Efficacy and Safety Study of Combination Therapy to Treat Uncomplicated Obesity

Inclusion Criteria: * Female and male subjects, 18 to 60 years of age * Have body mass index (BMI) of 30 to 40 kg/m2 * Free from clinically significant illness or disease as determined by medical history and physical examination * Non-smoker and no use of tobacco or nicotine products for at least 6 months prior to baseline * Normotensive (systolic \<140 mm Hg; diastolic \<90 mm Hg). Anti-hypertensive medications are allowed with the exception of adrenergic blockers, beta-blockers and clonidine. Medical regimen must be stable for at least 6 weeks * LDL cholesterol \< 190 mg/dL and triglycerides \< 400 mg/dL. Medications for treatment of dyslipidemia are allowed as long as medical regimen has been stable for at least 6 weeks * No clinically significant abnormality of serum albumin, blood urea nitrogen, creatinine, calcium and phosphorus * Bilirubin, ALT and AST within 1.5 x ULN * No clinically significant abnormality of hematocrit, white blood cell count, white cell differential, or platelets * Fasting glucose less than 140 mg/dL on no hypoglycemic agents * No clinically significant abnormality on urinalysis * TSH within 1.5 x ULN, normal T3, if TSH below lower limit of normal * Negative serum pregnancy test in women with intact uterus * Score \< 11 for depression and score \< 11 for anxiety on Hospital Anxiety and Depression (HAD) Scale * ECG: no clinically significant abnormality * Score of zero on the Mood Assessment questionnaire and a response of "No" to the Bipolar Disorder Questions * If female with child-bearing potential, must be non-lactating and agree to use effective contraception throughout the study period and 30 days after discontinuation of study drugs * Able to comply with all required study procedures and schedule * Willing and able to give written informed consent Exclusion Criteria: * Obesity of known endocrine origin (e.g., untreated hypothyroidism, Cushing's syndrome) * Serious medical condition or medical condition that limits participation in the prescribed exercise program: (e.g. unstable cardiovascular disease including congestive heart failure, angina pectoris, and myocardial infarction; stroke; claudication; acute limb ischemia; acute renal or hepatic disorder; renal, hepatic or respiratory insufficiency) * Active malignancy or history of malignancy (other than non-melanoma skin cancer or surgically cured cervical cancer) within 5 years of enrollment * Serious psychiatric condition (e.g., any history of bipolar disorder, psychosis, suicidal attempt or post-partum depression; a history of major depression, suicidal ideation or antidepressant use within 1 year) * Type I or Type II diabetes mellitus requiring pharmacotherapy * Excluded concomitant medications: anorectic agents; weight loss agents; dietary supplements to promote muscle building, enhance mood, or reduce appetite; adrenergic blockers; beta blockers; anti-psychotic agents; clonidine; theophylline; cimetidine; oral corticosteroids; anti-depressant; topiramate; Depo-Provera®, smoking cessation agents; frequent, known use of opioid or opioid-like analgesics * History of surgical intervention for obesity * History of seizure disorder or predisposition to seizures (e.g., history of cerebrovascular accident, significant head trauma, brain surgery, skull fracture, subdural hematoma, or febrile seizures) * History of bulimia or anorexia nervosa * History of drug or alcohol abuse within 5 years * History of treatment with bupropion, or naltrexone within 12 months * History of hypersensitivity to bupropion, or naltrexone * Use of drugs, herbs, or dietary supplements known to significantly affect body weight within one month of baseline * Use of investigational drug, device or procedure within 90 days * Participation in any previous clinical trial conducted by Orexigen Therapeutics * Any condition which in the opinion of the investigator makes the subject unsuitable for inclusion in this study