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    Summary
    EudraCT Number:2019-003051-11
    Sponsor's Protocol Code Number:HEP102
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-12-19
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2019-003051-11
    A.3Full title of the trial
    Randomized, placebo-controlled, double blind, multi-centre Phase IIb study to evaluate the efficacy and safety of HepaStem in patients with Acute on Chronic Liver Failure (ACLF) - DHELIVER
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This trial will evaluate the safety and efficacy of HepaStem compared to placebo in patients with a cirrhotic liver condition called Acute on Chronic Liver Failure (ACLF). The study will be performed in multiple centers and in a double-blinded manner, meaning neither the patients nor the treating physicians know who is on placebo or the study drug.
    A.3.2Name or abbreviated title of the trial where available
    HEP102 - DHELIVER
    A.4.1Sponsor's protocol code numberHEP102
    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 SponsorPromethera Therapeutics
    B.1.3.4CountryBelgium
    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 supportPromethera Therapeutics
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPromethera Therapeutics
    B.5.2Functional name of contact pointWelcome desk
    B.5.3 Address:
    B.5.3.1Street AddressRue Granbonpré, 11
    B.5.3.2Town/ cityMont-Saint-Guibert
    B.5.3.3Post codeB-1435
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3210394300
    B.5.5Fax number+3210394301
    B.5.6E-mailRegulatory@promethera.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 nameHepaStem
    D.3.2Product code HALPC
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman allogeneic liver-derived progenitor cells
    D.3.9.2Current sponsor codeHALPC
    D.3.9.3Other descriptive nameHuman allogeneic liver-derived progenitor cells
    D.3.9.4EV Substance CodeSUB199771
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 50
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberTissue engineered product (EMA/CAT/391889/2016) in the treatment of fibroinflammatory liver diseases.
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cirrhotic patients who are hospitalized for Acute on chronic liver failure (ACLF), ACLF combines an acute deterioration of liver function in an individual with pre-existing chronic liver disease and extrahepatic organ failures characterized by high short-term mortality (30-40% at 28days). The development of ACLF is associated with exacerbated systemic inflammation that may indeed cause organ failures.
    E.1.1.1Medical condition in easily understood language
    ACLF is an acute deterioration of liver function in an individual with cirrhosis and organ failures with systemic inflammation and high short term mortality.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level PT
    E.1.2Classification code 10077305
    E.1.2Term Acute on chronic liver failure
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg (7-day interval) on the overall survival proportion 90 days post-first infusion.
    E.2.2Secondary objectives of the trial
    • To assess the safety of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg BW (7 days apart) through 90 days post first infusion
    • To assess the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg BW (7 days apart):
    o on the percentage of patients alive and free of liver transplantation (LT) at 90 days post first infusion
    o on the percentage of patients alive, free of LT and free of ACLF at 90 days post first infusion
    o on the percentage of patients alive and free of LT with Model for End-Stage Liver Disease (MELD)-Na score < 15 at 90 days post first infusion
    o on the number of intensive care unit (ICU)-free days during the index hospitalization up to 90 days post first infusion
    o on the number of hospital-free days during the index hospitalization up to 90 days post first infusion
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must fulfill all of the following criteria in order to be eligible for trial enrollment:
    1. Are adults aged between 18 and 70 years old.
    2. Have an initial diagnosis of ACLF at the investigational site.
    3. Have ACLF grade 1 or 2 according to the EASL-CLIF Consortium definition.
    4. Have a total bilirubin ≥ 5 mg/dL.
    5. Are able to read, understand and give written informed consent.
    If the patient is unable to fully understand the study and based on the investigator's judgment, the ICF must be signed by a legal or authorized representative of the patient according to local regulation. In case of hepatic encephalopathy (HE), the ICF must be signed by the patient after encephalopathy improvement, if possible.
    E.4Principal exclusion criteria
    Patients presenting with any of the following criteria will not be included in the study:
    1. Have a MELD-Na score > 35.
    2. Have underlying cirrhosis due to biliary disease.
    3. Have underlying cirrhosis due to autoimmune hepatitis.
    4. Have active bleeding at a non-compressible site or at a compressible site that, in the opinion of the investigator, poses an unacceptable risk for the patient's participation in the study.
    5. Have received treatment for bleeding complications during the current hospitalization and has a persistent high risk for re-bleeding that, in the opinion of the investigator, poses an unacceptable risk for the patient's participation in the study.
    6. Have a complete portal vein thrombosis.
    7. Have coagulation disturbances defined as:
    o fibrinogen < 80 mg/dL
    o platelets < 50 x 10³/mm³
    8. Are requiring chronic dialysis therapy.
    9. Have had a cerebrovascular, myocardial, limb arterial thrombotic event, or history for both thrombotic and hemorrhagic cerebrovascular events within 12 months prior to the Screening and not considered stabilized by the investigator.
