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    Summary
    EudraCT Number:2011-000860-90
    Sponsor's Protocol Code Number:CRAD001M2304
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-30
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2011-000860-90
    A.3Full title of the trial
    A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures
    A.4.1Sponsor's protocol code numberCRAD001M2304
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/094/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Hungary Kft.
    B.5.2Functional name of contact pointPublic Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressBartók Béla út 43-47.
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post code1114
    B.5.3.4CountryHungary
    B.5.4Telephone number003614576500
    B.5.5Fax number003614576600
    B.5.6E-mailinfoph.hungary@novartis.com
    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 Votubia
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/764
    D.3 Description of the IMP
    D.3.1Product nameEverolimus
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Dispersible tablet
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.2Current sponsor codeRAD001
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 placeboDispersible tablet
    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
    Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC)
    E.1.1.1Medical condition in easily understood language
    Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC)
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10045138
    E.1.2Term Tuberous sclerosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the reduction in frequency of partial-onset seizures on each of two trough ranges of everolimus (3-7 ng/mL and 9-15 ng/mL) versus placebo in patients with TSC who are taking one to three AEDs
    E.2.2Secondary objectives of the trial
    Please refer to the protocol for all secondary objectives
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Using Diffusion Tensor Imaging (DTI) with Tractography to Measure the Treatment Effect of Everolimus in Tuberous Sclerosis Complex (TSC) patients with Epilepsy
    Date: 25-Mar-2016, Version 03
    For objectives, please refer to section 14.1 of the protocol.
    E.3Principal inclusion criteria
    1. Male or female between the ages of 2 and 65 years (except in Europe where the minimum age will be 1 at the request of the EMA).
    2. Clinically definite diagnosis of TSC per modified Gomez criteria
    3. Diagnosis of partial-onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in 2009.
    4. Uncontrolled partial-onset seizures; must meet the following:
    a. At least 16 reported quantifiable partial-onset seizures over the Baseline period with no continuous 21-day seizure-free period between Visit 1 (Screening Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries.
    b. Prior history of failure to control partial-onset seizures despite having been treated with two or more sequential regimens of single or combined antiepileptic drugs.
    c. Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the study.
    d. Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
    5. Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start of the 8-week prospective Baseline phase, remain on the same regimen throughout the Baseline phase, and intend to continue the same regimen throughout the 18-week double blind Core phase (rescue medications are permitted).
    6. If female of child bearing potential, documentation of negative pregnancy test at time of informed consent and must use highly effective contraception during the study and for 8 weeks after stopping treatment
    7. Sexually active males must use a condom during intercourse while taking study drug, and for 8 weeks after stopping study treatment
    8. Hepatic, renal and blood laboratory values within the following range at screening:
    a. AST and ALT levels < 2.5 x ULN
    b. serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert’s Syndrome)
    c. serum creatinine < 1.5 x ULN
    d. hemoglobin ≥ 9 g/dL
    e. platelets ≥ 80,000/mm3
    f. absolute neutrophil count ≥ 1,000/mm3
    9. Written informed consent. Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent.
    10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.
    E.4Principal exclusion criteria
    1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness
    2. Presence of only non-motor partial seizures (NOT APPLICABLE per Amendment 2)
    3. Patients with TSC who have SEGA in need of immediate surgical intervention
    4. Patients under 2 years of age with untreated infantile spasms
    5. Within 52 weeks prior to study entry, an episode of status epilepticus as defined in the protocol
    6. Patients with history of seizure clusters (where individual seizures cannot be accurately counted
    according to the judgment of the investigator) occurring within 26 weeks prior to study entry
    7. Patients who require rescue medication during the Baseline phase for more than 6 days
    8. Patients with non-TSC related progressive encephalopathy
    9. Patients who weigh less than 12 kg
    10. Patients with coexisting malignancies within the 3 years prior to randomization, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
    11. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
    a. Symptomatic congestive heart failure of New York Heart Association Class III or IV, history of left ventricular ejection fraction (LVEF) <50%, QTc interval >460ms, congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
    b. Significant symptomatic deterioration of lung function
    c. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption syndrome or small bowel resection)
    d. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
    e. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
    f. Active skin, mucosa, ocular or GI disorders of Grade > 1.
