Allogeneic ABCB5-positive Stem Cells for Treatment of Acute-on-Chronic Liver Failure

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)

This is an interventional, single arm, multicenter, phase I/IIa clinical trial. The study objective is to investigate the efficacy and safety of three i.v. doses of the investigational medicinal product (IMP) allo-APZ2-ACLF for the treatment of acute-on-chronic liver failure (ACLF). The allogeneic IMP allo-APZ2-ACLF contains skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors and stored in a donor cell bank.

This is an interventional, phase I/IIa clinical trial to investigate the efficacy (by changes in Model for End-Stage Liver Disease [MELD] score) and safety (by monitoring adverse events) of the IMP in patients with acute-on-chronic liver failure grade 2 and 3. The allogeneic IMP allo-APZ2-ACLF contains skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors and stored in a donor cell bank.

The clinical trial will be conducted in Germany and will consist of a screening, treatment and efficacy follow-up period, and a safety follow-up period.The total duration is planned to be about 3 years including the follow-up period.

The planned sample size is up to 18 treated patients. 2 x 10e6 cells/kg, each at Day 0, Day 5 (±1) and Day 13 (±1), will be administrated into peripheral vein (arm) by use of a perfusor. allo-APZ2-ACLF will be in a concentration of 1 x 10e7 cells/mL in HRG-solution. In patients which require dialysis, the IMP application has to be performed at least 3 hours after end of dialysis. This is necessary to ensure that cells and secreted molecules are not cleared from the system by the dialysis.

Patients will be followed up for 24 weeks with clinic visits at Weeks 3, 4, 8, 12, 16, 20 and 24 after IMP application. Further safety follow-ups will be scheduled as home interviews via telephone at Months 15 and 24. If necessary (at the discretion of the investigator), safety follow-ups at Months 15 and 24 can also be carried out as an on-site visit.

The first six patients will be enrolled into the clinical trial consecutively with an interval of 2 weeks between the third IMP-application of the first patient and the enrolment of the second patient, etc. During this period the patient receives all three applications and immediate severe adverse effects (allergic reactions, SIRS) that could occur after treatment would be reported before treatment start of the next patient.

The safety data of these first six patients will be reviewed by the Medical Monitor continuously, if required with assistance of the further members of the DSMB. The safety evaluation of the DSMB will be submitted to the PEI and recruitment can only be continued after approval of an amendment.

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 men, 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.

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 (HIV˗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.