Islet Transplantation in Type 1 Diabetes

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple
insulin injections or by a continuous supply of insulin through a wearable pump. Insulin
therapy allows long-term survival in individuals with type 1 diabetes; however, it does not
guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic
survivors often develop vascular complications, such as diabetic retinopathy, an eye disease
that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that
can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia
unawareness, a life-threatening condition that is not easily treatable with medication and
is characterized by reduced or absent warning signals for hypoglycemia. For such
individuals, transplantation of pancreatic islets is a possible treatment option.
Unfortunately, insulin independence among islet transplant recipients tends to decline over
time. New strategies aimed at promoting engraftment of transplanted islets are needed to
improve the clinical outcomes associated with this procedure. The purpose of this study is
determine the safety and efficacy of islet transplantation, when combined with an
immunosuppressive medication regimen, for treating type 1 diabetes in individuals
experiencing hypoglycemia unawareness and severe hypoglycemic episodes. This study will also
seek to improve the understanding of determinants of success and failure of islet
transplants for type 1 diabetes.

Eligible participants will be randomly assigned to this study or a site-specific Phase 2
islet transplantation study. Participants in this study will receive up to three separate
islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte
globulin (ATG), sirolimus, and low-dose tacrolimus. They will begin receiving ATG and
sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until
Day 2 post-transplant, and sirolimus will be given for the duration of the study. On Day 1
post-transplant, participants will receive tacrolimus, which will also be taken for the
duration of the study. Etanercept will be taken on the day of transplant and Days 3, 7, and
10 post-transplant.

Transplantations will involve an inpatient hospital stay and infusion of islets into a
branch of the portal vein. Participants who do not achieve or maintain insulin independence
by Day 75 post-transplant will be considered for a second islet transplant. Participants who
remain dependent on insulin for longer than 1 month after the second transplant and who show
partial graft function will be considered for a third islet transplant. Daclizumab or
basiliximab will be used in place of ATG for the second and third transplants, if they are
necessary. Participants who do not meet the criteria for a subsequent transplant and do not
have a functioning graft will enter a reduced follow-up period.

There will be up to 19 study visits following each transplant. A physical exam, review of
adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal
ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and
glomerular filtrating rate (GFR) testing will occur at some visits. Participants will also
test their own blood glucose levels at least five times per day throughout the study. A
24-month follow-up period will take place after the participant's last transplant.