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

Study Overview
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Brief Summary
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This is a single centre, two-arm, individually randomised, Phase II, double- blind, placebo-controlled trial of RAD001 (Everolimus) versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis (TSC). The IMP is a licensed medicine in this patient group but for a different target of effect. The current trial is a proof of principle study for memory and executive function outcomes. Following an eligibility visit, patients will be scheduled for baseline visit and randomization. They will then be followed up for 6 months undergoing both safety and neurocognitive assessments whilst taking either the placebo or study drug. 48 patients aged 16 to 60 years with tuberous sclerosis (TSC) who have IQ > 60 and a significant deficit in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to either RAD001 (Everolimus) or Placebo.

Official Title
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TRON: A Randomised, Double Blind, Placebo-controlled Study of RAD001 (Everolimus) in the Treatment of Neurocognitive Problems in Tuberous Sclerosis

Conditions
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Tuberous Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Everolimus (RAD001)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Definite TSC by current clinical criteria (28); Male or female aged 16 to 60 yrs; IQ over 60 by Wechsler Abbreviated Scales of Intelligence (WASI) and able to participate in direct neuropsychological tests; A score falling on, or below, the 5th percentile (approximately equivalent to -1.5 SD) in one or more of the primary outcome measures: 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; 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) ; 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; If sexually active - negative pregnancy test in females at the time of informed consent, contraception for males and pre-menopausal females on study); 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; Hepatitis B surface antigen negative, Hepatitis C antibody negative. 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; 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: Prior treatment with an mTOR inhibitor; Investigational agent <30 days prior to randomisation; Surgery in last 2 months; Previous brain neurosurgery; Significant haematological abnormality i.e. haemoglobin < 8g/dL, platelets <80,000/mm3, absolute neutrophil count < 1000/mm3); 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; 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; 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; 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; lymphangioleiomyomatosis with FEV1 <70% of predicted, or any other restrictive pulmonary disease; Bleeding diathesis or on oral anti-vitamin K medication other than low dose warfarin; Pregnancy/lactation; Live vaccine required during trial; Use of strong inhibitor of CYP3AE; Use of strong inducer of CYP3AE except for anti epileptic drugs; Intercurrent infection at time of randomisation; Inability to complete study materials (outcome measures) in English; History of significant trauma-related cognitive deficit; Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus (e.g. pancreatic insufficiency); Known sensitivity to Everolimus or other Rapamycin analogues or to its excipients; Inability to attend scheduled visits.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 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 (RAD001)<br>2x2.5mg daily | Drug: Everolimus (RAD001)<br>* 5mg daily administered for 6 months as two oral 2.5 mg tablets once daily<br>|
| Placebo Comparator: Placebo<br>2x2.5mg daily | Drug: Placebo<br>* 5mg daily administered for 6 months as two oral 2.5 mg tablets once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| List Learning test (from the BIRT Memory and Information Processing Battery) |  | 6 months | 
| Complex Figure test (from the BIRT Memory and Information Processing Battery) |  | 6 months | 
| CANTAB - Stockings of Cambridge (SOC) |  | 6 months | 
| CANTAB - Spatial Working Memory (SWM) |  | 6 months | 
| Telephone search dual task (from the Test of Everyday Attention) |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CANTAB - Rapid Visual Information Processing Battery (RVIP) |  | 6 months | 
| CANTAB - Spatial Span (SSP) |  | 6 months | 
| CANTAB - Attentional Set-shifting (IDED) |  | 6 month | 
| Verbal Fluency /Controlled Oral Word Association Test (COWAT) |  | 6 months | 
| Cancellation task |  | 6 months | 
| Symptom Checklist 90R (SCL-90R) |  | 6 months | 
| Quality of Life in Epilepsy (QOLIE) |  | 6 months | 
| Liverpool Seizure Severity Scale (LSSS) |  | 6 months | 
| Vineland Adaptive Behavior Scales-II (VABS-II) (survey form) |  | 6 months | 
| Social Responsiveness Scale - Adult version (SRS-A) |  | 6 months | 
| Social communication questionnaire (SCQ) |  | 6 months | 
| National Adult Reading Test (NART) |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberous Sclerosis, Everolimus, Neurocognitive functioning