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dc.contributor.authorSeelig, Eleonora
dc.contributor.authorHowlett, James
dc.contributor.authorPorter, Linsey
dc.contributor.authorTruman, Lucy
dc.contributor.authorHeywood, James
dc.contributor.authorKennet, Jane
dc.contributor.authorArbon, Emma L
dc.contributor.authorAnselmiova, Katerina
dc.contributor.authorWalker, Neil M
dc.contributor.authorAtkar, Ravinder
dc.contributor.authorPekalski, Marcin L
dc.contributor.authorRytina, Ed
dc.contributor.authorEvans, Mark
dc.contributor.authorWicker, Linda S
dc.contributor.authorTodd, John A
dc.contributor.authorMander, Adrian P
dc.contributor.authorBond, Simon
dc.contributor.authorWaldron-Lynch, Frank
dc.date.accessioned2018-11-22T00:33:04Z
dc.date.available2018-11-22T00:33:04Z
dc.date.issued2018-10-04
dc.identifier.issn2379-3708
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285685
dc.description.abstractBACKGROUND: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS: DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS: Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI -0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS: Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, NCT02265809. FUNDING: Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.
dc.description.sponsorshipSir Jules Thorn Trust Swiss National Science Foundation, Wellcome Trust JDRF, NIHR Cambridge Biomedical Research Centre.
dc.format.mediumElectronic
dc.languageeng
dc.publisherAmerican Society for Clinical Investigation
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectDiabetes Mellitus, Type 1
dc.subjectRecombinant Proteins
dc.subjectInterleukin-2
dc.subjectLymphocyte Count
dc.subjectTreatment Outcome
dc.subjectDrug Administration Schedule
dc.subjectFeasibility Studies
dc.subjectLymphocyte Activation
dc.subjectDose-Response Relationship, Drug
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectT-Lymphocytes, Regulatory
dc.subjectInterleukin-2 Receptor alpha Subunit
dc.subjectYoung Adult
dc.titleThe DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.
dc.typeArticle
prism.issueIdentifier19
prism.publicationDate2018
prism.publicationNameJCI Insight
prism.volume3
dc.identifier.doi10.17863/CAM.33037
dcterms.dateAccepted2018-08-21
rioxxterms.versionofrecord10.1172/jci.insight.99306
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10-04
dc.contributor.orcidHowlett, James [0000-0001-9274-5170]
dc.contributor.orcidEvans, Mark [0000-0001-8122-8987]
dc.contributor.orcidMander, Adrian [0000-0002-0742-9040]
dc.contributor.orcidBond, Simon [0000-0003-2528-1040]
dc.contributor.orcidWaldron-Lynch, Frank [0000-0002-0597-4328]
dc.identifier.eissn2379-3708
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idWellcome Trust (091157/Z/10/B)
cam.issuedOnline2018-10-04


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International