A Safety and Efficacy Study Comparing Naltrexone SR/Bupropion SR and Placebo in Obese Subjects With Type 2 Diabetes

• Sponsor: Orexigen Therapeutics, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00474630
• Collaborator: (none)
• Enrollment: 505
• Locations: 53
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is determine whether the combination of naltrexone SR and bupropion SR is safe and effective in treating obesity in subjects with type 2 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Overweight; Diabetes Mellitus, Type 2	Drug: Naltrexone SR 32 mg/bupropion SR 360 mg/ day; Drug: Placebo; Behavioral: Ancillary therapy	Phase 3

Detailed Description

Optimal care of patients with diabetes mellitus includes vigorous and persistent efforts to achieve physiologic control of blood glucose as well as other often associated conditions including hypertension, dyslipidemia and excess weight. Pharmacologic interventions for the treatment of obesity in type 2 diabetes have shown significant reductions in HbA1c. 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 the combination of naltrexone SR and bupropion SR compared to placebo in obese subjects with type 2 diabetes mellitus.

Study Design

• Study Type: Interventional
• Actual Enrollment: 505 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 Naltrexone 32 mg Sustained Release (SR)/Bupropion 360 mg Sustained Release (SR) and Placebo in Obese Subjects With Type 2 Diabetes Mellitus
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
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. Change in HbA1c Levels [Baseline, 56 weeks]

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

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

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

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

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

7. HbA1c- Proportion of Subjects With HbA1c <7% at Endpoint [Baseline, 56 weeks]

8. Percent of Subjects Requiring Rescue Medications for Diabetes [Baseline, 56 weeks]

9. Percent of Subjects With Dose Reduction in Oral Antidiabetes Medications [Baseline, 56 weeks]

10. Percent of Subjects With Dose Increase in Oral Antidiabetes Medications [Baseline, 56 weeks]

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

    HOMA-IR= Homeostasis Model Assessment-Insulin Resistance

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

13. HbA1c- Proportion of Subjects With HbA1c <6.5% at Endpoint [Baseline, 56 weeks]

14. 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

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

16. Percent of Subjects Discontinuing Due to Poor Glycemic Control [Baseline, 56 weeks]

    Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed. Odds ratio not calculated as there were no subjects in the NB32 group that discontinued due to poor glycemic control.

17. 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

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

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

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

21. 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.

22. 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).

23. 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 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female or male subjects aged 18 to 70 years of age (inclusive)

• Body mass index (BMI) ≥27 and ≤45 kg/m²

• Diagnosed with type 2 diabetes mellitus and on no injectable antidiabetes medication or inhaled insulin for more than 3 months prior to randomization

• Took stable doses of oral single or combination hypoglycemic medications (biguanides, thiazolidinediones, meglitinides, α-glucosidase inhibitors, sulfonylureas, DPP4 inhibitors) for at least 3 months prior to randomization or did not take medications for the treatment of type 2 diabetes mellitus

• Normotensive (systolic ≤145 mm Hg and diastolic ≤95 mm Hg). Antihypertensive medications were allowed with the exception of alpha-adrenergic blockers, and clonidine. Antihypertensive treatment was stable for at least 4 weeks prior to randomization.

• Medications for the treatment of dyslipidemia were allowed with the exception of cholestyramine and cholestypol as long as the medical regimen had been stable for at least 4 weeks prior to randomization.

• Free of opioid medication for 7 days prior to randomization

• HbA1c between 7% and 10%, fasting blood glucose <270 mg/dL, and fasting triglycerides <400 mg/dL

• No clinically significant abnormality of serum albumin, blood urea nitrogen (BUN), bilirubin, calcium, and phosphorus

• Creatinine levels were ≤1.4 mg/dL for female subjects and ≤1.5 mg/dL for male subjects

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were within 2.5 × upper limit of laboratory normal range (ULN)

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

• No clinically significant abnormality on urinalysis

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

• Female subjects of childbearing potential had a negative serum pregnancy test

• Negative urine drug screen

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

• Female subjects of childbearing potential were non-lactating and agreed to continue to use effective contraception throughout the study and 30 days after discontinuation of study drug

• Able to comply with all required study procedures and schedule

• Able to speak and read English

• Provided written informed consent

Exclusion Criteria:

• Type I diabetes mellitus

• "Brittle-diabetes" or any hospitalization or emergency room visit due to poor diabetic control within 6 months prior to screening, history of diabetes-related dehydration leading to hospitalization, or history or evidence of ketoacidosis

