Islet-Cell Transplants May Benefit Type 1 Diabetes Patients

Miriam E Tucker

April 28, 2016

Transplantation of an investigational purified human pancreatic islet-cell product may represent a safe and effective treatment option for patients with type 1 diabetes who experience frequent severe hypoglycemia despite currently available treatment, a new pivotal study finds.

The multicenter, single-arm, phase 3 study was conducted by the Clinical Islet Transplantation Consortium — established by the US National Institutes of Health — in consultation with the US Food and Drug Administration (FDA).

The results were published online April 18 in Diabetes Care by Bernhard J Hering, MD, of the Schulze Diabetes Institute and department of surgery, University of Minnesota, Minneapolis, and other consortium members. Dr Hering first reported the results at the American Diabetes Association meeting in 2014, although he did not reveal exact numbers there.

With the use of more advanced periprocedural approaches than have been available in the past for islet-cell transplantation, 87.5% of 48 adults with type 1 diabetes and hypoglycemic unawareness achieved the dual primary end points of HbA1c less than 7.0% and freedom from severe hypoglycemic episodes at 1 year. Just over half were fully insulin-independent at that time point.

"There is hope for availability of a cellular-based therapy to provide physiologic glucose control in our patients with type 1 diabetes," co–consortium investigator Michael R Rickels, MD, associate professor of medicine and medical director of the pancreatic islet-cell–transplant program at the Hospital of the University of Pennsylvania, Philadelphia, told Medscape Medical News.

This study is the first of two pivotal trials in support of FDA licensure of the islet product. The other, still ongoing, is investigating use of the product in 28 patients with type 1 diabetes who have already undergone kidney transplantation and therefore are already receiving immunosuppression.

While initially the FDA will consider the procedure only for patients with type 1 diabetes who fall into the categories of the current two trials (pending the results of the second trial), the idea is to ultimately expand islet-cell transplantation to a wider patient population, noted Dr Rickels.

"Our hope is with licensure of islets as a biological product, we'll be able to start to look beyond addressing acute complications of unstable glucose control, at the longer-term benefits of establishing near-normal glucose control. But that will require much larger numbers of patients to evaluate, and that wouldn't be affordable as long as islets remain only in the research space," he explained.

The current study population — those with hypoglycemic unawareness and/or marked glycemic lability and a history of severe hypoglycemic episodes despite adherence to frequent self-blood glucose monitoring and basal-bolus insulin regimens — represent approximately 3% of all people with type 1 diabetes, or 30,000 to 60,000 in the United States.

New Periprocedural Protocol Believed to Boost Success

The current study was phase 3, prospective, open label, and single arm (for ethical reasons), conducted at eight North American centers.

Subjects were aged 18 to 65 years, with type 1 diabetes for at least 5 years. Exclusion criteria included body mass index (BMI) above 30 kg/m2 and glomerular filtration rate (GFR) less than 80 mL/min/1.73 m2. Of the 48 subjects, 37 had used insulin pumps and 21 had used continuous glucose monitoring, yet all still experienced severe hypoglycemia with memory loss, confusion, uncontrollable/irrational behavior, and seizures.

The investigational purified human pancreatic islets were processed at each transplant site, using standardized lot-release criteria and test methods. Each infusion "dose" came from a single cadaveric donor, was processed within 12 hours of procurement, and infused into the patient via the portal vein.

In a change from previous approaches, all patients were kept on insulin treatment for 2 months after the procedure, while the islet cells stabilized and established sufficient blood supply.

"We know that a period of high glucose is detrimental for islet survival….Every patient gets as much insulin as they can without hypoglycemia….It ends up being less insulin than they were on before, but they're following a similar regimen. The islets will tell us when they're doing more by where the glucose is, so we'll back off on insulin dosing, but the approach is not to allow the glucose to get high," Dr Rickels explained.

