{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:56:04Z","timestamp":1791410164964,"version":"4.3.3"},"reference-count":38,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["2007-04031"],"award-info":[{"award-number":["2007-04031"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["SINT1A"],"award-info":[{"award-number":["SINT1A"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031584","name":"Deutsches Zentrum f\u00fcr Diabetesforschung","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100031584","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013295","name":"Helmholtz Zentrum M\u00fcnchen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100013295","id-type":"DOI","asserted-by":"crossref"}]},{"name":"BMBF","award":["01KX1818"],"award-info":[{"award-number":["01KX1818"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,10,8]]},"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of\n                      <jats:italic>Bifidobacterium infantis<\/jats:italic>\n                      from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      Infants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a &gt;10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of\n                      <jats:italic>B. infantis<\/jats:italic>\n                      EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universit\u00e4t Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04769037\">NCT04769037<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-052449","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T11:36:30Z","timestamp":1636457790000},"page":"e052449","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Supplementation with\n                    <i>Bifidobacterium longum<\/i>\n                    subspecies\n                    <i>infantis<\/i>\n                    EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct04769037","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Anette-Gabriele","family":"Ziegler","sequence":"first","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"},{"name":"Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, Medical Faculty, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Arnolds","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"K\u00f6lln","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Achenbach","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"},{"name":"Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, Medical Faculty, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Berner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Bonifacio","sequence":"additional","affiliation":[{"name":"Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universit\u00e4t Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Casteels","sequence":"additional","affiliation":[{"name":"Department of Pedriatrics, University Hospitals Leuven, Leuven, Belgium"},{"name":"Department of Development and Regeneration, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Elding Larsson","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Sk\u00e5ne University Hospital, Malm\u00f6, Sweden"},{"name":"Department of Paediatrics, Sk\u00e5ne University Hospital Lund, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2236-6604","authenticated-orcid":false,"given":"Melanie","family":"G\u00fcndert","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Hasford","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Kordonouri","sequence":"additional","affiliation":[{"name":"Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Lundgren","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Sk\u00e5ne University Hospital, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Oltarzewski","sequence":"additional","affiliation":[{"name":"Institute of Mother and Child, Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin L","family":"Pekalski","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Pfirrmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D","family":"Snape","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Oxford, Oxford, UK"},{"name":"NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Szypowska","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Todd","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"2025120618225786000_11.11.e052449.1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.6285"},{"key":"2025120618225786000_11.11.e052449.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-012-2472-x"},{"key":"2025120618225786000_11.11.e052449.3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-020018"},{"key":"2025120618225786000_11.11.e052449.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3514-y"},{"key":"2025120618225786000_11.11.e052449.5","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-019-1360-3","article-title":"Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence","volume":"17","author":"Hoffmann","year":"2019","journal-title":"BMC Med"},{"key":"2025120618225786000_11.11.e052449.6","article-title":"An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood","author":"Bonifacio","year":"2021","journal-title":"Diabetes Care"},{"key":"2025120618225786000_11.11.e052449.7","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/pedi.12870","article-title":"Identification of infants with increased type 1 diabetes genetic risk for enrollment into primary prevention Trials-GPPAD-02 study design and first results","volume":"20","author":"Winkler","year":"2019","journal-title":"Pediatr Diabetes"},{"key":"2025120618225786000_11.11.e052449.8","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2018-028578"},{"key":"2025120618225786000_11.11.e052449.9","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1676"},{"key":"2025120618225786000_11.11.e052449.