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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Tuberous Sclerosis Complex, TSC Related Cognitive Disability, TSC Related Autism, TSC Related Learning Problems

Intervention / Treatment
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* Drug: Everolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml | Drug: Everolimus<br>* Everolimus once daily titrated to trough levels of 5-10 ng/ml.<br>* Other names: Votubia;|
| Placebo Comparator: Placebo<br>Placebo treatment for 1 year. Tablets will be identical to everolimus tablets. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive ability measured by IQ | Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL) | 12 months | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberous Sclerosis Complex, TSC, Autism, Learning problems, Everolimus, RAD001, Treatment, Cognition, Intellectual disability