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

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

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

Study Overview

• Status: Terminated
• Conditions: Acute on Chronic Hepatic Failure
• Intervention / Treatment: Biological: Allogenic mesenchymal stem cells; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Pere Ginès, MD, PhD; Phone Number: 383249 0034 2275400; Email: Pgines@clinic.cat
• Study Contact Backup: Name: Javier Fernandez, MD, PhD; Phone Number: 3329 0034 2275400; Email: Jfdez@clinic.cat

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allogenic Mesenchymal stem cells; 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; Cell therapy
Placebo Comparator: Placebo; Solution without cells on days 1, 4, 11 and 18	Other: Placebo; Serum without stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Pere Gines
• Collaborators: Clinica Universidad de Navarra, Universidad de Navarra
• Investigators: Study Chair: Javier Fernandez, MD, PhD, Hospital Clinic

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: March 8, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (Estimated): August 5, 2016

Study Record Updates

• Last Update Posted (Estimated): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure, Acute; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure
• Other Study ID Numbers: 2012-003900-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES