A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01954693
• Date of registration: 05/09/2013
• Prospective Registration: No
• Primary sponsor: Cardiff University
• Public title: A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis TRON
• Scientific title: TRON: A Randomised, Double Blind, Placebo-controlled Study of RAD001 (Everolimus) in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
• Date of first enrolment: June 2012
• Target sample size: 48
• Recruitment status: Unknown status
• URL: https://clinicaltrials.gov/show/NCT01954693
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

United Kingdom

Contacts

• Name: Julian Sampson, Prof
• Affiliation: Cardiff University

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Definite TSC by current clinical criteria (28);

2. Male or female aged 16 to 60 yrs;

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:

5. Calculated GFR > 60ml/min/1.73m2 except in case of renal impairment associated with
TSC complicating kidneys, where a calculated GFR should be =30ml/min/1.73m2;

6. INR 1.5 or less (anticoagulation permitted if target INR on stable dose of warfarin or
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 ULN,
ALT and 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 AEDs in 6 months
prior to full recruitment and randomization at baseline. Doses of drugs may have been
changed in the 6 months prior to recruitment;

10. Hepatitis B surface antigen negative, Hepatitis C antibody negative.

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 inhibitor;

2. Investigational agent <30 days prior to randomisation;

3. Surgery in last 2 months;

4. 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 except in case of renal impairment associated
with TSC complication of kidneys, where urine protein/creatinine ratio should be
>0.1g/mmol for exclusion;

7. Serum creatinine > 1.5 x ULN except in case of renal impairment associated with TSC
complication of kidneys, where serum creatinine should be >300µmol/L for exclusion;

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, HIV seropositivity, organ transplant, malignancy
other than squamous or basal cell skin cancer;

10. lymphangioleiomyomatosis with 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 of CYP3AE;

15. Use of strong inducer of CYP3AE except for anti epileptic drugs;

16. Intercurrent infection at time of randomisation;

17. Inability to complete study materials (outcome measures) in English;

18. History of significant trauma-related cognitive deficit;

19. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of Everolimus (e.g. pancreatic insufficiency);

20. Known sensitivity to Everolimus or other Rapamycin analogues or to its excipients;

21. Inability to attend scheduled visits.



Age minimum: 16 Years
Age maximum: 60 Years
Gender: All

Health Condition(s) or Problem(s) studied

Tuberous Sclerosis

Intervention(s)

Drug: Placebo

Drug: Everolimus (RAD001)

Primary Outcome(s)

CANTAB - Spatial Working Memory (SWM) [Time Frame: 6 months]

CANTAB - Stockings of Cambridge (SOC) [Time Frame: 6 months]

Telephone search dual task (from the Test of Everyday Attention) [Time Frame: 6 months]

Complex Figure test (from the BIRT Memory and Information Processing Battery) [Time Frame: 6 months]

List Learning test (from the BIRT Memory and Information Processing Battery) [Time Frame: 6 months]

Secondary Outcome(s)

Liverpool Seizure Severity Scale (LSSS) [Time Frame: 6 months]

National Adult Reading Test (NART) [Time Frame: 6 months]

Cancellation task [Time Frame: 6 months]

CANTAB - Attentional Set-shifting (IDED) [Time Frame: 6 month]

CANTAB - Spatial Span (SSP) [Time Frame: 6 months]

Quality of Life in Epilepsy (QOLIE) [Time Frame: 6 months]

Social communication questionnaire (SCQ) [Time Frame: 6 months]

CANTAB - Rapid Visual Information Processing Battery (RVIP) [Time Frame: 6 months]

Symptom Checklist 90R (SCL-90R) [Time Frame: 6 months]

Verbal Fluency /Controlled Oral Word Association Test (COWAT) [Time Frame: 6 months]

Social Responsiveness Scale - Adult version (SRS-A) [Time Frame: 6 months]

Vineland Adaptive Behavior Scales-II (VABS-II) (survey form) [Time Frame: 6 months]

Secondary ID(s)

2011-004854-25

SPON803-10

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Novartis