A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
- Registration Number
- NCT01954693
- Lead Sponsor
- Cardiff University
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 48
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Everolimus (RAD001) Everolimus (RAD001) 2x2.5mg daily Placebo Placebo 2x2.5mg daily
- Primary Outcome Measures
Name Time Method 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 - Spatial Working Memory (SWM) 6 months CANTAB - Stockings of Cambridge (SOC) 6 months Telephone search dual task (from the Test of Everyday Attention) 6 months
- Secondary Outcome Measures
Name Time Method CANTAB - Rapid Visual Information Processing Battery (RVIP) 6 months Quality of Life in Epilepsy (QOLIE) 6 months Cancellation task 6 months Symptom Checklist 90R (SCL-90R) 6 months CANTAB - Spatial Span (SSP) 6 months Verbal Fluency /Controlled Oral Word Association Test (COWAT) 6 months CANTAB - Attentional Set-shifting (IDED) 6 month 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
Trial Locations
- Locations (1)
Cardiff University
🇬🇧Cardiff, United Kingdom