{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:34:12Z","timestamp":1793327652279,"version":"4.5.0"},"reference-count":33,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"unspecified","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Swedish Diabetes Association","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"ALF","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100004973","name":"Barndiabetesfonden","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004973","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research Council of Southeast Sweden","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Diamyd Medical AB","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,10,16]]},"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Type 1 diabetes (T1D) is an autoimmune disease leading to the destruction of the insulin-producing beta cells resulting in insulin deficiency and hyperglycaemic. Today, no approved therapy exists to halt this detrimental immunologic process. In a recent phase 2b study, intralymphatic administration of recombinant human glutamic acid decarboxylase 65\u2009kDa (rhGAD65) adsorbed to Alhydrogel adjuvant to individuals recently diagnosed with T1D and carrying the HLA DR3-DQ2 haplotype showed promising results in preserving endogenous insulin secretion, confirming the results of a large meta-analysis of three randomised placebo-controlled trials of subcutaneous rhGAD65. The aim of the current precision medicine phase 3 study is to determine whether intralymphatic administration of rhGAD65 preserves insulin secretion and improves glycaemic control in presumed responder individuals with recently diagnosed T1D carrying HLA DR3-DQ2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      Individuals \u226512\u2009and &lt;29 years recently diagnosed with T1D (&lt;6 months) will be screened for the HLA DR3-DQ2 haplotype, endogenous insulin production estimated by fasting C-peptide and presence of GAD65 antibodies. 330 patients are planned to be randomised to 3\u2009monthly intralymphatic injections of rhGAD65 or placebo (both accompanied by oral vitamin D supplementation), followed by 22 months of follow-up. The study is powered to detect a treatment effect in the two coprimary endpoints; change from baseline in AUC\n                      <jats:sub>(0-120min)<\/jats:sub>\n                      C-peptide levels during a mixed meal tolerance test, and change from baseline in glycaemic control estimated by haemoglobin A1c at 24 months. Secondary endpoints include effects on glucose patterns collected by masked continuous glucose monitoring, proportion of patients in partial remission and number of episodes of severe hypoglycaemia and\/or diabetic ketoacidosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The trial is approved by Ethics Committees in Poland (124\/2021), the Netherlands (R21.089), Sweden (2021-05063), Czech Republic (EK-1144\/21), Germany (2021361) and Spain (21\/2021). Results will be published in international peer-reviewed scientific journals and presented at national and international conferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      EudraCT identifier: 2021-002731-32, NCT identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05018585\">NCT05018585<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-061776","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T12:37:06Z","timestamp":1667219826000},"page":"e061776","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Phase III, randomised, double-blind, placebo-controlled, multicentre trial to evaluate the efficacy and safety of rhGAD65 to preserve endogenous beta cell function in adolescents and adults with recently diagnosed type 1 diabetes, carrying the genetic HLA DR3-DQ2 haplotype: the DIAGNODE-3 study protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct05018585","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05018585","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1695-5234","authenticated-orcid":false,"given":"Johnny","family":"Ludvigsson","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Link\u00f6ping University, Link\u00f6ping, Sweden"},{"name":"Crown Princess Victoria Children's Hospital, Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0137-359X","authenticated-orcid":false,"given":"Linnea","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Nowak","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"},{"name":"Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro F","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Widman","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Lindqvist","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaura","family":"Casas","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Link\u00f6ping University, Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Lind","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden"},{"name":"NU-Hospital Group and the Sahlgrenska University Hospital, Uddevalla and Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Hannelius","sequence":"additional","affiliation":[{"name":"Diamyd Medical AB, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"2025121605494622000_12.10.e061776.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31320-5"},{"key":"2025121605494622000_12.10.e061776.2","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-0830"},{"key":"2025121605494622000_12.10.e061776.3","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1111\/pedi.12477","article-title":"Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases","volume":"18","author":"Haynes","year":"2017","journal-title":"Pediatr Diabetes"},{"key":"2025121605494622000_12.10.e061776.4","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-0689"},{"key":"2025121605494622000_12.10.e061776.5","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1909"},{"key":"2025121605494622000_12.10.e061776.6","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-012-9388-1"},{"key":"2025121605494622000_12.10.e061776.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31506-X"},{"key":"2025121605494622000_12.10.e061776.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408214"},{"key":"2025121605494622000_12.10.e061776.9","doi-asserted-by":"publisher","DOI":"10.1089\/dia.2018.0384"},{"key":"2025121605494622000_12.10.e061776.10","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.1.250"},{"key":"2025121605494622000_12.10.e061776.11","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.26.3.832"},{"key":"2025121605494622000_12.10.e061776.12","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1080\/14737159.2016.1210513","article-title":"The clinical potential of low-level C-peptide secretion","volume":"16","author":"Ludvigsson","year":"2016","journal-title":"Expert Rev Mol Diagn"},{"key":"2025121605494622000_12.10.e061776.13","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-0567"},{"key":"2025121605494622000_12.10.e061776.14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012864"},{"key":"2025121605494622000_12.10.e061776.15","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60931-8"},{"key":"2025121605494622000_12.10.e061776.16","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1056\/NEJMoa2006136","article-title":"Golimumab and beta-cell function in youth with new-onset type 1 diabetes","volume":"383","author":"Quattrin","year":"2020","journal-title":"N Engl J Med"},{"key":"2025121605494622000_12.10.e061776.17","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-0494"},{"key":"2025121605494622000_12.10.e061776.18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81722"},{"key":"2025121605494622000_12.10.e061776.19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904452"},{"key":"2025121605494622000_12.10.e061776.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0804328"},{"key":"2025121605494622000_12.10.e061776.21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107096"},{"key":"2025121605494622000_12.10.e061776.22","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60895-7"},{"key":"2025121605494622000_12.10.e061776.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61309-4"},{"key":"2025121605494622000_12.10.e061776.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2014.02.006"},{"key":"2025121605494622000_12.10.e061776.25","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-0880"},{"key":"2025121605494622000_12.10.e061776.26","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-0238"},{"key":"2025121605494622000_12.10.e061776.27","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00125-016-4122-1","article-title":"GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis","volume":"60","author":"Beam","year":"2017","journal-title":"Diabetologia"},{"key":"2025121605494622000_12.10.e061776.28","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1056\/NEJMc1616343","article-title":"Intralymphatic injection of autoantigen in type 1 diabetes","volume":"376","author":"Ludvigsson","year":"2017","journal-title":"N Engl J Med"},{"key":"2025121605494622000_12.10.e061776.29","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.564921","article-title":"Glutamic acid decarboxylase injection into lymph nodes: beta cell function and immune responses in recent onset type 1 diabetes patients","volume":"11","author":"Casas","year":"2020","journal-title":"Front Immunol"},{"key":"2025121605494622000_12.10.e061776.30","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1007\/s00125-020-05227-z","article-title":"Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes","volume":"63","author":"Hannelius","year":"2020","journal-title":"Diabetologia"},{"key":"2025121605494622000_12.10.e061776.31","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-0318"},{"key":"2025121605494622000_12.10.e061776.32","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-2451"},{"key":"2025121605494622000_12.10.e061776.33","doi-asserted-by":"publisher","DOI":"10.1080\/10543400500265660"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-061776","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T13:49:57Z","timestamp":1765892997000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-061776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,31]]},"published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1136\/bmjopen-2022-061776"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-061776","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10]]}}}