Topical Everolimus in Patients With Tuberous Sclerosis Complex

Topical Everolimus Versus Placebo for the Treatment of Facial Angiofibromas in Patients With Tuberous Sclerosis Complex. A Phase II/III, Multicentre, Randomized, Double-blind, Placebo-controlled Study of 3 Doses of Topical Everolimus.

Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder characterized by the development of hamartomas in several organs (e.g. brain, heart, kidney, liver, lung), and skin in more than 90% of cases. Facial angiofibromas (FA), present in about 80% of patients, are a stigmatizing hallmark of the disease. Everolimus could be a candidate for use as a topical formulation to treat FA. This adaptive seamless Phase II/III study primary objective is to determine the dose of topical everolimus for treatment of FA and evaluate the efficacy and safety of topical everolimus versus placebo in patients with angiofibromas.

Inclusion Criteria:

• Patients over the age of 2 years
• With definite or possible diagnosis of TSC
• With at least 3 FA, diagnosed by a dermatologist
• Patients (or parents or legal guardians) who have provided written informed consent prior to participation in the study
• Willing and able to comply with study requirements
• With negative blood pregnancy test at the screening visit and using effective contraceptive methods for women of childbearing potential, up to 12 weeks after treatment discontinuation
• Covered by national health insurance

Exclusion Criteria:

• Systemic treatment by sirolimus, everolimus, or any other immunosuppressive drug, during the previous 6 months
• Use of topical tacrolimus or sirolimus on the face, during the previous 6 months
• Destructive treatment (laser therapy, surgery, cryotherapy) of facial angiofibromas during the previous 6 months
• Concomitant use of topical treatments that could affect facial erythema (e.g. Brimonidine)
• Known internal organ involvement requiring systemic mTOR inhibitor in the next 6 months
• Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
• Known chronic infectious disease Known hypersensitivity to mTOR inhibitor
• Neutropenia < 1000/mm3
• Thrombopenia < 75,000/mm3
• Chronic renal insufficiency (estimated Glomerular Filtration Rate < 60 mls/min)
• Chronic liver disease (SGOT or SGPT > 3 times upper normal limit)
• Uncontrolled dyslipidaemia
• Uncontrolled diabetes
• Brest feeding or pregnant women, or women on childbearing age without any effective method of contraception during treatment and up to 12 weeks after treatment discontinuation
• Subjects who, in the Investigator's opinion, are unable or unwilling to comply with the protocol.