Aim:  The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy.

Methods:  A randomized, double‐blind, placebo‐controlled, multicentre study was designed, comprising of a 3‐week dietary lead‐in followed by a 12‐week leptin or placebo treatment period. A total of 284 overweight and obese (body mass index 27–37.0 kg/m²) predominantly white (98%) women (66%) and men (34%) with a mean (±s.d.) 46.8 ± 10.4 years of age were randomized into three treatment groups with three matching placebo groups. Recombinant leptin was administered by subcutaneous injection [10 mg/morning, 10 mg/evening or 20 mg/day (10 mg twice daily)]. Patients were counselled at baseline to reduce dietary intake by 2100 kJ/day (500 kcal/day), and dietary advice was reinforced every 2–4 weeks.

Results:  No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. No clinically significant adverse effects were observed with the exception of an increase in injection‐site reactions in patients treated with recombinant leptin (83%) vs. placebo (36%).

Conclusions:  Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy‐restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. The hypothesis that nocturnal administration of recombinant leptin might have a specific effect on weight loss was not supported.