A Study of the Safety and Efficacy of Two Doses of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects

• Sponsor: Orexigen Therapeutics, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00532779
• Collaborator: (none)
• Enrollment: 1,742
• Locations: 34
• Arms: 3
• Duration (Months): 19
• Patients Per Site: 51.2
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether 2 doses of the combination of naltrexone SR and bupropion SR are safe and effective in the treatment of obesity.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Overweight	Drug: Naltrexone SR 16 mg/Bupropion SR 360 mg /day; Drug: Naltrexone SR 32 mg/Bupropion SR 360 mg /day; Drug: Placebo; Behavioral: Ancillary therapy	Phase 3

Detailed Description

Two Phase II clinical trials demonstrated that a combination of bupropion SR and naltrexone is associated with greater weight loss than bupropion SR alone, naltrexone alone, or placebo in subjects with uncomplicated obesity. The current study investigated the safety and efficacy of 2 doses of the combination of naltrexone SR and bupropion SR compared to placebo in obese subjects with uncomplicated obesity and in those with overweight/obesity and hypertension and/or dyslipidemia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1742 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study Comparing the Safety and Efficacy of Two Doses of Naltrexone Sustained Release (SR)/Bupropion Sustained Release (SR) and Placebo in Obese Subjects
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NB16 Naltrexone SR 16 mg/Bupropion SR 360 mg /day with ancillary therapy	Drug: Naltrexone SR 16 mg/Bupropion SR 360 mg /day; Other Names: NB16 ; Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling
Experimental: NB32 Naltrexone SR 32 mg/Bupropion SR 360 mg /day with ancillary therapy	Drug: Naltrexone SR 32 mg/Bupropion SR 360 mg /day; Other Names: NB32 ; Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling
Placebo Comparator: Placebo Placebo with ancillary therapy	Drug: Placebo; Behavioral: Ancillary therapy; Ancillary therapy consisting of diet instruction, advice on behavior modification, and exercise counseling

Outcome Measures

Primary Outcome Measures

1. Co-primary: Body Weight- Mean Percent Change [Baseline, 56 weeks]

2. Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease [Baseline, 56 weeks]

Secondary Outcome Measures

1. Body Weight- Proportion of Subjects With ≥10% Decrease [Baseline, 56 weeks]

2. Change in Waist Circumference [Baseline, 56 weeks]

3. Change in Fasting HDL Cholesterol Levels [Baseline, 56 weeks]

4. Change in Fasting Triglycerides Levels, Using Log-transformed Data [Baseline, 56 weeks]

5. Change in IWQOL-Lite Total Scores [Baseline, 56 weeks]

   IWQOL-Lite= Impact of Weight on Quality of Life-Lite Questionnaire Total score is based on a scale from 0 to 100, with 0 representing the poorest and 100 the best quality of life and where a score of 71-79 indicates moderate impairment

6. Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data [Baseline, 56 weeks]

7. Change in Fasting Insulin Levels, Using Log-transformed Data [Baseline, 56 weeks]

8. Change in Fasting Blood Glucose Levels [Baseline, 56 weeks]

9. Change in HOMA-IR Levels, Using Log-transformed Data [Baseline, 56 weeks]

   HOMA-IR= Homeostasis Model Assessment-Insulin Resistance

10. Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire [Baseline, 56 weeks]

    Question 19: Generally, how difficult has it been to control your eating? Scoring: 0=not at all difficult; 100=extremely difficult

11. Change in Fasting LDL Cholesterol Levels [Baseline, 56 weeks]

12. Change in Systolic Blood Pressure [Baseline, 56 weeks]

13. Change in Diastolic Blood Pressure [Baseline, 56 weeks]

14. Change in IDS-SR Total Scores [Baseline, 56 weeks]

    IDS-SR= Inventory of Depressive Symptoms-Subject Rated IDS-SR total score is based on 30 items. The total score can range from 0-84, with 0 being no depressive symptoms and 84 being very severe depressive symptoms. A total score ≤ 13 indicates no depression.

15. Change in Food Craving Inventory Sweets Subscale Score [Baseline, 56 weeks]

    The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The sweets subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome).