• Obesity of known endocrine origin other than diabetes mellitus (e.g., untreated hypothyroidism, Cushing's syndrome, established polycystic ovary syndrome)

• Diabetes mellitus secondary to pancreatitis or pancreatectomy

• Serious medical condition including but not limited to renal or hepatic insufficiency and Class III or IV congestive heart failure; history of myocardial infarction, angina pectoris, claudication, or acute limb ischemia within 6 months prior to screening; lifetime history of stroke

• History of malignancy with exception of non-melanoma skin cancer or surgically cured cervical cancer within 5 years prior to screening

• Loss or gain of more than 5.0 kg within the 3 months prior to screening

• Severe microvascular or macrovascular complications of diabetes, including but not limited to proliferative retinopathy, active limb ulcerations, amputation of metatarsals or above

• Serious psychiatric illness, including lifetime history of bipolar disorder, schizophrenia or other psychosis, bulimia, and anorexia nervosa; current serious personality disorder (e.g., borderline or antisocial); current severe major depressive disorder; recent (6 months prior to screening) suicide attempt or current active suicidal ideation; or recent hospitalization due to psychiatric illness

• Response to the bipolar disorder questions that indicated the presence of bipolar disorder

• Required medications for the treatment of a psychiatric disorder (with the exception of short term insomnia) within 6 months prior to screening

• History of drug or alcohol abuse or dependence within 1 year prior to screening

• Baseline ECG with a QTc interval (Bazett's formula) >450 msec (men) and >470 msec (women) or the presence of any clinically significant cardiac abnormalities, including but not limited to patterns consistent with recent myocardial ischemia, electrolyte abnormalities, or atrial or ventricular dysrhythmia or significant conduction abnormalities

• Received the following excluded concomitant medications: any psychotropic agents (including antipsychotic, antidepressant, anxiolytic, mood stabilizer, anticonvulsant agents, and 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 intervention for obesity (e.g., gastric banding)

• 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)

• Treatment with bupropion or naltrexone within 12 months prior to screening

• History of hypersensitivity or intolerance to bupropion or naltrexone

• Changes in smoking status or in tobacco or nicotine use within 3 months prior to screening or planned during study participation

• Participated in a weight loss management program within one month prior to randomization

• Females who were pregnant or breast-feeding or planned to become pregnant during the study period or within 30 days of discontinuing study drug

• Planned surgical procedure that could impact the conduct of the study

• Received any investigational drug or used an experimental device or procedure within the previous 30 days

