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ACOMPLIA (rimonabant) Clinical Development Program

The Phase III program on ACOMPLIA includes seven clinical trials that are part of two clinical development programs. The RIO (Rimonabant In Obesity) Program has enrolled over 6,600 overweight/obese patients worldwide in four clinical trials designed to explore the role of ACOMPLIA in obesity management – weight loss, prevention of weight regain after prior weight loss; and improvement of obesityrelated risk factors such as diabetes and dyslipidemia. RIO-North America and RIO-Europe are two-year studies. RIO-Lipids and RIO-Diabetes are one-year studies.

The STRATUS (STudies with Rimonabant And Tobacco USe) Program has enrolled over 6,500 patients in three Phase III trials worldwide. The studies are designed to explore the role of ACOMPLIA in smoking cessation and long-term abstinence and prevention of weight gain upon smoking cessation. STRATUS-US and STRATUS-EU are 10-week studies with a 42-week follow-up off treatment. STRATUS-WW is a one-year study with a one-year follow-up off treatment.

Rimonabant phase III programs in obesity and smoking cessation are due to be completed at the end of 2004; the product is yet non-approved for marketing.

Not news, the growing prevalence of obesity has stimulated the search for drugs to treat this condition. Various therapeutic strategies have been explored, including:

Serotonin and noradrenaline reuptake inhibitors (anorectic agents)
Lipase inhibitors
ß 3-adrenoreceptor agonists
Leptin agonists
Melanocortin-3 agonists

Sanofi-Aventis' approach is completely different to the above. It developed from the knowledge that cannabis smokers often experience extreme hunger pangs, which cannabis smokers refer to as "the munchies". Sanofi-Aventis worked on the premise that if cannabinoids stimulate appetite, blocking cannabinoid receptors in the brain might reduce appetite.

The central cannabinoid (CB1) receptors are believed to play a role in controlling food consumption and the phenomena of dependence / habituation. To develop suitable drugs against this target, the human cannabinoid receptor was first cloned and then expressed in cells.

Compounds with potential inhibitory activity against this receptor were then screened for inhibitory activity. Rimonabant emerged from this screening process as a potent CB1 receptor antagonist. Preclinical animal studies subsequently showed that it could reduce consumption of fats and sugars, which contribute to weight gain.

The promising preclinical findings with Acomplia (rimonabant) have been confirmed in a series of clinical studies, including pivotal phase III trials involving over 6,000 obese subjects that were carried out in both the US and Europe.

Two-year data from the phase III multicentre Rimonabant In Obesity (RIO) trials, which compared rimonabant at doses of 5mg and 20mg with placebo with respect to weight reduction and prevention of weight gain, showed that the positive results seen after a year's treatment were sustained over the full two-year trial period.

Consistent with the one-year data, the results showed that overweight and obese patients taking rimonabant 20mg/d achieved significant reductions in body weight, waist circumference (an indicator of abdominal obesity) and improved lipid and glycaemic profiles compared with placebo recipients. Rimonabant also had a significant impact on metabolic CVD risk factors, greater than that expected by weight loss alone.

Efficacy and safety in long-term use is important feature of any antiobesity drug. Some potential antiobesity medications have proved effective in the first six months of treatment only to lose effectiveness as subjects develop resistance to treatment.

Data from the RIO trials suggest rimonabant is effective for maintaining weight loss for periods of at least two years. Long-term safety is also a major concern. In the US, the FDA generally requires two years of safety data before approving antiobesity drugs.

Results from the phase III RIO trial programme suggest rimonabant is well tolerated in long-term use. Among patients who were randomly assigned to continue their first-year treatment for a second year, 6.7 percent, 8.3 percent and 6.0 percent discontinued from the placebo, rimonabant 5mg and 20mg groups respectively.

The ongoing phase IIIb trial programme for rimonabant includes studies in patients with diabetes (SERENADE), dyslipidaemia (ADAGIO) and cardiovascular disease (STRADIVARIUS, AUDITOR, CRESCENDO).

RIO-Lipids, an international multi-center, double-blind, placebo-controlled study, enrolled 1,036 overweight or obese patients with dyslipidemia and a Body Mass Index (BMI) between 27 and 40 kg/m2. Patients were randomized to receive either a daily, fixed dose of ACOMPLIA 5 mg or 20 mg or placebo along with a reduced calorie diet for one year.

Patients treated for one year with rimonabant 20 mg per day lost 8.6 kg (almost 20 lbs) vs. a loss of only 2.3 kg (5 lbs) on placebo (p<0.001). Nearly 75% (p<0.001 vs. placebo) of patients treated for one year with ACOMPLIA 20 mg lost over 5% of their body weight as compared to 41.8% (p = 0.002 vs. placebo) of patients on ACOMPLIA 5 mg and 27.6% of patients in the placebo group. Moreover, 44.3% (p<0.001 vs. placebo) lost more than 10% of their body weight when treated for one year with ACOMPLIA 20 mg vs. 16.3% of patients on ACOMPLIA 5 mg or 10.3% of patients on placebo.

In addition to weight loss, RIO-Lipids was designed to assess a number of associated important cardiovascular risk factors. All improvements in risk factors were statistically significant vs. the control group. In fact, the number of patients diagnosed as having metabolic syndrome at baseline (52.9%) was reduced by half (25.8%) after treatment with ACOMPLIA 20 mg (p<0.0001 compared to placebo).

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