Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes

Abstract

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for !12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

“…3 A and B ). Insulin independence, measured stringently across multiple parameters, was achieved in 52% of subjects and with fewer transplants per subject and smaller doses of islets than in previous multicenter trials (14,22,23); it persisted at 2 years in at least 80% of those who achieved it by year 1. Subjects experienced 22 study-related SAEs in year 1 and 2 study-related SAEs in year 2.…”

Tissue Engineering Approaches to Cell-Based Type 1 Diabetes Therapy

“…With recent improvements to the initial Edmonton protocol and the immunosuppressive cocktail, insulin independence has increased to 5 years posttransplantation in 50% of patients. 7,128 However, long-term transplanted islets still lose viability and efficacy. The techniques described within this review could further improve the clinical outcome of islet transplantation by lengthening viability of islets in vitro prior to transplantation or in vivo post-transplantation and enhancing insulin secretion.…”

Islet Cell Transplantion: Update on Current Clinical Trials

“…The results of this trial will hopefully help to establish islet transplantation as standard of clinical care in the US, enabling reimbursement through private health insurances. Further validating these results, an Australian multicenter trial using the same endpoints, found similar results in 17 islet recipients[39]. The primary endpoint of HbA1c <7% and cessation of severe hypoglycemia was reached by 82% of recipients, 53% achieved insulin independence for a median of 26 months and 35% were still insulin independent at the end of follow up[39].…”