Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomized trial

Background Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes with insulin autoimmunity often appearing in the first years of life. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and actions on immunity and the gut microbiome. Methods A phase I/II randomized controlled trial was performed in 44 islet autoantibody-negative children aged 6 months to 2 years with genetic risk for type 1 diabetes. Children were randomized 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months. Primary outcome was safety and immune efficacy pre-specified as hypoglycemia and induction of antibody or T cell responses to insulin, respectively. Results Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in both children who received insulin (55%) and placebo (67%), and were modified by the INSULIN gene. Among children with type 1 diabetes-susceptible INSULIN genotype, antibody responses to insulin were more frequent in insulin-treated (cumulative response, 75.8%) as compared to placebo-treated children (18.2%; P =0.0085), and T cell responses to insulin were modified by treatment-independent inflammatory episodes. Changes in the microbiome were related to INSULIN genotype. Conclusion The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe and engaged the adaptive immune system in an INSULIN genotype-dependent manner, and linked inflammatory episodes to the activation of insulin-responsive T cells. Trial registration [Clinicaltrials.gov][1] [NCT02547519][2] Funding German Center for Diabetes Research (DZD e.V.), Juvenile Diabetes Research Foundation (JDRF, grant 1-SRA-2018-546-S-B), Federal Ministry of Education and Research (BMBF, grant FKZ01KX1818). ### Competing Interest Statement A patent has been filed (PLA17A05; international patent application no: WO 2019/002364) with the title "Method for determining the risk to develop type 1 diabetes" by Helmholtz Zentrum Muenchen Deutsches Forschungszentrum fuer Gesundheit und Umwelt (GmbH). P.A., E.B., and A.G.Z are listed as inventors. The patent describes a method for determining genetic risk for personalized strategies to prevent type 1 diabetes, including oral immunotherapy with the insulin dose examined in the manuscript. R.A., J.K., K.L.H., M.P., J.Z.G., A.H., A.E., M.W., C.M., J.R., Y.F., M.B., A.W., M.H., K.H., S.M.H., J.H., J.P., P.A., E.B., and A.G.Z have declared that no other conflict of interest exists. ### Clinical Trial NCT02547519 ### Funding Statement The Pre-POINT-early clinical trial was supported by the German Center for Diabetes Research (DZD e.V.), the Juvenile Diabetes Research Foundation (JDRF grant 1-SRA-2018-546-S-B), and the Federal Ministry of Education and Research (BMBF, grant FKZ01KX1818). The authors did not receive payment or services from a third party. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the independent ethics committee of the School of Medicine of the Technical University of Munich (206/15). The parents or legal guardians of each child provided written informed consent. The study was performed in compliance with the current version of the Helsinki declaration. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All reasonable requests for raw and analyzed data and materials will be promptly reviewed by the corresponding author to determine whether the request is subject to confidentiality obligations. Any data and materials that can be shared will be available from the corresponding author on reasonable request, with appropriate additional ethical approvals, and released via a material transfer agreement. [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02547519&atom=%2Fmedrxiv%2Fearly%2F2020%2F07%2F21%2F2020.06.12.20129189.atom