Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

INTRODUCTION: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource. Hepatic macrophages can promote both liver fibrogenesis and fibrosis regression. The safety and feasibility of peripheral infusion of ex vivo matured autologous monocyte-derived macrophages in patients with compensated cirrhosis has been demonstrated. METHODS AND ANALYSIS: The efficacy of autologous macrophage therapy, compared with standard medical care, will be investigated in a cohort of adult patients with compensated cirrhosis in a multicentre, open-label, parallel-group, phase 2, randomised controlled trial. The primary outcome is the change in Model for End-Stage Liver Disease score at 90 days. The trial will provide the first high-quality examination of the efficacy of autologous macrophage therapy in improving liver function, non-invasive fibrosis markers and other clinical outcomes in patients with compensated cirrhosis. ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by Scotland A Research Ethics Committee (reference 15/SS/0121), National Health Service Lothian Research and Development department and the Medicine and Health Care Regulatory Agency-UK. Final results will be presented in peer-reviewed journals and at relevant conferences. TRIAL REGISTRATION NUMBERS: ISRCTN10368050 and EudraCT; reference 2015-000963-15.

Safety profile of autologous macrophage therapy for liver cirrhosis.

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.

Allogeneic Ex Vivo Expanded Corneal Epithelial Stem Cell Transplantation: A Randomized Controlled Clinical Trial.

Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue. We performed a controlled multicenter study to examine the feasibility, safety, and efficacy of allogeneic corneal epithelial stem cells in the treatment of bilateral LSCD. Patients were randomized to receive corneal epithelial stem cells cultured on amniotic membrane (AM): investigational medicinal product (IMP) or control AM only. Patients received systemic immunosuppression. Primary endpoints were safety and visual acuity, secondary endpoint was change in composite ocular surface score (OSS). Sixteen patients were treated and 13 patients completed all assessments. Safety was demonstrated and 9/13 patients had improved visual acuity scores at the end of the trial, with no significant differences between IMP and control groups. Patients in the IMP arm demonstrated significant, sustained improvement in OSS, whereas those in the control arm did not. Serum cytokine levels were measured during and after the period of immune suppression and we identified strongly elevated levels of CXCL8 in the serum of patients with aniridia, which persisted throughout the trial. This first randomized control trial of allogeneic corneal epithelial stem cells in severe bilateral LSCD demonstrates the feasibility and safety of this approach. Stem Cells Translational Medicine 2019;8:323-331.

Experience of implementing a National pre-hospital Code Red bleeding protocol in Scotland.

INTRODUCTION: The Scottish Transfusion and Laboratory Support in Trauma Group (TLSTG) have introduced a unified National pre-hospital Code Red protocol. This paper reports the results of a study aiming to establish whether current pre-hospital Code Red activation criteria for trauma patients successfully predict need for in hospital transfusion or haemorrhagic death, the current admission coagulation profile and Concentrated Red Cell (CRC): Fresh Frozen Plasma (FFP) ratio being used, and whether use of the protocol leads to increased blood component discards? METHODS: Prospective cohort study. Clinical and transfusion leads for each of Scotland's pre-hospital services and their receiving hospitals agreed to enter data into the study for all trauma patients for whom a pre-hospital Code Red was activated. Outcome data collected included survival 24h after Code Red activation, survival to hospital discharge, death in the Emergency Department and death in hospital. RESULTS: Between June 1st 2013 and October 31st 2015 there were 53 pre-hospital Code Red activations. Median Injury Severity Score (ISS) was 24 (IQR 14-37) and mortality 38%. 16 patients received pre-hospital blood. The pre-hospital Code Red protocol was sensitive for predicting transfusion or haemorrhagic death (89%). Sensitivity, specificity, positive and negative predictive values of the pre-hospital SBP <90mmHg component were 63%, 33%, 86% and 12%. 19% had an admission prothrombin time >14s and 27% had a fibrinogen <1.5g/L. CRC: FFP ratios did not drop to below 2:1 until 150min after arrival in the ED. 16 red cell units, 33 FFP and 6 platelets were discarded. This was not significantly increased compared to historical data. CONCLUSIONS: A National pre-hospital Code Red protocol is sensitive for predicting transfusion requirement in bleeding trauma patients and does not lead to increased blood component discards. A significant number of patients are coagulopathic and there is a need to improve CRC: FFP ratios and time to transfusion support especially FFP provision. Training clinicians to activate pre-hospital Code Red earlier during the pre-hospital phase may give blood bank more time to thaw and prepare FFP and may improve FFP administration times and ratios so long as components are used upon their availability.