• Participated in any previous clinical trial conducted by Orexigen

• Had any condition that in the opinion of the investigator made the subject unsuitable for inclusion into the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SelfCenter, PC	Fairhope	Alabama	United States	36532
2	Pivotal Research Centers	Peoria	Arizona	United States	85381
3	HOPE Research Institute	Phoenix	Arizona	United States	85050
4	HealthStar Research	Hot Springs	Arkansas	United States	71913
5	Impact Clinical Trials	Beverly Hills	California	United States	90211
6	Northern California Research	Carmichael	California	United States	98608
7	Sierra Medical Research	Fresno	California	United States	93710
8	Advance Clinical Research Institute	Orange	California	United States	92869
9	Affiliated Research Institute	San Diego	California	United States	92108
10	VA San Diego Healthcare System	San Diego	California	United States	92161
11	Apex Research Institue	Santa Ana	California	United States	92705
12	Chase Medical Research, LLC	Waterbury	Connecticut	United States	06708
13	LCFP Inc.	Fort Myers	Florida	United States	33907
14	Miami Research Associates	Miami	Florida	United States	33143
15	Suncoast Clinical Research	Palm Harbor	Florida	United States	34684
16	University Clinical Research	Pembroke Pines	Florida	United States	33024
17	CSRA Partners in Health, Inc	Augusta	Georgia	United States	30909
18	East-West Medical Research Institute	Honolulu	Hawaii	United States	96814
19	Deaconess Clinic	Evansville	Indiana	United States	47713
20	Northwest Indiana Center for Clinical Research	Valparaiso	Indiana	United States	46383
21	Central Kentucky Research Associates, Inc.	Lexington	Kentucky	United States	40509
22	L-Marc	Louisville	Kentucky	United States	40213
23	Trover Center for Clinical Studies	Madisonville	Kentucky	United States	42431
24	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70808
25	Medical Research Institute	Slidell	Louisiana	United States	70458
26	Health Trends Research, LLC	Baltimore	Maryland	United States	21209
27	FutureCare Studies	Springfield	Massachusetts	United States	01103
28	Twin Cities Clinical Research	Brooklyn Center	Minnesota	United States	55430
29	The Center for Pharmaceutical Research	Kansas City	Missouri	United States	64114
30	Mercy Health Research	St. Louis	Missouri	United States	63141
31	Radiant Research, Inc.	St. Louis	Missouri	United States	63141
32	Center for Nutrition and Metabolic Diseases, Univ. of Nevada	Reno	Nevada	United States	89557
33	Endocrinology & Diabetes Consultants	Dover	New Hampshire	United States	03820
34	Lovelace Scientific Resources	Albuquerque	New Mexico	United States	87108
35	Diabetes care and Information Center	Flushing	New York	United States	11365
36	Central New York Clinical Research	Manlius	New York	United States	13104
37	Rochester Clinical Research, Inc	Rochester	New York	United States	14609
38	Metrolina Medical Research	Charlotte	North Carolina	United States	28209
39	Rapid Medical Research, Inc.	Cleveland	Ohio	United States	44122
40	Central Ohio Nutrition Center, Inc.	Columbus	Ohio	United States	43213
41	Wells Institute for Health Awareness	Kettering	Ohio	United States	45429
42	Your Diabetes Endocrine and Nutrition Group	Mentor	Ohio	United States	44060
43	Mountain View Clinical Research	Greer	South Carolina	United States	29349
44	Palmetto Medical Research	Mt. Pleasant	South Carolina	United States	29464
45	ClinSearch	Chattanooga	Tennessee	United States	37404
46	Clinical Research Associates, Inc.	Nashville	Tennessee	United States	37203
47	The Cooper Institute	Dallas	Texas	United States	75230
48	Baylor Endocrine Center	Dallas	Texas	United States	75246
49	Diabetes Center of the Southwest	Midland	Texas	United States	79705
50	InVisions Consultants, LLC	San Antonio	Texas	United States	78217
51	Diabetes & Glandular Disease Research Associates, Inc.	San Antonio	Texas	United States	78229-4801
52	Summit Research Network, Inc.	Seattle	Washington	United States	98104
53	Northside Internal Medicine	Spokane	Washington	United States	99208

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: NCT00474630
• Other Study ID Numbers: NB-304; COR-Diabetes
• First Posted: May 17, 2007
• Last Update Posted: Nov 21, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Orexigen Therapeutics, Inc: Obesity; Overweight; Diabetes Mellitus, Type 2
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight; Naltrexone; Bupropion

Study Results

Participant Flow

Arm/Group Title	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Period Title: Overall Study
STARTED	335	170
COMPLETED	175	100
NOT COMPLETED	160	70

Baseline Characteristics

Arm/Group Title	NB32	Placebo	Total
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo	Total of all reporting groups
Overall Participants	335	170	505
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.02 (9.05)	53.46 (9.83)	53.83 (9.32)
Sex: Female, Male (Count of Participants)
Female	195 58.2%	90 52.9%	285 56.4%
Male	140 41.8%	80 47.1%	220 43.6%
Race/Ethnicity, Customized (participants) [Number]
White	261 77.9%	140 82.4%	401 79.4%
Black or African American	63 18.8%	18 10.6%	81 16%
Asian	7 2.1%	5 2.9%	12 2.4%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	1 0.2%
American Indian or Alaska Native	2 0.6%	2 1.2%	4 0.8%
Other	1 0.3%	5 2.9%	6 1.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	104.22 (18.93)	105.08 (16.99)	104.51 (18.28)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	36.40 (4.75)	36.40 (4.50)	36.40 (4.66)

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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Least Squares Mean (Standard Error) [percentage of body weight]	-5.03 (0.34)	-1.75 (0.43)

Statistical Analysis 1

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	-3.28
	Confidence Interval	() 95%; -4.34 to -2.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in HbA1c 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/bupropion SR 360 mg/ day	Placebo
Measure Participants	222	137
Least Squares Mean (Standard Error) [percent]	-0.63 (0.07)	-0.14 (0.09)

Statistical Analysis 1

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	-0.49
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	44.53 13.3%	18.87 11.1%

Statistical Analysis 1

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	3.44
	Confidence Interval	(2-Sided) 95%; 2.15 to 5.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	222	135
Least Squares Mean (95% Confidence Interval) [percent change]	-11.20	-0.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.4
	Confidence Interval	(2-Sided) %; to
	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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	222	135
Least Squares Mean (Standard Error) [mg/dL]	3.03 (0.49)	-0.29 (0.61)

