Naltrexone/Bupropion Cardiovascular Outcomes Study
Condition: Obesity; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Intervention: Naltrexone HCl/Bupropion HCl ER; Placebo
Intervention description: Naltrexone HCl 8 mg/bupropion HCl 90 mg ER combination tablets; Naltrexone HCl/bupropion HCl placebo-matching tablets
Intervention MeSH terms: Naltrexone; Bupropion
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 67.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to evaluate cardiovascular (CV) safety of naltrexone
      hydrochloride (HCl) and bupropion HCl extended release combination (NB) compared with placebo
      and rule out excess risk of major adverse cardiovascular events (MACE) when given in
      combination with standard of care in overweight and obese participants with documented
      history of CV disease.
    

Eligibility criteria:

        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.