12-week randomized double-blind placebo-controlled dose-ranging study of tesamorelin (1 mg and 2 mg/day) in 61 HIV-positive patients with central fat accumulation, demonstrating dose-related visceral fat reduction by CT and DXA, increased IGF-1, and improved quality of life—establishing the 2 mg/day dose as the optimal dose for phase III development. Definitive dose-finding study for tesamorelin. Provides the dose-selection evidence for tesamorelin's clinical development—establishing that 2 mg/day produced maximal visceral fat reduction with acceptable tolerability, informing the dose selection for the pivotal phase III trials and FDA submission.
Abstract
OBJECTIVE: To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation.
DESIGN AND METHODS: Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters.
RESULTS: TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo). Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo. Subcutaneous fat (SAT) was preserved and did not change between or within groups. Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo. Treatment was generally well tolerated without changes in glucose.
CONCLUSIONS: TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation. TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.