Abstract Importance A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. Objective To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. Design A double-blind multicenter superiority randomized clinical in trial in two parallel arms. Setting Eleven French University Hospital Centers. Participants Adults with CRO (body mass index &gt; 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. Interventions Exenatide or placebo injected subcutaneously twice a day during 26 weeks. Main Outcomes and Measures The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. Results At week 26, weight decreased from baseline by a mean of −3.8 (SD 4.3) kg for exenatide and −1.6 (3.8) kg for placebo. The adjusted mean treatment difference was −3.1 kg (95% confidence interval [CI] −7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: −2.3, 95% CI −4.5 to −0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). Conclusions and Relevance Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.< Réduire