Naltrexone/Bupropion Cardiovascular Outcomes Study

Inclusion Criteria: 1\. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2\. Participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 3\. Has body mass index (BMI) ≥27.0 kg/m\^2 at Screening. 4. Is male or female and aged ≥18 years at Screening. 5. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent through 12 weeks after the last dose of study medication. 6\. Participant meets at least 1 the following categories of cardiovascular (CV) disease (a-c): 1. Documented coronary artery disease (at least 1 of the following 2 criteria must be satisfied): 1. A documented history of myocardial infarction (MI) occurring greater than 3 months prior to Screening. 2. History of coronary revascularization with at least 1 of the following: 1. Coronary artery bypass graft surgery occurring greater than 3 months prior to Screening. 2. Percutaneous coronary intervention (PCI) occurring greater than 3 months prior to Screening. 2. Documented peripheral arterial disease (at least 1 of the following 3 criteria must be satisfied): 1. Current intermittent claudication or verified ischemic ulcer(s) together with documented ankle-brachial index ≤0.85. 2. History of previous vascular intervention for intermittent claudication or resting limb ischemia greater than 3 months prior to Screening (example: amputation for arterial disease, peripheral bypass, or history of angioplasty/stenting). 3. History of symptomatic carotid artery disease (requiring revascularization with carotid endarterectomy or stenting) greater than 3 months prior to Screening or ≥50% stenosis on at least one carotid artery documented by duplex ultrasonography, magnetic resonance angiography, computed tomographic angiography, or catheter-based contrast angiography. 3. Documented cerebrovascular disease (at least 1 of the following 2 criteria must be satisfied): 1. A history of transient ischemic attack confirmed by a neurologist greater than 3 months prior to Screening and clinically and neurologically stable at Screening. 2. A history of ischemic stroke (with a Modified Rankin Scale Score ≤3) greater than 3 months prior to Screening and clinically and neurologically stable at Screening. Exclusion Criteria: 1. Has received any investigational compound or investigational device within 3 months prior to Screening. 2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 3. Has had an MI or unstable angina within 3 months of Screening. 4. Has planned bariatric surgery, cardiac surgery, coronary revascularization, or peripheral artery revascularization. 5. Has history of bariatric surgery (eg, Roux-en-Y gastric bypass, duodenal switch, or sleeve gastrectomy). 6. Has had a procedure for weight loss other than bariatric surgery (eg, gastric banding or any other devices that maybe used in obesity treatment) within past 12 months prior to Screening. 7. Has a history of hypersensitivity or allergies to any component of naltrexone hydrochloride (HCl) and bupropion HCl extended release combination (NB) or excipients. 8. Has a history of cancer that has been in remission for \<5 years prior to Screening. A history of basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin is allowed. 9. Is hemodynamically unstable, including severe heart failure (New York Heart Association Class IV) at Screening. 10. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 2 years prior to Screening. 11. Has been randomized into a previous NB (Contrave) study or has been exposed to commercially available NB (Contrave) for any period of time prior to Screening. 12. Is taking excluded medications within 28 days of Screening. 13. Has uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mm Hg and/or ≥100 mm Hg diastolic blood pressure (DBP) on the average of two seated blood pressure measurements after being at rest at least 5 minutes, confirmed on 2 separate days during the Screening Period. 14. Has severe renal impairment defined by estimated glomerular filtration rate (eGFR) \<30 ml/min/1.73 m\^2 based on the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) at Screening. 15. Has a clinical history of liver failure. 16. Has a known infection with human immunodeficiency virus that is being treated with ritonavir, lopinavir or efavirenz. 17. Has known acute hepatitis at Screening. 18. Has chronic use of opioids, defined as longer than 3 months prior to Screening. 19. Has a positive drug screen for cocaine, methamphetamine, methadone, opiates, oxycodone, phencyclidine, and propoxyphene at Screening. A positive screen for amphetamines, barbiturates, benzodiazepines, and cannabinoids is exclusionary if abuse or dependence is suspected. 20. Has a history of seizures (including febrile seizures), cranial trauma, or other conditions that predispose the participant to seizures. 21. Has a history of mania, history of or current diagnosis of bipolar disorder or current diagnosis of active psychosis, active bulimia or anorexia nervosa (binge eating disorder is not exclusionary). 22. Is at risk for suicide attempts based on the judgment of the investigator. 23. If female, the participant is pregnant (confirmed by laboratory testing at screening) or lactating or intending to become pregnant from signing the informed consent through 12 weeks after last dose of study medication; or intending to donate ova during such time period. 24. Has a history of severe ischemic stroke (with a Modified Rankin Scale Score ≥4). 25. Has any major illness or condition that, in the investigator's opinion, prohibits the participant from participating in the study or meeting the planned visit schedule. 26. Is unable to understand verbal or written English or any other language, for which a certified translation of the approved informed consent is available. Additional exclusion criteria to be assessed at Visit3 prior to Randomization: 1. Participant takes \<75% or \>125% of the Lead-in study medication. 2. Participant discontinues study medication treatment or has a known major adverse cardiovascular events (MACE) reported by investigator during the Double-Blind Lead-in Period.