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    Summary
    EudraCT Number:2016-001447-39
    Sponsor's Protocol Code Number:AB15003
    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:2017-03-24
    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 number2016-001447-39
    A.3Full title of the trial
    A 24-week with possible extension, prospective, multicenter, randomized, double blind, placebo-controlled, 2-parallel group with a randomization 1:1, phase III study to compare efficacy and safety of oral masitinib to placebo in treatment of patients with Smouldering or Indolent Severe Systemic mastocytosis with handicap, unresponsive to optimal symptomatic treatment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 24-week with possible extension study to compare efficacy and safety of masitinib to placebo in treatment of patients with Smouldering or Indolent Severe Systemic mastocytosis
    A.4.1Sponsor's protocol code numberAB15003
    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 SponsorAB SCIENCE
    B.1.3.4CountryFrance
    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 supportAB Science
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAB SCIENCE
    B.5.2Functional name of contact pointAlain Moussy
    B.5.3 Address:
    B.5.3.1Street Address3 avenue Georges V
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75008
    B.5.3.4CountryFrance
    B.5.4Telephone number+33147202311
    B.5.5Fax number+33147202411
    B.5.6E-maila.moussy@ab-science.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 Information not present in EudraCT
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberE/3/04/242
    D.3 Description of the IMP
    D.3.1Product nameMasitinib
    D.3.2Product code AB1010
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 Information not present in EudraCT
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberE/3/04/242
    D.3 Description of the IMP
    D.3.1Product nameMasitinib
    D.3.2Product code AB1010
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 placeboFilm-coated 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
    Smouldering or Indolent Severe Systemic mastocytosis
    E.1.1.1Medical condition in easily understood language
    A 24-week with possible extension study to compare efficacy and safety of masitinib to placebo in treatment of patients with Smouldering or Indolent Severe Systemic mastocytosis
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study objective is to compare the efficacy and safety of oral masitinib versus placebo in the treatment of patients suffering from documented Smouldering or Indolent Severe Systemic mastocytosis with handicap unresponsive to optimal symptomatic treatment
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient with one of the following documented mastocytosis:
     Smouldering Systemic Mastocytosis (SSM)
     Indolent Systemic Mastocytosis (ISM)
    2. Patients meet the retained classification of SM based on the presence of one of the three criteria and an excess of mast cells or a presence of abnormal mast cells in at least two organs (first one is skin and the second being bone-marrow or GI Tract):
    I. Bone marrow biopsy and/or aspirate associated with at least a sign of abnormality of mast cells:
    a) Abnormal aggregates of mast cells in a sample in bone marrow:
    The criteria is deemed satisfied if the aggregate i) is quantified and is strictly above 15 mast cells per aggregated (corresponding to WHO major criterion), or ii) is not quantified but is described as nodule, seat, cluster, focus, or granuloma and therefore pathological;
    b) ≥25% atypical mast cells in a sample of bone marrow (corresponding to WHO minor criterion);
    c) c-Kit point mutation at codon 816 in bone marrow (corresponding to WHO minor criterion);
    d) Abnormal mast cells in the sample of bone marrow while microscopic testing that can be described by the following words: Spindled; Abnormal; Atypical; Fusiform; Dystrophic; Pathologic; Dysmorphic (corresponding to WHO minor criterion);
    e) Abnormal immunohistochemistry signs: mast cells in bone marrow express CD2 or/and CD25 present (corresponding to WHO minor criterion);
    f) Abnormal infiltration of mast cells in the bone marrow:
    The criteria is deemed satisfied if the infiltration i) is quantified and is strictly above 3% in the biopsy, or ii) is not quantified but is abnormal as described with infiltration, contingent of mast cells, or proliferation and therefore pathological.
    II. Detection of c-kit 816 in the bone marrow without evidence of mast cells in bone marrow but with evidence of c-Kit 816 in skin, justifying clonality;
    III. Excess of mast cells in digestive organs.
    3. Patient with severe symptoms over the 14-day run-in period defined as at least one of the following:
     Pruritus score ≥ 9
     Number of flushes per week ≥ 8
     Hamilton rating scale for depression (HAMD-17) score ≥ 19
    4. Patient with documented treatment failure of his/her symptom (s) (within last two years) with at least two of the failure symptomatic treatment used at optimized dose (Minimal duration of each treatment should be at least 8 weeks):
     Anti H1
     Anti H2
     Proton pump inhibitor
     Antidepressants
     Cromoglycate Sodium
     Antileukotriene
    5. Patients must be on a stable dose of Anti-H1 for a minimum of 4 weeks before screening and should remain at a stable dose throughout the study period. For other symptomatic treatments, if the patient takes corticosteroids, Anti-H2 or PPI or Antidepressants or Cromoglycate Sodium or Antileucotriene, the treatment must have started at least 4 weeks before Screening and must be stable throughout the study.
    6. Documented age between 18 to 75 years (inclusive).
    E.4Principal exclusion criteria
    1. Cutaneous mastocytosis, SM associated with hematological neoplasm, Mast Cell Leukemia and Aggressive SM.
    2. Previous treatment with any Tyrosine Kinase Inhibitor.
    3. Any change in the symptomatic treatment of SM, including the systemic corticosteroids, or administration of any new treatment for SM within 4 weeks prior to screening.
    E.5 End points
    E.5.1Primary end point(s)
    Cumulative response on 3 severe symptoms (Pruritus, Flush, Depression) from week 8 to week 24.
    Severe symptomd for primary objective is defined as: Pruritus score ≥ 9, number of Flushes per week ≥ 8, Depression ≥ 19.

