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

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  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0132144 Publication Model: Print Cited Medium: Internet ISSN: 1534-6080 (Electronic) Linking ISSN: 00411337 NLM ISO Abbreviation: Transplantation
    • Publication Information:
      Publication: Hagerstown, MD : Lippincott Williams & Wilkins
      Original Publication: Baltimore, Williams & Wilkins.
    • Subject Terms:
      Islets of Langerhans Transplantation*; Dextran Sulfate/*therapeutic use ; Inflammation/*prevention & control; Adult ; Aged ; C-Peptide/biosynthesis ; Complement Activation/drug effects ; Complement System Proteins/immunology ; Female ; Glucose Tolerance Test ; Heparin/therapeutic use ; Humans ; Immune Tolerance/drug effects ; Immunity, Innate ; Islets of Langerhans/cytology ; Male ; Middle Aged ; Molecular Weight ; Norway ; Partial Thromboplastin Time ; Quality of Life ; Sweden
    • Abstract:
      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 Clinical Islet Transplantation consortium 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 activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant.
      Results: Low molecular dextran sulfate 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.
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    • Grant Information:
      U01 AI065192 United States AI NIAID NIH HHS; U01 DK070431 United States DK NIDDK NIH HHS
    • Molecular Sequence:
      ClinicalTrials.gov NCT00789308
    • Accession Number:
      0 (C-Peptide)
      9005-49-6 (Heparin)
      9007-36-7 (Complement System Proteins)
      9042-14-2 (Dextran Sulfate)
    • Publication Date:
      Date Created: 20180914 Date Completed: 20190805 Latest Revision: 20200309
    • Publication Date:
      20240829
    • Accession Number:
      PMC6389380
    • Accession Number:
      10.1097/TP.0000000000002425
    • Accession Number:
      30211831