E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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. |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10077305 |
E.1.2 | Term | Acute on chronic liver failure |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Whether the patients are still alive will be recorded up to Day 90 |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include: • 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
North Macedonia |
Estonia |
Austria |
Belgium |
Bulgaria |
Denmark |
France |
Germany |
Italy |
Latvia |
Lithuania |
Netherlands |
Poland |
Slovakia |
Spain |
United Kingdom |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 30 |