title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity.
  
  
  BACKGROUND
  Orexigen Therapeutics.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. frank.greenway@pbrc.edu
authors.forename: Frank L
authors.initials: FL
authors.lastname: Greenway
authors.forename: Ken
authors.initials: K
authors.lastname: Fujioka
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Plodkowski
authors.forename: Sunder
authors.initials: S
authors.lastname: Mudaliar
authors.forename: Maria
authors.initials: M
authors.lastname: Guttadauria
authors.forename: Janelle
authors.initials: J
authors.lastname: Erickson
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Kim
authors.forename: Eduardo
authors.initials: E
authors.lastname: Dunayevich
mesh_terms: D000328:Adult; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D016642:Bupropion / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage*; D009765:Obesity / Q000188:drug therapy*; D050177:Overweight / Q000188:drug therapy*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D003692:Delayed-Action Preparations; D016642:Bupropion; D009271:Naltrexone