A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blinded, randomised, placebo-controlled trial

Facial angiofibromas (FA) are a major feature of tuberous sclerosis complex (TSC).Topical rapamycin can successfully treat FA. A new stabilised cream formulation which protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. To assess the efficacy and safety of a novel stabilised topical rapamycin cream formulation. This multicentre, double-blind, randomised, placebo-controlled, dose-response phase II/III study with a parallel design included participants aged 6 - 65 years with FA of mild or moderate severity using the investigator's global assessment (IGA) scale.Participants were randomised to one of three treatment arms: topical rapamycin 0.5%, 1%, or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182.The primary endpoint was the percentage of subjects achieving 'clear' or 'almost clear' IGA scores after 26 weeks of treatment. Secondary measures included facial angiofibroma severity index (FASI) and subject and clinician-reported percentage-based improvement.Safety measures included the incidence of treatment emergent adverse event and blood rapamycin concentration changes over time. Participants (107) were randomised to receive either rapamycin 1% (n = 33), 0.5% (n = 36), or placebo (n = 38). All treated participants were included in the final analysis.The percentage of subjects with a two-grade IGA improvement was greater in the 0.5% treatment group (11.1%) and 1% group (9.1%) than the placebo group (5.3%). However, this was not statistically significant (0.5%: OR 1.71, 95% CI 0.36-8.18, p = 0.499; 1%: OR 1.68, 95% CI 0.33-8.40, p = 0.530). Subjects with at least a one-grade IGA improvement were significantly different compared to placebo (0.5%: 55.6%, OR 4.73, 95% CI 1.59-14.10, p = 0.005; 1%: 60.6%, OR 5.14, 95% CI 1.70-15.57, p = 0.004; Placebo: 23.7%). Skin adverse reactions were more common in patients following rapamycin application (64%) compared to placebo (29%). Both 0.5% and 1% rapamycin cream formulations are well tolerated treatments, and either strength can lead to clinical benefit in the treatment of FA.Trial registration: ClinicalTrials.gov NCT03826628.