Open Randomized Mult-Center Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation (CIT-01)

Brief Summary

Detailed Description

Type I diabetes, also known as insulin-dependent diabetes, is a chronic disease in which the pancreas produces insufficient insulin to properly regulate blood sugar levels. Hypoglycemia, or low blood sugar, and hyperglycemia, or high blood sugar, can lead to significant complications in people with type 1 diabetes. Intensive insulin therapy has been shown to reduce the risk of chronic complications in people who achieve near normalization of glycemia. However, this therapy is labor intensive, difficult to implement, and associated with an increased frequency of severe hypoglycemia. Transplantation of islets from a healthy pancreas has been successful in restoring normal blood sugar levels and has led to initial insulin independence in people with type 1 diabetes. Rejection of these islets by the recipient's immune system, however, can make the treatment ineffective. An immune response known as instant blood-mediated inflammatory reaction (IBMIR) results in the disruption of islet integrity and islet loss within an hour of transfusion. LMW-SD inhibits IBMIR by preventing the cascade that triggers it, when combined with pancreatic islets. The purpose of this study is to determine the safety and efficacy of LMW-SD given with islet transfusion and post-transfusion along with immunosuppressive therapy, including mycophenolate mofetil or sirolimus, tacrolimus or cyclosporine, and thymoglobulin or basiliximab, on the success of islet transplantation in people with type 1 diabetes. This study will last for 1 year after the final islet transplant. Participants may receive up to 3 islet transplants while participating in this study. Participants eligible for this study will have clinic visits every 6 months. Once a preparation of islets becomes available, participants will be randomly assigned to Arm 1 or Arm 2. Participants in Arm 1 will receive LMW-DS during and for 5 hours after infusion. Participants in Arm 2 will receive heparin at the time of infusion. In addition, all participants will receive anticoagulation prophylaxis agents consisting of Klexzane® (Enoxaparinsodium) and Trombyl® or Albyl-E® (Acetylsalicylic acid). All participants will also receive the oral immunosuppression medications consisting of mycophenolate mofetil or sirolimus and tacrolimus or cyclosporine throughout the study. In addition, they will receive intravenous thymoglobulin on days -2, -1, day 0 (transplant), +1, and +2 for the first transplant or intravenous basiliximab at the time of transplant and on Day 4 for the second and third transplant. Enbrel® (Etanercept) will be given to all participants for anti-inflammatory therapy. Islet infusions will occur at the hospital and will be given intravenously. Participants will be eligible to receive second and third islet infusions if previous infusions fail and they continue to meet the eligibility criteria. After each infusion, study visits will occur on Days 1, 3, 7, 14, 21, 28, and 75 and Months 6 and 12. At these visits, physical exams and blood collection will occur. At some visits, urine collection will also occur.

Primary Outcomes

Secondary Outcomes

• Proportion of participants with full graft function(At 70 to 80 days after first islet transfusion and after the final islet infusion)
• C-peptide to glucose creatinine ratio(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Glycemic lability index (LI)(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Incidence and severity of adverse events related to islet infusion procedure(At 70 to 80 days and 350 to 379 days after the first islet transfusion)
• HbA1c level(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Percent reduction in insulin requirements(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Ryan hypoglycemia severity score ( HYPO) score(: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Mean amplitude of glycemic excursions (MAGE)(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Basal (fasting) and 90-minute glucose and c-peptide derived from MMTT(: At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Number of participants who achieve and maintain a 7.0% HbA1c level(Throughout Study)
• Number of severe hypoglycemic events(Throughout study)
• Proportion of participants receiving a second islet infusion and proportion of participants receiving a third islet transfusion(At 70 to 80 days after first islet transfusion and after the final islet infusion)
• Incidence of worsening retinopathy(At 350 to 379 days after the first islet transfusion)
• Clarke hypoglycemia awareness score(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Beta-score(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Incidence of immune sensitization defined by detecting anti-HLA antibodies not present prior to transplantation(At 70 to 80 days and 350 to 379 days after the first islet transfusion)
• Acute insulin response to glucose, insulin sensitivity, and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance (FSIGT) test,(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Glucose variability and hypoglycemic duration derived from continuous glucose monitoring system(CGMS)(At 70 to 80 days after first islet transfusion, At 365 days after first and final islet infusion)
• Incidence of a change in the immunosuppression drug regimen(At 70 to 80 days and 350 to 379 days after the first islet transfusion)