Craniopharyngioma (CP) is a rare embryonic brain tumor of the sellar and parasellar region. Despite its benign histologic characteristics, it is locally aggressive and may cause severe morbidity from invasion into adjacent tissues and structures. Hypothalamic damage due to the tumor or its management is responsible for rapid and massive obesity, one of the most severe sequelae in patients with craniopharyngioma. Current treatment of craniopharyngioma is neurosurgical, possibly completed by radiotherapy. For preventing hypothalamic damage, surgery is the most "sparing" possible for the hypothalamus, possibly completed by a highly conformation radiation treatment, such as proton beam therapy.
Despite these therapeutic advances, obesity remains a significant problem in 30 to 50% of cases today. Most studies showed that the mean BMI at diagnosis of childhood craniopharyngioma was 0.5-0.8 ± 1.5 SD score, the mean BMI gain was +2 to +3 ± 2 SD score within 3 years, with a relative stabilization or a slow increase after 3 years. When there is an anterior and posterior hypothalamic involvement (about 50% of the cases), the mean BMI gain is even higher (+4 ± 3 SD score within 3 years).
Semaglutide, a GLP1RA in weekly injection, has shown its great effectiveness for losing weight in obese adults and adolescents (mean difference in BMI change - 16.7% with semaglutide vs. placebo after 68 weeks). Preliminary data in obese children with craniopharyngioma have shown a mean 25% difference in annual BMI gain (with semaglutide treatment compared to the previous year with no semaglutide in the same children).
Age 12 to 17 years
surgical treatmentsurgery for the solid area (non-cystic portion) of the tumor was >6 months ago and whose tumor is considered stable
irradiation treatment
Appropriate pituitary replacements (including recombinant growth hormone replacement in case of growth hormone deficiency), as assessed by the attending child's physician, according to international recommendations.
Other weight loss treatments within 90 days before screening
Previous surgical treatment for obesity
Other chronic diseases
History of pancreatitis (acute or chronic, regardless of the number of years)
Parallel
Semaglutide (Wegovy) weekly injection
DrugA 40-week randomized, controlled, double-blind semaglutide (versus placebo) intervention (versus placebo), followed by an open phase from weeks 40 to 80 where all participants receive semaglutide. In first 40 weeks period (0-40 weeks), Semaglutide is initiated at a dose of 0.25 mg once weekly for the first 4 weeks, followed by escalation every 4 weeks to 0.50, 1.0, 1.70, and 2.40 mg. In second 40 weeks period (40-80 weeks), Semaglutide is maintened at maximum tolerated dose form 1st period. The recommended target maintenance dose of semaglutide or placebo is 2.4 mg once weekly. Participants are encouraged to reach the recommended semaglutide or placebo target maintenance dose of 2.4 mg once weekly. Those unable to tolerate this dose will be permitted to stay at a lower dose (maximum tolerated dose). At least one attempt to re-escalate to the immediate upper dose is recommended.
Placebo weekly Injection
DrugA 40-week randomized, placebo double-blind controlled intervention (versus semaglutide injection), followed by an open phase from weeks 40 to 80 where all participants receive semaglutide. In first 40 weeks period (between 0-40 weeks), placebo is initiated in same timing than semaglutide (in other arm). In second 40 weeks period (between 40-80 weeks), Semaglutide is initiated at a dose of 0.25 mg once weekly for the first 4 weeks, followed by escalation every 4 weeks to 0.50, 1.0, 1.70, and 2.40 mg. The recommended target maintenance dose of semaglutide or placebo is 2.4 mg once weekly. Participants are encouraged to reach the recommended semaglutide or placebo target maintenance dose of 2.4 mg once weekly. Those unable to tolerate this dose will be permitted to stay at a lower dose (maximum tolerated dose). At least one attempt to re-escalate to the immediate upper dose is recommended.
Change in BMI SD score (according to french references) at 40 weeks
Co-primary 1 (S40 - RCT): Change in BMI (in SD for age and sex according to French references) after 40 weeks of treatment with semaglutide (dose escalation over 16 weeks followed by a maintenance dose of 2.4 mg/week for 24 weeks) compared to placebo
Change in BMI SD score (according to french references) at 80 weeks
Co-primary 2 (S80 - delayed-start): Change in BMI-SD from baseline to S80: "semaglutide group starting at S0" vs "semaglutide group starting at S40"
Change in BMI in kg/m at 40 weeks compared between semaglutide and placebo
Evaluation of the variation in Body Mass Index (BMI), expressed in kg/m², from baseline (inclusion) to week 40. This will be compared between two groups: one receiving Semaglutide from the start of the study and the other receiving a placebo for the initial 40 weeks
Change in BMI in kg/m at 80 weeks between compared between semaglutide and placebo
Evaluation of the variation in BMI, expressed in kg/m², from baseline (inclusion) to week 80. This will be compared between two groups: one receiving Semaglutide from the start of the study and the other receiving a placebo for the initial 40 weeks
Intra-individual progression of BMI-DS at each visit depending on Semaglutide treatment
Intra-individual progression of BMI-SDS values measured at the scheduled visits outlined in the protocol from week 0 to week 80 depending on Semaglutide treatment periods.
Effects of 40 weeks of weekly semaglutide treatment on height
Comparison of height between patient with 40 weeks of weekly semaglutide treatment (dose escalation over 16 weeks followed by a maximum maintenance dose of 2.4 mg/week during 24 weeks depending on treatment tolerance) versus placebo
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