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

Caroline M Apovian, Louis Aronne, Domenica Rubino, Christopher Still, Holly Wyatt, Colleen Burns, Dennis Kim, Eduardo Dunayevich, COR-II Study Group, Caroline Apovian, Louis Aronne, Bruce Berwald, Brian Bortnick, Susan Braun, Robert Buynak, Joseph Cleaver, Martin Conway, Milissa Cooper, Neil Dubin, Steven Folkerth, Martin Fritzhand, Forrest Hanke, Jonathan G A Henry, Lawrence Koehler, Burton Lazar, Michael T Levy, Norman Lunde, Richard Mills, Nadar Oskooilar, Troy Oxner, Sanford Plevin, Anthony Puopolo, George Raad, Domenica Rubino, Nathan Segall, Stephan C Sharp, Timothy Smith, Phillip Snell, Joseph Soufer, Christopher Still, Paul Tung, James Vogt, Claire Waltman, Kevin Wingert, Holly Wyatt, Douglas Young, Douglas Zmolek, Caroline M Apovian, Louis Aronne, Domenica Rubino, Christopher Still, Holly Wyatt, Colleen Burns, Dennis Kim, Eduardo Dunayevich, COR-II Study Group, Caroline Apovian, Louis Aronne, Bruce Berwald, Brian Bortnick, Susan Braun, Robert Buynak, Joseph Cleaver, Martin Conway, Milissa Cooper, Neil Dubin, Steven Folkerth, Martin Fritzhand, Forrest Hanke, Jonathan G A Henry, Lawrence Koehler, Burton Lazar, Michael T Levy, Norman Lunde, Richard Mills, Nadar Oskooilar, Troy Oxner, Sanford Plevin, Anthony Puopolo, George Raad, Domenica Rubino, Nathan Segall, Stephan C Sharp, Timothy Smith, Phillip Snell, Joseph Soufer, Christopher Still, Paul Tung, James Vogt, Claire Waltman, Kevin Wingert, Holly Wyatt, Douglas Young, Douglas Zmolek

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.

Copyright © 2013 The Obesity Society.

Figures

FIGURE 1
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

FIGURE 2

Participant flow chart.

FIGURE 2

Participant flow chart.

FIGURE 2
Participant flow chart.

FIGURE 3

A) Percent weight loss (observed;…

FIGURE 3

A) Percent weight loss (observed; LS mean ± SE) by visit in the…

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.
FIGURE 2
FIGURE 2
Participant flow chart.
FIGURE 3
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.

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