of cardiovascular death in number of study patients receiving NB compared with number of study patients receiving placebo. | Treatment initiation through 1 year following treatment termination. | 
| Occurrence of Non-fatal Myocardial Infarction (MI) | Occurrence of MI in number of study patients receiving NB compared with number of study patients receiving placebo. MI will be identified using current standard diagnostic criteria, such as the 2017 Cardiovascular and Stroke Endpoints Definitions for Clinical Trials. | Treatment initiation through 1 year following treatment termination. | 
| Occurrence of Non-fatal Stroke | Occurrence of non-fatal stroke in number of study patients receiving NB compared with number of study patients receiving placebo. Stroke will be identified using current standard diagnostic criteria, such as the 2017 Cardiovascular and Stroke Endpoints Definitions for Clinical Trials. | Treatment initiation through 1 year following treatment termination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparative Rates of Cardiovascular Death | Comparative rates of cardiovascular death between number of study patients receiving NB compared to number of study patients receiving placebo. | Treatment initiation through 1 year following treatment termination. | 
| Comparative Rates of Non-fatal Myocardial Infarction (MI) | Comparative rates of non-fatal MI between number of study patients receiving NB compared to number of study patients receiving placebo. | Treatment initiation through 1 year following treatment termination. | 
| Comparative Rates of Non-fatal Stroke | Comparative rates of non-fatal stroke between number of study patients receiving NB compared to number of study patients receiving placebo. | Treatment initiation through 1 year following treatment termination. |