Trial Outcomes & Findings for A Safety and Efficacy Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects (NCT NCT00567255)

NCT ID: NCT00567255

Last Updated: 2014-11-21

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1496 participants

Primary outcome timeframe

Baseline, 28 weeks

Results posted on

2014-11-21

Participant Flow

Participant milestones

Participant milestones
Measure	NB32 Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo Placebo
Overall Study STARTED	1001	495
Overall Study COMPLETED	538	267
Overall Study NOT COMPLETED	463	228

Reasons for withdrawal

Reasons for withdrawal
Measure	NB32 Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo Placebo
Overall Study Adverse Event	241	68
Overall Study Lost to Follow-up	77	48
Overall Study Withdrawal by Subject	75	56
Overall Study Lack of Efficacy	19	33
Overall Study Protocol Violation	20	8
Overall Study Pregnancy	6	0
Overall Study Drug noncompliance,moved,other	25	15

Baseline Characteristics

A Safety and Efficacy Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	NB32 n=1001 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=495 Participants Placebo	Total n=1496 Participants Total of all reporting groups
Age, Continuous	44.27 years STANDARD_DEVIATION 11.16 • n=5 Participants	44.41 years STANDARD_DEVIATION 11.38 • n=7 Participants	44.32 years STANDARD_DEVIATION 11.23 • n=5 Participants
Sex: Female, Male Female	847 Participants n=5 Participants	420 Participants n=7 Participants	1267 Participants n=5 Participants
Sex: Female, Male Male	154 Participants n=5 Participants	75 Participants n=7 Participants	229 Participants n=5 Participants
Race/Ethnicity, Customized White	835 participants n=5 Participants	414 participants n=7 Participants	1249 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	133 participants n=5 Participants	72 participants n=7 Participants	205 participants n=5 Participants
Race/Ethnicity, Customized Asian	12 participants n=5 Participants	4 participants n=7 Participants	16 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	10 participants n=5 Participants	2 participants n=7 Participants	12 participants n=5 Participants
Race/Ethnicity, Customized Other	8 participants n=5 Participants	2 participants n=7 Participants	10 participants n=5 Participants
Weight	100.3 kg STANDARD_DEVIATION 16.55 • n=5 Participants	99.21 kg STANDARD_DEVIATION 15.86 • n=7 Participants	99.95 kg STANDARD_DEVIATION 16.33 • n=5 Participants
BMI	36.22 kg/m^2 STANDARD_DEVIATION 4.45 • n=5 Participants	36.09 kg/m^2 STANDARD_DEVIATION 4.27 • n=7 Participants	36.17 kg/m^2 STANDARD_DEVIATION 4.39 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 28 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	NB32 n=825 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Co-primary: Body Weight- Mean Percent Change From Baseline to Week 28	-6.45 percentage of body weight Standard Error 0.20	-1.89 percentage of body weight Standard Error 0.26

PRIMARY outcome

Timeframe: Baseline, 28 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	NB32 n=825 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Co-primary: Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 28	55.64 percentage of participants Interval 52.25 to 59.03	17.54 percentage of participants Interval 14.05 to 21.03

SECONDARY outcome

Timeframe: Baseline, 56 weeks

Beginning at Week 28 through Week 44, NB32-treated subjects who failed to achieve or maintain at least 5% body weight loss from baseline were re-randomized (1:1 ratio) to continue NB32 or begin treatment with a higher dose of naltrexone SR - naltrexone SR 48 mg/bupropion SR 360 mg (referred to as NB48) (daily dose of bupropion SR was 360 mg for NB32 and NB48).The analysis of NB32 vs. placebo at Week 56 was completed using a weighted analysis. This analysis was referred to as the weighted LOCF analysis. Subjects treated with NB32 who were re-randomized to NB48 were not included. Subjects re-randomized to NB32 were double-weighted and subjects who were not re-randomized were single-weighted. Subjects in the placebo group were single-weighted. The double weighting analysis restored the influence of poor performers at Weeks 28 to 44 in the NB32 group without including any data from the higher dose group (NB48).