16. Change in Food Craving Inventory Carbohydrates Subscale Score [Baseline, 56 weeks]

    The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The carbohydrates subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female and male subjects, 18 to 65 years of age;

• Have BMI ≥30 and ≤45kg/m² for subjects with uncomplicated obesity, and BMI of ≥27 and ≤45kg/m² for subjects with obesity and controlled hypertension and/or dyslipidemia;

• Normotensive (systolic ≤140 mm Hg; diastolic ≤90 mm Hg). Anti-hypertensive medications are allowed with the exception of alpha-adrenergic blockers and clonidine; medical regimen must be stable for at least 6 weeks prior to randomization;

• Medications for treatment of dyslipidemia are allowed as long as medical regimen has been stable for at least 6 weeks prior to randomization;

• Free of opioid medication for 7 days prior to randomization;

• No clinically significant abnormality of serum albumin, blood urea nitrogen, creatinine, bilirubin, sodium, potassium, chloride, calcium or phosphorus;

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 2.5 x upper limit of normal range (ULN);

• No clinically significant abnormality of hematocrit, white blood cell (WBC) count, white cell differential, or platelets;

• Fasting glucose < 126 mg/dL on no hypoglycemic agents, fasting triglycerides <400 mg/dL;

• No clinically significant abnormality on urinalysis;

• TSH within normal limits or normal T3, if TSH is below normal limits;

• Negative serum pregnancy test in women of child-bearing potential;

• Negative urine drug screen;

• IDS-SR scores < 2 on items 5 (sadness), 6 (irritability), 7 (anxiety/tension) and 18 (suicidality), and IDS-SR total score < 30;

• Women of child bearing potential had to be non-lactating and agree to use effective contraception throughout the study period and 30 days after discontinuation of study drug;

• Able to comply with all required study procedures and schedule;

• Able to speak and read English;

• Willing and able to give written informed consent.

Exclusion Criteria:

• Obesity of known endocrine origin (e.g., untreated hypothyroidism, Cushing's syndrome, established Polycystic Ovary Syndrome);

• Serious medical conditions (including but not limited to ongoing renal or hepatic insufficiency, Class III or IV congestive heart failure; myocardial infarction, history of angina pectoris, claudication, or acute limb ischemia within the previous 6 months; lifetime history of stroke);

• History of malignancy within the previous 5 years with exception of non-melanoma skin cancer or surgically cured cervical cancer;

• A lifetime history of serious psychiatric illness, including lifetime history of bipolar disorder, schizophrenia or other psychosis, bulimia, or anorexia nervosa;

• Current serious psychiatric illness including severe personality disorder, (e.g. borderline or antisocial), current severe major depressive disorder, recent (previous 6 months) suicide attempt, current active suicidal ideation, or recent hospitalization due to psychiatric illness;

• A response to bipolar disorder questions indicating the presence of bipolar disorder;

• In need of medications for the treatment of a psychiatric disorder (with the exception of short-term insomnia) within the previous 6 months prior to randomization;

• History of drug or alcohol abuse or dependence (with the exception of nicotine dependence) within 1 year prior to study initiation;

• Type 1 or Type 2 diabetes mellitus;

• Screening ECG with a corrected QT interval by the method of Bazett (QTcB) >450 msec (men) and > 470 millisecond (msec) (women) or the presence of any clinically significant cardiac abnormalities, including but not limited to patterns consistent with myocardial ischemia, electrolyte abnormalities, or atrial or ventricular dysrhythmia or significant conduction abnormalities;

• Excluded concomitant medications: any psychotropic agents (including antipsychotic, antidepressant, anxiolytic, mood stabilizer, anticonvulsant agents or agents for the treatment of Attention Deficit Disorder) with the exception of low dose benzodiazepine or hypnotic agents for the treatment of insomnia (up to 2 mg lorazepam/day or equivalent dose of a benzodiazepine or hypnotic agent); any anorectic or weight loss agents; any over-the-counter dietary supplements or herbs with psychoactive, appetite or weight effects; alpha-adrenergic blockers; dopamine agonists; clonidine; coumadin; theophylline; cimetidine; oral corticosteroids; cholestyramine, cholestypol, Depo Provera®; smoking cessation agents; use of opioid or opioid-like medications, including analgesics and antitussives;

