Allogenic Bone Marrow Mesenchymal Stem Cell Therapy in Acute-on-chronic Liver Failure

Study Overview
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Brief Summary
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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
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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.

Official Title
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Therapeutic Effects of Allogenic Mesenchymal Stem Cells in Cirrhotic Patients With Acute-on-chronic Liver Failure. A Double-blind Randomized Placebo-controlled Trial

Conditions
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Acute on Chronic Hepatic Failure

Intervention / Treatment
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* Biological: Allogenic mesenchymal stem cells
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allogenic Mesenchymal stem cells<br>Intravenous allogenic bone marrow derived mesenchymal stem cells: 4 doses of 2 x 106/kg administered on days 1, 4, 11 and 18 | Biological: Allogenic mesenchymal stem cells<br>* Cell therapy<br>|
| Placebo Comparator: Placebo<br>Solution without cells on days 1, 4, 11 and 18 | Other: Placebo<br>* Serum without stem cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in organ function: chronic liver failure-sequential organ failure assessment (CLIF-SOFA) |  | Change from Baseline CLIF-SOFA score at 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child-Pugh score as a marker of liver function | Child-Pugh | Change from Baseline Child-Pugh score at 28 days, 90 days, one year and 2 years | 
| Model for End-stage Liver Disease (MELD) score as a marker of liver function | MELD scores | Change from Baseline MELD score at 28 days, 90 days, one year and 2 years | 
| serum bile acids as a surrogate marker of liver function | serum bile acids | Change from Baseline serum bile acids at 28 days | 
| ammonia levels as a surrogate marker of liver function | ammonia | Change from Baseline serum ammonia at 7, 21 and 28 days | 
| Lactate levels as a surrogate marker of liver function | lactate levels | Change from Baseline serum lactate levels at 7, 21 and 28 days | 
| Hepatic portal venous gradient (HPVG) | HPVG in mmHg | Change from Baseline HPVG at 21 days | 
| Endothelial function measured by nitric oxide levels | Nitric oxide | Change from Baseline serum nitric oxide levels at 7, 21 and 28 days | 
| Endothelial function measured by von Willebrand factor levels | von Willebrand factor | Change from Baseline serum von Willebrand factor levels at 7, 21 and 28 days | 
| Renal function measured by serum creatinine | serum creatinine | Change from Baseline serum creatinine at 7, 21 and 28 days | 
| Renal function measured by Blood urea nitrogen (BUN) | serum BUN | Change from Baseline serum BUN at 7, 21 and 28 days | 
| urine neutrophil gelatinase-associated lipocalin (NGAL) as a surrogate marker of renal function | urine neutrophil gelatinase-associated lipocalin (NGAL) | Change from Baseline NGAL at 7, 21 and 28 days | 
| Inflammatory response | Serum cytokine panel | Change from Baseline cytokine panel at 4, 11 and 18 days | 
| Transcriptome analysis | Transcriptome analysis of monocytes and polymorphonuclear cells from peripheral blood | Change from Baseline transcriptome analysis at 7-8 days and 12-18 days | 
| Number of participants alive |  | Number of participants alive at 28 days, 3 months, 12 months and 2 years | 
| Number of participants with treatment-related adverse events as assessed by World Health Organization (WHO) classification for acute and subacute toxicity |  | Number of participants with treatment-related adverse events as assessed by WHO classification for acute and subacute toxicity at 2 years | 
| Change in chronic liver failure C acute on chronic liver failure score (clif C ACLF) |  | Change from Baseline clif C ACLF score at 28 days |