Outcome measures

Outcome measures
Measure	NB32 n=702 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Body Weight- Mean Percent Change From Baseline to Week 56	-6.40 percentage of body weight Standard Error 0.25	-1.23 percentage of body weight Standard Error 0.33

SECONDARY outcome

Timeframe: Baseline, 56 weeks

Outcome measures

Outcome measures
Measure	NB32 n=702 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Body Weight- Proportion of Subjects With ≥5% Decrease From Baseline to Week 56	50.48 percentage of participants Interval 46.9 to 54.07	17.11 percentage of participants Interval 13.46 to 20.75

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=825 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Body Weight- Proportion of Subjects With ≥10% Decrease From Baseline to Week 28	27.27 percentage of participants Interval 24.23 to 30.31	7.02 percentage of participants Interval 4.67 to 9.36

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=622 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=315 Participants Placebo
Change in Waist Circumference	-6.16 cm Standard Error 0.28	-2.74 cm Standard Error 0.38

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=625 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=308 Participants Placebo
Change in Fasting HDL Cholesterol Levels	1.19 mg/dL Standard Error 0.30	-1.40 mg/dL Standard Error 0.42

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=625 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=308 Participants Placebo
Change in Fasting Triglycerides Levels, Using Log-transformed Data	-7.32 percent change Interval -9.8 to -4.76	-1.36 percent change Interval -5.02 to 2.43

SECONDARY outcome

Timeframe: Baseline, 28 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

Outcome measures

Outcome measures
Measure	NB32 n=628 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=317 Participants Placebo
Change in IWQOL-Lite Total Scores	9.94 units on a scale Standard Error 0.41	6.17 units on a scale Standard Error 0.56

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=607 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=304 Participants Placebo
Change in High-sensitivity C Reactive Protein (Hs-CRP) Levels, Using Log-transformed Data	-9.38 percent change Interval -14.78 to -3.63	-1.14 percent change Interval -9.11 to 7.52

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=589 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=286 Participants Placebo
Change in Fasting Insulin Levels, Using Log-transformed Data	-14.14 percent change Interval -17.86 to -10.24	-0.50 percent change Interval -6.49 to 5.88

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=628 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=310 Participants Placebo
Change in Fasting Blood Glucose Levels	-2.11 mg/dL Standard Error 0.38	-1.73 mg/dL Standard Error 0.52

SECONDARY outcome

Timeframe: Baseline, 28 weeks

HOMA-IR= Homeostasis Model Assessment-Insulin Resistance

Outcome measures

Outcome measures
Measure	NB32 n=580 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=278 Participants Placebo
Change in HOMA-IR Levels, Using Log-transformed Data	-16.44 percent change Interval -20.37 to -12.31	-4.15 percent change Interval -10.43 to 2.57

SECONDARY outcome

Timeframe: Baseline, 28 weeks

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

Outcome measures

Outcome measures
Measure	NB32 n=731 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=409 Participants Placebo
Change in Question 19 From 21-Item COE (Control of Eating) Questionnaire	-18.32 units on a scale Standard Error 0.85	-11.09 units on a scale Standard Error 1.12

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=620 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=308 Participants Placebo
Change in Fasting LDL Cholesterol Levels	-4.36 mg/dL Standard Error 0.90	0.00 mg/dL Standard Error 1.25

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=824 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Change in Systolic Blood Pressure	-0.93 mm Hg Standard Error 0.31	-1.23 mm Hg Standard Error 0.42

SECONDARY outcome

Timeframe: Baseline, 28 weeks

Outcome measures

Outcome measures
Measure	NB32 n=824 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=456 Participants Placebo
Change in Diastolic Blood Pressure	0.20 mm Hg Standard Error 0.22	-0.67 mm Hg Standard Error 0.30

SECONDARY outcome

Timeframe: Baseline, 28 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.

Outcome measures

Outcome measures
Measure	NB32 n=825 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=455 Participants Placebo
Change in IDS-SR Total Score	-0.23 units on a scale Standard Error 0.17	-0.28 units on a scale Standard Error 0.23

SECONDARY outcome

Timeframe: Baseline, 28 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).

Outcome measures

Outcome measures
Measure	NB32 n=753 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=418 Participants Placebo
Change in Food Craving Inventory Sweets Subscale Score	-3.20 units on a scale Standard Error 0.17	-3.18 units on a scale Standard Error 0.22

SECONDARY outcome

Timeframe: Baseline, 28 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).

