Back to resultsAllogeneic ABCB5-positive Stem Cells for Treatment of Acute-on-Chronic Liver Failure
Primary Purpose
Acute-On-Chronic Liver Failure
Status
Terminated
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
allo-APZ2-ACLF
Sponsored by
About this trial
This is an interventional treatment trial for Acute-On-Chronic Liver Failure focused on measuring 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
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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;
- 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.
Sites / Locations
- Universitätsklinikum Carl-Gustav-Carus an der TU Dresden, Medizinische Klinik I
- Universitätsklinikum Essen, Klinik für Gastroenterologie und Hepatologie, Medizinisches Forschungszentrum
- Universitätsklinikum Frankfurt, Medizinische Klinik 1, Sektion Translationale Hepatologie
- Universitätsklinikum Magdeburg A.ö.R., Medizinische Fakultät der Otto-von-Guericke-Universität
- Medizinische Fakultät Mannheim der Universität Heidelberg, II. Medizinische Klinik
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
allo-APZ2-ACLF
Arm Description
Application of IMP into peripheral vein (arm) by use of a perfusor.
Outcomes
Primary Outcome Measures
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.
Assessment of adverse event (AE) occurrence
All AEs occurring during the clinical trial will be registered, documented and evaluated.
Secondary Outcome Measures
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.
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.
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.
Overall survival time until Week 24
Assessment of overall survival time.
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).
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
Infections (proven infection necessitating systemic use of antibiotics)
All infections occurring during the clinical trial will be registered, documented and evaluated.
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.
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).
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.
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.
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.
Duration of the initial hospital stay
Initial hospitalisation time will be evaluated.
Duration of initial intensive care stay
The duration of initial intensive care stay will be evaluated.
Optional: Evaluation of liver biopsy (necrosis quantification)
Extent of necrosis will be quantified by the pathologist of the clinical trial center.
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.
Vital signs at Week 24: Body temperature
Body temperature will be measured.
Vital signs at Week 24: Blood pressure
Blood pressure will be measured.
Vital signs at Week 24: Heart rate
Heart rate will be measured.
Vital signs at Week 24: Respiratory rate
Respiratory rate will be measured.
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.
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.
Coagulation parameter "factor V" at Week 24
The coagulation value for "factor V" will be measured.
Coagulation parameter "INR" at Week 24
The coagulation value for "INR" will be measured.
Overall survival at Week 24 and at Month 24
Overall survival at Week 24 and at Month 24 will be evaluated.
Full Information
NCT ID
NCT03860155
First Posted
January 31, 2019
Last Updated
November 9, 2021
Sponsor
RHEACELL GmbH & Co. KG
Collaborators
FGK Clinical Research GmbH, Ticeba GmbH
1. Study Identification
Unique Protocol Identification Number
NCT03860155
Brief Title
Allogeneic ABCB5-positive Stem Cells for Treatment of Acute-on-Chronic Liver Failure
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)
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Terminated
Why Stopped
Very slow recruitment of patients and the current COVID-19 pandemic situation.
Study Start Date
March 22, 2019 (Actual)
Primary Completion Date
March 26, 2021 (Actual)
Study Completion Date
March 26, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
RHEACELL GmbH & Co. KG
Collaborators
FGK Clinical Research GmbH, Ticeba GmbH
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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). 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute-On-Chronic Liver Failure
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)
8. Arms, Groups, and Interventions
Arm Title
allo-APZ2-ACLF
Arm Type
Experimental
Arm Description
Application of IMP into peripheral vein (arm) by use of a perfusor.
Intervention Type
Biological
Intervention Name(s)
allo-APZ2-ACLF
Other Intervention Name(s)
Skin-derived ABCB5-positive mesenchymal stem cells
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Description
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.
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].
Title
Assessment of adverse event (AE) occurrence
Description
All AEs occurring during the clinical trial will be registered, documented and evaluated.
Time Frame
Between Screening and Month 24
Secondary Outcome Measure Information:
Title
Change of MELD score at Weeks 3, 4, 8, 12, 16 and 20
Description
Model for End-Stage Liver Disease score is measured as absolute change to baseline score.
Time Frame
Weeks 3, 4, 8, 12, 16 and 20
Title
Change of Child-Pugh-Score at Weeks 3, 4, 8, 12, 16, 20 and 24
Description
Child-Pugh-Score to assess the prognosis of chronic liver disease and cirrhosis is measured as absolute change to baseline score.
Time Frame
Weeks 3, 4, 8, 12, 16, 20 and 24
Title
Change of CLIF-C ACLF score at Weeks 3, 4, 8, 12, 16, 20 and 24
Description
CLIF-C ACLF score to assess the mortality in Acute-on-chronic liver failure patients is measured as absolute change to baseline score.
