Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults - A randomized, dose-ranging study

Context Obese individuals tend to resist the weight-regulating effects of exogenously administered leptin. A genetically engineered recombinant human variant ciliary neurotrophic factor (rhvCNTF) that signals through leptinlike pathways in the hypothalamus has been shown to bypass leptin resistance in animal models of obesity. Objective To identify a safe and well-tolerated dose of rhvCNTF that causes weight loss in obese adults. Design, Setting, and Patients Twelve-week, double-blind, randomized, parallel-group, dose-ranging, multicenter clinical trial conducted at 2 university obesity clinics and at 5 independent clinical research clinics from March 2000 to August 2001, and including 173 nondiabetic obese adults, 82.6% of whom were women, with a mean (SD) body mass index of 41.1 (4.1). Interventions Patients were randomly assigned to receive daily for 12 weeks subcutaneous injections of placebo (n = 32) or 0.3 mug/kg (n = 32), 1.0 mug/kg (n = 38), or 2.0 mug/kg (n=33) of rhvCNTF. Another group received 1.0 mug/kg for 8 weeks and placebo for 4 weeks (n=38), but they were not included in the primary analysis. All participants received instructions for a reduced-calorie diet (World Health Organization formula minus 500 kcal/d). Main Outcome Measures Change in weight during the 12-week double-blind treatment period and proportion of patients who achieved a weight loss of at least 5%. Results Of the 173 randomized patients, 123 (71%) completed the double-blind dosing period. Mean (SEM) changes in kilograms from baseline body weights were 0.1 (0.6) for placebo and -1.5 (0.6) for the 0.3, -4.1 (0.6) for the 1.0, and -3.4 (0.7) for the 2.0 mug/kg of rhvCNTF dosage groups (P<.001, test for trend). Two patients (8.7%) in the placebo and 2 (8.3%) in the 0.3-μg/kg, 8 (29.6%) in the 1.0-μg/kg, and 5 (26%) in the 2.0-μg/kg treatment groups achieved a weight loss of at least 5%. Recombinant human variant CNTF was generally well tolerated although adverse events occurred in 75% of patients receiving placebo and 78% to 93% of patients receiving rhvCNTF, in a dose-related fashion, with mild injection site reactions as the most frequently reported adverse event. Conclusions In this initial, dose-ranging, 12-week study, treatment with rhvCNTF resulted in more weight loss than placebo. These preliminary findings require confirmation in large prospective clinical trials.