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    Summary
    EudraCT Number:2017-002697-39
    Sponsor's Protocol Code Number:MPOH03
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-07
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-002697-39
    A.3Full title of the trial
    Treatment of steroid refractory gastro-intestinal acute graft-versus-Host disEase afteR AllogeneiC hematopoietic stem celL transplantation with fEcal microbiota transfer (HERACLES)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of gastro-intestinal graft vs. host disease with rectal infusion of bacteria in patients not responsive to steroids.
    A.3.2Name or abbreviated title of the trial where available
    HERACLES
    A.4.1Sponsor's protocol code numberMPOH03
    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 SponsorMaaT Pharma
    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 supportMaaT Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMaaT Pharma
    B.5.2Functional name of contact pointEmilie Plantamura
    B.5.3 Address:
    B.5.3.1Street Address317 avenue Jean Jaurès
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69007
    B.5.3.4CountryFrance
    B.5.6E-maileplantamura@maat-pharma.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 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 nameMaaT013
    D.3.2Product code 7P010
    D.3.4Pharmaceutical form Rectal suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPRectal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeMaaT013
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number30 to 90
    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
    Steroid refractory gastro-intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
    E.1.1.1Medical condition in easily understood language
    Medical complication not treatable with steroids following the receipt of transplanted tissue from a genetically different person.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of the gastrointestinal response (Complete Response (CR) and Very Good Partial Response (VGPR)) at D28 of steroid refractory (SR) gastro-intestinal (GI) acute graft-versus-host disease (aGVHD) patients treated with allogeneic Fecal Microbiota Transfer (FMT).
    E.2.2Secondary objectives of the trial
    •Evaluation of overall aGVHD response (CR and VGPR)
    •Evaluation of overall and best response rates (CR, VGPR and Partial Response (PR)) for GI and overall aGVHD
    •Evaluation of the durable overall response rate
    •Evaluation of the duration of response
    •Evaluation of safety within 24 hours after FMT as well as overall safety.
    •Evaluation of feasibility of allogeneic FMT procedure and acceptance by the patient
    •Evaluation of clinical safety and performance of MaaT Pharma’s medical device
    •Evaluation of the number of patients receiving the full treatment sequence (3 FMTs)
    •Evaluation of FMT activity and/or impact on:
    - Steroid-free, progression-free survival, relapse of the initial disease, GVHD-free survival, GVHD and relapse-free survival, overall survival 0
    - Infectious disorders
    - Multi-Drug Resistant Bacteria (MDRB) carriage
    - Clinical symptoms of skin/liver aGVHD associated with SR-GI-aGVHD
    - Stool evaluation (volume of diarrhea, Bristol stool chart)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients who develop a first episode of Grade III or IV aGVHD (= gastrointestinal Stages 2 to 4) with gut predominance if other organs involved (Przepiorka D, 1995), resistant to a first-line therapy with steroids, defined as any of the following:
    a. Lack of improvement after 5 to 7 days of treatment with CS at 2mg/kg/d methylprednisolone equivalent dose.
    b. Progression after 3 days of treatment with CS at 2 mg/kg/d methylprednisolone equivalent dose.
    c. Patients treated with 1 mg/kg/d of CS because the physician deemed they would not tolerate 2 mg/kg/d and who correspond to the definition of SR patients.
    2. Age ≥ 18 years old
    3. Allo-HSCT with any type of donor, stem cell source, GVHD prophylaxis or conditioning regimen
    4. Patients able to have a minimum of 12 hours discontinuation of systemic antibiotics in order to perform the allogeneic FMT (for patients who require antibiotics, using antibiotics that have limited impact on the gut microbiota should be considered in priority. The complete list of recommended and not recommended antibiotics is in Appendix 6)
    5. Signature of informed and written consent by the subject or by the subject’s legally acceptable representative for patients under guardianship or trusteeship
    E.4Principal exclusion criteria
    1. Grade IV hyper-acute GVHD as defined by the MD Anderson’s criteria (Saliba RM, 2007)
    2. Overlap chronic GVHD as defined by the NIH Consensus Criteria (Jagasia MH, 2015)
    3. Acute GVHD after donor lymphocytes infusion (DLI)
    4. Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
    5. Active uncontrolled infection according to the attending physician
    6. Current or past veno-occlusive disease or other uncontrolled complication unless otherwise agreed in writing by the sponsor.
    7. Systemic drugs other than corticosteroids for GvHD treatment, including extra-corporeal photopheresis (ECP), unless treatments began before or concomitantly with corticosteroid treatment. New therapies after corticosteroids are a definitive non-inclusion criterium.
    Drugs for GVHD prevention (e.g., calcineurin inhibitors, Mycophenolate mofetil (MMF), ECP…), are allowed as long as treatment began before or concomitantly with the corticosteroid treatment.
    8. Absolute neutrophil count < 0.5 x 109 /L
    9. Absolute platelet count < 10 000
    10. Patient with negative IgG EBV serology
    11. Current or past evidence of toxic megacolon, bowel obstruction or gastrointestinal perforation on abdominal X-ray
    12. Known allergy or intolerance to trehalose or maltodextrin
    13. Vulnerable patients such as: minors, persons deprived of liberty, persons in Intensive Care Unit unable to provide informed consent prior to the intervention
    14. Pregnancy: positive urinary or blood test in females of childbearing potential; lactation; absence of effective contraceptive method for females of childbearing potential throughout the entire duration of the study
    15. Other ongoing interventional protocol that might interfere with the current study’s primary endpoint.

    E.5 End points
    E.5.1Primary end point(s)
    Efficacy of FMT in the treatment of SR-GI-aGVHD at D28 post inclusion (V4):
    Number and proportion of patients achieving GI aGVHD response by D28, defined as Complete Response or Very Good Partial Response.
    E.5.1.1Timepoint(s) of evaluation of this end point
    D28 post inclusion (V4)
    E.5.2Secondary end point(s)
    1) Efficacy of FMT in the treatment of overall aGVHD at D28 post inclusion (V4)
    2) Evaluation of overall and best response rates (CR, VGPR and Partial Response (PR)) for both GI and overall aGVHD

    3) Evaluation of the durable overall response rate

    4) Evaluation of the duration of response

    5) Safety of FMT in patients with SR-GI-aGVHD

    6) Feasibility of allogeneic FMT procedure and acceptability by the Patient
    Number of patients receiving 3 FMTs

    8) Clinical safety and performance of MaaT Pharma’s medical device (Directive 9342 CE, med dev 2.7.1)

    9) Evaluation of FMT activity and/or impact on steroid-free, progression-free survival, relapse of the initial disease, GVHD-free survival, GVHD and relapse-free survival and overall survival

    10) Evaluation of FMT activity and/or impact on infectious disorders

    11) Evaluation of FMT activity and/or impact on MDRB carriage

    12) Evaluation of FMT activity and/or impact on clinical symptoms of skin/liver aGVHD associated with SR-GI-aGVHD

    13) Stool evaluation (volume of diarrhea, Bristol stool chart)

    14) Evaluation of microbiota reconstitution

    15) Chronic GVHD incidence and severity

    16) Assessment of a microbiota signature (Exploratory)

    17) Impact of FMT on the immune system (Exploratory)
    E.5.2.1Timepoint(s) of evaluation of this end point
    D28 post inclusion (V4), M3 (V5), M6 (V6) and M12 (V7)
    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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months24
    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 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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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
    Subject´s legally acceptable representative may sign the informed and written consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 24
    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
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-26
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