Time Frame
Weeks 3, 4, 8, 12, 16, 20 and 24
Title
Overall survival time until Week 24
Description
Assessment of overall survival time.
Time Frame
Between Screening and Week 24
Title
Complications of ACLF (hepatorenal syndrome [HRS], variceal bleeding, ascites, hepatic encephalopathy [HE], spontaneous bacterial peritonitis [SBP])
Description
Assessment, documentation and evaluattion of ACLF related complications (hepatorenal syndrome, variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis).
Time Frame
Between Screening and Week 24
Title
Transient elastography assessment at Weeks 4, 12 and 24
Description
Mapping of the elastic properties and the stiffness of the tissue as assessed by transient elastography imaging
Time Frame
Weeks 4, 12 and 24
Title
Infections (proven infection necessitating systemic use of antibiotics)
Description
All infections occurring during the clinical trial will be registered, documented and evaluated.
Time Frame
Between Screening and Month 24
Title
Change of levels of C-reactive protein in serum at Weeks 3, 4, 8, 12, 16, 20 and 24
Description
C-reactive protein levels in the serum will be measured.
Time Frame
Weeks 3, 4, 8, 12, 16, 20 and 24
Title
Liver Function Test (ALT, AST, AP, Albumin, Bilirubin, GGT) at Weeks 3, 4, 8, 12, 16, 20 and 24
Description
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).
Time Frame
Weeks 3, 4, 8, 12, 16, 20 and 24
Title
Changes in the profile of 80 different immunomodulatory cytokines at Weeks 3, 4, 8, 12, 16, 20 and 24
Description
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.
Time Frame
Weeks 3, 4, 8, 12, 16, 20 and 24
Title
Changes in dialytic treatment until Week 24
Description
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.
Time Frame
Between Screening and Week 24
Title
Time to respiratory failure after first IMP administration until Week 24
Description
Timespan to respiratory failure after first IMP administration until Week 24 will be measured.
Time Frame
Between Day 0 (after first IMP administration) and Week 24
Title
Duration of the initial hospital stay
Description
Initial hospitalisation time will be evaluated.
Time Frame
Between Screening and Week 24
Title
Duration of initial intensive care stay
Description
The duration of initial intensive care stay will be evaluated.
Time Frame
Between Screening and Week 24
Title
Optional: Evaluation of liver biopsy (necrosis quantification)
Description
Extent of necrosis will be quantified by the pathologist of the clinical trial center.
Time Frame
Between Week 8 and Week 24
Title
Physical examination at Week 24
Description
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.
Time Frame
Week 24
Title
Vital signs at Week 24: Body temperature
Description
Body temperature will be measured.
Time Frame
Week 24
Title
Vital signs at Week 24: Blood pressure
Description
Blood pressure will be measured.
Time Frame
Week 24
Title
Vital signs at Week 24: Heart rate
Description
Heart rate will be measured.
Time Frame
Week 24
Title
Vital signs at Week 24: Respiratory rate
Description
Respiratory rate will be measured.
Time Frame
Week 24
Title
Hematological laboratory parameters at Week 24
Description
The hematological laboratory values for "hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count" will be measured.
Time Frame
Week 24
Title
Clinical chemistry parameters at Week 24
Description
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.
Time Frame
Week 24
Title
Coagulation parameter "factor V" at Week 24
Description
The coagulation value for "factor V" will be measured.
Time Frame
Week 24
Title
Coagulation parameter "INR" at Week 24
Description
The coagulation value for "INR" will be measured.
Time Frame
Week 24
Title
Overall survival at Week 24 and at Month 24
Description
Overall survival at Week 24 and at Month 24 will be evaluated.
Time Frame
Week 24, Month 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Exclusion Criteria:
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;
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthias Ebert, Prof. Dr.
Organizational Affiliation
Med. Fakultät Mannheim der Universität Heidelberg, II. Med. Klinik, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitätsklinikum Carl-Gustav-Carus an der TU Dresden, Medizinische Klinik I
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Universitätsklinikum Essen, Klinik für Gastroenterologie und Hepatologie, Medizinisches Forschungszentrum
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Universitätsklinikum Frankfurt, Medizinische Klinik 1, Sektion Translationale Hepatologie
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Universitätsklinikum Magdeburg A.ö.R., Medizinische Fakultät der Otto-von-Guericke-Universität
City
Magdeburg
ZIP/Postal Code
39120
Country
Germany
Facility Name
Medizinische Fakultät Mannheim der Universität Heidelberg, II. Medizinische Klinik
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33011075
Citation
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.
Results Reference
derived
Learn more about this trial
Allogeneic ABCB5-positive Stem Cells for Treatment of Acute-on-Chronic Liver Failure
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