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    Summary
    EudraCT Number:2019-001530-33
    Sponsor's Protocol Code Number:DR190041
    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:2019-04-01
    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 number2019-001530-33
    A.3Full title of the trial
    TOPical sirolimus in linGUal microkystic lymphatic malformation-TOPGUN
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TOPical sirolimus in linGUal microkystic lymphatic malformation-TOPGUN
    A.3.2Name or abbreviated title of the trial where available
    TOPGUN
    A.4.1Sponsor's protocol code numberDR190041
    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 supportCHRU-TOURS
    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 - Wiebe de JONG
    B.5.3 Address:
    B.5.3.1Street AddressDRCI-CPCQ boîte95, 2 bd Tonnellé
    B.5.3.2Town/ cityTOURS
    B.5.3.3Post code37044
    B.5.3.4CountryFrance
    B.5.4Telephone number+33247474680
    B.5.5Fax number+33247474662
    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.2.1.1.1Trade name RAPAMUNE
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Information not present in EudraCT
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSirolimus 1mg/mL
    D.3.2Product code L04AA10
    D.3.4Pharmaceutical form Oral liquid
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOromucosal use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Lingual microcystic lymphatic malformations (LMLM) in children and adults
    E.1.1.1Medical condition in easily understood language
    Lingual microcystic lymphatic malformations (LMLM) present as congenital vascular malformations, presenting as clusters of cysts filled with lymph fluid or blood.
    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
    Evaluate the efficacy and safety of a 1mg/mL sirolimus solution applied once daily on mild to moderate lingual microcystic lymphatic malformation in children and adults after 4, 8, 12, 16, 20 and 24 weeks of treatment as compared to usual care (no treatment).
    E.2.2Secondary objectives of the trial
    evaluate patient-reported global efficacy of the application of 1mg/mL sirolimus solution on mild to moderate lingual microcystic lymphatic malformation in children and adults.
    -Evaluate patient-reported specific efficacy of the application of 1mg/mL sirolimus solution on mild to moderate LMLM in children and adults, versus usual care, on the following symptoms: oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort.
    -Evaluate quality of life of patients before and after treatment with topical sirolimus.
    -Assess time to optimal results.
    - Safety: by measuring systemic passage of sirolimus and assessing tolerance (local tolerance and general safety data).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients ≥ 5 years
    - Lingual microcystic lymphatic malformation Wiegand stage I or IIa (Wiegand 2009) assessed by clinical examination and head-and-neck MRI imaging prior to study enrolment, with or without underlying syndromic malformation (CLAPO for instance)
    - Participants covered by or having the rights to social security
    - Written informed consent obtained from participant and participant’s legal representative if participant is under 18
    - Ability for participant to comply with the requirements of the study
    E.4Principal exclusion criteria
    -Patients with a lymphatic malformation requiring a continued background therapy (involving deep organs)
    -Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
    -Previous treatment with systemic or topical mTOR inhibitors within 12 months before inclusion (half-life of oral sirolimus is 60 days in adults).
    -Previous treatment with oral or topical steroids within 10 days before inclusion (half-life of corticosteroids is 12-36 hours)
    -Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
    -Ongoing neoplasia
    -Active chronic infectious disease (HBV, HCV, HIV, etc)
    -Local necrosis
    -Local fungal, viral (HSV, VZV, etc) or bacterial infection on the site of the LMLM (based on clinical examination)Known allergy to one of the components of the sirolimus solution
    -Soy bean or Peanut allergy
    -Pregnant or breastfeeding women
    -Women of child-bearing potential (including teenagers) not using a reliable contraceptive method until the end of the study
    -Already involved in another therapeutic trial
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will consist in the evaluation of global severity of the LMLM using PGA (Physical Global Assessment) 0 to 5 score, by three independent blinded experts, on monthly standardized photographs.
    A 1-point improvement versus baseline in PGA scale would already have a clinical relevance.
    Our primary analysis will focus on change in PGA after topical application of Sirolimus for 12 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 12
    E.5.2Secondary end point(s)
    - Investigator-assessed PGA at weeks 0, 4, 8, 12, 16, 20 and 24
    - Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort, each using a numeric scale from 0 to 10 (0: clear, 10: very severe), at weeks 0, 4, 8, 12, 16, 20 and 24.
    - Global evolution assessed by the patient from -10 to 10 (-10 = severe worsening, 0 = no change, 10 = complete recovery), at weeks 4, 8, 12, 16, 20 and 24.
    - Global Quality of life assessment (DLQI or children’s DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and W24.
    - Measurement of the lesion (length, width, thickness) by the investigator, at baseline, time of switch to treatment and W24.
    - Time to obtain optimal results
    - Safety:
    - Assessment of tolerance of topical sirolimus: record of local side effects at each visit after the patient has crossed over to the intervention
    - General side effects, physical examination, systolic and diastolic blood pressure measurement.
    - Assessment of sirolimus blood passage by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until W24
    - Evaluation of biological safety at weeks 8, 16 and 24 of exposure compared to baseline (we will perform biological measurements that are required for assessing safety of oral sirolimus: complete blood count, liver (ASAT, ALAT, GGT) and renal (serum creatinine) functions, lipids [cholesterol and triglycerides] and glycaemia)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 1. at weeks 0, 4, 8, 12, 16, 20 and 24
    -2. at weeks 0, 4, 8, 12, 16, 20 and 24.
    -3 at weeks 4, 8, 12, 16, 20 and 24.
    -QOL at baseline, time of switch to treatment and W24.
    -Measurement of the lesion at baseline, time of switch to treatment and W24.
    -Time to obtain optimal results
    - Assessment of tolerance of topical sirolimus: record of local side effects at each visit after the patient has crossed over to the intervention
    - General side effects, physical examination, systolic and diastolic blood pressure measurement.
    - Assessment of sirolimus blood passage by measuring residual sirolimus blood concentration: after 4 w of treatment, 8 w, then every 8 w until W24
    - Evaluation of biological safety at weeks 8, 16 and 24 of exposure compared to baseline
    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 No
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    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
    Stepped-wedge
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 concerned2
    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 years1
    E.8.9.1In the Member State concerned months5
    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: 12
    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: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) No
    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 state12
    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 Decision2019-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-29
    P. End of Trial
    P.End of Trial StatusOngoing
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