Islet Transplantation in Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The primary purpose of this study is to demonstrate the safety of allogeneic islet
      transplantation in type 1 diabetic patients performed at the University of Illinois at
      Chicago (UIC). The purpose is to reproduce the Edmonton protocol to demonstrate that
      pancreatic islets isolated at UIC are safe and of sufficient quality to provide reproducible
      graft function.
    

Detailed description: 
      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.
    

Intervention name(s): Islet Cell Transplant; Islet Cell Transplant plus
Intervention type(s): Drug; Drug
Intervention description(s): 1-3 allogeneic islet transplants; two doses of basiliximab 20 mg iv.; sirolimus po trough levels 10-15 ng/ml X 3 months, then 7-10 ng/ml; tacrolimus po trough levels 3-6 ng/ml; 1-3 allogeneic Islets of Langerhans transplantations; two doses of basiliximab 20 mg iv.; sirolimus po daily to maintatin serum levels 12-15 ng/mL for 3 months, and 7-10 ng/mL thereafter; tacrolimus po twice daily to maintain serum levels 3-6 ng/mL; etanercept 50 mg IV before islet transplant, 25 mg subcutaneously post-transplant days 3, 7, 10; exenatide subcutaneously 5 mcg pre-transplant and twice daily for I week, then increased to 10-mcg twice daily for 6 months after the last islet transplant.
Other intervention name(s): Allogeneic islets; Islet Cell Transplant + Etanercept + Exenatide
Intervention MeSH terms: Exenatide; Etanercept
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetes Mellitus, Type 1; Islets of Langerhans Transplantation; Exenatide; Soluble tumor necrosis factor receptor