Contrave® Clinical Data
Efficacy
In July 2005, we initiated a Phase IIb trial exploring bupropion sustained release (SR) paired with three different doses of naltrexone immediate release (IR). Results at 24 weeks are summarized as follows:
The protocol for this study permitted participants to continue on Contrave or bupropion for an additional 24 weeks of open-label treatment. The placebo arm of the trial was discontinued at this point. The results at 48 weeks are summarized as follows:
Discontinuation of study drug due to an adverse event generally occurred early in treatment. As a result, in the intent-to-treat analysis, the 48mg naltrexone IR plus 400mg bupropion SR treatment appears somewhat less effective than other Contrave dosages. Use of the last-observation-carried-forward, or LOCF, method implies that data for patients who drop out of the study prior to completion are carried forward in the analysis. Thus, limited weight loss observed early in the course of treatment in patients who discontinue treatment early averages down the efficacy observed in patients who remained on therapy for longer periods of time. This effect is illustrated when comparing the intent-to-treat results to the completer analysis.
Safety
There were no serious adverse events related to treatment with Contrave. Overall the Contrave 32/400mg group experienced the lowest rate of discontinuation due to adverse events at approximately 15.9%. Nausea was the most common adverse event reported in the trial. It typically occurred on initial drug exposure and was transient and mild. Discontinuations due to nausea through 24 weeks were substantially lower in the 32/400mg group (7.9%) than in the higher dose 48/400mg group (18.0%). Other adverse events included headache, dizziness and insomnia.
Secondary Endpoints
Visceral Fat In a subset of patients who had a DEXA scan or an abdominal CAT scan at baseline and week 24, the mean reduction in visceral fat ranged from 13.7% to 16.7% across the Contrave groups compared to a 0.1% to 4.6% mean reduction for patients receiving either of the monotherapies or placebo. These results suggest that weight loss associated with Contrave therapy results primarily from fat tissue loss, including a loss of visceral fat.
Visceral fat is located inside the abdominal cavity and surrounds vital organs such as the liver. Visceral fat accumulation, as opposed to subcutaneous fat found just underneath the skin, is associated with increased risk of heart disease and Type II diabetes.
Metabolic Measures On secondary outcome measures, Contrave showed improvements in both serum lipids and glycemic indices at week 24, the primary trial endpoint. In this trial, the optimal treatment results were observed in the Contrave 32/400mg dose group. This group demonstrated statistically significantly greater improvement when compared to either the placebo or monotherapy groups on measures of fasting glucose and insulin resistance (log (HOMA) and the insulin check index (QUICKI)). Significant improvements were also observed when compared with at least one of the control groups in waist circumference, insulin, triglycerides, and homeostatic model assessment of insulin resistance (HOMA).
The chart below summarizes these secondary endpoint data.
Mean Change from Baseline (± SE)
Week 24 Completer Population
|
Placebo |
Naltrexone 48 |
Bupropion |
Contrave 32/400mg |
Weight (% change) 1 |
-1.1 ± 0.6*** |
-1.7±0.9*** |
-3.1± 0.7*** |
-7.1± 0.7 |
DEXA Fat Mass (% change)2 |
-4.0 ± 2.0** |
-3.2 ± 2.5** |
-4.1 ± 2.9* |
-12.0 ± 1.7 |
CT Measured Visceral Fat (% change)2 |
-4.6 ± 2.7* |
-0.1 ± 3.6** |
-2.3 ± 4.3* |
-14.0 ± 2.4 |
Waist (cm)1 |
-1.0 ± 5.4** |
-3.8 ± 12.7 |
-2.9 ± 6.0 |
-5.4 ± 7.6 |
Fasting Glucose (mg/dL)1 |
1.9 ± 1.3* |
3.4 ± 1.7* |
3.5 ± 1.5* |
-2.0 ± 1.5 |
Insulin (μU/mL)1 |
0.9 ± 0.9** |
1.7 ± 1.3** |
-0.5 ± 1.1 |
-3.0 ± 1.1 |
Triglyceride (mg/dL)1 |
-15.0 ± 7.7* |
-17.6 ± 10.4 |
-18.4 ± 9.0* |
-43.6 ± 8.8 |
HOMA1 |
0.3 ± 0.2** |
0.5 ± 0.3** |
-0.1 ± 0.3 |
-0.8 ± 0.3 |
Log (HOMA)1 |
0.023 ± 0.029** |
0.037 ± 0.039** |
-0.004 ± 0.034* |
-0.141 ± 0.033 |
QUICKI1 |
-0.002 ± 0.003*** |
-0.003 ± 0.004** |
-0.000 ± 0.004** |
0.017 ± 0.004 |
Comparisons with NB32: *P-value = 0.05; **P-value = 0.01; ***P-value = 0.001.
1 24 Week Completer Population from overall NB-201 study
2 24 Week Subset Completer Population
Ongoing Phase III Trials
NB-301 In October 2007, Orexigen initiated enrollment in NB-301, a 56-week Phase III clinical trial designed to assess the safety, tolerability and efficacy of Contrave in healthy, nondiabetic, obese patients. The trial is taking place at 34 centers nationwide and has randomized 1,742 patients. In April 2008, Orexigen completed enrollment of this trial.
NB-302 In April 2007, Orexigen initiated enrollment in NB-302, a 56-week Phase III clinical trial designed to evaluate the Contrave weight loss potential alone or when combined with intense diet, exercise and behavior modification. This trial is taking place at nine centers nationwide and has enrolled approximately 800 patients. In November 2007, Orexigen completed enrollment of this trial.
NB-303 In December 2007, Orexigen initiated enrollment in NB-303, a 56-week Phase III clinical trial designed to assess the safety, tolerability and efficacy of Contrave at two different doses in healthy, nondiabetic, obese patients. The trial is taking place at 36 centers nationwide and has randomized 1,496 patients. In May 2008, Orexigen completed enrollment of this trial.
NB-304 In May 2007, Orexigen initiated enrollment in NB-304, a 56-week Phase III clinical trial designed to assess both the safety and efficacy of Contrave in obese Type II diabetic patients. This trial is designed to evaluate Contrave effects on weight loss, glycemic control and markers of cardiovascular disease risk. The trial is taking place at 51 centers nationwide and has randomized approximately 500 patients. In May 2008, Orexigen completed enrollment of this trial.