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Acute-On-Chronic Liver FailurePhase 1/2NCT03860155

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

A Phase 1/2 study testing allo-APZ2-ACLF in people with Acute-On-Chronic Liver Failure, run by RHEACELL GmbH & Co. KG at 5 sites in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 20 to 75 years
Conditions the study is for
Acute-On-Chronic Liver Failure
What is being tested?
allo-APZ2-ACLF
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
5 sitesGermany
Study dates
22 Mar 2019to 26 Mar 2021
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female patients, aged 20 to 75 years;
  • Diagnosed ACLF of grade 2 or 3 according to EASL-CLIF definition;
  • Patients are not eligible for liver transplant (confirmed by transplantation board);
  • Histology result of liver biopsy not older than 4 weeks before screening;
  • Women of childbearing potential must have a negative blood pregnancy test at screening;
  • 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;
  • 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.

Who cannot join

  • Patients without cirrhosis;
  • Patients with ACLF grade 1 according to EASL-CLIF definition;
  • Patient with septic shock;
  • Patients with known hepatopulmonal syndrome (HPS);
  • Patients with known pulmonary embolism that needs anticoagulative treatment;
  • Patients with pre-existing lung disease with necessity of respiratory support;
Show all 14Show fewer
  • Active malignancy or history of malignancy within 5 years prior to trial entry;
  • Known infection with human immunodeficiency virus (HIV˗1, HIV-2);
  • Any known allergies to components of the IMP;
  • Current or previous (within 30 days of enrolment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
  • Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
  • 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;
  • Pregnant or nursing women;
  • Employees of the sponsor, or employees or relatives of the investigator.

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Germany5 sites

  • Universitätsklinikum Carl-Gustav-Carus an der TU Dresden, Medizinische Klinik I

    Dresden, 01307

  • Universitätsklinikum Essen, Klinik für Gastroenterologie und Hepatologie, Medizinisches Forschungszentrum

    Essen, 45147

  • Universitätsklinikum Frankfurt, Medizinische Klinik 1, Sektion Translationale Hepatologie

    Frankfurt, 60590

  • Universitätsklinikum Magdeburg A.ö.R., Medizinische Fakultät der Otto-von-Guericke-Universität

    Magdeburg, 39120

  • Medizinische Fakultät Mannheim der Universität Heidelberg, II. Medizinische Klinik

    Mannheim, 68167

Other trials in Germany

About this study

Official title: 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.

Read the detailed description

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.

Being tested
allo-APZ2-ACLF
Keywords
Acute-on-Chronic Liver Failure, ACLF, ABCB5, ATP Binding Cassette Subfamily B Member 5, allogeneic, mesenchymal stem cells, advanced therapy medicinal product, somatic cell therapy, phase I/IIa
Medical subject headings
Acute-On-Chronic Liver Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • allo-APZ2-ACLFBiological

    Also called Skin-derived ABCB5-positive mesenchymal stem cells

    Administration of 2 x 10e6 allogeneic ABCB5-positive stem cells/kg bodyweight, each at Day 0, Day 5 (±1) and Day 13 (±1) into peripheral vein (arm) intravenously with a flow rate of 1-2 ml/min. Infusion of the product via a central venous catheter (CVC), a Port-a-Cath (Port) or a similar catheter is also possible. Allo-APZ2-ACLF will be in a concentration of 1 x 10e7 cells/mL in Human Serum Albumin/Ringer-Lactate/Glucose (HRG)-solution.

Study groups in NCT03860155
Study groupRoleWhat they receive
allo-APZ2-ACLFExperimentalApplication of IMP into peripheral vein (arm) by use of a perfusor.
Receives: Biological: allo-APZ2-ACLF

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change of Model for End-Stage Liver Disease (MELD) score at Week 24 or last available post-baseline measurement if the Week 24 score is missing.

    Model for End-Stage Liver Disease (MELD) score for assessing the severity of chronic liver disease is measured as absolute change to baseline score at Week 24 or last available post-baseline measurement if the Week 24 score is missing.

    Measured: Week 24, or last available post-baseline measurement of Days 5 (±1) or 13 (±1) or Weeks 3, 4, 8, 12, 16 or 20 if the Week 24 measurement is missing [LOCF].

  2. Assessment of adverse event (AE) occurrence

    All AEs occurring during the clinical trial will be registered, documented and evaluated.

    Measured: Between Screening and Month 24

Secondary outcomes (25)

  1. Change of MELD score at Weeks 3, 4, 8, 12, 16 and 20

    Model for End-Stage Liver Disease score is measured as absolute change to baseline score.

    Measured: Weeks 3, 4, 8, 12, 16 and 20

  2. Change of Child-Pugh-Score at Weeks 3, 4, 8, 12, 16, 20 and 24

    Child-Pugh-Score to assess the prognosis of chronic liver disease and cirrhosis is measured as absolute change to baseline score.

    Measured: 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

    CLIF-C ACLF score to assess the mortality in Acute-on-chronic liver failure patients is measured as absolute change to baseline score.

    Measured: Weeks 3, 4, 8, 12, 16, 20 and 24

  4. Overall survival time until Week 24

    Assessment of overall survival time.

    Measured: Between Screening and Week 24

  5. Complications of ACLF (hepatorenal syndrome [HRS], variceal bleeding, ascites, hepatic encephalopathy [HE], spontaneous bacterial peritonitis [SBP])

    Assessment, documentation and evaluattion of ACLF related complications (hepatorenal syndrome, variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis).

