William R. Clarke’s research while affiliated with University of Iowa and other places

Allogeneic islet transplantation offers a minimally invasive option for β‐cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplantation (CIT06), a National Institutes of Health (NIH)‐sponsored phase 3, prospective, open‐label, single‐arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy (IIT). PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events (SHE) and HbA1c≤6.5% or reduced by ≥ 1 percentage point at 1‐year post transplant. Median HbA1c declined from 8.1% before to 6.0% at 1‐year and 6.3% at 2‐ and 3‐years following transplantation (p<0.001 for all vs. baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health‐related and diabetes‐related quality‐of‐life. The procedure was safe and kidney allograft function remained stable after 3‐years. These results add to evidence establishing allogeneic islet transplantation as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post renal transplant setting.

Eight manufacturing facilities participating in the NIH-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for manufacture of the allogeneic Purified Human Pancreatic Islet (PHPI) product evaluated in a Phase 3 trial in subjects with Type 1 Diabetes. Manufacturing was controlled by a common Master Production Batch Record (MPBR), standard operating procedures including acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis (CoA) and test methods. The process was compliant with current Good Manufacturing Practices (cGMP) and Good Tissue Practices (cGTP).This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results of the manufacturing process including lot release. The results demonstrated the feasibility of implementing a harmonized process at multiple facilities for manufacture of a complex cellular product. The quality systems, regulatory and operational strategies developed by the CIT consortium yielded product lots that met the pre-specified characteristics of safety, purity, potency and identity, and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no case of primary non-function were observed.

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.

Erratum in Lancet. 2015 Feb 14;385(9968):606. Abstract BACKGROUND: High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. METHODS: In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140-220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. FINDINGS: Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16-37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference -7·0 [95% CI -8·5 to -5·6] mm Hg/-3·5 [-4·4 to -2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference -9·5 [95% CI -11·8 to -7·2] mm Hg/-5·0 [-6·4 to -3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison-the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91-1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90-1·22; p=0·55). INTERPRETATION: In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke. FUNDING: UK Medical Research Council. Copyright © 2015 Bath et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Background: In long-standing type 1 diabetes (T1D), loss of endogenous insulin secretion and glucose dysregulation can lead to severe hypoglycemia and associated complications. Here, we report the serial consistency and the correlation between different scores that characterize glucose dysregulation using self-monitoring of blood glucose (SMBG), in a cohort of T1D individuals being evaluated for transplant eligibility in Clinical Islet Transplantation Consortium trials. Subjects and methods: In total, 152 C-peptide-negative T1D subjects with at least one severe hypoglycemia episode in the prior year documented SMBG at enrollment and every 6 months until deemed ineligible or transplanted. SMBG was used to calculate the HYPO score, Lability Index (LI), and mean amplitude of glycemic excursion (MAGE). Additionally, a blinded continuous glucose monitoring system (CGMS) was worn for 72 h at enrollment and every 12 months. Results: In this cohort, LI was the most consistent (intraclass correlation coefficient=0.70) over time, followed by the HYPO score (0.51), with MAGE being the least consistent (0.36). Although MAGE and LI were highly correlated with each other, neither correlated with CGMS SD or glucose coefficient of variation (CV). Subjects spent a median of 97 min/day at <54 mg/dL using CGMS. The HYPO score correlated with CGMS time below 54 mg/dL and glucose CV. Conclusions: The HYPO score and LI are more consistent than MAGE in patients with established T1D experiencing severe hypoglycemic events and may be especially useful both for identifying subjects experiencing the greatest difficulty in maintaining glycemic control and for longitudinal assessment of novel interventions.