A Safety and Efficacy Study of Naltrexone SR/Bupropion SR and Placebo in Overweight and Obese Subjects Participating in an Intensive Behavior Modification Program

• Sponsor: Orexigen Therapeutics, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00456521
• Collaborator: (none)
• Enrollment: 793
• Locations: 9
• Arms: 2
• Duration (Months): 21.1
• Patients Per Site: 88.1
• Patients Per Site Per Month: 4.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a combination of naltrexone SR and bupropion SR is safe and effective in treating obesity and leads to greater weight loss when given with a group lifestyle modification program than with group lifestyle modification alone.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Overweight	Drug: Naltrexone SR 32 mg/ bupropion SR 360 mg/ day; Drug: Placebo; Behavioral: Intensive group lifestyle modification counseling	Phase 3

Detailed Description

The combination of group lifestyle modification counseling and pharmacotherapy has recently been shown to result in nearly twice the average weight loss at one year (12.1 kg) as pharmacotherapy alone (sibutramine, 5.0 kg) or lifestyle modification counseling alone (6.7 kg). Combining pharmacotherapy with a comprehensive program of diet, exercise and group lifestyle modification counseling may provide the best weight loss regimen. This study evaluated weight loss in subjects participating in such a comprehensive program who received a combination of naltrexone SR and bupropion SR, or placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 793 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 Sustained Release (SR)/Bupropion SR and Placebo in Subjects With Obesity Participating in a Behavior Modification Program
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NB32 Naltrexone SR 32 mg/ bupropion SR 360 mg/ day with intensive group lifestyle modification counseling	Drug: Naltrexone SR 32 mg/ bupropion SR 360 mg/ day; Other Names: NB32 ; Behavioral: Intensive group lifestyle modification counseling
Placebo Comparator: Placebo Placebo with intensive group lifestyle modification counseling	Drug: Placebo; Behavioral: Intensive group lifestyle modification 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 Triglycerides Levels, Using Log-transformed Data [Baseline, 56 weeks]

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

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

6. 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

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

   HOMA-IR= Homeostasis Model Assessment-Insulin Resistance

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

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

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

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

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

13. 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.

14. Change in Food Craving Inventory Sweets Subscale Scores [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).

15. Change in Food Craving Inventory Carbohydrates Subscale Scores [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).

16. 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

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Female or male subjects aged 18 to 65 years (inclusive)

• Body mass index (weight [kg]/height [m²]) ≥30 and ≤45 kg/m² for subjects with uncomplicated obesity, and BMI of ≥27 and ≤45 kg/m² for subjects with controlled hypertension and/or dyslipidemia

• Non-smoker and had not used tobacco or nicotine products for at least 6 months before screening

• Normotensive (systolic ≤140 mm Hg and diastolic ≤90 mm Hg). Anti-hypertensive medications were allowed with the exception of alpha-adrenergic blockers, beta-blockers, and clonidine. Medical regimen was to be stable for at least 8 weeks.

• Low-density lipoprotein level <190 mg/dL and triglycerides level <400 mg/dL. Medications for the treatment of dyslipidemia were allowed as long as the medical regimen had been stable for at least 8 weeks.

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

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

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

• Fasting glucose ≤126 mg/dL and not receiving hypoglycemic agents

• No clinically significant abnormality on urinalysis

• Thyroid stimulating hormone (TSH) within 1.5 times ULN or normal triiodothyronine (T3), if TSH was below normal limits

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

• 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

• Completed a food diary for 6 of 7 consecutive days during screening

• Able to comply with all required study procedures and schedule

• Able to speak and read English

• Provided written informed consent

Exclusion Criteria:

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

• Serious medical condition (including but not limited to renal or hepatic insufficiency; congestive heart failure, angina pectoris, myocardial infarction, stroke, claudication, or acute limb ischemia; history of malignancy with exception of non-melanoma skin cancer or surgically cured cervical cancer)