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0620-2"},{"key":"2025120618225786000_11.11.e052449.11","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1001\/jamapediatrics.2015.2757","article-title":"Association of early exposure of probiotics and islet autoimmunity in the TEDDY study","volume":"170","author":"Uusitalo","year":"2016","journal-title":"JAMA Pediatr"},{"key":"2025120618225786000_11.11.e052449.12","doi-asserted-by":"crossref","unstructured":"Garcia AR , Paterou A , Lee M . Peripheral tolerance to insulin is encoded by mimicry in the microbiome. bioRxiv 2019.doi:10.1101\/2019.12.18.881433v1","DOI":"10.1101\/2019.12.18.881433"},{"key":"2025120618225786000_11.11.e052449.13","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S2352-4642(17)30041-X","article-title":"Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial","volume":"1","author":"Hsiao","year":"2017","journal-title":"Lancet Child Adolesc Health"},{"key":"2025120618225786000_11.11.e052449.14","doi-asserted-by":"publisher","DOI":"10.1038\/nature23480"},{"key":"2025120618225786000_11.11.e052449.15","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3713"},{"key":"2025120618225786000_11.11.e052449.16","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2974"},{"key":"2025120618225786000_11.11.e052449.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0617-x"},{"key":"2025120618225786000_11.11.e052449.18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fped.2017.00111","article-title":"Early-life host-microbiome interphase: the key frontier for immune development","volume":"5","author":"Amenyogbe","year":"2017","journal-title":"Front Pediatr"},{"key":"2025120618225786000_11.11.e052449.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.007"},{"key":"2025120618225786000_11.11.e052449.20","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00678"},{"key":"2025120618225786000_11.11.e052449.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.01.001"},{"key":"2025120618225786000_11.11.e052449.22","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-11460-x","article-title":"Genetic risk for autoimmunity is associated with distinct changes in the human gut microbiome","volume":"10","author":"Russell","year":"2019","journal-title":"Nat Commun"},{"key":"2025120618225786000_11.11.e052449.23","doi-asserted-by":"crossref","DOI":"10.3390\/nu12061581","article-title":"Bifidobacterium longum Subspecies infantis (B. infantis) in pediatric nutrition: current state of knowledge","volume":"12","author":"Chichlowski","year":"2020","journal-title":"Nutrients"},{"key":"2025120618225786000_11.11.e052449.24","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1111\/pedi.12756","article-title":"Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe","volume":"19","author":"Insel","year":"2018","journal-title":"Pediatr Diabetes"},{"key":"2025120618225786000_11.11.e052449.25","doi-asserted-by":"publisher","DOI":"10.1111\/pai.12646"},{"key":"2025120618225786000_11.11.e052449.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2010.02416.x"},{"key":"2025120618225786000_11.11.e052449.27","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2018-1489"},{"key":"2025120618225786000_11.11.e052449.28","doi-asserted-by":"crossref","unstructured":"Smilowitz J , Moya J , Breck M . Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial. BMC Pediatrics 2017;17.doi:10.1186%2Fs12887-017-0886-9","DOI":"10.1186\/s12887-017-0886-9"},{"key":"2025120618225786000_11.11.e052449.29","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00501-17"},{"key":"2025120618225786000_11.11.e052449.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-019-0533-2"},{"key":"2025120618225786000_11.11.e052449.31","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.molmet.2016.02.003","article-title":"Primary prevention of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives","volume":"5","author":"Ziegler","year":"2016","journal-title":"Mol Metab"},{"key":"2025120618225786000_11.11.e052449.32","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0882"},{"key":"2025120618225786000_11.11.e052449.33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1313977"},{"key":"2025120618225786000_11.11.e052449.34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002548"},{"key":"2025120618225786000_11.11.e052449.35","doi-asserted-by":"crossref","DOI":"10.3390\/nu12113247","article-title":"Comparative Genome Analysis of Bifidobacterium longum subsp. infantis Strains Reveals Variation in Human Milk Oligosaccharide Utilization Genes among Commercial Probiotics","volume":"12","author":"Duar","year":"2020","journal-title":"Nutrients"},{"key":"2025120618225786000_11.11.e052449.36","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0638"},{"key":"2025120618225786000_11.11.e052449.37","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1104"},{"key":"2025120618225786000_11.11.e052449.38","unstructured":"Online referencing, 2017. Available: http:\/\/ec.europa.eu\/health\/\/sites\/health\/files\/files\/eudralex\/vol-10\/ethical_considerations_en.pdf [Accessed 12 Jun 2017]."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2021-052449","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T02:23:10Z","timestamp":1765074190000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2021-052449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,9]]},"published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1136\/bmjopen-2021-052449"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2021-052449","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11]]}}}