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    Summary
    EudraCT Number:2018-001359-11
    Sponsor's Protocol Code Number:PHRN17-AM-TOPICAL/DR180115
    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:2018-07-23
    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 number2018-001359-11
    A.3Full title of the trial
    0.1% topical sirolimus in the treatment of cutaneous microcystic lymphatic malformations in children and adults: phase II, split-body randomized, double-blind, vehicle-controlled clinical trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    0.1% topical sirolimus in the treatment of cutaneous microcystic lymphatic malformations in children and adults: phase II, split-body randomized, double-blind, vehicle-controlled clinical trial
    A.3.2Name or abbreviated title of the trial where available
    TOPICAL
    A.4.1Sponsor's protocol code numberPHRN17-AM-TOPICAL/DR180115
    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 SponsorCHRU TOURS
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHRU TOURS
    B.5.2Functional name of contact pointARC DRCI - Estelle BOIVIN
    B.5.3 Address:
    B.5.3.1Street AddressCellule Promotion et CQ, 2 bd Tonnellé
    B.5.3.2Town/ cityTOURS
    B.5.3.3Post code37044
    B.5.3.4CountryFrance
    B.5.4Telephone number02 47 47 46 20
    B.5.5Fax number02 47 47 46 62
    B.5.6E-mailcpcq@chu-tours.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 nameSirolimus 0,1% crème
    D.3.4Pharmaceutical form Cream
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    Dental use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSIROLIMUS
    D.3.9.1CAS number 53123-88-9
    D.3.9.4EV Substance CodeSUB10537MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % (W/W) percent weight/weight
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 placeboCutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cutaneous microcystic lymphatic malformations (CMLM) in children and adults
    E.1.1.1Medical condition in easily understood language
    Malformations (CMLM) present as clusters of vesicles full of lymph and blood of various extent, usually located in a segmental area (head/neck, lower limbs, gluteal area). In children and adults.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003229
    E.1.2Term Arteriovenous malformations
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation in children and adults, versus topical vehicle.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of a 6-week application period of 0.1% topical sirolimus, versus topical vehicle, and of a 12-week, 20-week application period :
    - by comparing times W0 and W12 on photographs
    - regarding each of the following complications of the CMLM at W12 and W20
    - by assessing the global self-reported efficacy of topical sirolimus vs vehicle at W12 and W20
    - by assessing the global efficacy by the physician at W12 and W20
    - by assessing functional and esthetic impairments at W20
    - by evaluating pain linked to the CMLM at W20
    - by evaluating a the effect on quality of life
    To measure systemic passage of sirolimus at W12 and W20
    To evaluate tolerance of 0.1% topical sirolimus at W12 and W20
    To measure the long-term efficacy by the investigator and the patient at M12
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients ≥ 6 years
    - Updated immunization schedule
    - Diagnosis of primary cutaneous microcystic lymphatic malformation (CMLM) confirmed by histopathological or dermoscopic examination, with or without an underlying malformation or a syndromic malformation (Protée syndrome for instance), responsible for impairment (oozing, bleeding and/or pain)
    - CMLM ≥ 20 cm2, that can be divided into 2 parts of similar severity
    - Informed, written consent of the subject and his/her parents if < 18 years
    - Rights to French social security (including CMU)
    E.4Principal exclusion criteria
    - Patients with lymphatic malformation requiring a continued backround therapy (involving deep organs)
    - Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
    - Previous treatment with oral or topical mTOR inhibitors within 12 months before inclusion
    - Previous treatment with oral or topical steroids within 10 days before inclusion
    - Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
    - Ongoing neoplasia
    - Active chronic infectious disease (HBV, HCV, HIV, etc)
    - Local fungal, viral (HSV, VZV, etc) or bacterial infection on the site of the CMLM (based on clinical examination)
    - Skin necrosis
    - Known allergy to one of the components of the topical sirolimus preparation or vehicle
    - Women of child-bearing potential (including teenagers) not using a reliable contraceptive method until the end of the study
    - Pregnant or breastfeeding women
    - Subject already involved in another therapeutic trial
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will consist in the PGA score (Physician Global Assessment) assessed by the investigator physician (blinded from the treatment). PGA score ranges from 0 (clear) to 5 (severe lesions), and is commonly used in several dermatologic conditions. For each patient, PGA of the area treated with the intervention (0.1% topical sirolimus) will be compared to PGA of the area treated with topical vehicle (inactive comparator).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 12
    E.5.2Secondary end point(s)
    - Efficacy by PGA score
    - Efficacy by two independent experts on the basis of standardized photographs (instructions will be given for standardizing photographs) on each area of the CMLM. The experts will have to identify, at the end of the study, which area among both received the active treatment. In case of disagreement, a consensus will be reached between both experts; if consensus is not reached, a third expert will be sought for final decision
    - Efficacy by the investigator blinded to treatment regarding severity of oozing, bleeding, erythema, and thickness on both areas (treated with topical sirolimus and topical vehicle), with a visual analog scale (VAS) from 0 to 10
    - Self-assessment by the subject (and parents in case of children under 16) of the global improvement of CMLM in both areas using a VAS from 0 to 10
    - Self-assessment of functional and esthetic impairments (by the patient and parents if patient < 16, using a 0 to 10 VAS)
    - Self-assessment of pain by the patient on a 0 to 10 VAS linked to the CMLM (a VAS adapted to children will be used for subjects under 16 years)
    - Self-assessment of quality of life using the validated DLQI scale (Dermatology Life Quality Index), or Child-DLQI for children
    - Evaluation of systemic passage of sirolimus
    - Tolerance of topical sirolimus: record of local side effects in both areas treated with topical sirolimus and vehicle ; record of general side effects
    - Biological safety (we will perform biological measurements that are required for assessing safety of oral sirolimus: blood cell count, liver and renal functions, ionogram, lipids [cholesterol and triglycerides] and glycemia)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PGA at baseline, W6, W20 and M12
    - Photographs at baseline and W12
    - VAS for severity of oozing, bleeding, erythema, and thickness on both areas at baseline, W12, W20 and M12
    - Self-assessment by the subject at W12, W20 and M12
    - VAS for functional and esthetic impairments at baseline, W20 and M12
    - VAS for pain at baseline, W20 and M12
    - DLQI or Child-DLQI scale at baseline, W20 and M12
    - Dosage of serum level of sirolimus at W6, W12 and W20
    - Biological safety at baseline, W12 and W20
    W12 is the end of the double-blinded period
    W20 is the end of the open application of 0.1% topical sirolimus on the whole CMLM
    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 Yes
    E.8.1.7.1Other trial design description
    Intra-individual comparison test
    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 trial1
    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 concerned16
    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
    The last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 30
    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.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    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 Decision2019-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-25
    P. End of Trial
    P.End of Trial StatusOngoing
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