A randomised, double blind, placebo-controlled study of RAD001 (Everolimus) in the treatment of neurocognitive problems in tuberous sclerosis

• Register: ISRCTN
• Last refreshed on: 10 April 2023
• Main ID: ISRCTN09739757
• Date of registration: 28/12/2011
• Prospective Registration: Yes
• Primary sponsor: Cardiff University (UK)
• Public title: A randomised, double blind, placebo-controlled study of RAD001 (Everolimus) in the treatment of neurocognitive problems in tuberous sclerosis
• Scientific title: A randomised, double blind, placebo-controlled study of RAD001 (Everolimus) in the TReatment Of Neurocognitive problems in tuberous sclerosis (TRON)
• Date of first enrolment: 31/12/2011
• Target sample size: 48
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN09739757
• Study type: Interventional
• Study design: Single-centre two-arm individually randomised phase II double-blind placebo-controlled trial (Treatment)
• Phase: Phase II

Countries of recruitment

United Kingdom, Wales

Contacts

• Name: Cheney Drew

• Name: Julian Sampson

Key inclusion & exclusion criteria

Inclusion criteria:
1. Definite TSC by current clinical criteria
2. Male or female aged 16 to 60 years
3. IQ over 60 by Wechsler Abbreviated Scales of Intelligence (WASI) and able to participate in direct neuropsychological tests
4. A score falling on, or below, the 5th percentile (approximately equivalent to -1.5 SD) in one or more of the primary outcome measures (updated 24/04/2019. Previously: Deficit of - 2 S.D. or more below normal population mean on a primary outcome measure)
5. Calculated glomerular filtration rate (GFR) > 60ml/min/1.73m2
6. International Normalized Ratio (INR) 1.5 or less (anticoagulation permitted if target INR on stable dose of warfarin or Low molecular weight (LMW) heparin for > 2 weeks at time of randomisation)
7. Adequate liver function as shown by: serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN), alanine aminotranferease (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x ULN
8. If sexually active - negative pregnancy test in females at the time of informed consent, contraception for males and pre-menopausal females on study
9. Seizure free or stable seizures as defined by no change in type of antiepileptic drugs (AEDs) in 6 months prior to recruitment. Doses of drugs may have been changed in the 6 months prior to recruitment
10. Negative Hepatitis B virus (HBV) DNA and Hepatitis C virus (HCV) RNA , polymerase chain reaction (PCR) testing at screening for patients with a positive history of risk factors and/or confirmation of prior HBV/HCV infection
11. All patients must be able to communicate well with the investigator, to understand and comply with the requirements of the study, understand and sign the written informed consent
12. Female patients of childbearing potential must be prepared to use two acceptable methods of contraception, (e.g. intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening

Exclusion criteria:
1. Prior treatment with an mTOR (mammalian target of rapamycin) inhibitor
2. Investigational agent <30 days prior to randomisation
3. Surgery in last 2 months
4. Previous brain neurosurgery with the exception of SEGA (sub-ependymal giant cell astrocytoma) removal surgery or radiosurgery 5 or more years ago (updated on 24/04/2019. Previously: Previous brain neurosurgery)
5. Significant haematological abnormality i.e. haemoglobin < 8g/dL, platelets <80,000/mm3, absolute neutrophil count < 1000/mm3)
6. Urine protein/creatinine >0.02g/mmol
7. Serum creatinine > 1.5 x ULN
8. Uncontrolled hyperlipidaemia (fasting cholesterol > 300mg/dL or >7.75 mmol/L and fasting triglycerides >2.5 x ULN, or diabetes with fasting serum glucose > 1.5 x ULN
9. History of myocardial infarction, angina or stroke related to atherosclerosis, or any other significant cardiac disease, human immunodeficiency virus (HIV) seropositivity, organ transplant, malignancy other than squamous or basal cell skin cancer
10. Lymphangioleiomyomatosis with forced expiratory volume in 1 second (FEV1) <70% of predicted, or any other restrictive pulmonary disease
11. Bleeding diathesis or on oral anti-vitamin K medication other than low dose warfarin
12. Pregnancy/lactation
13. Live vaccine required during trial
14. Use of strong inhibitor or inducer of CYP3AE except for anti epileptic drugs
15. Intercurrent infection at time of randomisation
16. Inability to complete study materials (outcome measures) in English
17. History of significant trauma-related cognitive deficit
18. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus (e.g. pancreatic insufficiency)
19. Known sensitivity to Everolimus or other Rapamycin analogues or to its excipients
20. Inability to attend scheduled visits


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Tuberous sclerosis
Nervous System Diseases
Tuberous sclerosis

Intervention(s)

RAD001 (Everolimus) versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis (TSC)

Primary Outcome(s)

1. List Learning test (from the BIRT Memory and Information Processing Battery)
2. Complex Figure test (from the BIRT Memory and Information Processing Battery)
3. CANTAB - Stockings of Cambridge (SOC)
4. CANTAB - Spatial Working Memory (SWM)
5. Telephone search dual task (from the Test of Everyday Attention

Secondary Outcome(s)

1. CANTAB - Rapid Visual Information Processing Battery (RVIP)
2. CANTAB - Spatial Span (SSP)
3. CANTAB - Attentional Set-shifting (IDED)
4. Verbal Fluency /Controlled Oral Word Association Test (COWAT)
5. Cancellation task
6. Symptom Checklist 90R (SCL-90R)
7. Quality of Life in Epilepsy (QOLIE)
8. Liverpool Seizure Severity Scale (LSSS)
9. Vineland Adaptive Behavior Scales-II (VABS-II) (survey form)
10. Social Responsiveness Scale (SRS)
11. Social communication questionnaire (SCQ)

Secondary ID(s)

2011-004854-25

NCT01954693

SPON803-10

Source(s) of Monetary Support

Novartis Pharmaceuticals UK Limited

Ethics review

Status:
Approval date:
Contact:

Approved 09/11/2011, Wales REC 3 (Health and Care Research Support Centre, Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB, UK; [phone]; [e-mail]), ref: 11/WA/0308

Results

• Results available: Yes
• Date Completed: 06/08/2018