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

Abstract

Objective: Impaired 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 methods: This 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.

Results: The 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.

Conclusions: Transplanted 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.

Trial registration: ClinicalTrials.gov NCT00434811.

Figure 1

Primary composite end point and components. A: Proportion of subjects meeting the primary end point (with HbA_1c <7.0% [53 mmol/mol]) at baseline, day 365, and day 730 after the first islet transplant (ADA criterion). N = 48. An exact one-sided test for proportion ≤0.5 vs. >0.5 was performed at days 365 and 730. The Bonferroni method was used to adjust the level of significance for these two comparisons in order to preserve the overall type I error rate. B: Proportion of subjects meeting the key secondary end point (with HbA_1c ≤6.5% [48 mmol/mol]) at screening, day 365, and day 730 after the first islet transplant. N = 48. An exact one-sided test for proportion ≤0.5 vs. >0.5 was performed at days 365 and 730. The Bonferroni method was used to adjust the level of significance for these two comparisons in order to preserve the overall type I error rate. C: Percentage of subjects with HbA_1c <7.0% (53 mmol/mol) at baseline (N = 48) and at days 75 (N = 46), 365 (N = 45), and 730 (N = 40) after the first islet transplant. A McNemar test for paired binomial outcomes was used to compare the proportion of subjects with HbA_1c <7% (53 mmol/mol) between baseline and day 75, between baseline and day 365, and between baseline and day 730. The Bonferroni method was used to adjust the level of significance for these three comparisons in order to preserve the overall type I error rate of 0.05. D: Box plots of HbA_1c levels at baseline (N = 48), at day 75 (N = 46), at day 365 (N = 45), and at day 730 (N = 40) after the first islet transplant. The Wilcoxon signed rank test for paired outcomes was used to compare the median HbA_1c levels between baseline and day 75, between baseline and day 365, and between baseline and day 730. The Bonferroni method was used to adjust the level of significance for these three comparisons in order to preserve the overall type I error rate of 0.05. E: Percentage of subjects with at least one SHE during the year before the first islet transplant and from day 28 to day 365 and day 730 inclusive, after the first islet transplant. Based on diabetologist’s medical report, a McNemar test for paired binomial outcomes was used to compare the proportion of subjects with at least one severe episode of hypoglycemia at baseline (N = 48) to the proportion at day 365 (N = 45) and to the proportion at day 730 (N = 42). The Bonferroni method was used to adjust the level of significance for both comparisons in order to preserve the overall type I error rate of 0.05. The adjusted P values for both tests are <0.0002. F: Box plots of the number of episodes of severe hypoglycemia experienced per subject during the year before the first islet transplant and from day 28 to day 365 and day 730 inclusive, after the first islet transplant. Based on subject recall over the year prior to enrollment. The Wilcoxon signed rank test for paired outcomes was used to compare the median number of severe episodes of hypoglycemia between baseline (N = 48) and day 365 (N = 45) and between baseline and day 730 (N = 42). The Bonferroni method was used to adjust the level of significance for both comparisons in order to preserve the overall type I error rate of 0.05. The adjusted P values for both tests are <0.0002.