• History of surgical or device (e.g., gastric banding) intervention for obesity;

• History of seizures of any etiology, or of predisposition to seizures (e.g., history of cerebrovascular accident, head trauma with ≥5 minutes loss of consciousness, concussion symptoms lasting ≥15 minutes, brain surgery, skull fracture, subdural hematoma, or febrile seizures);

• History of treatment with bupropion or naltrexone within the preceding 12 months;

• History of hypersensitivity or intolerance to bupropion or naltrexone;

• Initiation or discontinuation of tobacco products including inhaled tobacco (such as cigarettes, cigars, pipes, etc), chewing tobacco or snuff in the 3 months prior to randomization or planned during study participation. Use of nicotine replacement products (nicotine gum, patch) during study participation was not allowed;

• Use of drugs, herbs, or dietary supplements believed to significantly affect body weight or participation in a weight loss management program within one month prior to randomization;

• Loss or gain of more than 4.0 kilograms within 3 months prior to randomization;

• Pregnant or breast-feeding women or planning to become pregnant during the study period or within 30 days of discontinuing study drug;

• Planned surgical procedure that can impact the conduct of the study;

• Use of investigational drug, device or procedure within the previous 30 days;

• Participation in any previous clinical trial sponsored by Orexigen Therapeutics;

• Any condition which in the opinion of the investigator makes the subject unsuitable for inclusion in the study;

• Investigators, study personnel, sponsor representatives and their immediate families.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radiant Research	Birmingham	Alabama	United States	35209
2	SelfCenter, PC	Fairhope	Alabama	United States	36532
3	Radiant Research, Phoenix Southeast	Chandler	Arizona	United States	85225
4	Advanced Clinical Research Institute	Anaheim	California	United States	92801
5	Advance Clinical Research Institute	Orange	California	United States	92869
6	Scripps Clinic Del Mar	San Diego	California	United States	92130
7	VA San Diego Healthcare System	San Diego	California	United States	92161
8	Miami Research Associates	Miami	Florida	United States	33143
9	University Clinical Research	Pembroke Pines	Florida	United States	33024
10	Georgia Clinical Research	Atlanta	Georgia	United States	30308
11	CSRA Partners in Health, Inc	Augusta	Georgia	United States	30909
12	East-West Medical Research Institute	Honolulu	Hawaii	United States	96814
13	Radiant Research	Chicago	Illinois	United States	60610
14	Welborn Clinic	Evansville	Indiana	United States	47713
15	Radiant Research Kansas City	Overland Park	Kansas	United States	66202
16	Central Kentucky Research Associates, Inc.	Lexington	Kentucky	United States	40509
17	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70808
18	Medical Research Institute	Slidell	Louisiana	United States	70458
19	Health Trends Research, LLC	Baltimore	Maryland	United States	21209
20	FutureCare Studies	Springfield	Massachusetts	United States	01103
21	Center for Nutrition and Metabolic Disorders	Reno	Nevada	United States	89557
22	Center for Nutrition and Preventive Medicine	Charlotte	North Carolina	United States	28211
23	Wake Research Associates, LLC	Raleigh	North Carolina	United States	27612
24	Rapid Medical Research, Inc.	Cleveland	Ohio	United States	44122
25	Central Ohio Nutrition Center, Inc.	Columbus	Ohio	United States	43213
26	Lynn Health Science Institute	Oklahoma City	Oklahoma	United States	73112
27	Summit Research Network (Oregon), Inc.	Portland	Oregon	United States	97210
28	Internal Medicine Associates of Cordova	Cordova	Tennessee	United States	38018
29	Jackson Clinic, PA	Jackson	Tennessee	United States	38305
30	Covance Clinical Research Unit Austin	Austin	Texas	United States	78752
31	Radiant Research	Dallas	Texas	United States	75231
32	Baylor Endocrine Center	Dallas	Texas	United States	75246
33	Radiant Research	San Antonio	Texas	United States	78217
34	Oakwell Clinical Research	San Antonio	Texas	United States	78218

