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    Summary
    EudraCT Number:2011-004854-25
    Sponsor's Protocol Code Number:SPON803-10
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-004854-25
    A.3Full title of the trial
    TRON: A randomised, double blind, placebo-controlled study of RAD001 (Everolimus) in the treatment of neurocognitive problems in tuberous sclerosis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TRON: A trial to examine the effectiveness of the study drug (Everolimus) in the treatment of cognitive problems experienced by patients with tuberous sclerosis.
    A.3.2Name or abbreviated title of the trial where available
    TRON (version 1.0)
    A.4.1Sponsor's protocol code numberSPON803-10
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCardiff University
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharmaceuticals UK LTD
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEverolimus
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameRAD001
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Tuberous Sclerosis Complex (TSC)
    E.1.1.1Medical condition in easily understood language
    Tuberous sclerosis, is a rare genetic condition that causes non-cancerous tumours to develop in the brain, heart, eyes, kidneys and lungs as well as cognitive difficulties.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10002649
    E.1.2Term Anorexia nervosa
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to determine how effective Everolimus is compared to a placebo for recall memory (remembering events or information) and executive function (the ability to organise thoughts and activities, prioritise tasks, manage time and make decisions) in people with tuberous sclerosis over a 6 month period.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to assess the effects of treatment with Everolimus or placebo for 6 months on wider aspects of neurocognitive functioning, seizures and daily life in people with tuberous sclerosis. Also to assess the safety of the study drug using the National Cancer Institute common terminology criteria for adverse event Version 4.0. An additional exploratory objective is to determine whether an effect of treatment with Everolimus or placebo is detectable at 1 month and 3 months after starting therapy to establish whether any early markers of change are present.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Definite TSC by current clinical criteria; 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) Deficit of -2S.D. or more below normal population mean on a primary outcome measure; 5) Calculated GFR > 60ml/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 recruitment. Doses of drugs may have been changed in the 6 months prior to recruitment; 10) Negative HBV DNA and HCV RNA 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.
    E.4Principal 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; 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, 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 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.
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome measures are the following neurological tests and questionnaires; 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)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Following an eligibility visit (Visit 1), patients will be scheduled for baseline visit and randomisation (Visit 2, week 0) and then followed up for 6 months with study visits taking place at week 2 (safety) week 4 (safety, some neurocognition), week 6 (safety), week 12 (full neurocognition) and week 24 (full neurocognition at the end of the treatment phase) within 12 hours after the last drug administration. A further assessment will be carried out 12 weeks after the end of the last drug or placebo administration, at week 36.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 2
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 46
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    To ensure patient safety, each pregnancy in a patient on study drug occurring after the patient begins taking study drug and until 30 days after the patient has stopped taking the study drug must be reported to the Sponsor within 24 hours of learning of its occurrence. If the father is taking the study drug, a pregnancy in the partner occurring up to 3 months after stopping the study drug will be reported to the Sponsor as soon as possible after consent to report information regarding …
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-06
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