Figure 2

Key secondary end points. A: Proportion of insulin-independent subjects at day 75, day 365, and day 730 after the first islet infusion (N = 48). At day 75, insulin independence could not be evaluated for 11 subjects because of insufficient data; these subjects were imputed as failures. At day 365, insulin independence could not be evaluated for 10 subjects, 8 of whom provided insufficient data and 2 of whom were no longer enrolled in the study; all of these were imputed as failures. At day 730, insulin independence could not be evaluated for 28 subjects, 22 of whom provided insufficient data, and 6 of whom were no longer enrolled in the study; all of these were imputed as failures. B: Box plots of daily insulin usage (units/kilogram/day) at baseline, day 75, day 365, and day 730. The Wilcoxon signed rank test for paired outcomes was used to compare the median insulin use (measured in units per kilogram of body weight) between baseline (N = 48) and day 75 (N = 45), between baseline and day 365 (N = 44), and between baseline and day 730 (N = 34). The Bonferroni method was used to adjust the level of significance for these three comparisons in order to preserve the overall type I error rate of 0.05 The adjusted P values for these three tests are <0.0003. C: Box plots of serum C-peptide levels before (zero minutes) and 60 and 90 min after MMTT was performed at baseline, day 75, day 365, and day 730 after the first islet infusion. The Wilcoxon signed rank test was used to compare the zero minute C-peptide level between baseline (N = 47) and day 75 (N = 46), between baseline and day 365 (N = 45), and between baseline and day 730 (N = 39). Comparisons between baseline and day 75 and between baseline and day 365 were performed in a similar manner for the 60-min C-peptide levels as well as the 90-min C-peptide levels. Within each set of three readings, the Bonferroni method was used to adjust the level of significance for the three comparisons made between baseline and day 75, between baseline and day 365, and between baseline and day 730. The three adjusted P values for each set of readings are <0.0003. D: Box plots of serum glucose levels before (zero minutes) and 60 and 90 min after MMTTs performed at baseline, day 75, day 365, and day 730 after the first islet infusion. The Wilcoxon signed rank test was used to compare the zero minute serum glucose level between baseline (N = 47) and day 75 (N = 46), between baseline and day 365 (N = 45), and between baseline and day 730 (N = 39). Comparisons between baseline and day 75 and between baseline and day 365 were performed in a similar manner for the 60-min serum glucose levels as well as the 90-min serum glucose levels. Within each set of three readings, the Bonferroni method was used to adjust the level of significance for the three comparisons made between baseline and day 75, between baseline and day 365, and between baseline and day 730. The adjusted P value for the zero minute comparison between baseline and day 75 is 0.002. The adjusted P value for the zero minute comparison between baseline and day 365 is 0.0005. The adjusted P value for the zero minute comparison between baseline and day 730 is 0.0034. All other adjusted P values are <0.0003.

Figure 3

Other efficacy end points. A: Clarke score at baseline, day 365, and day 730 after the first islet infusion. The Wilcoxon signed rank test for paired outcomes was used to compare the median Clarke score between baseline (N = 48) and day 365 (N = 44). The P value for this test is <0.0001. B: Natural logarithm of the HYPO score at baseline and day 365 after the first islet infusion. HYPO score was not collected at day 730. The Wilcoxon signed rank test for paired outcomes was used to compare the median HYPO score between baseline (N = 40) and day 365 (N = 28). The P value for this test is <0.0001. C: Glycemic LI at baseline, at day 75, and at day 365 after the first islet infusion. Glycemic LI was not collected at day 730. The Wilcoxon signed rank test for paired outcomes was used to compare the median glycemic LI between baseline (N = 40) and day 75 (N = 40) and between baseline and day 365 (N = 28). The Bonferroni method was used to adjust the level of significance for these two comparisons in order to preserve the overall type I error rate of 0.05. The adjusted P values for these two tests are both <0.0002. D: MAGEs at baseline, day 75, and day 365 after the first islet infusion. MAGE was not collected at day 730. The Wilcoxon signed rank test for paired outcomes was used to compare the median MAGE between baseline (N = 46) and day 75 (N = 43) and between baseline and day 365 (N = 37). The Bonferroni method was used to adjust the level of significance for these two comparisons in order to preserve the overall type I error rate of 0.05. The adjusted P values for these two tests are both <0.0002. E: Box plots of the number of CGMS-determined hypoglycemic excursions (<54 mg/dL) per day (24 h) at baseline, day 75, day 365, and day 730 after the first islet infusion. The Wilcoxon signed rank test was used to compare the median number of hypoglycemic excursions between baseline (N = 41) and day 75 (N = 34), between baseline and day 365 (N = 32), and between baseline and day 730 (N = 25). The Bonferroni method was used to adjust the level of significance for these three comparisons in order to preserve the overall type I error rate of 0.05. The adjusted P value for the comparison between baseline and day 75 is 0.0003. The adjusted P value for the comparison between baseline and day 365 is 0.0258. The adjusted P value for the comparison between baseline and day 730 is 0.0015. F: Time to first severe hypoglycemic episode. The Kaplan-Meier estimate of the survival function for the time to first severe hypoglycemic episode is shown. Three subjects experienced SHEs. The first two subjects experienced events beginning prior to day 365 after the initial transplant, and a third subject had two SHEs between days 365 and 730 after the initial transplant. The time to censoring for subjects who did not experience a SHE was the number of days between the initial transplant and the date of the last blood sugar diary reading. The median SHE-free survival time is >730 days after the initial transplant.