title: Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Schulze Diabetes Institute and Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.affiliation: Clinical Trials Statistical and Data Management Center, University of Iowa, Iowa City, IA bhering@umn.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Clarke
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Bridges
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Eggerman
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Alejandro
authors.affiliation: Schulze Diabetes Institute and Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: Melena D
authors.initials: MD
authors.lastname: Bellin
authors.affiliation: Clinical Trials Statistical and Data Management Center, University of Iowa, Iowa City, IA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chaloner
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Czarniecki
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Goldstein
authors.affiliation: Clinical Trials Statistical and Data Management Center, University of Iowa, Iowa City, IA.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hunsicker
authors.affiliation: Division of Transplantation, Department of Surgery, University of Wisconsin, Madison, WI.
authors.forename: Dixon B
authors.initials: DB
authors.lastname: Kaufman
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
authors.affiliation: Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.affiliation: Institute for Diabetes, Obesity and Metabolism and Departments of Surgery and Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Division of Transplantation, University of Illinois Hospital and Health Sciences System, Chicago, IL.
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Posselt
authors.affiliation: Institute for Diabetes, Obesity and Metabolism and Departments of Surgery and Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rickels
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Robien
authors.affiliation: Clinical Islet Transplant Program and Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Senior
authors.affiliation: Clinical Islet Transplant Program and Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Stock
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Turgeon
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000601:surgery*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism / Q000517:prevention & control*; D007165:Immunosuppression Therapy / Q000379:methods; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009656:North America; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human