Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation

Background When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods The CIT-01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an APTT of 150±10 and 50±5 seconds respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results LMW-DS was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75±5 days after the first transplant) between the 2 arms (1.33±1.10 versus 1.56±1.36 ng/mL, p=0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life and safety were similar between the 2 treatments groups. Conclusions Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding author: Bengt von Zur-Mühlen, Department of Transplantation surgery, University hospital in Uppsala, S-751 85 Uppsala, Sweden, Phone: + 476 18 611 31 70; E-mail: bengt.muhlen@medsci.uu.se ClinicalTrials.gov ID: NCT00789308 Authorship page Authorship: B.Z-M. and T.L. contributed equally B.Z-M. contributed to the design of the study, analysed the data, performed pre and posttransplant care of the patients and wrote the article T.L. designed the study, analysed the data, performed pre and posttransplant care of the patients and wrote the article L.B. executed analysis plan, coordinated DCC protocol, managed data and statistical analysis, assisted writing final study report and edited the article C.B. designed the study and edited the article N.D.B. designed the study, provided safety oversight as the NIAID Medical Monitor and edited the article W.C. designed the study, managed data and statistical analysis T.E. designed the study and coordinated the study with the Clinical Islet Transplantation Consortium, NIDDK and the DSMB A.F. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article J.G. designed the study and cleared regulatory pathways T.J. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article C.J. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article Y.M. contributed to the design of the study, coordinated study and funding M.R. contributed to the design of the study and edited the article T.S. executed analysis plan, coordinated DCC protocol, managed data and statistical analysis, assisted writing final study report and edited the article G.T. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the study B.N. designed the study, performed experiments, analysed the data and wrote the article O.K. conceived, designed and directed the study, performed islet isolation, analysed the data and wrote the article Conflicts of interest: The authors have no financial disclosures to report. Funding: The study was funded by grants from: The National Institute of Allergy and Infectious Disease of the National Institutes of Health (2U01AI065192-06) The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as the funding agency for the DCC at University of Iowa (U01DK070431) Swedish Medical Research Council (K2015-54X-12219-19-4 and K2013-64X-08268-26-3) Swedish national strategic research initiative EXODIAB (Excellence Of Diabetes Research in Sweden) Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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