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

Tuberous Sclerosis Complex Clinical Trial

— RAPIT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01730209
• Other study ID #: NL38619.078.11
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: October 26, 2012
• Last updated: May 4, 2015
• Start date: November 2012
• Est. completion date: November 2016

Study information

• Verified date: May 2015
• Source: Erasmus Medical Center
• Contact: M.C.Y. de Wit, MD. PhD.
• Phone: +31 10 703 6956
• Email: tubereuzesclerose[@]erasmusmc.nl
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: November 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 4 Years to 15 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Autistic Disorder
• Sclerosis
• TSC Related Autism
• TSC Related Cognitive Disability
• TSC Related Learning Problems
• Tuberous Sclerosis
• Tuberous Sclerosis Complex

Intervention

Drug:
• Everolimus
Everolimus once daily titrated to trough levels of 5-10 ng/ml.
• Placebo

Locations

Country	Name	City	State
Netherlands	Erasmus Medical Center	Rotterdam

Sponsors (2)

Lead Sponsor	Collaborator
Erasmus Medical Center	Utrecht University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	School level	Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores	12 Months	No
Other	Pharmacokinetics	Assessed by measuring trough levels of everolimus	12 Months	Yes
Other	Safety	Levels of and abnormalities in blood control values	12 Months	Yes
Primary	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	No
Secondary	Autistic features	Assessed by Autism Diagnostic Observation Schedule (ADOS)	12 Months	No
Secondary	Social and communicational skills	Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires	12 Months	No
Secondary	Working memory and attention, information processing	Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)	6 and 12 Months	No
Secondary	Visual-motor integration	Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard	12 Months	No
Secondary	Child behavior	Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires	12 Months	No
Secondary	Executive functioning	Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version	12 Months	No
Secondary	Sleeping problems	Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire	12 Months	No
Secondary	Child health	Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire	12 Months	No
Secondary	Sensory related difficulties	Assessed by Short Sensory Profile (SSP) questionnaire	12 Months	No
Secondary	Epilepsy	Comparison of epilepsy frequency during month previous to study start and last month of trial participation.; EEG abnormalities	12 Months	No

External Links

•   ENCORE TSC expertise center