Dificulties to recruit patients and dificulties to obtain MSCs.

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

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.

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