Allogenic Bone Marrow Mesenchymal Stem Cell Therapy in Acute-on-chronic Liver Failure (Liveradvance)
Primary Purpose
Acute on Chronic Hepatic Failure
Status
Unknown status
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
Allogenic mesenchymal stem cells
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Acute on Chronic Hepatic Failure
Eligibility Criteria
Inclusion Criteria:
- Liver cirrhosis
- ACLF grade 1, 2 or 3 (Canonic criteria)
- Signed informed consent
Exclusion Criteria:
- Acute or subacute liver failure without cirrhosis
- ACLF grade 1 with response to medical therapy
- Evidence of current malignancy including hepatocellular carcinoma (any grade) or alphafetoprotein > 400 ng/ml
- Previous personal history of malignancy (active or in complete remission) or familiar history of hereditary cancer.
- Moderate or severe chronic heart failure (NYHA III-IV)
- Renal replacement therapy
- Severe chronic pulmonary disease (GOLD III-IV)
- Gastrointestinal bleeding in the last 5 days
- Previous liver transplantation
- Immunosuppressive therapy
- Extrahepatic cholestasis
- HIV infection
- Pregnant of breastfeeding women
- Pre-menopausal women who are of child bearing potential and are not practicing an acceptable method of birth control.
- Participation in any investigational trial in the last 3 months
- Active addition to illegal drugs
- Refusal to participate
- Patients who can not provide prior informed consent
Sites / Locations
- Hospital Clinic de BarcelonaRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Allogenic Mesenchymal stem cells
Placebo
Arm Description
Intravenous allogenic bone marrow derived mesenchymal stem cells: 4 doses of 2 x 106/kg administered on days 1, 4, 11 and 18
Solution without cells on days 1, 4, 11 and 18
Outcomes
Primary Outcome Measures
Change in organ function: chronic liver failure-sequential organ failure assessment (CLIF-SOFA)
Secondary Outcome Measures
Child-Pugh score as a marker of liver function
Child-Pugh
Model for End-stage Liver Disease (MELD) score as a marker of liver function
MELD scores
serum bile acids as a surrogate marker of liver function
serum bile acids
ammonia levels as a surrogate marker of liver function
ammonia
Lactate levels as a surrogate marker of liver function
lactate levels
Hepatic portal venous gradient (HPVG)
HPVG in mmHg
Endothelial function measured by nitric oxide levels
Nitric oxide
Endothelial function measured by von Willebrand factor levels
von Willebrand factor
Renal function measured by serum creatinine
serum creatinine
Renal function measured by Blood urea nitrogen (BUN)
serum BUN
urine neutrophil gelatinase-associated lipocalin (NGAL) as a surrogate marker of renal function
urine neutrophil gelatinase-associated lipocalin (NGAL)
Inflammatory response
Serum cytokine panel
Transcriptome analysis
Transcriptome analysis of monocytes and polymorphonuclear cells from peripheral blood
Number of participants alive
Number of participants with treatment-related adverse events as assessed by World Health Organization (WHO) classification for acute and subacute toxicity
Change in chronic liver failure C acute on chronic liver failure score (clif C ACLF)
Full Information
NCT ID
NCT02857010
First Posted
March 8, 2016
Last Updated
August 4, 2016
Sponsor
Pere Gines
Collaborators
Clinica Universidad de Navarra, Universidad de Navarra
1. Study Identification
Unique Protocol Identification Number
NCT02857010
Brief Title
Allogenic Bone Marrow Mesenchymal Stem Cell Therapy in Acute-on-chronic Liver Failure
Acronym
Liveradvance
Official Title
Therapeutic Effects of Allogenic Mesenchymal Stem Cells in Cirrhotic Patients With Acute-on-chronic Liver Failure. A Double-blind Randomized Placebo-controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
August 2016
Overall Recruitment Status
Unknown status
Study Start Date
February 2016 (undefined)
Primary Completion Date
February 2018 (Anticipated)
Study Completion Date
February 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Pere Gines
Collaborators
Clinica Universidad de Navarra, Universidad de Navarra
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Double-blind placebo randomized controlled trial evaluating the clinical efficacy of allogenic bone marrow derived mesenchymal stem cells in cirrhotic patients with acute-on-chronic liver failure
Detailed Description
Introduction: The most important cause of death in patients with cirrhosis is the development of Acute-on-Chronic Liver Failure (ACLF), a syndrome recently redefined with high mortality. The only effective treatment for ACLF is liver transplantation. However, available organs are limited. Other treatments, such as artificial liver support systems, do not improve survival. ACLF is characterized by increased systemic inflammatory state together with impaired liver regeneration what leads to multiorgan failure. Mesenchymal stem cell (MSC) therapy is an attractive strategy for ACLF owing to the immunomodulatory and regenerative properties of these cells. Aim: To investigate the effects of allogeneic bone marrow MSCs transplantation on liver and other organ functions and systemic inflammation in patients with ACLF. Altruist bone marrow donors will be the source of MSCs. Design and methodology: randomized, double-blind phase I placebo-controlled trial aimed at comparing placebo (solution without cells) and MSCs (4 doses of 2 x 106/kg administered on days 1, 4, 11 and 18). Thirty patients, 15 per group will be included. ACLF will be defined by the CLIF SOFA score and patients stratified according to severity. Outcomes evaluated will be: 1) Organ function (CLIF SOFA and CLIF-C ACLF score); 2) Liver (Child-Pugh and MELD scores,serum bile acids, ammonia and lactate levels), circulatory (systemic and splanchnic hemodynamics, renin, noradrenalin) and endothelial function (nitric oxide, von Willebrand factor); 3 Inflammatory response (serum cytokine panel and transcriptomic analysis of monocytes and polymorphonuclear cells from peripheral blood); 4) Survival at 28 days, 3 and 12 months; and 5) Safety. Expected results: Therapy with MSCs could have beneficial effects on the evolution of patients with ACLF (modulation of inflammatory response and improvement of liver and extra-hepatic organ function) what could translate into an improvement on short-term survival.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute on Chronic Hepatic Failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Allogenic Mesenchymal stem cells
