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CONTRAVE Clinical Data

Phase 3 Efficacy Results

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COR-I study

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COR-I study*

Demonstrated Weight Loss with CONTRAVE vs. Placebo1

Mean change in body weight was -5.4% in the CONTRAVE 32 mg/360 mg group vs. -1.3% in the placebo group (primary endpoint, ITT population).1

Mean change in weight over 56 weeks in the completer population

Treatment response graph of the mean percent change from baseline body weight for CONTRAVE (32 mg/360 mg) +diet and exercise (n=269) and placebo +diet and exercise (n=290). Weight change from baseline from 0 to -10 percent in the increments of 2 (0, -2, -4, -6, -8. -10). Treatment duration in weeks from baseline to 56, with measurements taken at baseline, and at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. In the group that completed the treatment (completers), the mean percent change in body weight was -8.1% (8.2 kg) for CONTRAVE + diet and exercise and -1.8% (1.8 kg) for placebo + diet and exercise. In the intention to treat population (ITT), the percent change from baseline body weight was four times greater in the CONTRAVE group -5.4% (5.5 kg) compared to -1.3% (1.4 kg) for placebo. The values included last observation carried forward (LOCF) and the difference between groups was statistically significant (p <0.001).

4X more weight loss with CONTRAVE in the ITT population (primary endpoint, LOCF)

-1.3% (1.4 kg) placebo

-5.4% (5.5 kg) CONTRAVE (p<0.001)

ITT: intention to treat; LOCF: last observation carried forward.
Adapted from the product monograph.1

50.1% of patients in the placebo group and 49.2% of patients in the CONTRAVE group discontinued treatment.1

Demonstrated Effect of CONTRAVE on Cardiovascular and Metabolic Parameters1
The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.1

Change in cardiovascular and metabolic parameters from baseline to week 56 in patients with overweight or with obesity, and without diabetes

Treatment responses in the CONTRAVE +diet and exercise (n=471) and placebo +diet and exercise (n=511) patients.1 Cardiovascular and metabolic parameters included waist circumference (cm), triglycerides (% mmol/L), HDL-C (high-density lipoprotein cholesterol) (% mmol/L), LDL-C (low-density lipoprotein cholesterol) (% mmol/L), systolic BP (mmHg), diastolic BP (mmHg), and heart rate (bpm).1 Change from baseline (0) from +10 to -10 in the increments of 2 (10, 8, 6, 4, 2, 0, -2, -4, -6, -8. -10). Values are least square means, from all randomised subjects who had a baseline measurement and had at least one post-baseline body weight measurement while on study drug. Based on LOCF with the last on-drug observation carried forward.1 Treatment response rates for CONTRAVE + diet and exercise, and placebo + diet and exercise patents, respectively: 1 Waist circumference (cm): -6.2, -2.5 Triglycerides (% mmol/L): -11.6, 1.7. Triglyceride values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference. HDL-C (% mmol/L): 8.0, 0.8 LDL-C (% mmol/L): -2.0, -0.5 Systolic BP (mmHg): 0, -1.9 Diastolic BP (mmHg): 0, -0.9 Heart rate (bpm): 1.0, -0.2

Full analysis set: based on LOCF with the last on-drug observation carried forward.
BP: blood pressure; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol.
†Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference.
‡Least square means, from all randomised subjects who had a baseline measurement and had at least one post-baseline body weight measurement while on study drug. Based on LOCF with the last on-drug observation carried forward.
Adapted from the product monograph.1

