Trial Information

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.

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.