Islet Allotransplantation in Type 1 Diabetes

Overview

Islet transplantation can provide physiologic insulin replacement to patients with type 1 diabetes without the complications associated with whole pancreas transplantation. The purpose of this study is to achieve insulin-independence in patients with type 1 diabetes, thereby eliminating the need for exogenous insulin injections to maintain normal glucose levels, ameliorating severe hypoglycemia and potentially decreasing the development of diabetes-related complications. This study will investigate islet transplantation in subjects who have preserved renal function and subjects who have undergone cadaveric renal transplantation, since the latter subjects are already on immunosuppression. This is a single center, prospective trial of islet transplantation in subjects receiving islets alone or islets after kidney transplant. This is a phase I study investigating the use of islet transplantation for the treatment of type 1 diabetes. Subjects will be eligible for an islet transplant if they meet all of the inclusion criteria and none of the exclusion criteria outlined in the protocol. In brief, the aims of this study are to establish an islet transplant program at the Ohio State University, determine the safety of islet transplantation in islet alone and kidney transplant recipients, determine whether islet transplantation will reduce the frequency of severe hypoglycemic events, determine whether a novel steroid-free immunosuppressive protocol will prevent rejection in islet transplants and to achieve insulin independence at one year after the final islet transplant.

Hypothesis - Insulin independence (insulin injections no longer needed) will be achieved in subjects with type 1 diabetes receiving islet transplantation using the immunosuppressive regimen of cyclosporine and sirolimus. Amelioration of severe hypoglycemia will also be achieved in these groups. Primary Objective To determine the safety of islet transplantation in islet alone and in kidney transplant recipients. Safety analyses include: * Incidence, timing and severity of adverse events and their relationship to the transplant protocol, islet infusion and immunosuppressive medications * Proportion without protocol-related serious adverse events (SAE) at 1 year * Incidence, type and severity of infectious complications * Incidence and severity of procedural-related events, such as bleeding and portal vein thrombosis * Incidence and severity of liver function test elevations * Incidence and severity of hypoglycemia * Incidence and severity of creatinine clearance and urine microalbumin changes * Incidence and severity of lipid abnormalities * Proportion of those who develop donor-specific alloantibody Secondary Objective To determine the efficacy of islet transplantation in islet alone and in kidney transplant recipients. Efficacy analyses include: * Time to insulin independence, defined as freedom from insulin use (insulin injections not needed) for 14 or more consecutive days * Proportion of those that achieve insulin independence at any time during the first year * Proportion of those one year after final transplant who have: * Positive C-peptide (≥0.3 ng/ml after stimulation) * Full function of their graft * Partial function of their graft * Marginal function of their graft * Mixed meal stimulated C-peptide \>1.0 ng/ml at 6, and 12 months * Proportion of those that have an acute insulin response to glucose (AIRg) \>20uU/ml during frequently sampled intravenous glucose tolerance test (FSIGT) at 6 and 12 months * Proportion of those with blood glucose level \<140 mg/dl two hours after oral glucose tolerance test (OGTT) at 6 and 12 months * Proportion of those that have improved QOL at 6 and 12 months compared with baseline * Proportion of those that have improved hypoglycemia and glycemic lability scores at 6 and 12 months compared with baseline Definition of full islet function: * Insulin independence * A1C ≤ 6.5% * Absence of severe hypoglycemic episodes * Fasting glucose ≥140 mg/dl less than 3 times a week * Post-prandial glucose (2 hours) \>180 mg/dl less than 4 times a week Definition of partial islet function: * Insulin requirement less than 50% of pre-transplant insulin requirement * C-peptide positive (≥0.3 ng/ml after stimulation) * A1C ≤ 6.5% * No severe hypoglycemia Definition of marginal islet function: * C-peptide positive (≥0.3 ng/ml after stimulation) * A1C ≤ 7.5% * No severe hypoglycemia This trial will have two study groups consisting of N=10 subjects with type 1 diabetes. One group (IA) will include subjects with preserved kidney function. A second group (IAK) will include subjects with renal failure secondary to diabetes who have received a prior kidney transplant at least 6 months previously and have stable renal function on a steroid-free immunosuppressive regimen. Potential study participants will be recruited from the Endocrinology and Transplant clinics at the Ohio State University, and community physician referrals. Those who are potentially eligible will undergo a screening evaluation after review of the medical records. If the subject remains eligible, he/she will be enrolled in the islet transplant study and will be placed on a waiting list for an islet transplant. Once a transplant becomes available, the subject will be admitted to the hospital to undergo the transplant procedure. Frequent follow-up visits in the transplant clinic will occur throughout the following year after the transplant. Subjects will be closely monitored for adverse events and insulin requirements. If the subject does not achieve insulin independence, he/she may be eligible for a subsequent transplant. There will be a 10-year enrollment with 12-month follow-up after last transplant. Since subjects may be eligible for a subsequent transplant within 18 months of the first transplant, the total duration may be up to 30 months after the first transplant in some subjects. The study will be completed one year after the last islet transplant. Subjects who have undergone the islet transplant procedure and have completed the post-transplant evaluations one year after their last transplant will be considered to have completed the study.