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

Acute on Chronic Hepatic Failure Clinical Trial

— 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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02857010
• Other study ID #: 2012-003900-11
• Status: Terminated
• Phase: Phase 1
• Start date: February 2016
• Est. completion date: February 2020

Study information

• Verified date: February 2024
• Source: Hospital Clinic of Barcelona
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 23
• Est. completion date: February 2020
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute on Chronic Hepatic Failure
• Acute-On-Chronic Liver Failure
• End Stage Liver Disease
• Hepatic Insufficiency
• Liver Failure

Intervention

Biological:
• Allogenic mesenchymal stem cells
Cell therapy

Other:
• Placebo
Serum without stem cells

Locations

Country	Name	City	State
Spain	Hospital Clinic de Barcelona	Barcelona

Sponsors (2)

Lead Sponsor	Collaborator
Pere Gines	Clinica Universidad de Navarra, Universidad de Navarra

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in organ function: chronic liver failure-sequential organ failure assessment (CLIF-SOFA)		Change from Baseline CLIF-SOFA score at 28 days
Secondary	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
Secondary	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
Secondary	serum bile acids as a surrogate marker of liver function	serum bile acids	Change from Baseline serum bile acids at 28 days
Secondary	ammonia levels as a surrogate marker of liver function	ammonia	Change from Baseline serum ammonia at 7, 21 and 28 days
Secondary	Lactate levels as a surrogate marker of liver function	lactate levels	Change from Baseline serum lactate levels at 7, 21 and 28 days
Secondary	Hepatic portal venous gradient (HPVG)	HPVG in mmHg	Change from Baseline HPVG at 21 days
Secondary	Endothelial function measured by nitric oxide levels	Nitric oxide	Change from Baseline serum nitric oxide levels at 7, 21 and 28 days
Secondary	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
Secondary	Renal function measured by serum creatinine	serum creatinine	Change from Baseline serum creatinine at 7, 21 and 28 days
Secondary	Renal function measured by Blood urea nitrogen (BUN)	serum BUN	Change from Baseline serum BUN at 7, 21 and 28 days
Secondary	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
Secondary	Inflammatory response	Serum cytokine panel	Change from Baseline cytokine panel at 4, 11 and 18 days
Secondary	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
Secondary	Number of participants alive		Number of participants alive at 28 days, 3 months, 12 months and 2 years
Secondary	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
Secondary	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