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

Abstract

OBJECTIVEImpaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.RESEARCH DESIGN AND METHODSThis multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.RESULTSThe primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.CONCLUSIONSTransplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Clinical Islet Cell Transplantation – Recent Advances

“…According to the regulations by the FDA, for clinical islet transplantation to be considered as a standard therapy, it is mandatory to demonstrate its efficacy using clinical trials. The CIT consortium trials were designed for this purpose and results of these trials have offered promising data on the significant decrease in SHEs in T1DM patients 17 . This multicentre single-arm, phase-3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centres in North America and 48 adults experiencing T1DM for over 5 years were included in the study.…”

Hope vs hype: where are we in type 1 diabetes?

“…However, an international trial using that protocol did not have equivalent success [16], perhaps related to differences in sites in experience both with the complex preparation of human islets for transplantation and clinical experience in the routine management of immunosuppressive therapies [17]. Nonetheless, there has been a progressive improvement in outcomes [18], and the Clinical Islet Transplantation Consortium has completed a Phase III trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycaemia [19]. Compared with pancreas transplantation, the procedure is less invasive and is associated with less morbidity, but the requirement for chronic immunosuppression remains.…”

Type 1 diabetes: where are we in 2017?

“…Islet transplantation can eliminate severe hypoglycemia in patients with type 1 diabetes (39). Recently as part of an ongoing study (Allogeneic Islet Cells Transplanted onto the Omentum; Clinicaltrials.gov number, NCT02213003), a 43-year-old woman with type 1 diabetes for 25 years underwent islet cell transplantation onto the omentum.…”