A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)

Abstract

Objective: To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants.

Design and methods: CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m(2) ) or overweight (27-45 kg/m(2) with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥ 5% weight loss at week 28.

Results: Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (-6.5% vs. -1.9%) and week 56 (-6.4% vs. -1.2%). More NB32-treated participants (P < 0.001) experienced ≥ 5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo.

Conclusion: NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option.

FIGURE 1

Following screening, participants were randomized via a centrally administered interactive voice response system in a 2:1 ratio, stratified by study site, to receive a combined oral formulation of 32 mg/day naltrexone SR + 360 mg/day bupropion SR (NB32) or matching placebo, administered in divided doses twice daily. Naltrexone was initiated at one-eighth or one-quarter of the maintenance dose and bupropion was initiated at one-quarter of the maintenance dose; doses were escalated linearly over the first 3-4 weeks, and the maintenance dose was reached by the start of week 5. To evaluate the efficacy and safety of a dose increase in participants with suboptimal response, NB32 participants with <5% weight loss at visits between weeks 28 and 44 inclusive were re-randomized (double-blind, 1:1 ratio) to continue receiving NB32 or escalate to NB48 (48 mg/day naltrexone SR + 360 mg/day bupropion SR) for the remainder of the study. Study visits occurred at baseline (week 0) and every 4 weeks thereafter.

FIGURE 2

Participant flow chart.

FIGURE 3

A) Percent weight loss (observed; LS mean ± SE) by visit in the week 28 and 56 completers populations (NB32 data are weighted for weeks 32-56), and percent weight loss for the week 28 and 56 mITT-LOCF populations. ***P < 0.001 for NB32 vs. Placebo. B) Categorical weight loss in week 28 and 56 mITT-LOCF and Completers populations. ***P < 0.001 for NB32 vs. Placebo. In both panels, week 56 data for NB32 are weighted as described in the Statistical analyses section.