The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and was conducted by the NIH-sponsored Clinical Islet Transplantation Consortium. The investigators designed the study in consultation with the U.S. Food and Drug Administration to enable potential future licensure of the manufacture of purified human pancreatic islets.
“The findings suggest that for people who continue to have life-altering severe hypoglycemia despite optimal medical management, islet transplantation offers a potentially lifesaving treatment that in the majority of cases eliminates severe hypoglycemic events while conferring excellent control of blood sugar,” Anthony S. Fauci, MD, Director of the NIAID, said in a statement to the press.
“While still experimental, and with risks that must be weighed carefully, the promise of islet transplantation is undeniable and encouraging,” said NIDDK Director Griffin P. Rodgers, MD. “Even with the best care, about 30% of people with type 1 diabetes aren't aware of dangerous drops in blood glucose levels.”
The study included 48 patients with type 1 diabetes for more than 5 years who had persistent impaired awareness of hypoglycemia and severe hypoglycemic events despite expert management by a diabetologist or endocrinologist for at least 1 year prior to study enrollment.
All study participants received at least one transplant of islet cells injected into the portal vein. Participants who still needed insulin 75 days after transplant were eligible for another islet infusion. Twenty-five participants received a second transplant, and one received a third transplant.
The primary outcome measure was achievement of a hemoglobin A1c level of <7.0% (the glycemic goal recommended by the American Diabetes Association at the time of the study) at day 365 and lack of severe hypoglycemic events from day 28 to day 365 following the first islet transplant.
As expected, the treatment carried risks, including infections and lowered kidney function as a result of people taking the immune-suppressing drugs needed to prevent rejection of the donor islets. Although some of the side effects were serious, none led to death or disability. In the United States, islet transplantation is currently available only in clinical trials.
Nearly 90% of Patients Achieved Freedom From Severe Hypoglycemic Events
One year after the first transplant of islet cells, 88% of study participants were free of severe hypoglycemic events, had established near-normal control of glucose levels, and had restored hypoglycemic awareness. After two years, 71% of participants continued to meet these criteria for transplant success.
Freedom from insulin was achieved in 52% of patients at 1 year and 43% at 2 years.
Weighing the Risks and Benefits of Islet Transplantation
A total of 30 serious adverse events occurred in 21 patients in the first year following treatment, and were primarily related to the transplant procedure (eg, bleeding requiring transfusion or surgical intervention) and/or immunosuppression (eg, cytopenias, abdominal pain with or without vomiting, toxic drug levels, adverse drug reactions).
“For people unable to safely control type 1 diabetes, islet transplantation offers real hope for preventing severe, life-threatening hypoglycemia,” said study coauthor Tom Eggerman, MD, PhD, NIDDK scientific officer for the CIT Consortium. “However, as immunosuppression drugs required for transplantation can have significant adverse side effects, the treatment only makes sense for people who have frequent severe hypoglycemia despite optimal diabetes management, or for those already on immunosuppressant drugs for a kidney transplant, a group being studied in another Phase 3 trial.”
The researchers are continuing to follow participants to determine whether the benefits of restoring near-normal blood glucose control and protection from severe hypoglycemic events will outweigh the risks associated with chronic immunosuppression.
First License-Enabling Trial
“This is the first license-enabling trial of a cellular product for treatment of type 1 diabetes,” said coauthor Nancy D. Bridges, MD, Chief of the NIAID Transplantation Branch. “Licensure is critical because it will ensure the quality, consistency, and safety of the islet product; provide greater patient access to islet transplantation; and accelerate continued research that we hope would make this procedure suitable for a broader population of people with type 1 diabetes.”
“This study further highlights the tremendous benefits and improved quality of life in patients with diabetes following islet cell transplant and re-establishment of automatic physiologic insulin replacement,” commented Timothy Kieffer, PhD, Professor of Medicine in the Department of Cellular and Physiological Sciences and Department of Surgery at University of British Columbia in Canada.
“The study therefore supports the efforts underway to generate an unlimited supply of insulin producing cells from stem cells so such a cell transplant can become a widely available therapy,” said Dr. Kieffer, who is part of the research team that developed a multistep protocol to convert human embryonic stem cells into insulin-producing cells to reverse diabetes in approximately 40 days in an animal model.
“Exciting progress also is being made in finding stealthy ways to protect transplanted cells from immune rejection without the use of immunosuppressive drugs,” Dr. Kieffer said. “This includes both tiny microcapsules around cell clusters that can be infused into the body and larger macrocapsules that are thin-like credit cards and designed to contain large numbers of cells and slip under the skin.”
Dr. Kieffer believes that eliminating the requirement for immunosuppressive drugs will considerably reduce the risk of the procedure and thus make it available to a greater patient population, not just those suffering from severe hypoglycemic events.
May 6, 2016
Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016; DOI: 10.2337/dc15-1988.
National Institute of Allergy and Infectious Diseases. Islet transplantation restores blood sugar awareness and control in type 1 diabetes. Released April 16, 2016. Available at: https://www.niaid.nih.gov/news/newsreleases/2016/Pages/Islet-Transplantation.aspx
Rezania A, Bruin JE, Arora P, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121-1133.