    10. Have a previous history of myocardial infarction and/or cardiac failure, with an ejection fraction rate (EFR) ≤ 40%.
    11. Have an inability to maintain mean blood pressure (BP) > 60 mmHg despite use of vasopressors.
    12. Have severe pulmonary arterial hypertension defined as mean pulmonary arterial pressure (MPAP) ≥ 45 mmHg (or right ventricular systolic pressure ≥ 50 mmHg) by echocardiography.
    13. Have hepatopulmonary syndrome.
    14. Are receiving mechanical ventilation due to respiratory failure.
    15. Have known or suspected hypersensitivity or allergy to any of the components of the HepaStem diluent, dimethyl sulfoxide (DMSO), or bovine serum albumin.
    16. Have a history of severe allergies to drugs and/or a history of severe anaphylactic reactions.
    17. Have undergone a major invasive procedure within 2 weeks of randomization. These are open surgeries (the proper healing of the scar should be verified by the investigator).
    o Liver biopsy (transjugular or percutaneous), paracentesis, and transjugular intrahepatic portosystemic shunt (TIPS) are not considered as major invasive procedures.
    18. Had a previous organ transplantation and/or treatment with cell-based therapy.
    19. Are accepted as High Urgency status patient by the organ allocation system.
    20. Have active primary or recurrent malignant disease (including hepatocellular carcinoma) or have been in remission from clinically significant malignancy for < 5 years.
    o Patients with cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease for at least 3 years may participate in the study.
    o Patients with basal cell or squamous epithelial skin cancers that have been completely resected with no evidence of recurrence for at least 3 years may participate in the study.
    21. Are receiving immunosuppressive drugs, except glucocorticoids.
    o Patients receiving glucocorticoids administered for treatment of severe alcoholic hepatitis may participate in the study.
    22. Have a contraindication to or are unwilling to take glucocorticoids to prevent infusion-like reaction.
    23. Have persistently positive blood cultures despite 48 hours of antibiotic therapy that indicates uncontrolled bacterial infection.
    24. Have diagnosis of invasive aspergillosis.
    25. Have known infection with human immunodeficiency virus (HIV).
    26. Have a history of hepatitis D virus infection.
    27. Are women of childbearing potential and decline to use highly effective contraception methods during the study.
    28. Are women who have been using hormonal oral contraception within 8 weeks of study entry.
    29. Are pregnant (i.e., positive blood or urine β-hCG test) or nursing/breastfeeding.
    30. Have participated in any other interventional study within 4 weeks of study entry, or participation and/or under follow-up in another interventional clinical trial.
    31. Have any significant medical or social condition or disability that, in the investigator's opinion, may interfere with the patient's optimal participation or compliance with the study procedures.
    32. Are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
    33. Are employees of the Sponsor or investigator, or otherwise dependent on them.
    E.5 End points
    E.5.1Primary end point(s)
    Survival at Day 90: Whether the patients are still alive will be recorded
    up to Day 90. Time and reason of death will be recorded.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Whether the patients are still alive will be recorded up to Day 90
    E.5.2Secondary end point(s)
    • Liver transplant-free survival (TFS) at Day 90.
    • TFS at Day 90 while free of ACLF.
    • TFS at Day 90 with MELD-Na score < 15.
    • Duration of overall hospitalization and hospitalization in ICU and non-ICU during the index hospitalization up to Day 90.
    The secondary safety endpoints include:
    • Number, nature, severity, seriousness and relationship of AEs during the whole study. This includes but is not limited to clinically changes in clinical examinations, vital signs, laboratory tests, and imaging.
    • Occurrence of systemic infection (sepsis/shock, bacteremia, invasive fungal infection).
    • Presence of anti-HLA Abs and donor-specific Abs (DSA) (thresholds > 1500 mean fluorescence intensity [MFI] and > 5000 MFI).
    • Quantitative measurement of coagulation parameters: PT, INR, aPTT, fibrinogen, platelets, D-dimer.
    • Any change in laboratory data at all visits, including data on serology, hematology, biochemistry. Abnormal laboratory results will only constitute an AE, and will be reported as such, if they are considered abnormal within the pathology of this study population.
    • Physical examination and vital signs at all visits.
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to Day 90
    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 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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    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
    North Macedonia
    Austria
    Belgium
    Bulgaria
    Denmark
    Estonia
    France
    Germany
    Italy
    Latvia
    Lithuania
    Netherlands
    Poland
    Slovakia
    Spain
    United Kingdom
    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 months30
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months30
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the patient is unable to fully understand the study, the ICF must be signed by a legal or authorized representative according to local regulation. In case of HE, the ICF must be signed by the patient after encephalopathy improvement, if possible.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 100
    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)
    After the completion of the study, all patients who received at least 1 infusion of HepaStem will be invited to be included in the long-term follow-up PROLONGSTEM study for 5 additional years.
    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 Decision2019-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-24
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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