{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T17:41:59Z","timestamp":1781545319576,"version":"3.54.5"},"reference-count":114,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"<jats:p>It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and\/or restore functional \u03b2-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further \u201cde-risk\u201d development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.<\/jats:p>","DOI":"10.2337\/dc22-0308","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T15:13:58Z","timestamp":1663946038000},"page":"2189-2201","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":23,"title":["Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes"],"prefix":"10.2337","volume":"45","author":[{"given":"Randy L.","family":"Anderson","sequence":"first","affiliation":[{"name":"1Global Mission Board, JDRF, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8033-6078","authenticated-orcid":false,"given":"Linda A.","family":"DiMeglio","sequence":"additional","affiliation":[{"name":"2Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian P.","family":"Mander","sequence":"additional","affiliation":[{"name":"3Centre for Trials Research, Cardiff University School of Medicine, Cardiff, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin M.","family":"Dayan","sequence":"additional","affiliation":[{"name":"4Centre for Endocrine and Diabetes Science, Cardiff University School of Medicine, Cardiff, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8960-4307","authenticated-orcid":false,"given":"Peter S.","family":"Linsley","sequence":"additional","affiliation":[{"name":"5Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1534-6613","authenticated-orcid":false,"given":"Kevan C.","family":"Herold","sequence":"additional","affiliation":[{"name":"6Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjana","family":"Marinac","sequence":"additional","affiliation":[{"name":"7JDRF International, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simi T.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"8New York Stem Cell Foundation Research Institute, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"2023053115511735500_B1","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.2337\/diabetes.52.5.1059","article-title":"Guidelines for intervention trials in subjects with newly diagnosed type 1 diabetes","volume":"52","author":"Greenbaum","year":"2003","journal-title":"Diabetes"},{"key":"2023053115511735500_B2","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\u2014the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives","volume":"5","author":"Ziegler","year":"2016","journal-title":"Mol Metab"},{"key":"2023053115511735500_B3","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.2337\/db18-0065","article-title":"Strength in numbers: opportunities for enhancing the development of effective treatments for type 1 diabetes-the TrialNet experience","volume":"67","author":"Greenbaum","year":"2018","journal-title":"Diabetes"},{"key":"2023053115511735500_B4","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2337\/dci17-0065","article-title":"Are we there yet? 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