The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition

Study Overview
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Brief Summary
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This study will determine in obese subjects the direct effects of the weight loss drug rimonabant (ie independent of weight loss) on energy expenditure, fat metabolism and and body fat distribution. We hypothesise that rimonabant will increase energy expenditure. The fuel for the increased energy expenditure will come from fat. As a result of burning more fat there will be a decrease in fat in blood and an improvement in the body's response to insulin.

Detailed Description
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In obese subjects (BMI 33-38kg/m2) completing 12 months of treatment with the CB1 antagonist rimonabant (SR141716) there was an average weight loss from baseline of approximately 8.5 kg. These studies also showed the weight loss was accompanied by a decrease in plasma triglyceride (TG), an increase in HDL cholesterol and an improvement in insulin sensitivity measured by HOMA-IR. When adjusted for weight loss 50% of the improvements in TG, HDL cholesterol, and insulin sensitivity was not attributable to weight loss. This suggests that rimonabant has direct effects on fat metabolism. This study will investigate the direct effects of rimonabant (ie independent of weight loss) in a 2 group randomised study. One group will receive rimonabant for 12 weeks and the other group will have a dietary intervention to match the weight loss in the rimonabant group. Measurements of energy expenditure (using indirect calorimetry and Actiheart monitors),fatty acid and triglyceride metabolism (using stable isotope techniques) and body fat distribution (by magnetic resonance imaging) will be made before and after the intervention. To determine the possible mechanisms of the changes in metabolism, gene expression of key regulators of fatty acid metabolism in adipose and muscle tissue and circulating levels of adipokines will be measured.

Official Title
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The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition

Conditions
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Obesity

Intervention / Treatment
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* Drug: rimonabant
* Behavioral: Dietary intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Caucasian postmenopausal women BMI 30-38 Exclusion Criteria: Not currently weight-stable Diagnosed with diabetes Cardiovascular disease Endocrine disease Hepatic and renal disorders Neurological/psychological illness/history of depression Previous surgical procedures for weight loss Medications known to alter body weight or appetite β-blockers, fibrates and metformin Severe under-reporting of food intake based on a 4 day food diary

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Rimonabant treatment (20mg/d) for 12 weeks | Drug: rimonabant<br>* 20mg/d (oral) once daily for 12 weeks<br>* Other names: Acomplia;|
| Other: 2<br>Dietary intervention | Behavioral: Dietary intervention<br>* Dietary intervention to match weight loss in group 1. The energy prescription will be based on the estimate of the energy deficit estimated from the weight loss in group one. For example a weight loss of 5kg over 12 weeks equates to an approximate energy deficit of 30,000 kcal or a daily energy reduction of approximately 357 kcal. If this is achieved in group 1 the daily energy target for subjects in group 2 will be daily energy expenditure minus 357 kcal.For the subjects randomised to the dietary intervention group there will be a delay until group 1 subjects have completed the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The direct effect of rimonabant on energy expenditure |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body fatty acid production and oxidation rate. |  | 12 weeks | 
| Triglyceride synthesis and clearance rate. |  | 12 weeks | 
| Whole body fat distribution. |  | 12 weeks | 
| Adipose tissue and muscle mRNA levels of key regulators of fatty acid metabolism. |  | 12 weeks | 
| Insulin sensitivity. |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Energy expenditure, Fatty acid, Triglyceride