    Measured: Between Screening and Week 24

  6. Transient elastography assessment at Weeks 4, 12 and 24

    Mapping of the elastic properties and the stiffness of the tissue as assessed by transient elastography imaging

    Measured: Weeks 4, 12 and 24

  7. Infections (proven infection necessitating systemic use of antibiotics)

    All infections occurring during the clinical trial will be registered, documented and evaluated.

    Measured: Between Screening and Month 24

  8. Change of levels of C-reactive protein in serum at Weeks 3, 4, 8, 12, 16, 20 and 24

    C-reactive protein levels in the serum will be measured.

    Measured: 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

    The following laboratory variables will be measured and evaluated:

    Albumin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (AP).

    Measured: Weeks 3, 4, 8, 12, 16, 20 and 24

  10. Changes in the profile of 80 different immunomodulatory cytokines at Weeks 3, 4, 8, 12, 16, 20 and 24

    Fluorescence based analysis of 80 different immunomodulatory cytokine parameters in the patient's serum samples as assessed by a 80plex Human Cytokine Antibody Array Kit.

    Measured: Weeks 3, 4, 8, 12, 16, 20 and 24

  11. Changes in dialytic treatment until Week 24

    For patients with dialysis prior to Screening: Time to first dialysis after first IMP administration and time to last dialysis after first IMP administration until Week 24 will be assessed.

    For patients with no dialytic treatment prior to Screening the overall diaylsis timespan from first dialysis after first IMP administration until last dialysis will be measured.

    Measured: Between Screening and Week 24

  12. Time to respiratory failure after first IMP administration until Week 24

    Timespan to respiratory failure after first IMP administration until Week 24 will be measured.

    Measured: Between Day 0 (after first IMP administration) and Week 24

  13. Duration of the initial hospital stay

    Initial hospitalisation time will be evaluated.

    Measured: Between Screening and Week 24

  14. Duration of initial intensive care stay

    The duration of initial intensive care stay will be evaluated.

    Measured: Between Screening and Week 24

  15. Optional: Evaluation of liver biopsy (necrosis quantification)

    Extent of necrosis will be quantified by the pathologist of the clinical trial center.

    Measured: Between Week 8 and Week 24

  16. Physical examination at Week 24

    A physical body examination (e.g. general appearance, thyroid, head, lungs and thorax, ears, cardiovascular system, eyes, abdomen, nose-mouth-throat, musculoskeletal system, skin, extremities, lymph nodes, neurological system) will be performed and abnormal physical examination results will be evaluated and reported as AEs.

    Measured: Week 24

  17. Vital signs at Week 24: Body temperature

    Body temperature will be measured.

    Measured: Week 24

  18. Vital signs at Week 24: Blood pressure

    Blood pressure will be measured.

    Measured: Week 24

  19. Vital signs at Week 24: Heart rate

    Heart rate will be measured.

    Measured: Week 24

  20. Vital signs at Week 24: Respiratory rate

    Respiratory rate will be measured.

    Measured: Week 24

  21. Hematological laboratory parameters at Week 24

    The hematological laboratory values for "hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count" will be measured.

    Measured: Week 24

  22. Clinical chemistry parameters at Week 24

    The clinical chemistry values for "sodium, potassium, calcium, urea, creatinine, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma glytamyl transferase, alkaline phosphatase, CRP" will be measured.

    Measured: Week 24

  23. Coagulation parameter "factor V" at Week 24

    The coagulation value for "factor V" will be measured.

    Measured: Week 24

  24. Coagulation parameter "INR" at Week 24

    The coagulation value for "INR" will be measured.

    Measured: Week 24

  25. Overall survival at Week 24 and at Month 24

    Overall survival at Week 24 and at Month 24 will be evaluated.

    Measured: Week 24, Month 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Mar 2019
  2. Study start22 Mar 2019
  3. Primary completion26 Mar 2021
  4. Study completion26 Mar 2021

Why it stopped: Very slow recruitment of patients and the current COVID-19 pandemic situation.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03860155
Sponsor's protocol ID
allo-APZ2-ACLF-II-01
Status last verified
Sep 2021
First submitted
31 Jan 2019
Last updated
17 Nov 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Kerstan A, Niebergall-Roth E, Esterlechner J, Schroder HM, Gasser M, Waaga-Gasser AM, Goebeler M, Rak K, Schrufer P, Endres S, Hagenbusch P, Kraft K, Dieter K, Ballikaya S, Stemler N, Sadeghi S, Tappenbeck N, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA. Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy. 2021 Feb;23(2):165-175. doi: 10.1016/j.jcyt.2020.08.012. Epub 2020 Oct 1.

    PubMed 33011075

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing allo-APZ2-ACLF in people with Acute-On-Chronic Liver Failure, run by RHEACELL GmbH & Co. KG at 5 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 17 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Very slow recruitment of patients and the current COVID-19 pandemic situation.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change of Model for End-Stage Liver Disease (MELD) score at Week 24 or last available post-baseline measurement if the Week 24 score is missing. (time frame: Week 24, or last available post-baseline measurement of Days 5 (±1) or 13 (±1) or Weeks 3, 4, 8, 12, 16 or 20 if the Week 24 measurement is missing [LOCF].). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03860155, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Nov 2021.

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