    Response on a severe symptoms is defined as an improvement ≥ 75% for Pruritus, Flushes and Depression.

    In case of rescue medication to manage a severe symptom, all subsequent measures will be considered as “fail”.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 4 weeks from week 8
    E.5.2Secondary end point(s)
    1) Severe symptom
    The following secondary endpoints will be analysed using a Generalized Estimating Equations (GEE) model using Logit as link function. This statistical model will include all the responses (Yes/No) on handicaps observed from week 8 to week 24.

    This model will include treatment, handicap and visit as factors and all stratification factors as covariates:
    • Response on 4 severe symptoms (version 1) from week 8 to week 24.
    This analysis will include FSS score in addition to the three severe symptoms included in the primary endpoint.

    • Response on 4 severe symptoms (version 2) from W8 to W24.
    This analysis will include FIS score in addition to the three severe symptoms included in the primary endpoint.

    • Response 2 on severe symptoms from W8 to W24.
    This analysis will include pruritus and flush at Baseline.

    • Each individual severe symptoms (Pruritus, Flushes, Depression, fatigue (FIS), fatigue (FSS).

    Sensitivity analysis will be performed on the week 8 to week 48.

    2) Biological and Skin Parameters:
    • Tryptase:

    Tryptase will be analysed for patients with a baseline level higher than 20 µg/L.

    - Change from baseline in serum tryptase level at week 24 will be analyzed using Analysis of Covariance (ANCOVA) with baseline value as covariate for the absolute change from baseline and Wilcoxon’s non-parametric exact test for ranks for relative change from baseline.

    - Response: Defined as a diminution of at least 25% in tryptase level from baseline to week 24 will be analyzed using logistic regression. If logistic regression fails to estimate the treatment effects, Chi-Square test or Fisher’s exact test (depending the observations).

    • Urticaria Pigmentosa:

    a) “Darier Sign” disappearance:
    “Darier Sign” disappearance (Yes/No) for patients with “Darier’s sign” at baseline from W8 to W24 will be analyzed using Generalized Estimating Equation (GEE) with logit as link function. The model will include treatment and visit as factors.
    Sensitivity analysis will be performed using the same model as above for W8 to W48 period.
    b) Body Surface Area (BSA):
    The relative change from baseline in Body Surface Area (BSA) total score from week 8 to week 24 will be analyzed using mixed model repeated measures (MMRM) on ITT population. Treatment, baseline total score and visit will be added as factors.
    Sensitivity analysis will be performed using the same model as above for all visits between W8 and W48.
    c) Quality of Life:
    The MC-QoL questionnaire was developed specifically for the assessment of Quality of Life in patients with Mastocytosis. The change from baseline in MC-QoL from W8 at Week 24 will be analysed using mixed model repeated measures (MMRM) using treatment, baseline MC-QoL Score and stratification factors as covariates.

    Sensitivity analysis will be performed for MC-QoL from W8 to W48 using mixed model repeated measures (MMRM) with treatment and visit as factors and baseline score as covariate.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 4 weeks from week 8
    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 No
    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 Yes
    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) 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 trial2
    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 EEA8
    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
    Canada
    France
    Germany
    Italy
    Lithuania
    Netherlands
    Poland
    Romania
    Russian Federation
    Spain
    Ukraine
    United Kingdom
    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
    LVLS
    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 months5
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    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: 112
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 93
    F.4.2.2In the whole clinical trial 140
    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 Decision2019-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-09
    P. End of Trial
    P.End of Trial StatusOngoing
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