Naltrexone/Bupropion Cardiovascular Outcomes Study

The drug being tested in this study is called naltrexone hydrochloride (HCl) and bupropion
HCl extended release combination (NB). NB is being tested in this study to rule out excess
cardiovascular risk. This study will look at the occurrence of major adverse CV events in
people who take NB compared with placebo on top of standard of care.

The study will enroll approximately 8800 patients. After a 2-week lead-in period evaluating
tolerance to NB, participants will be randomly assigned (by chance, like flipping a coin) to
one of the two treatment groups—which will remain undisclosed to the patient and study
doctor during the study (unless there is an urgent medical need):

- Naltrexone HCl 8 mg/bupropion 90 mg extended release combination tablets

- Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has
no active ingredient

All participants will be asked to take tablet(s) in the AM and PM at the same time each day
throughout the study.

This multi-center trial will be conducted in the United States. The overall time to
participate in this study is up to 6 years. Participants will make multiple visits to the
clinic, and will be contacted by telephone 30 days after last dose of study drug for a
follow-up assessment.

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.