• Serious psychiatric illness (e.g., lifetime history of bipolar disorder, schizophrenia or other psychosis, bulimia, and anorexia nervosa; current serious personality disorder, e.g., borderline; severe major depressive disorder, recent [previous 6 months] suicide attempt or current active suicidal ideation, 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 the previous 6 months

• History of drug or alcohol abuse or dependence within 1 year

• Type I or Type II diabetes mellitus

• Baseline ECG with a corrected QT (QTc) interval (using Bazett's formula >450 millisecond (msec) [males] and >470 msec [females]) 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

• Received excluded concomitant medications: any psychotropic agents (including antipsychotic, antidepressant, anxiolytic, mood stabilizer or anticonvulsant agents) with the exception of low-dose benzodiazepine or hypnotic agents for the treatment of insomnia; any anorectic or weight loss agents; any over-the-counter dietary supplements with psychoactive, appetite or weight effects; alpha-adrenergic blockers; beta-blockers; clonidine; coumadin; theophylline; cimetidine; oral corticosteroids; topiramate, Depo-Provera®; smoking cessation agents; regular use of opioid or opioid-like analgesics

• History of surgical or device (e.g., lap band) 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

• Used drugs, herbs, or dietary supplements believed to significantly affect body weight or participated in a weight loss management program within one month prior to baseline

• Loss or gained >4.0 kilograms within the previous 3 months

• Females who were pregnant or breast-feeding or planning 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	University of California, San Diego: Dept of Family & Preventive Medicine	La Jolla	California	United States	92093
2	Center for Human Nutrition, University of Colorado Health Services Center	Denver	Colorado	United States	80220
3	Univ. of Florida, College of Public Health, and Health Professions	Gainesville	Florida	United States	32611
4	Washington Univ. Center for Human Nutrition	St. Louis	Missouri	United States	63110
5	New York Obesity Research Center, St. Luke's-Roosevelt Hospital Center	New York	New York	United States	10025
6	Center for Weight and Eating Disorders, School of Med., University of Penn.	Philadelphia	Pennsylvania	United States	19104
7	Center for Obesity Research and Education, Temple University	Philadelphia	Pennsylvania	United States	19140
8	Medical University of S. Carolina Weight Management Center	Charleston	South Carolina	United States	29425
9	Behavioral Medicine Research Center	Houston	Texas	United States	77030

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: NCT00456521
• Other Study ID Numbers: NB-302; COR-BMOD
• First Posted: Apr 5, 2007
• Last Update Posted: Dec 17, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by Orexigen Therapeutics, Inc: Obesity; Behavior Modification
• Additional relevant MeSH terms: Obesity; 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	591	202
COMPLETED	342	118
NOT COMPLETED	249	84

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	591	202	793
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.89 (10.42)	45.59 (11.35)	45.82 (10.66)
Sex: Female, Male (Count of Participants)
Female	528 89.3%	185 91.6%	713 89.9%
Male	63 10.7%	17 8.4%	80 10.1%
Race/Ethnicity, Customized (participants) [Number]
White	405 68.5%	149 73.8%	554 69.9%
Black or African American	145 24.5%	44 21.8%	189 23.8%
Asian	6 1%	2 1%	8 1%
Native Hawaiian or Other Pacific Islander	1 0.2%	0 0%	1 0.1%
American Indian or Alaska Native	7 1.2%	1 0.5%	8 1%
Other	27 4.6%	6 3%	33 4.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	100.16 (15.42)	101.88 (14.96)	100.60 (15.31)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	36.34 (4.16)	36.96 (4.18)	36.50 (4.17)

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	482	193
Least Squares Mean (Standard Error) [percentage of body weight]	-9.29 (0.40)	-5.08 (0.60)

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	-4.21
	Confidence Interval	() 95%; -5.56 to -2.86
	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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/ bupropion SR 360 mg/ day	Placebo
Measure Participants	482	193
Number (95% Confidence Interval) [percentage of participants]	66.39 11.2%	42.49 21%

