Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes

O’Connell, Philip J.; Holmes-Walker, D Jane; Goodman, D.J.; Hawthorne, Wayne J.; Loudovaris, Thomas; Gunton, Jenny E.; Thomas, Helen E.; Grey, Shane T.; Drogemuller, Chris; Ward, Glenn; Torpy, David J.; Coates, P. Toby; Kay, Thomas W. H.

doi:10.1111/ajt.12250

Cited by 102 publications

(82 citation statements)

References 38 publications

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“…3 A and B ). Insulin independence, measured stringently across multiple parameters, was achieved in 52% of subjects and with fewer transplants per subject and smaller doses of islets than in previous multicenter trials (14,22,23); it persisted at 2 years in at least 80% of those who achieved it by year 1. Subjects experienced 22 study-related SAEs in year 1 and 2 study-related SAEs in year 2.…”

Section: Discussionmentioning

confidence: 69%

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

et al. 2016

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OBJECTIVEImpaired 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 METHODSThis 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.RESULTSThe 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.CONCLUSIONSTransplanted 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.

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Section: Discussionmentioning

confidence: 69%

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

et al. 2016

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“…Pancreatic islet transplantation represents a promising therapy for type 1 diabetes that is effective in reducing HbA 1c and hypoglycemia (50,51) and is beginning to yield improved protection from diabetes-associated complications (52). Upon organ procurement, islets are separated from their dense capillary network and rich blood supply and are dependent upon the diffusion of oxygen and nutrients from the islet periphery until revascularization can occur.…”

Section: Implications Of the B-cell/ec Axis In Pancreatic Islet Transmentioning

confidence: 99%

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

et al. 2013

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Within the pancreatic islet, the β-cell represents the ultimate biosensor. Its central function is to accurately sense glucose levels in the blood and consequently release appropriate amounts of insulin. As the only cell type capable of insulin production, the β-cell must balance this crucial workload with self-preservation and, when required, regeneration. Evidence suggests that the β-cell has an important ally in intraislet endothelial cells (ECs). As well as providing a conduit for delivery of the primary input stimulus (glucose) and dissemination of its most important effector (insulin), intraislet blood vessels deliver oxygen to these dense clusters of metabolically active cells. Furthermore, it appears that ECs directly impact insulin gene expression and secretion and β-cell survival. This review discusses the molecules and pathways involved in the crosstalk between β-cells and intraislet ECs. The evidence supporting the intraislet EC as an important partner for β-cell function is examined to highlight the relevance of this axis in the context of type 1 and type 2 diabetes. Recent work that has established the potential of ECs or their progenitors to enhance the re-establishment of glycemic control following pancreatic islet transplantation in animal models is discussed.

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“…With recent improvements to the initial Edmonton protocol and the immunosuppressive cocktail, insulin independence has increased to 5 years posttransplantation in 50% of patients. 7,128 However, long-term transplanted islets still lose viability and efficacy. The techniques described within this review could further improve the clinical outcome of islet transplantation by lengthening viability of islets in vitro prior to transplantation or in vivo post-transplantation and enhancing insulin secretion.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Tissue Engineering Approaches to Cell-Based Type 1 Diabetes Therapy

Amer

Mahoney

Bryant

2014

Tissue Engineering Part B: Reviews

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Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of insulin-producing pancreatic b-cells. Cell-based therapies, involving the transplantation of functional b-cells into diabetic patients, have been explored as a potential long-term treatment for this condition; however, success is limited. A tissue engineering approach of culturing insulin-producing cells with extracellular matrix (ECM) molecules in threedimensional (3D) constructs has the potential to enhance the efficacy of cell-based therapies for diabetes. When cultured in 3D environments, insulin-producing cells are often more viable and secrete more insulin than those in two dimensions. The addition of ECM molecules to the culture environments, depending on the specific type of molecule, can further enhance the viability and insulin secretion. This review addresses the different cell sources that can be utilized as b-cell replacements, the essential ECM molecules for the survival of these cells, and the 3D culture techniques that have been used to benefit cell function.

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Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes

Cited by 102 publications

References 38 publications

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

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

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

Tissue Engineering Approaches to Cell-Based Type 1 Diabetes Therapy

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