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    Summary
    EudraCT Number:2016-001177-32
    Sponsor's Protocol Code Number:HEP101
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-04-12
    Trial results View 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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2016-001177-32
    A.3Full title of the trial
    Multicenter Phase II Safety and Preliminary Efficacy Study of two dose regimens of HepaStem in Patients with Acute on Chronic Liver Failure
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study will study the safety and preliminary efficacy of HepaStem in cirrhotic patients who are hospitalized for Acute on Chronic Liver Failure (ACLF) or acute decompensation at risk of developing ACLF.
    The study is divided in 4 periods: screening period, active study period divided in treatment period and evaluation period, and long-term safety follow-up.
    A.4.1Sponsor's protocol code numberHEP101
    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 Biosciences
    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 Biosciences
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPromethera Biosciences
    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 number003210394300
    B.5.5Fax number003210394301
    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 allogenic liver-derived progenitor cells
    D.3.9.2Current sponsor codeHALPC
    D.3.9.3Other descriptive nameHuman allogenic 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
    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) or Acute Decompensation at risk of
    developing 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 28
    days). 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008954
    E.1.2Term Chronic liver disease and cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10049844
    E.1.2Term Acute liver failure
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety of different dose regimens of HepaStem in cirrhotic Patients with ACLF or with acute decompensation at risk of developing ACLF up to Day 28 of the active study period.
    E.2.2Secondary objectives of the trial
    • Preliminary efficacy:
    To evaluate clinical and biological efficacy parameters following HepaStem infusion up to Day 28, up to Month 3 and up to Year 1 post first HepaStem infusion.
    • Long term safety:
    To assess the safety of HepaStem up to Month 3 and Year 1 post first HepaStem infusion.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult aged between 18 and 70 years old.
    2. Informed Consent.
    N.B: In case of hepatic encephalopathy, if the patient is not able to
    understand the study based on the investigator's judgment, the
    Informed Consent must be signed by patient's legal representative
    according to local regulation, and by the patient, if possible, after
    encephalopathy improvement.
    3. Cirrhosis as diagnosed by (1) liver histology or (2) by clinical and
    imaging examination (may include fibroscan).
    4. Patient with Acute Decompensation of cirrhosis
    5. Serum total Bilirubin ≥ 6 mg/dL (≥100 umol/L)
    E.4Principal exclusion criteria
    1. Thrombosis of the portal vein.
    2. Recurrent or ongoing thrombotic events or patients considered with
    high risk of thrombosis at the time of infusion.
    Any thrombosis history should be discussed with the medical monitor
    before exclusion / inclusion in the study, in a case by case discussion.
    3. Ongoing uncontrolled bleeding.
    4. Septic shock or non-controlled bacterial infection defined as persistent
    clinical signs of infection despite adequate antibiotic therapy for more
    than 48h.
    5. Clinical evidence of Aspergillus infection.
    6. Circulatory failure defined by inability to maintain a mean blood pressure ≥70 despite use of vasopressors.
    7. Mechanical ventilation due to respiratory failure.
    8. Coagulation disorders defined as:
    • Fibrinogen < 80 mg/dL
    • Platelets < 40.000/mm3
    9. Major invasive procedure within 4 weeks before the infusion (within
    1week for minor invasive procedure such as e.g. transjugular liver
    biopsy). The proper healing of the puncture site should be verified by the
    investigator.
    10. Treatment with corticosteroids for acute liver disease less than 1 day
    before the start of the screening period.
    11. MELD score > 35.
    12. Previous organ transplantation and/or ongoing immunosuppressive
    treatments.
    13. Postoperative-decompensation following hepatectomy.
    14. Renal failure due to chronic kidney disease.
    15. Clinically significant left-right cardiac shunt.
    16. Known or suspected hypersensitivity or allergy to any of the
    components of the HepaStem Diluent (human albumin, heparin sodium
    and sodium bicarbonate) or a history of multiple and/or severe allergies
    to drugs or foods or a history of severe anaphylactic reactions.
    17. Malignancies, other than curatively treated skin cancer, unless a
    complete remission over 5 years. In case of suspicion of HCC, all exam
    should be done to confirm or not the diagnosis prior enrolment.
    18. Refusal of abstinence from alcohol for at least 5 weeks from the
    study enrolment.
    19. Pregnancy (negative β-HCG test required) or women with
    childbearing potential who decline to use reliable contraceptive methods
    during the study.
    20. Participation to any other interventional study within the last 4
    weeks.
    21. Any significant medical or social condition or disability that, in the
    Investigator's opinion, may warrant a specific treatment, or may
    interfere with the patient's optimal participation or compliance with the
    study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    Safety assessment:
    AEs reported up to Day 28 of the active study period, assessed for seriousness, severity, relationship to IMP and/or IMP administration procedure
    The AEs will include but will not be limited to clinically significant changes in clinical examinations, vital signs, laboratory tests, abdominal echography and Doppler up to Day 28.
    The relationship will be assessed based on investigator assessment, and in addition by SMC and the sponsor pharmacovigilance in line with the ATMP guideline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse Events (AEs) reported up to Day 28 of the active study period.
    E.5.2Secondary end point(s)
    Clinical efficacy parameters will be assessed at Day 28, Month 3 and Year 1.
    • Mortality
    • Liver transplantation
    • Disease scoring: CLIF-OF score, CLIF-C ACLF score, CLIF ACLF grade, CLIF-C AD (pre-ACLF patients with Acute Decompensation), MELD score, Child Pugh score.

    Biological efficacy parameters will be assessed at Day 28, Month 3 and Year 1
    • Bilirubin, creatinine, INR and albumin values

    Long term safety follow-up
    • Adverse Events of Special Interest (AESIs) will be summarized at Month 3 and Year 1
    AESIs are SAE with fatal outcome, malignancies, AEs assessed by the investigator as possibly related to HepaStem, liver transplantation and outcome of liver transplantation New ACLF episode.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical efficacy parameters will be assessed at Day 28, Month 3 and Year 1
    Biological efficacy parameters will be assessed at Day 28, Month 3 and Year 1
    Long term safety follow-up:
    Adverse Events of Special Interest (AESIs) will be summarized at Month 3 and Year 1
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days4
    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: 18
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 3
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 21
    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 Decision2018-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-08-21
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