COR-I study design

*Phase 3, 56-week, multicentre, double-blinded, placebo-controlled study of patients with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one comorbidity (hypertension or dyslipidemia). Patients were randomized to naltrexone (16–50 mg/day) and/or bupropion (300–400 mg/day) or placebo. Results presented are for the recommended daily dose of two 8 mg/90 mg tablets taken twice daily for a total dose of 32 mg/360 mg. Treatment was initiated with a 3-week dose-escalation period followed by approximately 1 year of continued therapy. Treatment included a program consisting of instruction to follow a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity. Co-primary endpoints were percent change from baseline body weight and proportion of subjects achieving ≥5% total decreased body weight. Mean baseline weight: CONTRAVE group 99.8 kg (N=538); placebo group 99.5 kg (N=536). Other mean baseline values for CONTRAVE/placebo: waist circumference (cm) 108.8/110.0; triglycerides (mmol/L) 1.3/1.3; HDL-C (mmol/L) 1.3/1.3; LDL-C (mmol/L) 3.1/3.1; systolic blood pressure (mmHg) 118.9/119.0; diastolic blood pressure (mmHg) 77.1/77.3; heart rate (bpm) 72.1/71.8.1

Reference:

  1. CONTRAVE Product Monograph. Bausch Health Canada, March 2, 2022.

COR-Diabetes study

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COR-Diabetes study*

Patients with Overweight or Obesity and Type 2 Diabetes

Demonstrated Weight Loss with CONTRAVE vs. Placebo

Mean change in body weight was -3.7% in the CONTRAVE 32 mg/360 mg group vs -1.7% in the placebo group (primary endpoint, ITT population).1

Mean change in weight over 56 weeks in the completer population

Treatment response graph of the mean percent change from baseline body weight for CONTRAVE (32 mg/360 mg) (n=175) and placebo (n=100).2 In the group that completed the treatment (completers), the mean percent change in body weight was -5.9% (6.2 kg) for CONTRAVE and -2.2% (2.3 kg) for placebo.2 In the intention to treat population (ITT), the percent change from baseline body weight was 2.2 times greater in the CONTRAVE group -3.7% (3.9 kg) compared to --1.7% (1.8 kg) for placebo. The values included last observation carried forward (LOCF) and the difference between groups was statistically significant (p <0.001).

2.2X more weight loss with CONTRAVE in the ITT population (primary endpoint, LOCF)

-1.7% (1.8 kg) placebo

-3.7% (3.9 kg) CONTRAVE (p<0.001)

ITT: intention to treat; LOCF: last observation carried forward.
Adapted from the product monograph and Hollander et al. 20131,2

41.2% of patients in the placebo group and 47.8% of patients in the CONTRAVE group discontinued treatment.1

Demonstrated Effect of CONTRAVE on Cardiovascular and Metabolic Parameters1
The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.1

Change in cardiovascular and metabolic parameters from baseline to week 56 in patients with overweight or with obesity, and with diabetes

Treatment responses in the CONTRAVE (n=265) and placebo (n=159) patients.1 Cardiovascular and metabolic parameters included Hb1Ac (hemoglobin 1Ac); waist circumference (cm), triglycerides (% mmol/L), HDL-C(high-density lipoprotein cholesterol) (% mmol/L), LDL-C (low-density lipoprotein cholesterol) (% mmol/L), (% mmol/L), systolic BP (mmHg), diastolic BP (mmHg), and heart rate (bpm).1 Treatment response rates for CONTRAVE and placebo patients, respectively:1 HbA1c (%): -0.6, -0.1 Waist circumference (cm): -5.0, -2.9 Triglycerides (% mmol/L): -7.7, -8.6 Triglyceride values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference. HDL-C (% mmol/L): 7.4, -0.2 LDL-C (% mmol/L): 2.4, 4.2 Systolic BP (mmHg): 0, -1.1 Diastolic BP (mmHg): -1.1, -1.5 Heart rate (bpm): 0.7, -0.2

Full analysis set: based on LOCF with the last on-drug observation carried forward.
BP: blood pressure; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol.
†Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference.
‡Least square means, from all randomised subjects who had a baseline measurement and had at least one post-baseline body weight measurement while on study drug. Based on LOCF with the last on-drug observation carried forward.
Adapted from the product monograph.1

