E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute-on-Chronic Liver Failure |
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E.1.1.1 | Medical 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. |
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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 | 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 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. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. Historical confirmed histology result of liver biopsy or other diagnostic methods (like medical imaging such as computed tomography, ultrasound ect.) to exclude other liver diseases; 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. |
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E.4 | Principal 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 (HIVĖ1, 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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 |
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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) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and efficacy in patients |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |