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    Summary
    EudraCT Number:2018-002531-18
    Sponsor's Protocol Code Number:69HCL16_0062
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-07-11
    Trial 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 ConcernedFrance - ANSM
    A.2EudraCT number2018-002531-18
    A.3Full title of the trial
    Topical Everolimus versus placebo for the treatment of facial angiofibromas in patients with tuberous sclerosis complex.
    A phase II/III, multicentre, randomized, double-blind, placebo-controlled study of 3 doses of topical Everolimus. EVEROST
    « EVEROST – EVEROLIMUS TOPIQUE VERSUS PLACEBO DANS LE TRAITEMENT DES ANGIOFIBROMES FACIAUX DES PATIENTS ATTEINTS DE SCELOROSE TUBEREUSE DE BOURNEVILLE » ; Etude multicentrique, randomisée, en double aveugle, contrôlée de 3 doses d’éverolimus topique contre placebo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Topical Everolimus versus placebo for the treatment of facial angiofibromas in patients with tuberous sclerosis complex.
    EVEROLIMUS TOPIQUE VERSUS PLACEBO DANS LE TRAITEMENT DES ANGIOFIBROMES FACIAUX DES PATIENTS ATTEINTS DE SCELOROSE TUBEREUSE DE BOURNEVILLE
    A.4.1Sponsor's protocol code number69HCL16_0062
    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 SponsorHospices Civils de Lyon
    B.1.3.4CountryFrance
    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 supportMinistry of Health
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospices Civils de Lyon
    B.5.2Functional name of contact pointDRCI
    B.5.3 Address:
    B.5.3.1Street Address3 Quai des Célestins
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69002
    B.5.3.4CountryFrance
    B.5.4Telephone number472406829+33
    B.5.5Fax number472115190+33
    B.5.6E-maildrci_promo@chu-lyon.fr
    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 No
    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 Cream
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    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 nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (V/V) percent volume/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.3
    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.IMP: 2
    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 No
    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 Cream
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    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 nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (V/V) percent volume/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.7
    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.IMP: 3
    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 No
    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 Cream
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    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 nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (V/V) percent volume/volume
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 placeboCream
    D.8.4Route of administration of the placeboTopical use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    angiofibromas
    angiofibromes
    E.1.1.1Medical condition in easily understood language
    angiofibromas
    angiofibromes
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002429
    E.1.2Term Angiofibroma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 of the phase II study is to identify the most appropriate dose of topical everolimus in terms of efficacy and safety and in the phase III, to demonstrate its superiority versus placebo for treatment of FA in patients with TSC after 6 months of treatment.
    E.2.2Secondary objectives of the trial
    1. To evaluate the efficacy of topical everolimus versus placebo by: Clinical assessment of FA (composite score); Blinded assessment of the redness using Reactiv’IP system; Assessment of the FA size reduction with topical everolimus versus placebo; Assessment of FA global improvement from patient’s and dermatologist’s perspectives; Improvement of quality of life of patients.
    2. To correlate the results of the primary endpoint with the results of the clinical assessment of FA.
    3. To evaluate safety of topical everolimus: Local tolerance of topical everolimus; Systemic safety of topical everolimus.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
     Male and female subjects > 2 years old.
     Subjects meeting the criteria for a definite or possible diagnosis of TSC
     Subjects with at least 3 FA, diagnosed by a dermatologist
     Women of child-bearing potential with a negative blood pregnancy test at the inclusion.
     Subjects or their parents or legal guardians must provide written informed consent prior to participation in the study
     Subjects covered by French national health insurance
    E.4Principal exclusion criteria
     Systemic treatment by sirolimus, everolimus, or any other immunosuppressive drug, within 6 months pre inclusion.
     Use of topical tacrolimus or sirolimus on the face, within 6 months pre inclusion.
     Destructive treatment (laser therapy, surgery, cryotherapy) of facial angiofibroma, within 6 months pre inclusion.
     Current concomitant use of topical treatments that could affect facial erythema (e.g. bromonidine)
     Known internal organ involvement requiring systemic mTOR inhibitor in the next 6 months
     Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
     Known chronic infectious disease
     Known hypersensitivity to mTOR inhibitor
     Neutropenia < 1000/mm3
     Thrombopenia < 75,000/mm3
     Chronic renal insufficiency (estimated Glomerular Filtration Rate < 60 mls/min)
     Chronic liver disease (SGOT or SGPT > 3 times upper normal limit)
     Uncontrolled dyslipidaemia
     Uncontrolled diabetes
     Breast feeding or pregnant women, or women of childbearing potential without any effective method of contraception during treatment and up to 12 weeks after treatment discontinuation.
     Subjects who, in the Investigator’s opinion, are unable or unwilling to comply with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the mean reduction of the validated and published score for assessment of angiofibromas, the Facial Angiofibroma Severity Index (FASI) after 6 months of treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    - Efficacy assessments
    a. Clinical assessment of FA: Mean reduction of a composite clinical score (0-12) for FA.
    b. Blinded assessment of the redness and extension using Reactiv’IP system.
    c. FA size (in millimetres) of the 3 largest targeted FA papules.
    d. Global improvement of FA on a 7-point Likert scale
    i. Dermatologist’s global assessment of efficacy
    ii. Patient or parents self-assessment
    e. Dermatological quality of life of patients, self-assessment using 2 validated dermatological surveys, both available in French:
    i. DLQI (Dermatology Life Quality Index) for adults
    ii. CDLQI (Children's Dermatology Life Quality Index) for children
    2. Correlation of the results of FASI blindly assessed and the clinical assessment of FA
    3. Safety of topical everolimus
    a. Local tolerance of the topical formulation applied:
    i. Patient self-assessment: composite scores of 5 items (stinging, burning, itching, dryness, and scaling), each item consists of 3 states: 0=absent, 1=mild, 2=moderate and 3=severe.
    ii. The physicians will assess dryness and scaling scores.
    b. Safety of the topical formulation applied:
    i. Quantification of blood levels of topical everolimus.
    ii. Laboratory assessments (creatinine, serum electrolytes including Na, K, Cl, CO2, Ca, Total protein and Urea, liver enzymes, total cholesterol, triglycerides, glucose, complete blood count).
    iii. Adverse events and serious adverse events
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day-21, 1, month 1,month 2, month 3, month 4, month 5 et month 6
    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) 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 trial4
    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 concerned14
    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
    LVLP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months61
    E.8.9.1In the Member State concerned days15
    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: 146
    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) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 No
    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
    children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state146
    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)
    NONE
    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 Decision2018-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-31
    P. End of Trial
    P.End of Trial StatusOngoing
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