Arm Type
Experimental
Arm Description
Intravenous allogenic bone marrow derived mesenchymal stem cells: 4 doses of 2 x 106/kg administered on days 1, 4, 11 and 18
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Solution without cells on days 1, 4, 11 and 18
Intervention Type
Biological
Intervention Name(s)
Allogenic mesenchymal stem cells
Intervention Description
Cell therapy
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Serum without stem cells
Primary Outcome Measure Information:
Title
Change in organ function: chronic liver failure-sequential organ failure assessment (CLIF-SOFA)
Time Frame
Change from Baseline CLIF-SOFA score at 28 days
Secondary Outcome Measure Information:
Title
Child-Pugh score as a marker of liver function
Description
Child-Pugh
Time Frame
Change from Baseline Child-Pugh score at 28 days, 90 days, one year and 2 years
Title
Model for End-stage Liver Disease (MELD) score as a marker of liver function
Description
MELD scores
Time Frame
Change from Baseline MELD score at 28 days, 90 days, one year and 2 years
Title
serum bile acids as a surrogate marker of liver function
Description
serum bile acids
Time Frame
Change from Baseline serum bile acids at 28 days
Title
ammonia levels as a surrogate marker of liver function
Description
ammonia
Time Frame
Change from Baseline serum ammonia at 7, 21 and 28 days
Title
Lactate levels as a surrogate marker of liver function
Description
lactate levels
Time Frame
Change from Baseline serum lactate levels at 7, 21 and 28 days
Title
Hepatic portal venous gradient (HPVG)
Description
HPVG in mmHg
Time Frame
Change from Baseline HPVG at 21 days
Title
Endothelial function measured by nitric oxide levels
Description
Nitric oxide
Time Frame
Change from Baseline serum nitric oxide levels at 7, 21 and 28 days
Title
Endothelial function measured by von Willebrand factor levels
Description
von Willebrand factor
Time Frame
Change from Baseline serum von Willebrand factor levels at 7, 21 and 28 days
Title
Renal function measured by serum creatinine
Description
serum creatinine
Time Frame
Change from Baseline serum creatinine at 7, 21 and 28 days
Title
Renal function measured by Blood urea nitrogen (BUN)
Description
serum BUN
Time Frame
Change from Baseline serum BUN at 7, 21 and 28 days
Title
urine neutrophil gelatinase-associated lipocalin (NGAL) as a surrogate marker of renal function
Description
urine neutrophil gelatinase-associated lipocalin (NGAL)
Time Frame
Change from Baseline NGAL at 7, 21 and 28 days
Title
Inflammatory response
Description
Serum cytokine panel
Time Frame
Change from Baseline cytokine panel at 4, 11 and 18 days
Title
Transcriptome analysis
Description
Transcriptome analysis of monocytes and polymorphonuclear cells from peripheral blood
Time Frame
Change from Baseline transcriptome analysis at 7-8 days and 12-18 days
Title
Number of participants alive
Time Frame
Number of participants alive at 28 days, 3 months, 12 months and 2 years
Title
Number of participants with treatment-related adverse events as assessed by World Health Organization (WHO) classification for acute and subacute toxicity
Time Frame
Number of participants with treatment-related adverse events as assessed by WHO classification for acute and subacute toxicity at 2 years
Title
Change in chronic liver failure C acute on chronic liver failure score (clif C ACLF)
Time Frame
Change from Baseline clif C ACLF score at 28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Liver cirrhosis
ACLF grade 1, 2 or 3 (Canonic criteria)
Signed informed consent
Exclusion Criteria:
Acute or subacute liver failure without cirrhosis
ACLF grade 1 with response to medical therapy
Evidence of current malignancy including hepatocellular carcinoma (any grade) or alphafetoprotein > 400 ng/ml
Previous personal history of malignancy (active or in complete remission) or familiar history of hereditary cancer.
Moderate or severe chronic heart failure (NYHA III-IV)
Renal replacement therapy
Severe chronic pulmonary disease (GOLD III-IV)
Gastrointestinal bleeding in the last 5 days
Previous liver transplantation
Immunosuppressive therapy
Extrahepatic cholestasis
HIV infection
Pregnant of breastfeeding women
Pre-menopausal women who are of child bearing potential and are not practicing an acceptable method of birth control.
Participation in any investigational trial in the last 3 months
Active addition to illegal drugs
Refusal to participate
Patients who can not provide prior informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pere Ginès, MD, PhD
Phone
0034 2275400
Ext
383249
Email
Pgines@clinic.cat
First Name & Middle Initial & Last Name or Official Title & Degree
Javier Fernandez, MD, PhD
Phone
0034 2275400
Ext
3329
Email
Jfdez@clinic.cat
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Javier Fernandez, MD, PhD
Organizational Affiliation
Hospital Clinic
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
PERE GINES, MD PhD
Phone
0034932275400
Ext
1713
Email
PGINES@clinic.ub.es
First Name & Middle Initial & Last Name & Degree
Javier Fernandez, MD PhD
Phone
00342275400
Ext
3329
Email
Jfdez@clinic.cat
12. IPD Sharing Statement
Plan to Share IPD
Yes
Learn more about this trial
Allogenic Bone Marrow Mesenchymal Stem Cell Therapy in Acute-on-chronic Liver Failure
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