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    Summary
    EudraCT Number:2018-001240-61
    Sponsor's Protocol Code Number:allo-APZ2-ACLF-II-01
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-06-01
    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 ConcernedGermany - PEI
    A.2EudraCT number2018-001240-61
    A.3Full title of the trial
    An interventional, single arm, multicenter, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-ACLF for the treatment of acute-on-chronic liver failure (ACLF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial to investigate the efficacy and safety of allo-APZ2-ACLF administered intravenously to patients suffering from acute-on-chronic liver failure.
    A.4.1Sponsor's protocol code numberallo-APZ2-ACLF-II-01
    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 SponsorRHEACELL GmbH & Co. KG
    B.1.3.4CountryGermany
    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 supportRHEACELL GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRHEACELL GmbH & Co. KG
    B.5.2Functional name of contact pointInformation Office
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 517
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+496221718330
    B.5.5Fax number+4962217183329
    B.5.6E-mailoffice@rheacell.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 nameallo-APZ2-ACLF
    D.3.2Product code allo-APZ2-ACLF
    D.3.4Pharmaceutical form Suspension for injection
    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.3.9.2Current sponsor codeT202-3
    D.3.9.3Other descriptive nameAllogeneic skin-derived ABCB5-positive mesenchymal stem cells
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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
    Acute-on-Chronic Liver Failure
    E.1.1.1Medical condition in easily understood language
    Acute-on-Chronic Liver Failure (ACLF) is a syndrome, that is characterized by three main features: (1) acute decomposition of liver cirrhosis, (2) organ failures and (3) 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 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 aim of this clinical trial is to investigate the efficacy (by changes in Model for End-Stage Liver Disease [MELD] score) and safety (by monitoring adverse events [AEs]) of three doses of the IMP allo-APZ2-ACLF administered intravenously to patients suffering from ACLF.
    E.2.2Secondary objectives of the trial
    Not applicable.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients, aged 20 to 75 years;
    2. Diagnosed ACLF of grade 2 or 3 according to EASL-CLIF definition;
    3. Patients are not eligible for liver transplant (confirmed by transplantation board);
    4. Histology result of liver biopsy not older than 4 weeks before screening;
    5. Women of childbearing potential must have a negative blood pregnancy test at screening;
    6. Women of childbearing potential and fertile man, and their partners must be willing to use highly effective contraceptive methods during the course of the clinical trial;
    7. Written informed consent from patient, legal or authorized representative or a confirmation of justification of trial participation by an independent medical consultant. In case of confirmation by the independent medical consultant, a deferred informed consent from patient, legal or authorized representative has to be given.
    E.4Principal exclusion criteria
    1. Patients without cirrhosis;
    2. Patients with ACLF grade 1 according to EASL-CLIF definition;
    3. Patient with septic shock;
    4. Patients with known hepatopulmonal syndrome (HPS);
    5. Patients with known pulmonary embolism that needs anticoagulative treatment;
    6. Patients with pre-existing lung disease with necessity of respiratory support;
    7. Active malignancy or history of malignancy within 5 years prior to trial entry;
    8. Known infection with human immunodeficiency virus (HIVĖ—1, HIV-2);
    9. Any known allergies to components of the IMP;
    10. Current or previous (within 30 days of enrolment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
    11. Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
    12. Evidence of any other medical conditions (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the patient’s compliance, or place the patient at high risk of complications related to the treatment;
    13. Pregnant or nursing women;
    14. Employees of the sponsor, or employees or relatives of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    1. Primary efficacy endpoint: Change of MELD score at Week 24 or last available post-baseline measurement if the Week 24 score is missing (last observation carried forward [LOCF]).

    2. Primary safety endpoint: Adverse events.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Screening, Day 0, Week 24, or last available post-baseline measurement of Days 4 or 11 or Weeks 3, 4, 8, 12, 16 or 20 if the Week 24 measurement is missing [LOCF].

    2. A priori specification not possible; between Screening and Month 24.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    1. Change of MELD score at Weeks 3, 4, 8, 12, 16 and 20;
    2. Change of Child-Pugh-Score at Weeks 3, 4, 8, 12, 16, 20 and 24;
    3. Change of CLIF-C ACLF score at Weeks 3, 4, 8, 12, 16, 20 and 24;
    4. Overall survival time until Week 24;
    5. Complications of ACLF (hepatorenal syndrome [HRS)], variceal bleeding, ascites, hepatic encephalopathy [HE], spontaneous bacterial peritonitis [SBP]);
    6. Transient elastography assessment at Weeks 4, 12 and 24;
    7. Infections (proven infection necessitating systemic use of antibiotics);
    8. Change of levels of C-reactive protein in serum at Weeks 3, 4, 8, 12, 16, 20 and 24;
    9. Liver Function Test (ALT, AST, AP, Albumin, Bilirubin, GGT) at Weeks 3, 4, 8, 12, 16, 20 and 24;
    10. Changes in cytokine profile at Weeks 3, 4, 8, 12, 16, 20 and 24;
    11. Changes in dialytic treatment until Week 24;
    12. Time to respiratory failure after first IMP administration until Week 24;
    13. Duration of the initial hospital stay;
    14. Duration of initial intensive care stay;
    15. Optional: Evaluation of liver biopsy (necrosis quantification).

    Secondary safety endpoints:
    16. Physical examination and vital signs at Week 24;
    17. Laboratory parameters at Week 24;
    18. Overall survival at Week 24 and at Month 24.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Screening, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20
    2. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    3. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    4. Between SCR and Week 24
    5. Between SCR and Week 24
    6. Day 0, Weeks 4, 12, 24
    7. Between SCR and Month 24
    8. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    9. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    10. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    11. Between SCR and Week 24
    12. Between Day 0 and Week 24
    13. Between SCR and Week 24
    14. Between SCR and Week 24
    15. Between Week 8 and Week 24
    16. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    17. SCR, Days 0, 4, 11, Weeks 3, 4, 8, 12, 16, 20, 24
    18. Between SCR and Month 24
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Safety and efficacy in patients
    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 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 No
    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 years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned 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: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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
    It is likely that the severity of the disease (ACLF) will result in a proportion of patients unable to provide informed consent before the beginning of the trial either in oral or written form, mainly due to cerebral failures.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    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 final visit subjects will not receive any further study-specific treatment. They will be provided with standard of medical care treatment of ACLF, according to individual needs.
    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 Decision2018-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-19
    P. End of Trial
    P.End of Trial StatusRestarted
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