REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial

Abstract

IntroductionLiver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy.Methods and analysisPatients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1–5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1–5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×106 cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total).Ethics and disseminationThe trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Outcomes after multiple courses of granulocyte colony‐stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial

“…However, as discussed earlier, our group had an expectedly worse 12‐month survival and needed special attention. Moreover, other studies have also excluded the similar group of patients and some have already reported improved outcomes with G‐CSF in patients with ACLF …”

“…Three independent physicians assessed the suitability of the patients for the trial. Etiology of cirrhosis was based on the history of significant alcohol intake, positive viral markers or autoimmune markers, and features of metabolic syndrome …”

Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis

“…More recently, the Repeated AutoLogous Infusion of Stem cells In Cirrhosis (REALISTIC), a multicenter, phase II, open-label, randomized controlled trial of repeated autologous infusion of G-CSF-mobilized CD133? bone marrow stem cells in patients with cirrhosis, was announced in the UK [55]. Although the effectiveness and potential applications of cell therapy have been reported, several problems need to be overcome.…”

Liver Fibrosis: From Pathogenesis to Novel Therapies

“…Importantly, the heterogeneity and the role of macrophages in human liver fibrosis are less well understood than in mouse models [24] . Nevertheless, there is preliminary clinical evidence that infusion of BM-derived cells might be beneficial in end-stage liver disease, and a large controlled multicenter clinical trial, that is, the Repeated Autologous Infusions of Stem cells in Cirrhosis (REALISTIC), in which the outcome on cirrhosis in patients will be assessed that either receive G-CSF alone or G-CSF followed by repeated infusions of hematopoietic stem cells compared with standard conservative management [25] . However, although the results of this trial need to be awaited, recovery from advanced cirrhosis to normal tissue might be somewhat limited by the occurrence of irreversible matrix crosslinking conferring a relative resistance to degradation [26] .…”