Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex

Phase 2

• Conditions: TSC Related Cognitive Disability; TSC Related Autism; Tuberous Sclerosis Complex; TSC Related Learning Problems
• Interventions: Drug: Placebo; Drug: Everolimus

• Registration Number: NCT01730209
• Lead Sponsor: Erasmus Medical Center

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2012-10-26
• Study Start: 2012-11
• Study First Submitted QC: 2012-11-20
• Study First Posted: 2012-11-21
• Status Verified: 2015-05
• Last Update Submitted: 2015-05-04
• Last Update Posted: 2015-05-05
• Primary Completion: 2015-11
• Study Completion: 2016-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.
Everolimus	Everolimus	Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml

Primary Outcome Measures

Name	Time	Method
Cognitive ability measured by IQ	12 months	Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL)

Secondary Outcome Measures

Name	Time	Method
Autistic features	12 Months	Assessed by Autism Diagnostic Observation Schedule (ADOS)
Social and communicational skills	12 Months	Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires
Working memory and attention, information processing	6 and 12 Months	Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)
Visual-motor integration	12 Months	Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard
Sensory related difficulties	12 Months	Assessed by Short Sensory Profile (SSP) questionnaire
Child behavior	12 Months	Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires
Executive functioning	12 Months	Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version
Sleeping problems	12 Months	Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire
Child health	12 Months	Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire
Epilepsy	12 Months	Comparison of epilepsy frequency during month previous to study start and last month of trial participation.; EEG abnormalities

Trial Locations

Locations (1)

Erasmus Medical Center; 🇳🇱 Rotterdam, Netherlands