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A second aim was to determine whether the\n                      <jats:italic>HLA<\/jats:italic>\n                      -\n                      <jats:italic>DR3-DQ2<\/jats:italic>\n                      haplotype affected the treatment efficacy in delaying or preventing stage 3 type 1 diabetes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In the investigator-initiated RCT DiAPREV-IT (EUdraCT number 2008-007484-16\/ClinicalTrials.gov registration no. NCT01122446), children 4\u201317.99 years old with GADA and at least one additional islet autoantibody were randomised 1:1 to receive two subcutaneous injections of 20 \u00b5g GAD-alum (\n                      <jats:italic>n<\/jats:italic>\n                      =25) or placebo (\n                      <jats:italic>n<\/jats:italic>\n                      =25), 30 days apart, with a 5\u00a0year follow-up. Randomisation was stratified according to islet autoantibody status (two vs three or more islet autoantibodies), and participants were assigned randomisation numbers sequentially according to a prespecified randomisation list. All study personnel, participants and caregivers were masked to treatment allocation. The RCT did not reach significant treatment effect in delaying or preventing stage 3 type 1 diabetes in the predefined analyses. In this long-term follow-up, diagnosis and the date of onset of stage 3 type 1 diabetes were obtained from the Swedish National Diabetes Registry, or, for unregistered participants, through telephone interviews after informed consent. The time from treatment start to stage 3 type 1 diabetes diagnosis was analysed using Cox proportional hazards regression, with Kaplan\u2013Meier estimates being used to visualise survival curves and estimate median time to stage 3 type 1 diabetes diagnosis. Incidence rates were analysed using Poisson regression. Both analyses were performed in the full population and in the subgroups with and without the\n                      <jats:italic>HLA<\/jats:italic>\n                      -\n                      <jats:italic>DR3-DQ2<\/jats:italic>\n                      haplotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      After a median 12.9 years follow-up (range 1.0\u201313.8 years), 35 of 49 participants progressed to stage 3 type 1 diabetes. One of the original 50 participants was excluded from the analysis of the follow-up study due to their glucose values at the baseline OGTT in the original DiAPREV-IT study meeting the threshold for stage 3 type 1 diabetes. Among the 27 participants with the\n                      <jats:italic>HLA-DR3-DQ2<\/jats:italic>\n                      haplotype, 22 developed the disease. In the overall population, GAD-alum showed no significant effect on progression (HR 1.017; 95% CI 0.523, 1.977;\n                      <jats:italic>p<\/jats:italic>\n                      =0.960;\n                      <jats:italic>n<\/jats:italic>\n                      =49). In\n                      <jats:italic>HLA-DR3-DQ2<\/jats:italic>\n                      -positive participants, GAD-alum significantly delayed time to stage 3 type 1 diabetes (HR 0.315; 95% CI 0.120, 0.823;\n                      <jats:italic>p<\/jats:italic>\n                      =0.018;\n                      <jats:italic>n<\/jats:italic>\n                      =27), while an increased rate of progression was observed in individuals without the\n                      <jats:italic>HLA-DR3-DQ2<\/jats:italic>\n                      haplotype\n                      <jats:italic>(<\/jats:italic>\n                      HR 3.500; 95% CI 1.052, 11.630;\n                      <jats:italic>p<\/jats:italic>\n                      =0.040;\n                      <jats:italic>n<\/jats:italic>\n                      =22). In\n                      <jats:italic>HLA-DR3-DQ2<\/jats:italic>\n                      -positive participants, Kaplan\u2013Meier estimates showed a median time to stage 3 type 1 diabetes of 9.0 years with GAD-alum compared to 3.4 years with placebo (\n                      <jats:italic>p<\/jats:italic>\n                      =0.096), and the incidence rate ratio was 0.419 (95% CI 0.176, 0.997;\n                      <jats:italic>p<\/jats:italic>\n                      =0.049;\n                      <jats:italic>n<\/jats:italic>\n                      =27).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      In the current study, GAD-alum significantly delayed progression to stage 3 type 1 diabetes in\n                      <jats:italic>HLA-DR3-DQ2<\/jats:italic>\n                      -positive children with multiple islet autoantibodies, while the opposite was observed in the subgroup without this haplotype, supporting the importance of precision medicine-based study designs and the potential of GAD-alum as a treatment option to delay progression to clinical onset.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial registration<\/jats:italic>\n                      ClinicalTrials.gov NCT01122446\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06875-3","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:21:23Z","timestamp":1790616083000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delayed time to stage 3 type 1 diabetes after GAD-alum treatment in HLA-DR3-DQ2-positive children: follow-up of the randomised placebo-controlled Diabetes Prevention \u2013 Immune Tolerance trial"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5721-3946","authenticated-orcid":false,"given":"Hanna","family":"Samuelsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Hojjati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Lindqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"J\u00f6nsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-7689","authenticated-orcid":false,"given":"Markus","family":"Lundgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3306-1742","authenticated-orcid":false,"given":"Helena","family":"Elding Larsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"issue":"10394","key":"6875_CR1","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1016\/S0140-6736(23)00223-4","volume":"401","author":"T Quattrin","year":"2023","unstructured":"Quattrin T, Mastrandrea LD, Walker LSK (2023) Type 1 diabetes. 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We thank B. Jonsdottir, Department of Pediatrics, Landspitali University Hospital, Iceland and study nurse C. Nilsson, Department of Clinical Sciences Malm\u00f6, Lund University, Sweden, for their contributions to the original DiAPREV-IT study, as well as N. Murat, Department of Pediatrics, Sk\u00e5ne University Hospital, Sweden for collecting informed consent at the start of the follow-up study, and \u00c5. Lernmark, Department of Clinical Sciences Malm\u00f6, Lund University, Sweden for commenting on the final manuscript. Some of the data were presented as an abstract at the 50th Annual Conference of the International Society for Pediatric and Adolescent Diabetes in Lisbon, Portugal, from 16\u201319 October 2024.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"De-identified participant data supporting this article will be available from the corresponding author upon reasonable request for 5 years after the publication. Data will be shared with qualified researchers for scientific purposes, subject to institutional and ethical approval where applicable and a data-sharing agreement. Access is restricted due to participant confidentiality and data protection regulations.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Open access funding provided by Lund University. Research support for the initial trial was obtained from the JDRF (grant number 17-2011-576), the Swedish Childhood Diabetes Fund, the Swedish Diabetes Association, Sk\u00e5ne University Hospital Funds, Sk\u00e5ne County Council for Research and Development, the Physiographic Society Lund and the Swedish Medical Association. The follow-up study was funded by the Swedish Childhood Diabetes Fund, Sk\u00e5ne University Hospital Funds and Sk\u00e5ne County Council for Research and Development.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"SH, PT and AL are employees of Diamyd Medical. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"HS analysed and interpreted the data and wrote the manuscript. SH, PT and AL analysed the data. IJ collected data and performed laboratory analyses. ML collected the original data. HEL designed the study, collected the original data, analysed and interpreted the data, and wrote the manuscript. HEL is the guarantor of the work. All authors reviewed and approved the final version.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}