What were the pros and cons of a transplanted human pancreatic islets product in patients with type 1 diabetes and impaired awareness of hypoglycemia?
Transplantation of an experimental purified human pancreatic islets product improved glycemic control, impaired awareness of hypoglycemia (IAH), and severe hypoglycemic episodes in patients with T1DM and inadequate response to current therapy, according to results from a small non-randomized study published online in Diabetes Care.1
The study is the first to phase 3 trial to show effectiveness of any therapy in normalizing blood sugar and protecting recipients from severe hypoglycemia in patients with T1DM and problematic hypoglycemia.
“[T]his trial demonstrates that transplantation of human islets is an effective treatment for T1DM complicated by IAH and SHEs [severe hypoglycemic episodes], resulting in the restoration of hypoglycemia awareness, elimination of SHEs, and normal or near-normal glycemic control in 87.5% of participants,” wrote first author Bernhard Hering, MD, of the University of Minnesota, and colleagues with the Clinical Islet Transplantation (CIT) Consortium.
“Islet transplantation should be considered for patients with T1D and IAH in whom a stepped-care approach including current educational, pharmacological, and technological interventions, has failed to prevent life-threatening SHEs,” they added.
Because past studies of islet products have been considered inadequate for licensing purposes, the current trial, called CIT-07, was designed with that in mind. Due to ethical concerns about randomizing patients who had already failed expert management to continued management, the study had a single-arm, in agreement with FDA guidance that this was acceptable for a license-enabling study.
The phase 3 open-label study took place at eight centers in North America between October 2008 and May 2014. It included 48 adults who had T1DM for over five years, and no evidence of stimulated C-peptide. Participants had experienced impaired awareness of hypoglycemia and severe hypoglycemia episodes even with expert diabetes care for at least one year. All patients received immunosuppression and one or more transplants of an experimental purified human pancreatic islet product obtained from deceased donors and made using standardized criteria. An independent data and safety monitoring board sponsored by the National Institute of Diabetes and Digestive Kidney Disease oversaw the study. The primary endpoint was HbA1c ≤7.0% by day 365 after the first transplant, and freedom from severe hypoglycemia episodes from day 28 to day 365.
• Primary endpoint: achieved by 87.5% of participants
• HbA1c <7.0:
♦ Achieved by 87.5% by one year
♦ Achieved by 71% by two years
• Median HbA1c: Decreased significantly from 7.2% to 5.6% at one year (P<0.0003)
• Hypoglycemia awareness: Significant improvements in Clarke and HYPO scores (P>0.0001)
• Severe hypoglycemic episodes: Significant decrease at one year (P<0.003)
♦ 93% estimated probability of severe hypoglycemic episode-free survival at two years
• Insulin independence:
♦ Achieved by 52.1% by one year
♦ Achieved by 42% by two years
♦ Persisted in at least 80% who achieved insulin independence by one year
• Significant increase in C-peptide levels (P<0.003)
• Adverse events:
♦ 10.4% experienced severe bleeds requiring transfusions
♦ 4.1 % experienced infections related to immunosuppression
♦ Significant decrease in glomerular filtration (P=0.0008)
♦ Two participants developed donor-specific antibodies
The authors noted that the most concerning adverse effect was the drop in renal function, which was related to immunosuppression. They emphasized the importance of evaluating renal function when selecting transplant patients. Islet cell transplant may not be suitable for most patients with T1DM until better immunosuppression drugs become available, they pointed out.
The only other procedure that has produced similar results is vascularized pancreas transplantation, though it is commonly used only in patients who also need a kidney transplant, according to the authors. However, emerging technologies like next-generation and closed-loop pumps have not been compared to islet transplantation in patients with T1DM and problematic hypoglycemia. Diabetes technology and education have improved since the start of this trial, and now most patients with severe hypoglycemia are likely to improve with these methods.
“Only patients who continue to experience SHEs after having completed a stepped-care approach to prevention of SHEs, as is currently recommended, preferably under the supervision of a specialist hypoglycemia service or as part of a clinical trial, should be deemed unresponsive to medical therapy and thus be considered for evaluation for islet transplantation,” they concluded.
• A small, single-armed licensing study found 87.5% of participants with T1DM and problematic hypoglycemia achieved HbA1c ≤7.0% by one year, and freedom from severe hypoglycemia episodes from day 28 to day 365.
• Median HbA1c, hypoglycemic awareness, and C-peptide levels significantly improved.
• 52.1% of participants achieved insulin independence by one year, of whom 80% experienced persistence at two years.
• The most concerning adverse effect was drop in renal function.
• Patients who continue to have problematic hypoglycemia after receiving stepped-up, expert care may be considered for islet transplantation.
One or more authors reports consulting, grants, speaking, personal fees, and other support from one or more of the following: Genzyme, Eli Lilly, Conatus, Sanofi, Novartis, DompÃ©, J.F.M., Vicapsys, Pfizer, Novo Nordisk, and Semma Therapeutics. Dr. Camillo Ricardi is a co-inventor on patents related to islet isolation processing aspects used in part for current islet cell product manufacturing, but does not receive any financial benefit from these patents or from islet cell processing activities.
Reference: Hering BJ, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016 Apr 18.