Statistical Analysis 1

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	3.32
	Confidence Interval	(2-Sided) 95%; 1.80 to 4.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	264	158
Least Squares Mean (Standard Error) [mg/dL]	-11.87 (2.70)	-4.02 (3.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NB32, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.85
	Confidence Interval	(2-Sided) 95%; -16.21 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	208	124
Least Squares Mean (Standard Error) [cm]	-4.97 (0.47)	-2.89 (0.61)

Statistical Analysis 1

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	-2.08
	Confidence Interval	(2-Sided) 95%; -3.57 to -0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	18.49 5.5%	5.66 3.3%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	3.75
	Confidence Interval	(2-Sided) 95%; 1.79 to 7.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	HbA1c- Proportion of Subjects With HbA1c <7% at Endpoint
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	222	137
Number (95% Confidence Interval) [percentage of participants]	44.14 13.2%	26.28 15.5%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	2.46
	Confidence Interval	(2-Sided) 95%; 1.50 to 4.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percent of Subjects Requiring Rescue Medications for Diabetes
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	22.26 6.6%	35.22 20.7%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percent of Subjects With Dose Reduction in Oral Antidiabetes Medications
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	1.89 0.6%	1.26 0.7%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.27 to 7.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Percent of Subjects With Dose Increase in Oral Antidiabetes Medications
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	3.02 0.9%	1.26 0.7%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	2.63
	Confidence Interval	(2-Sided) 95%; 0.55 to 12.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	199	112
Least Squares Mean (95% Confidence Interval) [percent change]	-20.56	-14.67

Statistical Analysis 1

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	-5.89
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	201	113
Least Squares Mean (95% Confidence Interval) [percent change]	-13.48	-10.35

Statistical Analysis 1

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	-3.13
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	HbA1c- Proportion of Subjects With HbA1c <6.5% at Endpoint
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	222	137
Number (95% Confidence Interval) [percentage of participants]	20.72 6.2%	10.22 6%

Statistical Analysis 1

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	Odds Ratio (OR)
	Estimated Value	2.64
	Confidence Interval	(2-Sided) 95%; 1.36 to 5.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	241	153
Least Squares Mean (Standard Error) [units on a scale]	9.27 (0.70)	7.90 (0.86)

Statistical Analysis 1

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	1.37
	Confidence Interval	(2-Sided) 95%; -0.77 to 3.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	202	119
Least Squares Mean (95% Confidence Interval) [percent change]	-20.91	-13.29

Statistical Analysis 1

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	-7.62
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Percent of Subjects Discontinuing Due to Poor Glycemic Control
Description	Due to pre-specified hypothesis testing design, no formal statistical inference testing was performed. Odds ratio not calculated as there were no subjects in the NB32 group that discontinued due to poor glycemic control.
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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Number (95% Confidence Interval) [percentage of participants]	0 0%	1.89 1.1%

19. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	225	146
Least Squares Mean (Standard Error) [units on a scale]	-11.89 (1.39)	-6.91 (1.69)

Statistical Analysis 1

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	-4.98
	Confidence Interval	(2-Sided) 95%; -9.22 to -0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	220	134
Least Squares Mean (Standard Error) [mg/dL]	-1.44 (1.94)	-0.01 (2.44)

Statistical Analysis 1

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	-1.43
	Confidence Interval	(2-Sided) 95%; -7.48 to 4.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Least Squares Mean (Standard Error) [mm Hg]	0.03 (0.70)	-1.12 (0.88)

Statistical Analysis 1

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	1.16
	Confidence Interval	(2-Sided) 95%; -1.02 to 3.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Least Squares Mean (Standard Error) [mm Hg]	-1.06 (0.47)	-1.47 (0.59)

Statistical Analysis 1

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	0.41
	Confidence Interval	(2-Sided) 95%; -1.04 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	265	159
Least Squares Mean (Standard Error) [units on a scale]	0.01 (0.33)	-1.60 (0.42)

Statistical Analysis 1

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	1.62
	Confidence Interval	(2-Sided) 95%; 0.59 to 2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	241	155
Least Squares Mean (Standard Error) [units on a scale]	-1.97 (0.28)	-2.40 (0.34)

