A multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony stimulating factor mobilised CD133 + bone marrow stem cells in patients with cirrhosis

Background and Aims: Liver disease mortality and morbidity are rising and liver transplantation is limited by organ availability. Small scale human studies showed that autologous stem cell therapy whilst safe and readily available needed a well conducted randomised controlled trial. Methods: Patients with liver cirrhosis and MELD score 11.5-15.5 were randomised to Arm 1 - Conservative management; Arm 2 - Treatment with granulocyte colony stimulating factor (G-CSF) (Lenograstim) 15 mcg/kg od for 5 days or Arm 3 - Treatment with G-CSF 15 mcg/kg od for 5 days followed by leukapheresis, CD133⁺ cell isolation and infusion of freshly isolated CD133⁺ cells immediately and frozen doses at days 30/60 via peripheral vein (0.2 x 10⁶ cells/kg). Co-Primary objectives were to demonstrate improvement in the severity of liver disease (change in MELD) at 3 months, and its trend over time, across Arms. To detect a 0.8 point reduction in MELD with a 2-sided alpha = 5% (alpha = 0.1 split equally) and 80% power required 27 participants per Arm (81 in total). Analyses were performed on a modified intention-to-treat basis. Results: Mean (SD) age was 55 (8.8), 53 were male, 37 had alcoholrelated liver disease and 10 had HCV. One patient with drew fully from Arm 1 (day 30) and two from Arm 3 (day 8 and 98). 19 (68%) Arm 3 patients received the intended dose of CD133⁺ cells. 27 (96%) Arm 3 patients and 24 (92%) Arm 2 patients received the intended dose of GCSF. The primary outcome measures were not met. Median (IQR) change in MELD for the control, GCSF, and GCSF + cell arms was -0.3 (-1.5,1.1), -0.5 (-1.4, 0.5) & -0.7 (-1.3,1.0) respectively. There was no evidence of a difference in change in MELD between control and Arm 2 (p = 0.78) or Arm 3 (p = 1.0). Moreover, there was no evidence of a difference in trend of change in MELD over time. None of the conclusions differed following a per-protocol analysis. No evidence of a difference was found in UKELD or the individual components of liver function (bilirubin, albumin, INR and creatinine). Median (IQR) change in Fibroscan (to day 90) were 0.0 (-1.6, 8.6), 0.0 (-13.0, 12.0), -0.1 (-6.6, 9.8). There was no evidence of a difference in change in Chronic liver disease questionnaire domains from baseline to day 90. Two Arm 1 patients, three Arm 2 and seven Arm 3 had 1 or more serious adverse events in the 90-day period. Conclusions: In this large, powered, randomised controlled trial GCSF and purified haematopoietic stem cells did not have an impact on liver function or fibrosis.