BACKGROUND
Current islet transplantation into the portal vein of the liver has shown the unique ability of islets to stabilize blood glucose levels and prevent severe hypoglycemia in a selected group of subjects with type 1 diabetes. The main limitations of islet transplantation are the need for systemic immunosuppression to maintain function and the loss of islet function over time. Additionally, many studies have demonstrated that the current site of transplantation in the liver is not an ideal site due to several factors. These factors include (1) significant liver inflammation following islet infusion; (2) potential for life-threatening procedure-related complications such as bleeding and thrombosis; (3) high levels of immunosuppressive drugs and GI toxins in the liver contributing to islet toxicity; (4) the inability to retrieve islets after infusion; and (5) development of graft dysfunction in a number of recipients of intrahepatic allogeneic and autologous islets.
Based on these premises, development of a clinical protocol for the implantation of islets into the omentum is a desirable goal. As an attempt to maximize the engraftment of islet cell clusters onto the omentum, implantation site should promote islet adherence to the omental peritoneal layer and avoid cell pelleting. Dr. Alejandro's team at University of Miami has recently performed a series of experiments in animal models of diabetes to assess the feasibility of transplanting pancreatic islets in the omentum using a plasma-thrombin gel. With that approach, the islets are re-suspended in either donor or autologous plasma and distributed in the omental pouch (created by sutures) to avoid pelleting. Cell adherence is achieved by addition of clinical-grade recombinant human thrombin that reacts with plasma to create a biocompatible, degradable gel containing the islet graft.
The investigators have outlined the initial patient trial as 6 subjects, based on clinical judgment and extensive experience in clinical islet transplantation trials. If initial safety and efficacy is satisfactory (no adverse events related to the transplantation and efficacy in 2 of the 3 first transplanted subjects), the investigators will transplant 3 additional subjects.
OBJECTIVES
Primary Objective
Safety: To demonstrate the safety of islet transplantation into an omental pouch site for the treatment of subjects with type 1 diabetes (T1D).
Secondary Objective
Efficacy: To demonstrate the efficacy of islet transplantation into an omental pouch site for the treatment of T1D in subjects with hypoglycemia unawareness and a history of severe hypoglycemic episodes.
Primary Endpoints
The primary safety endpoint is to demonstrate patient safety throughout all stages of the trial.
The primary efficacy endpoint is the proportion of subjects with HbA1c ≤6.5% at 1 year AND free of severe hypoglycemic events from Day 28 to Day 365, inclusive, after the islet transplant.
Secondary Endpoints
Secondary efficacy endpoints: At 75±7, 365 ± 14 ,and 730 ± 14 days following the islet transplant(s): the percent reduction in insulin requirements; HbA1c; Mean Amplitude of Glycemic Excursions (MAGE); Lability Index (LI); Ryan hypoglycemia severity (HYPO) score; Clarke score; number of severe hypoglycemic episodes; basal (fasting) and 90-min glucose and c-peptide derived from the mixed-meal tolerance test (MMTT); beta-score; C-peptide creatinine ratio; acute insulin response to glucose (AIRglu), insulin sensitivity, and disposition index derived from the insulin-modified frequently-sampled intravenous glucose tolerance (FSIGT) test; glucose variability and hypoglycemia duration derived from the continuous glucose monitoring system® (CGMS); and Quality of life (QOL) measures: EuroQol five dimensions questionnaire (EQ-5D), Hypoglycemia Fear Survey (HFS), SF-36v2, Diabetes Distress scale).
Secondary safety endpoints: Safety, including incidence of post-transplant infections, malignancies, morbidity, and other adverse events (AEs) (e.g., increased body weight and hypertension) associated with conventional immunosuppression. Renal function as measured by serum creatinine, glomerular filtration rate (GFR) and other relevant laboratory parameters. Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol) over time.
At 75 ± 7 and 365 ± 14 days following the islet transplant, and at two years following the final islet transplant: the incidence and severity of AEs related to the islet transplant procedure including: bleeding (\>2 g/dL decrease in hemoglobin concentration); wound complication (infection or subsequent hernia); torsion of omentum; gastrointestinal obstruction; abscess; cysts; need for surgical intervention. The incidence and severity of AEs related to the immunosuppression including: allergy; reduction in GFR; addition or intensification of antihyperlipidemic therapy; gastrointestinal toxicity; neutropenia, anemia, or thrombocytopenia; viral, bacterial, or fungal infections; and benign or malignant neoplasms. The incidence of immune sensitization defined by presence of anti-HLA antibodies absent prior to transplantation. The incidence of discontinuation of immunosuppression.
PROCEDURES
Prior to transplantation, the patient is screened, qualified, listed for transplant, and signs the informed consent form.
At the time a suitable islet preparation becomes available, the patient will receive allogeneic islet cells placed in an omental pouch. The details of this surgical procedure will be addressed in Question 5.0.
Islet transplant will be performed under Anti-Thymocyte Globulin (ATG, Thymoglobulin®) induction immunosuppression (5 doses, day -2 prior to transplant to day 2 post-transplant). Maintenance mycophenolate mofetil (MMF) therapy (1-2 g/day as BID dosing) will be started on Day -1 pre-transplant. Tacrolimus will be administered orally twice daily on Day 1 post-transplant to maintain a trough level of 10-12 ng/mL for 3 months, then 6-10 ng/mL thereafter. Etanercept will be given IV before the islet transplant (50 mg), and then at 25 mg (subcutaneously) on post-operative day (POD) +3, +7 and +10.
FOLLOW UP
Subject will undergo a 24-month follow-up period following their islet transplant. 19 study visits during the first year after the transplant, and 4 more study visits during the 2nd year after the transplant.
