Completion of the first FDA phase 3 multicenter trial of Islet transplantation in type 1 diabetes by the NIH CIT consortium

Abstract

The Clinical Islet Transplantation (CIT) Consortium was established in 2005 by the NIH with the goals of advancing CIT through clinical trials, developing standard procedures for islet manufacturing and patient care, and generating the information needed for FDA licensure for islet products. In this FDA Phase 3 single-arm study (NCT #00434811), 8 centers and the CIT Data Coordinating Center evaluated the efficacy/safety of CIT for treatment of T1D in adults with hypoglycemia unawareness and a history of severe hypoglycemic episodes. The clinical study and islet manufacturing protocols were developed by the CIT consortium and are available online (http://www.isletstudy.org). Clinical protocols were approved by the NIH DSMB and local IRBs. Informed consent was obtained from all participants. All serious adverse events were reported to and reviewed regularly by the DSMB, the IRBs, and the FDA. 48 subjects received a total of 75 islet infusions, with 22 subjects (45.8%) receiving 1 infusion, 25 (52.1%) receiving 2 infusions, and 1 (2.0%) receiving 3 infusions.Total # IEQ transplanted per subject was 806,587±290,340 (mean±SD), corresponding to 11,476.4 ± 4,023.0 IEQ/kg. Induction immunosuppression (IS) was with rabbit antithymocyte globulin (rATG) and peri-transplant etanercept, anticoagulation and antimicrobial prophylaxis. In those who received a second islet infusion (>4000 IEQ/kg), basiliximab replaced rATG in the induction IS. Maintenance IS included sirolimus and reduced-dose tacrolimus. The primary endpoint was the proportion of subjects with an HbA1c <7.0% at day 365 and free of severe hypoglycemic events from day 28 to day 365 inclusive following the first islet transplant. Key secondary endpoints included also the proportion of insulin-independent subjects. Insulin usage dropped dramatically after transplantation (Figure). Islet graft function and insulin independence was achieved by 94% and 52.1% of subjects at day 365 after the first islet transplant.