Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-POINT Randomized Clinical Trial

JAMA. 2015 Apr 21;313(15):1541-9. doi: 10.1001/jama.2015.2928.

Abstract

Importance: 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.

Design, setting, and participants: 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.

Interventions: 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).

Main outcomes and measures: 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 and relevance: 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.

Trial registration: isrctn.org Identifier: ISRCTN76104595.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Autoantibodies / blood
  • Autoimmunity / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / prevention & control
  • Double-Blind Method
  • Female
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / immunology
  • Immunoglobulin A / blood
  • Immunoglobulin G / metabolism
  • Insulin / administration & dosage*
  • Insulin / immunology
  • Male
  • Pilot Projects

Substances

  • Autoantibodies
  • Hypoglycemic Agents
  • Immunoglobulin A
  • Immunoglobulin G
  • Insulin

Associated data

  • ISRCTN/ISRCTN76104595