*Phase 3, 56-week, multicentre, double-blinded, placebo-controlled study of patients with BMI greater than 27 kg/m2 and type 2 diabetes mellitus with or without hypertension and/or dyslipidemia and not achieving glycemic goal of a HbA1c less than 7% either with or without oral antidiabetic agents. Patients were randomized to naltrexone (16–50 mg/day) and/or bupropion (300–400 mg/day) or placebo. Results presented are for the recommended daily dose of two 8 mg/90 mg tablets taken twice daily for a total dose of 32 mg/360 mg. Treatment was initiated with a 3-week dose-escalation period followed by approximately 1 year of continued therapy. Treatment included a program consisting of instruction to follow a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioural counseling, and increased physical activity. Co-primary endpoints were percent change from baseline body weight and proportion of patients achieving ≥5% total decreased body weight. Mean baseline weight for CONTRAVE/placebo: 104.2 kg (N=321)/105.3 kg (N=166). Other mean baseline values for CONTRAVE/placebo: HbA1c (%) 8.0/8.0; fasting glucose (mmol/L) 8.9/9.1; waist circumference (cm) 115.6/114.3; triglycerides (mmol/L) 1.7/1.9; HDL-C (mmol/L) 1.2/1.2; LDL-C (mmol/L) 2.6/2.6; systolic blood pressure (mmHg) 125.0/124.5; diastolic blood pressure (mmHg) 77.5/77.4; heart rate (bpm) 72.9/73.1.1

Reference:

  1. CONTRAVE Product Monograph. Bausch Health Canada, March 2, 2022.
  2. Hollander P et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care 2013;36:4022–9.

COR-BMOD study

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COR-BMOD study*

In Conjunction with Intensive BMOD Counselling†
Demonstrated Weight Loss with CONTRAVE vs. Placebo1

Mean change in body weight was -8.1% in the CONTRAVE 32 mg/360 mg group vs. -4.9% in the placebo group (primary endpoint, ITT population).1

Mean change in weight over 56 weeks in the completer population

Treatment response graph of the mean percent change from baseline body weight for CONTRAVE (32 mg/360 mg) + intensive BMOD counselling (n=301) and placebo + intensive BMOD counselling (n=106).2 Weight change from baseline from 0 to -12 percent in the increments of 2 (0, -2, -4, -6, -8. -10, -12).1 Treatment duration in weeks from 0 to 56, with measurements taken at baseline, and at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. In the group that completed the treatment (completers), the mean percent change in body weight was -11.5% (11.5 kg) for CONTRAVE + intensive BMOD counselling and -7.3% (7.4 kg) for placebo + intensive BMOD counselling. 2 In the intention to treat population (ITT), the percent change from baseline body weight was significantly greater in the CONTRAVE group -8.1% (8.1 kg) compared to -4.9% (5.0 kg) for placebo group (p <0.001). The values included last observation carried forward (LOCF).

Significantly more weight loss with CONTRAVE in the ITT population (primary endpoint, LOCF)

-4.9% (5.0 kg) placebo

-8.1% (8.1 kg) CONTRAVE (p<0.001)

ITT: intention to treat; LOCF: last observation carried forward.
Adapted from the product monograph and Wadden et al. 2011.1,2

41.6% of patients in the placebo group and 42.1% of patients in the CONTRAVE group discontinued treatment.1

In Conjunction with Intensive BMOD Counselling†
Demonstrated Effect of CONTRAVE on Cardiovascular and Metabolic Parameters1
The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.1

Change in cardiovascular and metabolic parameters from baseline to week 56 in patients with overweight or with obesity, and without diabetes

Treatment responses in the CONTRAVE +diet and exercise (n=482) and placebo +diet and exercise (n=193) patients. Cardiovascular and metabolic parameters included waist circumference (cm), triglycerides (% mmol/L), high-density lipoprotein cholesterol) (% mmol/L), LDL-C (low-density lipoprotein cholesterol), systolic BP (mmHg), diastolic BP (mmHg), and heart rate (bpm). Treatment response rates for CONTRAVE + diet and exercise, and placebo + diet and exercise patents, respectively: Waist circumference (cm): -10.0, -6.8 Triglycerides (% mmol/L): -17.8, -7.4 Triglycerides values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference. HDL-C (% mmol/L): 9.4, 2.8 LDL-C (% mmol/L): 7.1, 10.0 Systolic BP (mmHg): -1.3, -3.9 Diastolic BP (mmHg): -1.4, -2.8 Heart rate (bpm): 1.1, 0.2[1BQ, p46-47]

