Real-World Evidence on the Cardiovascular Safety of CONTRAVE® in the United States (U.S.)

Study Overview
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Brief Summary
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The fixed-dose combination of naltrexone 8mg and bupropion 90mg extended-release oral tablet is marketed under the trade name CONTRAVE® in the U.S. In this protocol, the investigators propose to generate real-world evidence (RWE) from electronic health records (EHR) and linked claims data to assess the cardiovascular safety of CONTRAVE® and all NB in usual clinical practice.

Detailed Description
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The study will assess whether patients who initiate treatment with NB are at an elevated risk of MACE compared with patients who initiated treatment with lorcaserin, an active comparator chosen to reduce potential confounding. The cohorts for all study objectives will be drawn from a large electronic health records (EHR) data source, representing a geographically diverse patient population. The data will include diagnoses, procedures, medications (prescribed and administered), clinical measures (biometric and laboratory values), and observations derived from clinical notes. A subset of the population will have linked, adjudicated claims data available to support sensitivity analyses. The study's main objective is to compare the incidence of the primary endpoint (MACE) between initiators of NB and initiators of lorcaserin. The study will also compare the incidence of the secondary endpoint, consisting of each component of MACE, between initiators of NB and initiators of lorcaserin, across the following subgroups: Patients with obesity (i.e., most recent BMI measurement ≥30 kg/m2); Patients with a diagnosis of hypertension, regardless of BMI; Patients with a diagnosis of type 2 diabetes mellitus, regardless of BMI; Patients with a diagnosis of dyslipidemia, regardless of BMI. The study's additional objectives aimed at testing the robustness of the methods are: To assess the comparability of findings from an EHR study to those of a 2018 clinical trial, aligning with the RCT DUPLICATE Initiative; To quantify differences in cardiovascular safety endpoints between the clinical trial and the results of this EHR study; To conduct other sensitivity analyses, including a self-controlled, case-crossover analysis to quantify the potential effect of NB on MACE.

Official Title
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A Non-Interventional Study to Generate Real-World Evidence on the Cardiovascular Safety of CONTRAVE® in the United States (U.S.)

Conditions
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Obesity

Participation Criteria
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Eligibility Criteria
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For the main objective (1.0, 1.1), patients are eligible if they meet the following Inclusion Criteria: Have at least one prescription for NB between September 2014 and February 2020, including concurrent prescriptions (within 15 days) for naltrexone and bupropion; or have at least one prescription for lorcaserin; Have at least 180 days of data available prior to cohort entry with no evidence of prescriptions or dispensings of NB or lorcaserin; Have at least one BMI value available in the 180 days prior to cohort entry, inclusive of the index date; Have documentation of at least one outpatient medical visit 180 or more days prior to cohort entry, and at least one healthcare interaction in the 180 days prior to cohort entry; Are at least 18 years of age on the cohort entry date. For the main objective, patients are not eligible if they have a diagnosis of any of the following conditions in the 180 days before the cohort entry date: Epilepsy; Bulimia; Anorexia nervosa; Surgical procedure for weight loss.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| naltrexone 8mg and bupropion 90mg extended-release oral tablet (NB)<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, following titration. | |
| lorcaserin<br>A total of one 10 mg tablet administered orally twice daily; or one 20 mg tablet administered orally once daily. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of MACE between initiators of NB and initiators of lorcaserin. | The primary study endpoint is MACE, defined as the composite of: Medically attended non-fatal acute myocardial infarction; Medically attended non-fatal stroke; Cardiovascular-related death. | Patients will be followed starting the day after initial exposure until the first of the following censoring events: the study endpoint of interest, end of enrollment (plus addtl. 6 mo.) or end of study period (Dec2022). |