Outcome measures

Outcome measures
Measure	NB32 n=754 Participants Naltrexone SR 32 mg/bupropion SR 360 mg/day	Placebo n=418 Participants Placebo
Change in Food Craving Inventory Carbohydrates Subscale Score	-2.68 units on a scale Standard Error 0.16	-2.20 units on a scale Standard Error 0.21

Adverse Events

NB32/48

Serious events: 21 serious events

Other events: 671 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 244 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	NB32/48 n=992 participants at risk Naltrexone SR 32 mg/bupropion SR 360 mg/day or naltrexone SR 48 mg/bupropion SR 360 mg/day Beginning at Week 28 through Week 44, NB32-treated subjects who failed to achieve or maintain at least 5% body weight loss from baseline were re-randomized (1:1 ratio) to continue NB32 or begin treatment with a higher dose of naltrexone SR - naltrexone SR 48 mg/bupropion SR 360 mg (referred to as NB48) (daily dose of bupropion SR was 360 mg for NB32 and NB48). NB32/48 group includes all participants in the safety analysis set randomized to NB32 at baseline, regardless of re-randomization status.	Placebo n=492 participants at risk Placebo
Gastrointestinal disorders Constipation	19.1% 189/992 • Number of events 199 • Baseline, 56 weeks 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.	7.1% 35/492 • Number of events 36 • Baseline, 56 weeks 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.
Gastrointestinal disorders Diarrhoea	5.5% 55/992 • Number of events 57 • Baseline, 56 weeks 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.	3.7% 18/492 • Number of events 21 • Baseline, 56 weeks 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.
Gastrointestinal disorders Dry mouth	9.1% 90/992 • Number of events 91 • Baseline, 56 weeks 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.	2.6% 13/492 • Number of events 13 • Baseline, 56 weeks 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.
Gastrointestinal disorders Nausea	29.2% 290/992 • Number of events 329 • Baseline, 56 weeks 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.	6.9% 34/492 • Number of events 41 • Baseline, 56 weeks 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.
Gastrointestinal disorders Vomiting	8.5% 84/992 • Number of events 95 • Baseline, 56 weeks 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.	2.0% 10/492 • Number of events 10 • Baseline, 56 weeks 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.
Infections and infestations Bronchitis	1.4% 14/992 • Number of events 14 • Baseline, 56 weeks 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.	5.1% 25/492 • Number of events 26 • Baseline, 56 weeks 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.
Infections and infestations Nasopharyngitis	8.3% 82/992 • Number of events 93 • Baseline, 56 weeks 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.	8.1% 40/492 • Number of events 45 • Baseline, 56 weeks 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.
Infections and infestations Sinusitis	5.1% 51/992 • Number of events 63 • Baseline, 56 weeks 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.	7.1% 35/492 • Number of events 41 • Baseline, 56 weeks 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.
Infections and infestations Upper respiratory tract infection	8.7% 86/992 • Number of events 98 • Baseline, 56 weeks 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.	11.2% 55/492 • Number of events 70 • Baseline, 56 weeks 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.
Musculoskeletal and connective tissue disorders Arthralgia	3.8% 38/992 • Number of events 42 • Baseline, 56 weeks 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.	5.7% 28/492 • Number of events 30 • Baseline, 56 weeks 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.
Nervous system disorders Dizziness	6.9% 68/992 • Number of events 76 • Baseline, 56 weeks 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.	3.5% 17/492 • Number of events 19 • Baseline, 56 weeks 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.
Nervous system disorders Headache	17.5% 174/992 • Number of events 197 • Baseline, 56 weeks 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.	8.7% 43/492 • Number of events 47 • Baseline, 56 weeks 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.
Psychiatric disorders Insomnia	9.8% 97/992 • Number of events 106 • Baseline, 56 weeks 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.	6.7% 33/492 • Number of events 34 • Baseline, 56 weeks 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.

Additional Information

Senior Vice President, Head of Global Development

Orexigen Therapeutics, Inc.

Phone: (858) 875-8600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER