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Recombinant Variant of Ciliary Neurotrophic Factor for Weight Loss in Obese Adults

Published on Jan 1, 2017
Mark P. Ettinger18
Estimated H-index: 18
,
Thomas W. Littlejohn4
Estimated H-index: 4
+ 8 AuthorsCatherine Vicary1
Estimated H-index: 1
Abstract
Context Obese individuals tend to resist the weight-regulating effects of exog- enously administered leptin. A genetically engineered recombinant human variant cili- ary neurotrophic factor (rhvCNTF) that signals through leptinlike pathways in the hy- pothalamus 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 sub- cutaneous injections of placebo (n=32) or 0.3 µg/kg (n=32), 1.0 µg/kg (n=38), or 2.0 µg/kg (n=33) of rhvCNTF. Another group received 1.0 µg/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 Organiza- tion formula minus 500 kcal/d). Main Outcome Measures Change in weight during the 12-week double-blind treat- ment 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 µg/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 fre- quently 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 confir- mation in large prospective clinical trials.
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Abstract Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CN...
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