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	2.89
	Confidence Interval	() 95%; 2.02 to 4.13
	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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/ bupropion SR 360 mg/ day	Placebo
Measure Participants	482	193
Number (95% Confidence Interval) [percentage of participants]	41.49 7%	20.21 10%

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	2.92
	Confidence Interval	(2-Sided) 95%; 1.95 to 4.37
	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	NB32	Placebo
Arm/Group Description	Naltrexone SR 32 mg/ bupropion SR 360 mg/ day	Placebo
Measure Participants	391	141
Least Squares Mean (Standard Error) [cm]	-9.98 (0.48)	-6.77 (0.75)

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	-3.21
	Confidence Interval	(2-Sided) 95%; -4.82 to -1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. 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	392	144
Least Squares Mean (95% Confidence Interval) [percent change]	-16.62	-8.51

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	0.004
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.11
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. 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	386	144
Least Squares Mean (95% Confidence Interval) [percent change]	-27.98	-15.45

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	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.53
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. 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	392	144
Least Squares Mean (Standard Error) [mg/dL]	4.10 (0.51)	0.87 (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	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.23
	Confidence Interval	(2-Sided) 95%; 1.52 to 4.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. 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	448	178
Least Squares Mean (Standard Error) [units on a scale]	13.43 (0.56)	10.29 (0.86)

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	3.14
	Confidence Interval	(2-Sided) 95%; 1.23 to 5.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. 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	385	143
Least Squares Mean (95% Confidence Interval) [percent change]	-29.93	-16.56

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	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-13.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. 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	386	143
Least Squares Mean (95% Confidence Interval) [percent change]	-25.87	-16.89

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	0.165
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. 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	393	144
Least Squares Mean (Standard Error) [mg/dL]	-2.36 (0.62)	-1.08 (0.96)

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	-1.28
	Confidence Interval	(2-Sided) 95%; -3.34 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change in Fasting LDL Cholesterol
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	392	143
Least Squares Mean (Standard Error) [mg/dL]	5.43 (1.36)	8.13 (2.13)

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	-2.70
	Confidence Interval	(2-Sided) 95%; -7.26 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. 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	482	193
Least Squares Mean (Standard Error) [mmHg]	-1.32 (0.47)	-3.87 (0.71)

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	2.55
	Confidence Interval	(2-Sided) 95%; 0.97 to 4.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. 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	482	193
Least Squares Mean (Standard Error) [mmHg]	-1.41 (0.33)	-2.78 (0.50)

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%; 0.25 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. 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	482	193
Least Squares Mean (Standard Error) [units on a scale]	0.09 (0.23)	-0.00 (0.35)

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	0.09
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change in Food Craving Inventory Sweets Subscale Scores
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	448	180
Least Squares Mean (Standard Error) [units on a scale]	-2.54 (0.22)	-2.43 (0.33)

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	-0.11
	Confidence Interval	(2-Sided) 95%; -0.85 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change in Food Craving Inventory Carbohydrates Subscale Scores
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 with intensive group behavioral lifestyle modification counseling naltrexone SR/bupropion SR combination Intensive group lifestyle modification counseling: Group lifestyle modification counseling	Placebo
Measure Participants	448	180
Least Squares Mean (Standard Error) [units on a scale]	-2.06 (0.20)	-1.97 (0.31)

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	-0.09
	Confidence Interval	(2-Sided) 95%; -0.78 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. 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	436	178
Least Squares Mean (Standard Error) [units on a scale]	-13.75 (1.17)	-8.46 (1.75)

