Effect of naltrexone plus bupropion on weight loss in overweight and obese adults
(COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3
trial.
Author(s): Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim
DD, Dunayevich E; COR-I Study Group.
Collaborators: Acampora M, Baron M, Borders JL, Burch FX, Carter D, Church T,
Dahdul A, Duckor S, Fitz-Patrick D, Fujioka K, Gilderman L, Geohas J, Graves MW,
Griffin C, Harper W, Hollander P, Jain AK, Jenkins J, Kaufmann RS, Kempf K,
Kerzner B, Krieger D, Loper JF, Mudaliar S, Petit CA, Plodkowski R, Reynolds M,
Riff DS, Schumacher D, Self KS, Severance RJ, Smith D, Smith W, Stewart W Jr,
Walthall W 4th, Woodruff C.
Affiliation(s): Pennington Biomedical Research Center, Louisiana State University System, Baton
Rouge, LA 70808, USA. frank.greenway@pbrc.edu
Publication date & source: 2010, Lancet. , 376(9741):595-605
BACKGROUND: Despite increasing public health concerns regarding obesity, few safe
and effective drug treatments are available. Combination treatment with
sustained-release naltrexone and bupropion was developed to produce complementary
actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I
(COR-I) study assessed the effect of such treatment on bodyweight in overweight
and obese participants.
METHODS: Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45
kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or
hypertension were eligible for enrolment in this randomised, double-blind,
placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants
were prescribed mild hypocaloric diet and exercise and were randomly assigned in
a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus
sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also
known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release
bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or
matching placebo twice a day, given orally for 56 weeks. The trial included a
3-week dose escalation. Randomisation was done by use of a centralised,
computer-generated, web-based system and was stratified by study centre.
Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight
and proportion of participants who achieved a decrease in bodyweight of 5% or
more. The primary analysis included all randomised participants with a baseline
weight measurement and a post-baseline weight measurement while on study drug
(last observation carried forward). This study is registered with
ClinicalTrials.gov, number NCT00532779.
FINDINGS: 1742 participants were enrolled and randomised to double-blind
treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus
bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of
treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the
primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE
0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion
group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus
bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo
had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to
naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to
naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse
event in participants assigned to combination treatment was nausea (naltrexone 32
mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155
[27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and
dry mouth were also more frequent in the naltrexone plus bupropion groups than in
the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and
diastolic blood pressure was followed by a reduction of around 1 mm Hg below
baseline in the naltrexone plus bupropion groups. Combination treatment was not
associated with increased depression or suicidality events compared with placebo.
INTERPRETATION: A sustained-release combination of naltrexone plus bupropion
could be a useful therapeutic option for treatment of obesity.
FUNDING: Orexigen Therapeutics.
Erratum in
Lancet. 2010 Oct 23;376(9750):1392.
Lancet. 2010 Aug 21;376(9741):594.
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