Design of INFORMUS, a pragmatic, randomized, double-blind, placebo-controlled study of cardiovascular outcomes with the extended-release, fixed-dose combination of naltrexone and bupropion.

Background: Obesity is associated with cardiovascular (CV) risk. Several medications previously used for weight management have been withdrawn or contraindicated in individuals with hypertension due to concerns about adverse CV effects, including major adverse CV events (MACE). The fixed-dose, extended-release combination of naltrexone and bupropion (NB-ER) is approved for chronic weight management in adults. A previous phase 3 CV outcomes trial (LIGHT; NCT01601704) evaluating the effect of NB-ER on MACE in adults with obesity or overweight at an elevated CV risk was terminated early. Existing evidence from LIGHT and other data suggest that NB-ER does not increase CV risk, and regulatory agencies requested another CV outcomes safety trial. Here, we describe the design of INFORMUS, a prospective phase 4 pragmatic clinical trial evaluating CV outcomes associated with NB-ER use. Methods: INFORMUS (NCT06098079) is a phase 4, randomized, double-blind, placebo-controlled study in the US that will assess the effect of NB-ER on MACE incidence. Eligible participants are adults ≥18 years with overweight and ≥1 weight-related comorbidity or obesity, all with elevated CV risk. Approximately 8600 participants will be randomized 1:1 to NB-ER (final dose of 32 mg naltrexone ER, 360 mg bupropion ER) or placebo. Data collection continues until 212 adjudicated MACE events have accrued. Results: The primary objective of this ongoing trial is to assess CV safety by comparing time to first MACE between participants receiving NB-ER vs placebo. Planned secondary endpoints include comparative rates of MACE component events and MACE+ events (MACE or any coronary, cerebrovascular, and peripheral revascularization events, or hospitalizations for heart failure), all-cause death, and time to all-cause death. The incidence of other adverse events will also be monitored throughout the trial. Conclusion: Findings from INFORMUS will further characterize CV risk associated with NB-ER in adults with obesity or overweight at increased CV risk.