A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/ day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18 - 75 y with a body mass index greater than or equal to30 kg/m(2) and <50 kg/m(2) in the absence of comorbidities, or ≥27 kg/m(2) and <50 kg/m(2) in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose ( modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/ day treatment groups lost 7.0, 9.1, and 9.7%, respectively (P<0.001, MITT, last observation carried forward). Weight loss ≥5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/ day, respectively; weight loss ≥10% was achieved by 6 vs 29, 40, and 44%, respectively ( P<0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/ +1.0, - 3.1/ - 1.3, - 5.7/ - 3.4, and - 4.6/ - 2.4 mmHg were observed for placebo, topiramate 96 mg/ day, 192 mg/ day, and 256 mg/ day, respectively, P<0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.