Sponsors and Collaborators

• Orexigen Therapeutics, Inc

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Orexigen Therapeutics, Inc
• ClinicalTrials.gov Identifier: NCT00532779
• Other Study ID Numbers: NB-301; COR-I
• First Posted: Sep 20, 2007
• Last Update Posted: Nov 21, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Orexigen Therapeutics, Inc: Obesity; Antiobesity agents; Antiobesity drugs; Overweight drug therapy; Obese drug therapy; Weight loss drug effects; Bupropion administration and dosage; Naltrexone administration and dosage; Double blind method; Combination drug therapy; Delayed action preparations
• Additional relevant MeSH terms: Overweight; Naltrexone; Bupropion

Study Results

Participant Flow

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Period Title: Overall Study
STARTED	578	583	581
COMPLETED	284	296	290
NOT COMPLETED	294	287	291

Baseline Characteristics

Arm/Group Title	NB16	NB32	Placebo	Total
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo	Total of all reporting groups
Overall Participants	578	583	581	1742
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.35 (11.25)	44.41 (11.14)	43.66 (11.14)	44.14 (11.17)
Sex: Female, Male (Count of Participants)
Female	490 84.8%	496 85.1%	496 85.4%	1482 85.1%
Male	88 15.2%	87 14.9%	85 14.6%	260 14.9%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	13 2.2%	18 3.1%	17 2.9%	48 2.8%
Asian	4 0.7%	6 1%	4 0.7%	14 0.8%
Native Hawaiian or Other Pacific Islander	6 1%	5 0.9%	4 0.7%	15 0.9%
Black or African American	122 21.1%	106 18.2%	110 18.9%	338 19.4%
White	427 73.9%	440 75.5%	440 75.7%	1307 75%
Other	6 1%	8 1.4%	6 1%	20 1.1%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	99.49 (14.76)	99.70 (15.88)	99.45 (14.31)	99.55 (14.99)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	36.22 (4.28)	36.10 (4.35)	36.18 (4.00)	36.17 (4.21)

