A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis (TRON)
Primary Purpose
Tuberous Sclerosis
Status
Unknown status
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Placebo
Everolimus (RAD001)
Sponsored by
About this trial
This is an interventional treatment trial for Tuberous Sclerosis focused on measuring Tuberous Sclerosis, Everolimus, Neurocognitive functioning
Eligibility Criteria
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.
Sites / Locations
- Cardiff University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Everolimus (RAD001)
Placebo
Arm Description
2x2.5mg daily
2x2.5mg daily
Outcomes
Primary Outcome Measures
List Learning test (from the BIRT Memory and Information Processing Battery)
Complex Figure test (from the BIRT Memory and Information Processing Battery)
CANTAB - Stockings of Cambridge (SOC)
CANTAB - Spatial Working Memory (SWM)
Telephone search dual task (from the Test of Everyday Attention)
Secondary Outcome Measures
CANTAB - Rapid Visual Information Processing Battery (RVIP)
CANTAB - Spatial Span (SSP)
CANTAB - Attentional Set-shifting (IDED)
Verbal Fluency /Controlled Oral Word Association Test (COWAT)
Cancellation task
Symptom Checklist 90R (SCL-90R)
Quality of Life in Epilepsy (QOLIE)
Liverpool Seizure Severity Scale (LSSS)
Vineland Adaptive Behavior Scales-II (VABS-II) (survey form)
Social Responsiveness Scale - Adult version (SRS-A)
Social communication questionnaire (SCQ)
National Adult Reading Test (NART)
Full Information
NCT ID
NCT01954693
First Posted
September 5, 2013
Last Updated
January 29, 2018
Sponsor
Cardiff University
Collaborators
Novartis
1. Study Identification
Unique Protocol Identification Number
NCT01954693
Brief Title
A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
Acronym
TRON
Official Title
TRON: A Randomised, Double Blind, Placebo-controlled Study of RAD001 (Everolimus) in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
Study Type
Interventional
2. Study Status
Record Verification Date
January 2018
Overall Recruitment Status
Unknown status
Study Start Date
June 2012 (undefined)
Primary Completion Date
August 6, 2018 (Anticipated)
Study Completion Date
August 6, 2018 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cardiff University
Collaborators
Novartis
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberous Sclerosis
Keywords
Tuberous Sclerosis, Everolimus, Neurocognitive functioning
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
48 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Everolimus (RAD001)
Arm Type
Experimental
Arm Description
2x2.5mg daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
2x2.5mg daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
5mg daily administered for 6 months as two oral 2.5 mg tablets once daily.
Intervention Type
Drug
Intervention Name(s)
Everolimus (RAD001)
Intervention Description
5mg daily administered for 6 months as two oral 2.5 mg tablets once daily
Primary Outcome Measure Information:
Title
List Learning test (from the BIRT Memory and Information Processing Battery)
Time Frame
6 months
Title
Complex Figure test (from the BIRT Memory and Information Processing Battery)
Time Frame
6 months
Title
CANTAB - Stockings of Cambridge (SOC)
Time Frame
6 months
Title
CANTAB - Spatial Working Memory (SWM)
Time Frame
6 months
Title
Telephone search dual task (from the Test of Everyday Attention)
Time Frame
6 months
Secondary Outcome Measure Information:
Title
CANTAB - Rapid Visual Information Processing Battery (RVIP)
Time Frame
6 months
Title
CANTAB - Spatial Span (SSP)
Time Frame
6 months
Title
CANTAB - Attentional Set-shifting (IDED)
Time Frame
6 month
Title
Verbal Fluency /Controlled Oral Word Association Test (COWAT)
Time Frame
6 months
Title
Cancellation task
Time Frame
6 months
Title
Symptom Checklist 90R (SCL-90R)
Time Frame
6 months
Title
Quality of Life in Epilepsy (QOLIE)
Time Frame
6 months
Title
Liverpool Seizure Severity Scale (LSSS)
Time Frame
6 months
Title
Vineland Adaptive Behavior Scales-II (VABS-II) (survey form)
Time Frame
6 months
Title
Social Responsiveness Scale - Adult version (SRS-A)
Time Frame
6 months
Title
Social communication questionnaire (SCQ)
Time Frame
6 months
Title
National Adult Reading Test (NART)
Time Frame
6 months
Other Pre-specified Outcome Measures:
Title
Wechsler Abbreviated Scale of Intelligence (WASI) (4 subtests)
Description
Eligibility visit screening measure
Time Frame
Eligibility visit
Title
Edinburgh Handedness Test
Description
Eligibility visit screening measures
Time Frame
Eligibility visit
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julian Sampson, Prof
Organizational Affiliation
Cardiff University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cardiff University
City
Cardiff
ZIP/Postal Code
CF14 4YS
Country
United Kingdom
12. IPD Sharing Statement
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A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
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