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	-5.29
	Confidence Interval	(2-Sided) 95%; -9.16 to -1.42
	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 30 days post last dose.
Arm/Group Title	NB32		Placebo
Arm/Group Description	Naltrexone SR 32 mg/ bupropion SR 360 mg/ day		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	22/584 (3.8%)		1/200 (0.5%)
Cardiac disorders
Atrial flutter	1/584 (0.2%)	1	0/200 (0%)	0
Gastrointestinal disorders
Epiploic appendagitis	1/584 (0.2%)	1	0/200 (0%)	0
General disorders
Non-cardiac chest pain	1/584 (0.2%)	1	0/200 (0%)	0
Hepatobiliary disorders
Biliary colic	1/584 (0.2%)	1	0/200 (0%)	0
Cholecystitis	4/584 (0.7%)	4	0/200 (0%)	0
Infections and infestations
Bacterial infection	1/584 (0.2%)	1	0/200 (0%)	0
Bronchitis acute	1/584 (0.2%)	1	0/200 (0%)	0
Bursitis infective	1/584 (0.2%)	1	0/200 (0%)	0
Cellulitis	2/584 (0.3%)	2	0/200 (0%)	0
Gastroenteritis viral	1/584 (0.2%)	1	0/200 (0%)	0
Respiratory tract infection viral	1/584 (0.2%)	1	0/200 (0%)	0
Staphylococcal infection	1/584 (0.2%)	1	0/200 (0%)	0
Injury, poisoning and procedural complications
Joint injury	1/584 (0.2%)	1	0/200 (0%)	0
Tibia fracture	0/584 (0%)	0	1/200 (0.5%)	1
Metabolism and nutrition disorders
Dehydration	1/584 (0.2%)	1	0/200 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/584 (0.2%)	1	0/200 (0%)	0
Intervertebral disc protrusion	1/584 (0.2%)	1	0/200 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma	1/584 (0.2%)	1	0/200 (0%)	0
Nervous system disorders
Migraine	1/584 (0.2%)	1	0/200 (0%)	0
Radiculopathy	1/584 (0.2%)	1	0/200 (0%)	0
Renal and urinary disorders
Calculus ureteric	1/584 (0.2%)	1	0/200 (0%)	0
Nephrolithiasis	1/584 (0.2%)	1	0/200 (0%)	0
Reproductive system and breast disorders
Menorrhagia	1/584 (0.2%)	1	0/200 (0%)	0
Ovarian cyst	1/584 (0.2%)	1	0/200 (0%)	0
Uterine prolapse	1/584 (0.2%)	1	0/200 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/584 (0.2%)	1	0/200 (0%)	0
Other (Not Including Serious) Adverse Events
	NB32		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	465/584 (79.6%)		132/200 (66%)
Ear and labyrinth disorders
Tinnitus	31/584 (5.3%)	33	1/200 (0.5%)	1
Gastrointestinal disorders
Abdominal pain upper	32/584 (5.5%)	33	3/200 (1.5%)	4
Constipation	141/584 (24.1%)	157	28/200 (14%)	32
Diarrhoea	43/584 (7.4%)	45	15/200 (7.5%)	16
Dry mouth	47/584 (8%)	48	6/200 (3%)	6
Nausea	199/584 (34.1%)	228	21/200 (10.5%)	21
Vomiting	64/584 (11%)	76	13/200 (6.5%)	13
General disorders
Fatigue	31/584 (5.3%)	35	13/200 (6.5%)	13
Infections and infestations
Nasopharyngitis	36/584 (6.2%)	41	15/200 (7.5%)	18
Upper respiratory tract infection	38/584 (6.5%)	40	18/200 (9%)	19
Musculoskeletal and connective tissue disorders
Back pain	28/584 (4.8%)	33	12/200 (6%)	12
Nervous system disorders
Dizziness	85/584 (14.6%)	96	9/200 (4.5%)	10
Headache	139/584 (23.8%)	167	35/200 (17.5%)	42
Tremor	34/584 (5.8%)	41	2/200 (1%)	2
Psychiatric disorders
Anxiety	30/584 (5.1%)	34	7/200 (3.5%)	7
Insomnia	51/584 (8.7%)	51	12/200 (6%)	13
Respiratory, thoracic and mediastinal disorders
Cough	28/584 (4.8%)	35	15/200 (7.5%)	18
Nasal congestion	20/584 (3.4%)	23	10/200 (5%)	12
Pharyngolaryngeal pain	29/584 (5%)	36	17/200 (8.5%)	19
Sinus congestion	18/584 (3.1%)	20	13/200 (6.5%)	15

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.