Outcome Measures

1. Primary Outcome

Title	Co-primary: Body Weight- Mean Percent Change
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT (Full Analysis Set): Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	471	511
Least Squares Mean (Standard Error) [percentage of body weight]	-5.00 (0.31)	-6.14 (0.31)	-1.33 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.67
	Confidence Interval	() 95%; -4.50 to -2.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.81
	Confidence Interval	(2-Sided) 95%; -5.63 to -3.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	471	511
Number (95% Confidence Interval) [percentage of participants]	39.49 6.8%	47.98 8.2%	16.44 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.42
	Confidence Interval	() 95%; 2.52 to 4.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.86
	Confidence Interval	() 95%; 3.60 to 6.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Body Weight- Proportion of Subjects With ≥10% Decrease
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	471	511
Number (95% Confidence Interval) [Percentage of participants]	20.17 3.5%	24.63 4.2%	7.44 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.21
	Confidence Interval	(2-Sided) 95%; 2.14 to 4.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.19
	Confidence Interval	(2-Sided) 95%; 2.82 to 6.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Waist Circumference
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	342	356	348
Least Squares Mean (Standard Error) [cm]	-5.04 (0.43)	-6.24 (0.42)	-2.46 (0.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.58
	Confidence Interval	(2-Sided) 95%; -3.74 to -1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.78
	Confidence Interval	(2-Sided) 95%; -4.93 to -2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Fasting HDL Cholesterol Levels
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	333	359	345
Least Squares Mean (Standard Error) [mg/dL]	3.36 (0.47)	3.42 (0.45)	-0.06 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.42
	Confidence Interval	(2-Sided) 95%; 2.17 to 4.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.48
	Confidence Interval	(2-Sided) 95%; 2.26 to 4.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Fasting Triglycerides Levels, Using Log-transformed Data
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	333	359	345
Least Squares Mean (95% Confidence Interval) [percent change]	-7.96	-12.69	-3.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.046
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.88
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.61
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in IWQOL-Lite Total Scores
Description	IWQOL-Lite= Impact of Weight on Quality of Life-Lite Questionnaire Total score is based on a scale from 0 to 100, with 0 representing the poorest and 100 the best quality of life and where a score of 71-79 indicates moderate impairment
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	422	417	468
Least Squares Mean (Standard Error) [units on a scale]	11.68 (0.54)	12.69 (0.54)	8.55 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.13
	Confidence Interval	(2-Sided) 95%; 1.72 to 4.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.14
	Confidence Interval	(2-Sided) 95%; 2.73 to 5.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	331	353	340
Least Squares Mean (95% Confidence Interval) [percent change]	-28.02	-28.98	-16.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.016
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11.36
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.008
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.32
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change in Fasting Insulin Levels, Using Log-transformed Data
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	309	344	326
Least Squares Mean (95% Confidence Interval) [percent change]	-11.84	-17.14	-4.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.063
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.27
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.57
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change in Fasting Blood Glucose Levels
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	336	361	348
Least Squares Mean (Standard Error) [mg/dL]	-2.39 (0.57)	-3.24 (0.55)	-1.30 (0.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) 95%; -2.60 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.010
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.94
	Confidence Interval	(2-Sided) 95%; -3.42 to -0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change in HOMA-IR Levels, Using Log-transformed Data
Description	HOMA-IR= Homeostasis Model Assessment-Insulin Resistance
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	305	341	325
Least Squares Mean (95% Confidence Interval) [percent change]	-14.33	-20.19	-5.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.43
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-14.29
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire
Description	Question 19: Generally, how difficult has it been to control your eating? Scoring: 0=not at all difficult; 100=extremely difficult
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	410	409	453
Least Squares Mean (Standard Error) [units on a scale]	-12.49 (1.10)	-14.52 (1.09)	-8.68 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.81
	Confidence Interval	(2-Sided) 95%; -6.68 to -0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.84
	Confidence Interval	(2-Sided) 95%; -8.71 to -2.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change in Fasting LDL Cholesterol Levels
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	332	358	345
Least Squares Mean (Standard Error) [mg/dL]	-3.67 (1.21)	-4.41 (1.17)	-3.28 (1.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -3.62 to 2.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.484
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.13
	Confidence Interval	(2-Sided) 95%; -4.29 to 2.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change in Systolic Blood Pressure
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	471	511
Least Squares Mean (Standard Error) [mm Hg]	0.29 (0.40)	-0.11 (0.41)	-1.94 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.23
	Confidence Interval	(2-Sided) 95%; 1.16 to 3.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change in Diastolic Blood Pressure
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	471	511
Least Squares Mean (Standard Error) [mm Hg]	0.09 (0.29)	0.04 (0.29)	-0.86 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change in IDS-SR Total Scores
Description	IDS-SR= Inventory of Depressive Symptoms-Subject Rated IDS-SR total score is based on 30 items. The total score can range from 0-84, with 0 being no depressive symptoms and 84 being very severe depressive symptoms. A total score ≤ 13 indicates no depression.
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	471	470	511
Least Squares Mean (Standard Error) [units on a scale]	0.02 (0.21)	-0.27 (0.21)	-0.72 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; -0.09 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change in Food Craving Inventory Sweets Subscale Score
Description	The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The sweets subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome).
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	423	418	470
Least Squares Mean (Standard Error) [units on a scale]	-2.08 (0.21)	-2.62 (0.21)	-2.77 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.14 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change in Food Craving Inventory Carbohydrates Subscale Score
Description	The Food Craving Inventory is a 33-item self-report measure designed to assess specific food cravings and is organized into 4 subscales (high fats, sweets, carbohydrates/starches, and fast-food fats). A craving was defined as an intense desire to consume a particular food (or food type) that was difficult to resist over the past month. Subjects rated their frequency of cravings for each of the 33 items using a 5-point scale, where 1=never, 2=rarely, 3=sometimes, 4=often, and 5=always. The carbohydrates subscale consisted of 8 items and the score ranges from 8 (better outcome) to 40 (worse outcome).
Time Frame	Baseline, 56 weeks

Outcome Measure Data

Analysis Population Description

Modified ITT: Included all subjects who were randomized, had a baseline weight measurement, and had at least one post-baseline weight measurement while on study drug. Missing data were imputed with the LOCF method.

