Acute on Chronic Hepatic Failure
Conditions
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.
Interventions
BIOLOGICALAllogenic mesenchymal stem cells
Cell therapy
OTHERPlacebo
Serum without stem cells
Sponsors
Clinica Universidad de Navarra, Universidad de Navarra
Pere Gines
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| Model for End-stage Liver Disease (MELD) score as a marker of liver function | Change from Baseline MELD score at 28 days, 90 days, one year and 2 years | MELD scores |
| serum bile acids as a surrogate marker of liver function | Change from Baseline serum bile acids at 28 days | serum bile acids |
| ammonia levels as a surrogate marker of liver function | Change from Baseline serum ammonia at 7, 21 and 28 days | ammonia |
| Lactate levels as a surrogate marker of liver function | Change from Baseline serum lactate levels at 7, 21 and 28 days | lactate levels |
| Hepatic portal venous gradient (HPVG) | Change from Baseline HPVG at 21 days | HPVG in mmHg |
| Endothelial function measured by nitric oxide levels | Change from Baseline serum nitric oxide levels at 7, 21 and 28 days | Nitric oxide |
| Endothelial function measured by von Willebrand factor levels | Change from Baseline serum von Willebrand factor levels at 7, 21 and 28 days | von Willebrand factor |
| Child-Pugh score as a marker of liver function | Change from Baseline Child-Pugh score at 28 days, 90 days, one year and 2 years | Child-Pugh |
| Renal function measured by Blood urea nitrogen (BUN) | Change from Baseline serum BUN at 7, 21 and 28 days | serum BUN |
| urine neutrophil gelatinase-associated lipocalin (NGAL) as a surrogate marker of renal function | Change from Baseline NGAL at 7, 21 and 28 days | urine neutrophil gelatinase-associated lipocalin (NGAL) |
| Inflammatory response | Change from Baseline cytokine panel at 4, 11 and 18 days | Serum cytokine panel |
| Transcriptome analysis | Change from Baseline transcriptome analysis at 7-8 days and 12-18 days | Transcriptome analysis of monocytes and polymorphonuclear cells from peripheral blood |
| 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 | — |
| Renal function measured by serum creatinine | Change from Baseline serum creatinine at 7, 21 and 28 days | serum creatinine |
Countries
Spain
Outcome results
None listed