E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The study will recruit 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. |
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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 (28-day mortality rate: 30-40%). |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008954 |
E.1.2 | Term | Chronic liver disease and cirrhosis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049844 |
E.1.2 | Term | Acute liver failure |
E.1.2 | System Organ Class | 100000004871 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient must fulfill all of the following criteria to be eligible to participate in the study: 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) |
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E.4 | Principal exclusion criteria |
Any of the following criteria will exclude a patient from the study: 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse Events (AEs) reported up to Day 28 of the active study period. |
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E.5.2 | Secondary 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 - 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 will be summarized at Month 3 and Year 1
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E.5.2.1 | Timepoint(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 - SAE with fatal outcome, malignancies, AEs assessed by the investigator as possibly related to HepaStem, liver transplantation and outcome of liver transplantation and new ACLF episode will be summarized at Month 3 and Year 1 |
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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 | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 4 |