Arm/Group Title	NB16	NB32	Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day	Naltrexone SR 32 mg/Bupropion SR 360 mg /day	Placebo
Measure Participants	423	418	469
Least Squares Mean (Standard Error) [units on a scale]	-1.85 (0.20)	-2.11 (0.20)	-1.84 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB16, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.80 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline, 56 weeks
Adverse Event Reporting Description	The safety analysis set includes all randomized subjects who took study drug and were assessed by investigator after their first dose, whether or not they discontinue the study. Treatment-emergent adverse events were defined as events that started or worsened in the double-blind treatment phase after the first dose and before 7 days post last dose.
Arm/Group Title	NB16		NB32		Placebo
Arm/Group Description	Naltrexone SR 16 mg/Bupropion SR 360 mg /day		Naltrexone SR 32 mg/Bupropion SR 360 mg /day		Placebo
All Cause Mortality
	NB16		NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NB16		NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/569 (1.6%)		9/573 (1.6%)		8/569 (1.4%)
Cardiac disorders
Cardiac failure	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Myocardial infarction	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Pericardial effusion	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Small intestinal obstruction	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
General disorders
Chest discomfort	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Chest pain	1/569 (0.2%)	1	1/573 (0.2%)	1	0/569 (0%)	0
Non-cardiac chest pain	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Hepatobiliary disorders
Cholecystitis chronic	1/569 (0.2%)	1	1/573 (0.2%)	1	0/569 (0%)	0
Hepatitis cholestatic	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Infections and infestations
Cellulitis	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Diverticulitis	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Enterocolitis infectious	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Gastroenteritis	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Gastroenteritis viral	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Infection	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Urinary tract infection	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/569 (0.2%)	1	0/573 (0%)	0	1/569 (0.2%)	1
Foot fracture	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Joint dislocation	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Rib fracture	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Spinal fracture	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Whiplash injury	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer in situ	1/569 (0.2%)	1	0/573 (0%)	0	0/569 (0%)	0
Nervous system disorders
Cervical myelopathy	0/569 (0%)	0	0/573 (0%)	0	1/569 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Dyspnoea	0/569 (0%)	0	1/573 (0.2%)	1	0/569 (0%)	0
Other (Not Including Serious) Adverse Events
	NB16		NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	345/569 (60.6%)		365/573 (63.7%)		230/569 (40.4%)
Gastrointestinal disorders
Constipation	90/569 (15.8%)	99	90/573 (15.7%)	98	32/569 (5.6%)	36
Diarrhoea	31/569 (5.4%)	38	26/573 (4.5%)	28	28/569 (4.9%)	33
Dry mouth	42/569 (7.4%)	44	43/573 (7.5%)	44	11/569 (1.9%)	12
Nausea	155/569 (27.2%)	182	171/573 (29.8%)	197	30/569 (5.3%)	32
Vomiting	36/569 (6.3%)	51	56/573 (9.8%)	63	14/569 (2.5%)	14
Infections and infestations
Nasopharyngitis	32/569 (5.6%)	40	29/573 (5.1%)	33	31/569 (5.4%)	33
Sinusitis	34/569 (6%)	39	30/573 (5.2%)	34	34/569 (6%)	39
Upper respiratory tract infection	49/569 (8.6%)	62	57/573 (9.9%)	77	64/569 (11.2%)	83
Nervous system disorders
Dizziness	44/569 (7.7%)	52	54/573 (9.4%)	65	15/569 (2.6%)	17
Headache	91/569 (16%)	107	79/573 (13.8%)	91	53/569 (9.3%)	58
Psychiatric disorders
Insomnia	36/569 (6.3%)	38	43/573 (7.5%)	44	29/569 (5.1%)	30
Vascular disorders
Hot flush	13/569 (2.3%)	15	30/573 (5.2%)	33	7/569 (1.2%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If not already published by Sponsor as part of a multi-center publication, 18 months after conclusion of the study at all study centers, PI may publish the results for PI's study center individually. Prior to such publication, PI must provide Sponsor with at least 60 days to review and comment on the proposed publication. The review period may be extended by an additional 30 days upon request. Sponsor may delay publication for up to an additional 6 month period to file for patent protection.