Islet Transplantation in Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression

Diabetes mellitus is becoming an unbearable burden for the health care system worldwide. The incidence of disease has increased over the past 50 years, both for type I and type II diabetes. In 2002, the expenditure for direct and indirect costs of diabetes reached the astronomical amount of $132 billion for the USA alone. The burden suffered by patients is also grave when we consider that diabetic neuropathy and retinopathy are now the leading causes of renal failure and blindness in industrialized countries. Although major improvements in insulin treatment and glycemic control have been achieved, the development of hypoglycemic unawareness still represents a challenging clinical problem in the management of diabetes. Severe hypoglycemic episodes are not only acutely life threatening but lead to overall impairment of the quality of life of diabetic patients. Even under ideal study conditions the pathophysiology of hypoglycemic unawareness is not fully understood. It seems that each hypoglycemic episode reduces the counterregulatory hormone responses and the subjective awareness of the following episode, generating a self-worsening mechanism. Islet transplantation can effectively eliminate severe hypoglycemia and restore good glycemic control. However, there are still several limitations to the widespread application of islet transplantation. First, insulin independence is mostly achieved by transplanting a high number of islets that are harvested from 2-4 donors. Second, post-transplant insulin-independence is progressively lost over time despite continued endogenous insulin secretion. Lastly, current immunosuppression carries potential risks and can only incompletely prevent sensitization of the host and rejection. At present, clinical trials in islet transplantation face stringent federal regulations, which define islets as a biological drug and islet transplantation as an experimental procedure. Limited resources impose small and uncontrolled trials investigating a limited number of new interventions to improve outcomes. This study is a Phase 1/2 single center, uncontrolled trial in which 1-3 allogeneic pancreatic islet transplants are performed for each study subject. Post-transplant follow-up continues for 64 weeks after the final islet transplantation. Thereafter, subjects are enrolled for a 5-year follow-up study and a 5 to 10 year follow-up study. The safety of islet transplantation depends primarily on the incidence of serious and unexpected complications or adverse events and the ability of the cell isolation laboratory to produce uncontaminated islet cell preparations with minimal endotoxin content. All study subjects are followed for safety for one year. An independent Data Monitoring Committee (DMC), composed of 3 members who have training in medicine and/or organ transplantation, will review eligibility and safety data approximately 2 weeks after each islet transplantation and every two months thereafter. An independent monitor knowledge on Good Clinical Practice(GCP) guidelines and regulations monitors the study for compliance with 21 CFR and according to ICH GCP Guidelines. Within the Clinical Research Center, the Scientific Advisory Committee and the Research Subject Advocacy Program monitor safety. These entities report to the Institutional Review Board, which also reviews safety data annually and on occurrence of serious adverse events. The principal investigator also report serious adverse events to the US Food and Drug Administration (FDA). Success: Islet transplantation is considered a success when subjects do not use insulin and they achieve a fasting glucose level not exceeding 140 mg/dL more than three times in a week, and not exceeding two-hour post-prandial values of 180 mg/dL more than four times in a week. Partial Success: Subjects who have a reduction in insulin requirements but who do not achieve insulin independence and present with a reduction in HbA1c and number of hypoglycemic episodes are considered to have partial success of islet transplantation. Reduction in insulin-requirements are assessed by comparing the pre-transplant insulin requirement recorded over two consecutive days (expressed as insulin units per kg) with the requirement on the two consecutive days preceding the subsequent islet infusion, and the requirements on two consecutive days at six months and again on two consecutive days at one year after the final transplant. Failure: Absence of measurable levels of C-peptide after transplantation is considered as failure of islet cell transplantation.