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

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.

Study Overview

• Status: Unknown
• Conditions: Tuberous Sclerosis Complex; TSC Related Cognitive Disability; TSC Related Autism; TSC Related Learning Problems
• Intervention / Treatment: Drug: Placebo; Drug: Everolimus

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 Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: M.C.Y. de Wit, MD. PhD.; Phone Number: +31 10 703 6956; Email: tubereuzesclerose@erasmusmc.nl

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Center
    • Contact: M.C.Y. de Wit, MD. PhD.; Phone Number: +31 10 703 6956; Email: tubereuzesclerose@erasmusmc.nl
    • Principal Investigator: M.C.Y. de Wit, MD. PhD.
    • Sub-Investigator: I.E. Overwater, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus; Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml	Drug: Everolimus; Everolimus once daily titrated to trough levels of 5-10 ng/ml.; Other Names: RAD001; Votubia
Placebo Comparator: Placebo; Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.	Drug: Placebo

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
School level	Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores	12 Months
Pharmacokinetics	Assessed by measuring trough levels of everolimus	12 Months
Safety	Levels of and abnormalities in blood control values	12 Months

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Utrecht University
• Investigators: Principal Investigator: M.C.Y. de Wit, MD. PhD., Erasmus Medical Center

Publications and helpful links

General Publications

• Overwater IE, Rietman AB, Mous SE, Bindels-de Heus K, Rizopoulos D, Ten Hoopen LW, van der Vaart T, Jansen FE, Elgersma Y, Moll HA, de Wit MY; ENCORE Expertise Centre for Neurodevelopmental Disorders. A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology. 2019 Jul 9;93(2):e200-e209. doi: 10.1212/WNL.0000000000007749. Epub 2019 Jun 19.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Anticipated): November 1, 2015
• Study Completion (Anticipated): November 1, 2016

Study Registration Dates

• First Submitted: October 26, 2012
• First Submitted That Met QC Criteria: November 20, 2012
• First Posted (Estimate): November 21, 2012

Study Record Updates

• Last Update Posted (Estimate): May 5, 2015
• Last Update Submitted That Met QC Criteria: May 4, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Treatment; Tuberous Sclerosis Complex; Everolimus; Autism; Cognition; TSC; RAD001; Learning problems; Intellectual disability
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Autism Spectrum Disorder; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Autistic Disorder; Tuberous Sclerosis; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: NL38619.078.11