Full analysis set: based on LOCF with the last on-drug observation carried forward.
BP: blood pressure; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol.
‡Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference.
§Least square means, from all randomised subjects who had a baseline measurement and had at least one post-baseline body weight measurement while on study drug. Based on LOCF with the last on-drug observation carried forward.
Adapted from the product monograph.1

BMOD: behavioural modification.

*A phase 3, 56-week multicentre, double-blinded, placebo-controlled study of patients with obesity (BMI ≥30 kg/m2) or with overweight (BMI ≥27 kg/m2) and at least one comorbidity (hypertension or dyslipidemia). Patients were randomized to naltrexone (16–50 mg/day) and/or bupropion (300–400 mg/day) or placebo. Results presented are for the recommended daily dose of two 8 mg/90 mg tablets taken twice daily for a total dose of 32 mg/360 mg. Treatment was initiated with a 3-week dose-escalation period followed by approximately 1 year of continued therapy. Treatment included an intensive behavioural modification program consisting of 28 group counselling sessions over 56 weeks as well as a prescribed diet and exercise program. Co-primary endpoints were percent change from baseline body weight and proportion of patients achieving ≥5% total decreased body weight. Mean baseline weight for CONTRAVE/placebo: 100.3 kg (N=565)/101.8 kg (N=196). Other mean baseline values for CONTRAVE/placebo: waist circumference (cm) 109.3/109.0; triglycerides (mmol/L) 1.24/1.16; HDL-C (mmol/L) 1.6/1.4; LDL-C (mmol/L) 2.8/2.8; systolic blood pressure (mmHg) 116.9/116.7; diastolic blood pressure (mmHg) 78.2/77.2; heart rate (bpm) 70.7/70.4.1

†Intensive behavioural modification program consisting of 28 group counselling sessions over 56 weeks combined with a prescribed diet and exercise program.

Reference:

  1. CONTRAVE Product Monograph. Bausch Health Canada, March 2, 2022.

CONTRAVE Demonstrated Safety and Tolerability Profile

Safety profile

The most frequently reported adverse reactions for CONTRAVE (incidence ≥5% and twice the incidence in placebo) vs. placebo were nausea (33% vs. 7%), constipation (19% vs. 7%), vomiting (11% vs. 3%), dizziness (10% vs. 3%) and dry mouth (8% vs. 2%). Headache was also more commonly observed in CONTRAVE patients than in placebo (18% vs. 10%).1

Nausea

The vast majority of subjects treated with CONTRAVE who experienced nausea reported the event within four weeks of starting treatment. Events were generally self-limited; the majority of events resolved within four weeks and almost all resolved by Week 24. The incidence of severe nausea was low, but was higher with CONTRAVE than placebo (severe nausea: naltrexone / bupropion 1.9%, placebo <0.1%).1

Gastrointestinal events for patients with type 2 diabetes

Patients with type 2 diabetes treated with CONTRAVE demonstrated a higher incidence of gastrointestinal adverse events, primarily nausea, vomiting, and diarrhea, than subjects without diabetes. Patients with type 2 diabetes may be more prone to these events due to concomitant medicinal product use (e.g., metformin) or may be more likely to have underlying gastrointestinal disorders (e.g., gastroparesis) predisposing to gastrointestinal symptoms.1

Tolerability profile

24% of CONTRAVE patients discontinued treatment due to an adverse event vs. 12% for placebo. The most frequent adverse reactions leading to discontinuation with CONTRAVE were nausea (6%), headache (2%), dizziness (1%) and vomiting (1%).1

Reference:

  1. CONTRAVE Product Monograph. Bausch Health Canada, March 2, 2022.

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