At 2 months, an attempt was made to taper the patients off insulin. Those who could not maintain normal glycemic levels by day 75 were resumed on insulin and became eligible for a second infusion up to 8 months after the first dose and subsequently 30 days after a second dose.

All patients had a 4-month stabilization period prior to assessment of the primary end point.

In contrast to some of the earlier attempts at islet-cell transplantation, in the current study induction immunosuppression — antithymocyte antiglobulin — was initiated 48 hours prior to the transplant. But the maintenance immunosuppression used, comprising sirolimus and low-dose tacrolimus, is virtually unchanged from that used in the Edmonton Protocol over a decade ago, Dr Rickels noted.

Nearly All Benefited, Half Achieved Insulin Independence

In all, 22 patients received one infusion of islet cells, 25 received two, and one received three. Forty-two of the 48 (87.5%) achieved both eradication of severe hypoglycemic episodes and an HbA1c less than 7% by 1 year. Median HbA1c levels dropped from 7.2% at baseline to 5.9% at day 75 to 5.6% at 1 year (P < .0003).

Whereas all the subjects had experienced at least one severe hypoglycemic episode in the prior year, just two reported having a total of four episodes in the year following islet transplant (P < .0003). In both, the episodes were judged to be due to excessive administration of exogenous insulin and not to ongoing hypoglycemic unawareness.

Insulin independence was achieved by 23% of the subjects at day 75, by 52.1% at 1 year, and by 41.6% at 2 years. Among the 25 who were insulin independent at 1 year, 13 had received just one islet infusion and 12 received two.

Overall, the median insulin use dropped from 0.49 units/kg at baseline to 0.13 units/kg at day 75 and 0.00 units/kg at 1 year (P < .0003).

At 2 years, 34 of 48 subjects (71%) successfully achieved the criteria set for the 1-year primary end point, including one subject who failed at year 1 because of an HbA1c level of 7.3%.

Dr Rickels pointed out that the primary end points chosen for the study reflect lessons learned from the Edmonton Protocol experience: even though the majority of those patients eventually needed to resume reduced doses of insulin therapy, they were much better able to maintain near-normal glucose control without experiencing the severe hypoglycemia or marked lability that had led them to seek transplant.

"So with this study, that became the primary objective….If we could maintain a long-term islet graft protecting them from problematic hypoglycemia and glucose lability with a small amount of insulin, that would still be considered a successful outcome."

Adverse Events Include Reduced Kidney Function

A total of 30 serious adverse events were reported in 21 subjects in the first year, with 22 attributed to the transplant procedure and/or the immunosuppression. None resulted in death or disability, nor did any require expedited reporting to the FDA.

Median GFR decreased from 102 mL/min/1.73 m2 at baseline, to 98 mL/min/1.73 m2 at day 75 (P = .09), and to 90 mL/min/1.73 m2 at 1 year (P = .0008 vs baseline). The median GFR at 2 years (n = 35) was 82 mL/min/1.73 m2 (P < .0001 vs baseline).

According to Dr Rickels, "We did see a decline over the 2 years in eGFR as a measure of kidney function, but not to levels that would be considered dangerous. We don't know what the natural decline in kidney function would be if followed for a similar period of time in type 1 diabetes patients of similar duration."

This GFR decline is seen in other organ-transplant patients, as a result of the immunosuppressive drugs, he noted.

However, he added that because patients had to have normal kidney function at baseline to enter the pivotal study, "patients with impaired kidney function wouldn't likely be candidates for this approach until we have safer immunosuppressive drugs in the future."

This research was supported by grants to the eight consortium institutions from the National Institute of Allergy and Infectious Diseases and the National Institute for Diabetes and Digestive and Kidney Diseases. Dr Rickels has no relevant financial relationships. Dr Hering is a consultant for Sanofi, Novartis, and Dompé. Disclosures for the coauthors are listed in the article.

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Diabetes Care. Published online April 18, 2016. Abstract

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