    g. Active (acute or chronic) or uncontrolled severe infections
    h. A known history of HIV seropositivity or other active viral infections
    12. Patients with an active, bleeding diathesis
    13. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN
    14. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
    15. Patients with a prior history of organ transplant
    16. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at randomization or who change the dose of the AEDs during 4 weeks before screening or during the baseline period
    17. Patients being treated with felbamate, unless treatment has been continuous for ≥ 1 years
    18. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.)
    19. Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.
    20. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
    21. Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 24 months of study entry. Patients who have received prior treatment with a topical mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 4 weeks of study entry.
    22. Patients with a known hypersensitivity to everolimus or other rapamycinanalogues (sirolimus, temsirolimus) or to its excipients.
    23. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
    24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
    25. Patients with a Score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, or any "yes" on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale at Screening or Baseline , who upon follow up with a healthcare professional are found to be severely depressed or suicidal
    26. Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of screening
    E.5 End points
    E.5.1Primary end point(s)
    EMA: Response rate
    FDA: Percentage reduction in partial onset seizure frequency
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, Week 6 to Week 12 (during maintenance period of core study)
    E.5.2Secondary end point(s)
    1. Seizure free rate
    2. Proportion of patients with at least a 25% reduction in partial onset seizure frequency
    3. Categorical variable of six levels of reduction from baseline in partial-onset seizure frequency
    4. Frequency of seizure free days
    5. Treatment duration
    6. Overall Quality of Life global scores
    7. Sub-test scores for neurocognitive, neurodevelopmental, and neurobehavioral tests
    8. Percentage reduction in seizure frequency/frequency of selected adverse events
    9. Pre-dose concentrations of antiepileptic drugs (AEDs) alone and post-baseline (AEDs plus everolimus)
    10. 50% response rate from Baseline by time interval over the extension phase
    11. Seizure free days in partial onsent seizure by time interval over the extension phase
    12. Frequency of adverse events
    13. Frequency of abnormal laboratory values
    14. Frequency of Columbia Suicide Severity Rating Scale (C-SSRS) outcomes
    15. Frequency of serious adverve events (SAEs) referring to a positive suicidal evaluation
    E.5.2.1Timepoint(s) of evaluation of this end point
    1&2&4: Week 6 to 18 of treatment (during maintenance of core phase)
    3.Baseline, Week 6 to 18 (during maintenance of core phase)
    5.Randomization to Week 18 of treatment
    6.Baseline, Week 18, End of Treatment*
    7.Baseline, End of Core (18 weeks), Every 6 months during Extension, End of Treatment Extension*
    8.Baseline,end of study (if patient completes range from 74 to 142 weeks)
    9.Baseline,Week 5
    10&11:Start of Extension (Week 18) to End of Treatment Extension*
    12.to 15.:Baseline to End of Treatment Extension*

    *(time when patient completes or leaves study.Range from 74 to 142 weeks)
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Biomarkers analysis
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA64
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Colombia
    Japan
    Korea, Republic of
    Russian Federation
    Taiwan
    Thailand
    Turkey
    United States
    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
    Please refer to section 4.1.4 of the protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 283
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 198
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 82
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 72
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent. For more details please see inclusion criterion 9.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 355
    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)
    With the protocol amendment 03, the End of the Study is extended until a date when either, everolimus could be
    commercially available to study participants or until it would be reasonable to expect that a roll over protocol could be opened at study sites, so that patients benefiting from continued treatment with everolimus, prior to the commercial availability of the drug, could exit this study, and enter the rollover protocol.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-25
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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