Statistical Analysis 1

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	0.43
	Confidence Interval	(2-Sided) 95%; -0.42 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. 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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg/day	Placebo
Measure Participants	241	155
Least Squares Mean (Standard Error) [units on a scale]	-1.48 (0.26)	-1.52 (0.32)

Statistical Analysis 1

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	0.04
	Confidence Interval	(2-Sided) 96%; -0.76 to 0.85
	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	NB32		Placebo
Arm/Group Description	Naltrexone SR 32 mg/Bupropion SR 360 mg daily		Placebo
All Cause Mortality
	NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/333 (3.9%)		8/169 (4.7%)
Cardiac disorders
Angina pectoris	0/333 (0%)	0	2/169 (1.2%)	2
Arrhythmia	0/333 (0%)	0	1/169 (0.6%)	1
Atrial fibrillation	0/333 (0%)	0	2/169 (1.2%)	2
Coronary artery occlusion	1/333 (0.3%)	1	0/169 (0%)	0
Myocardial infarction	1/333 (0.3%)	1	0/169 (0%)	0
Ear and labyrinth disorders
Vertigo	1/333 (0.3%)	1	0/169 (0%)	0
Gastrointestinal disorders
Inguinal hernia, obstructive	1/333 (0.3%)	1	0/169 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/333 (0.3%)	1	0/169 (0%)	0
Immune system disorders
Anaphylactic reaction	0/333 (0%)	0	1/169 (0.6%)	1
Infections and infestations
Cellulitis	1/333 (0.3%)	1	1/169 (0.6%)	1
Diverticulitis	1/333 (0.3%)	1	0/169 (0%)	0
Gastroenteritis	1/333 (0.3%)	1	0/169 (0%)	0
Lobar pneumonia	1/333 (0.3%)	1	0/169 (0%)	0
Staphylococcal infection	0/333 (0%)	0	1/169 (0.6%)	1
Investigations
Troponin increased	0/333 (0%)	0	1/169 (0.6%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/333 (0.3%)	1	0/169 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/333 (0%)	0	1/169 (0.6%)	1
Colon cancer	1/333 (0.3%)	1	0/169 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/333 (0%)	0	1/169 (0.6%)	1
Grand mal convulsion	1/333 (0.3%)	1	0/169 (0%)	0
Syncope vasovagal	2/333 (0.6%)	2	0/169 (0%)	0
Renal and urinary disorders
Calculus ureteric	0/333 (0%)	0	1/169 (0.6%)	1
Other (Not Including Serious) Adverse Events
	NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	275/333 (82.6%)		109/169 (64.5%)
Gastrointestinal disorders
Abdominal pain upper	17/333 (5.1%)	18	3/169 (1.8%)	4
Constipation	59/333 (17.7%)	69	12/169 (7.1%)	13
Diarrhoea	52/333 (15.6%)	60	16/169 (9.5%)	21
Dry mouth	21/333 (6.3%)	22	5/169 (3%)	5
Nausea	141/333 (42.3%)	196	12/169 (7.1%)	13
Vomiting	61/333 (18.3%)	80	6/169 (3.6%)	7
General disorders
Oedema peripheral	2/333 (0.6%)	3	10/169 (5.9%)	15
Infections and infestations
Influenza	9/333 (2.7%)	9	9/169 (5.3%)	9
Nasopharyngitis	28/333 (8.4%)	32	23/169 (13.6%)	25
Sinusitis	16/333 (4.8%)	19	14/169 (8.3%)	19
Upper respiratory tract infection	26/333 (7.8%)	30	16/169 (9.5%)	22
Metabolism and nutrition disorders
Diabetes mellitus	15/333 (4.5%)	16	15/169 (8.9%)	15
Hypoglycaemia	25/333 (7.5%)	65	12/169 (7.1%)	18
Musculoskeletal and connective tissue disorders
Back pain	9/333 (2.7%)	11	9/169 (5.3%)	9
Pain in extremity	13/333 (3.9%)	15	12/169 (7.1%)	13
Nervous system disorders
Dizziness	39/333 (11.7%)	52	9/169 (5.3%)	11
Headache	46/333 (13.8%)	53	15/169 (8.9%)	18
Tremor	22/333 (6.6%)	26	4/169 (2.4%)	4
Psychiatric disorders
Anxiety	18/333 (5.4%)	20	2/169 (1.2%)	2
Insomnia	37/333 (11.1%)	42	9/169 (5.3%)	10
Vascular disorders
Hypertension	33/333 (9.9%)	33	7/169 (4.1%)	8

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.