Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian target of rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies suggests that mTOR inhibitors improve learning and development in patients with TSC.

Randomized double-blind placebo controlled intervention study in children with TSC between age 4 and 15 years with an intelligence quotient (IQ) estimated <80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.

Patients are randomised to receive everolimus or placebo during a period of 12 months.

Inclusion Criteria:

• Children with a definite diagnosis of TSC between 4 and 15 years.
• With an IQ estimated <80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.
• Written informed consent by parents/care-takers, and the patient if he or she is 12 years or older and cognitively able to consent.
• In girls after menarche, appropriate contraception must be used or abstinence practiced.

Exclusion Criteria:

• Hepatic dysfunction

• Surgery <6wk

• Current infection at time of inclusion

• Developmental age estimated below 3.5 years

• Intractable epilepsy with more than 1 seizure/week

• Inability to comply with the treatment protocol

• Additional diseases or disorders that may influence the endpoints, including:

  • SEGA requiring treatment
  • Uncontrolled diabetes mellitus
  • Known impaired lung function

• Allergy for any of the components of the study medication

• Prior treatment with mTOR inhibitors

• HIV seropositivity

• Bleeding diathesis or oral anti-vitamin K medication

• Serum creatinine > 1.5 x ULN

• Uncontrolled hyperlipidemia (fasting serum cholesterol > 7.75 mmol/L, fasting serum triglycerides > 2.5 x ULN)

• Use of investigational drug within 30 days prior to inclusion

• History of myocardial infarction, angina or stroke related to atherosclerosis, organ transplantation, malignancy in the past 2 years

• Pregnancy or breastfeeding

• Children at risk for Hepatitis B (HB), unless hepatitis B serology is normal. Risk groups are children who have lived in Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece, children with known or suspected past or current hepatitis B infection, current or prior IV illicit drug use, current or prior dialysis, household contact with hepatitis B infected patient(s), current or prior high-risk sexual activity, body piercing or tattoos, mother known to have hepatitis B history. If vaccinated, presence of HBs Ab is normal.

• Known or suspected hepatitis C infection, unless hepatitis C serology is normal.