title: Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial.
abstract: OBJECTIVE
  Exposing the oral mucosa to antigen may stimulate immune tolerance. It is unknown whether treatment with oral insulin can induce a tolerogenic immune response in children genetically susceptible to type 1 diabetes.
  
  
  OBJECTIVE
  To assess the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children.
  
  
  METHODS
  The Pre-POINT study, a double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical pilot study performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolling 25 islet autoantibody-negative children aged 2 to 7 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Follow-up was completed in August 2013.
  
  
  METHODS
  Children were randomized to receive oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Nine children received insulin with dose escalations from 2.5 to 7.5 mg (n = 3), 2.5 to 22.5 mg (n = 3), or 7.5 to 67.5 mg (n = 3) after 6 months; 6 children only received doses of 22.5 mg (n = 3) or 67.5 mg (n = 3).
  
  
  METHODS
  An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin.
  
  
  RESULTS
  Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4+ T-cell proliferative responses to insulin were observed in 2 of 10 (20% [95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7% [95% CI, 0.1%-46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[ 95% CI, 0.1%-46%]) treated with 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%-71%]) treated with 22.5 mg, and 5 of 6 (83.3% [ 95% CI, 53%-99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events).
  
  
  CONCLUSIONS
  In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.
  
  
  BACKGROUND
  isrctn.org Identifier: ISRCTN76104595.
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany2Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Technische Universität Dresden, Dresden, Germany3Forschergru.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.affiliation: Forschergruppe Diabetes e.V., Neuherberg, Germany4Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora.
authors.forename: Georgeanna
authors.initials: G
authors.lastname: Klingensmith
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Edith
authors.initials: E
authors.lastname: Schober
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Munich, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Rottenkolber
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Theil
authors.affiliation: DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Eugster
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Puff
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Peplow
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München.
authors.forename: Florian
authors.initials: F
authors.lastname: Buettner
authors.affiliation: Department of Medical Psychology, Hannover Medical School, Hannover, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Lange
authors.affiliation: Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hasford
authors.affiliation: Forschergruppe Diabetes e.V., Neuherberg, Germany4Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Achenbach
mesh_terms: D000284:Administration, Oral; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D010865:Pilot Projects
chemical_list: D001323:Autoantibodies; D007004:Hypoglycemic Agents; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007328:Insulin