High Density Lipoprotein Turnover

Study Overview
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Brief Summary
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The objective of the study is to evaluate the effect of Rimonabant 20mg in comparison to placebo, on HDL and VLDL lipoprotein kinetics, over a 12 months period. Primary objectives: To assess effect of Rimonabant on HDL ApoA-I fractional catabolic rate (FCR). Secondary objectives: To assess effect of Rimonabant on HDL ApoA-I production rate (PR) and on other lipoprotein kinetics. To assess effect of Rimonabant on lipids, glycemic and inflammatory parameters To assess effect of Rimonabant on body composition To assess safety of Rimonabant

Official Title
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A Randomized, Double-blind, Two Arm, Parallel, Placebo Controlled Study of Rimonabant 20 mg Effect on High Density Lipoprotein Kinetics in Patients With Abdominal Obesity and Additional Cardiometabolic Risk Factors

Conditions
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Obesity

Intervention / Treatment
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* Drug: Placebo
* Drug: Rimonabant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Abdominally obese patients with additional cardiometabolic risk factors Females must be post-menopausal BMI > 27 kg/m² and < 40 kg/m² Men or women with abdominal obesity according to NCEP/ATPIII criteria: Waist Circumference > 88 cm in women; > 102 cm in men With at least one lipid abnormality defined as: Fasting Triglycerides level > 1.7 mmol/L (150 mg/dL) and < 4.5 mmol/L (400 mg/dL) HDL < 1.03 mmol/L (40 mg/dL) in men and < 1.29 mmol/L (50 mg/dL) in women Exclusion Criteria: HDL ≤ 0.60 mmol/L (23 mg/dl) Plasma LDL-Cholesterol > 155 mg/dl (4.00 mmol/L) or total cholesterol 250 mg/dl (> 6.5mmol/L) or genetic hyperlipidaemia Fasting triglycerides > 400 mg/dL (4.5 mmol/L) Known heterozygous or homozygous familial hypercholesterolaemia or know type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia) ApoE2/E2 homozygosity, Apo E4/E4 homozygosity Type 2 diabetes treated with oral agents and/or insulin Diet treated type 2 diabetic patients with HbA1c ≥ 7% History of cardio vascular disease Systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg. Very low-calorie diet (1200 calories a day or less) or history of surgical procedures for weight loss (e.g., stomach stapling, bypass) Body weight fluctuation > 5 Kg during the previous 3 months History of bulimia or anorexia nervosa by DSM-IV criteria Presence of any clinically significant endocrine disease according to the investigator, Cushing syndrome, obesity secondary to hypothalamic/pituitary disorder. Abnormal TSH and free T4 at baseline (Patients treated with thyroid replacement therapy must be on fixed and stable dose for at least 3 months prior to screening and must be in euthyroïd status.) Severe hepatic impairment known by the investigator or AST or ALT > 3 times the ULN at screening. Known severe renal dysfunction (creatinine clearance < 30 ml/min) or urine analysis (performed at screening by dipstick) showing 2+ or more protein Presence of any condition (medical, including clinically significant abnormal laboratory test, psychological, social or geographical) actual or anticipated that the investigator feels would compromise the patient safety or limit his/her successful participation to the study Patient treated for epilepsy Ongoing major depressive illness Uncontrolled psychiatric illness History of alcohol and/or drug abuse Smoker or smoking cessation within the past 3 months Marijuana or hashish users Previous participation in a Rimonabant study or to any other clinical trial within 4 weeks to study start Hypersensitivity/intolerance to the active substance or to any of the excipients such as lactose Blood donation within the past 3 months prior to the study or planned during the study or within the 3 months from the study completing Recent history of active peptic ulcer Willebrand disease or other hemorrhagic diatheses Administration of any of the following within 3 months prior to screening visit and susceptible to be prescribed during the study treatment period: Lipid-lowering drugs intake Anti obesity drugs Other drugs for weight reduction (phentermine, amphetamines) Herbal preparations for weight reduction Other drugs known to affect lipid metabolism: retinoids, antiretroviral, estrogens and hormone replacement therapy, cyclosporine, glitazones, benfluorex, fish oils, plant sterols. Thiazids (including fixed combination) at daily dose higher than 12.5 mg Unselective beta-blockers Prolonged use (more than one week) of systemic corticosteroids, neuroleptics Anticoagulants Ongoing antidepressive treatment The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 2<br>Administration of one rimonabant placebo tablet once daily in the morning | Drug: Placebo<br>* Undistinguishable placebo tablets<br>|
| Experimental: 1<br>Administration of one tablet containing 20 mg of active rimonabant once daily in the morning | Drug: Rimonabant<br>* White film-coated, for oral administration containing 20 mg of active rimonabant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The fractional catabolic rate (FCR) of HDL ApoA-I |  | After 12 months of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Production Rate (PR) of HDL ApoA-I and A-II, (FCR) of HDL ApoA-II |  | All across the study | 
| PR and FCR of VLDL1 and VLDL2 Apo B, VLDL1 and VLDL2 TG, IDL Apo B and LDL Apo B |  | All across the study | 
| Variation in ApoA-I, ApoA-II, Lp-AI, Lp-AII, pre-beta-HDL HDL2a, HDL2b, HDL3a, HDL3b, HDL3c, Apo B, Apo C III, TG, LDL-C, HDL-C levels |  | All across the study | 
| Variation in Glucose, insulin, HbA1c, leptin, adiponectin |  | All across the study | 
| Variation in hs-CRP, TNF-alpha, CETP, PLTP and LCAT activities, lipoprotein and hepatic lipase activities in post-heparin plasma |  | All across the study | 
| Variation in whole body fat |  | All across the study | 
| Variation in abdominal sub-cutaneous and visceral fat |  | All across the study | 
| Variation in liver fat |  | All across the study | 
| Variation in blood pressure |  | All across the study | 
| Variation in body weight, waist circumference, waist/hip ratio |  | From the beginning to the end of the study | 
| CE/TG ratio in HDL |  | All across the study | 
| Adverse events |  | From the beginning to the end of the study |