Background and objective: Hypothalamic obesity is characterized by rapid and severe weight-gain with increased risk of cardiovascular and metabolic disorders. Currently, there are no approved or effective pharmacological treatments and conventional weight management remain largely ineffective in hypothalamic obesity. This trial investigated safety and efficacy of Tesomet (0.5 mg tesofensine and 50 mg metoprolol) in hypopituitary patients with hypothalamic obesity.
Methods: Twenty-one (16 females) hypopituitary patients with hypothalamic obesity were randomized double blinded 2:1 to receive daily Tesomet or placebo for 24-weeks (NCT03845075). All subjects received diet- and lifestyle counseling for weight management. The primary endpoint was safety based on heart rate, blood pressure and adverse events. Secondary endpoints included antropometrics, metabolic and pituitary hormone replacements The median age of subjects was 50 years [range 25–70], 52% had BMI 30 kg/m2, and 38% BMI > 40 kg/m2. Almost half had a history of craniopharyngeomas, 86% had undergone pituitary/hypothalamic surgery, 52% irradiation. All patients received one or more anterior pituitary hormone replacements; 52% had diabetes insipidus.
Results: Four subjects, two in the placebo- and two in the treatment-group, discontinued treatment before the end of the 24-week period. Discontinuation in the treatment arm was secondary to anxiety (n = 1) and dry mouth (n = 1), both improved after drug discontinuation. Adverse events were otherwise mild to moderate and included sleep disturbances (62%), dry mouth (46%), dizziness (46%) and headache (38%), known side-effects of tesofensine or metoprolol. No significant differences in heart rate or blood pressure were observed between the two groups. Eighteen of the 21 patients completed the 24-week placebo-controlled part of the study. Compared with placebo (weight loss 0.3%), Tesomet treatment resulted in an additional mean [95%-CI] weight loss of 6.3% [1.3%, 11.3%] at week 24 (P = 0.017); a significant increase in the proportion of patients with 5% reduction in body weight (Tesomet n = 8; 61.5%; placebo n = 1; 12.5%) (P = 0.046); a significant reduction in waist circumference at week 16 and 20, approaching significance (P = 0.052) at week 24 with a mean reduction of 5.0% [0.1%, 10.1%]. Odds-ratio of subjects achieving 5% weight loss compared with placebo was 11.2 [1.0–120.4] (P = 0.046).
Conclusion: Tesomet treatment was generally well tolerated, did not affect heart rate or blood pressure and resulted in additional significant progressive reductions in body weight and waist circumference compared to placebo in this small cohort of hypopituitary patients with hypothalamic obesity, all receiving the same dietary guidance. These results support the continued development of Tesomet for hypothalamic obesity.
05 Sep 2020 - 09 Sep 2020