The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT

Carter, Kym; Cheung, Wai-Yee; Hutchings, Hayley; Fegan, Greg; Holland, Gail; Luzio, Steve; Dunseath, Gareth; Hiles, Stephen; Marques-Jones, Susie; Gregory, John W; Tatovic, Danijela; Taylor, Peter; Bowen-Morris, Jane; Stenson, Rachel; Hanna, Stephanie; Mahmood, Zainab; Yang, Jennie; Williams, Evangelia; Tree, Timothy; Marwaha, Ashish; Dayan, Colin M; Cheung, Ivy; Hiles, Steve

doi:10.3310/fqln7416

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The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT

Kym Carter

, Wai-Yee Cheung

, Hayley Hutchings

, Greg Fegan

, Gail Holland

, Steve Luzio

, Gareth Dunseath

, Stephen Hiles

, Susie Marques-Jones, John W Gregory

, Danijela Tatovic

, Peter Taylor

, Jane Bowen-Morris

, Rachel Stenson

, Stephanie Hanna

, Zainab Mahmood

, Jennie Yang

, Evangelia Williams

, Timothy Tree

, Ashish Marwaha

, Colin M Dayan

, Ivy Cheung, Steve Hiles

Efficacy and Mechanism Evaluation, Volume: 12, Issue: 1, Pages: 1 - 66

Swansea University Authors: Kym Carter , Hayley Hutchings , Gail Holland , Steve Luzio , Gareth Dunseath , Ivy Cheung, Steve Hiles

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Copyright © 2025 Carter et al. This work was produced by Carter et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence.
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DOI (Published version): 10.3310/fqln7416

Abstract

Background: Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s): To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/inte...

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Published in:	Efficacy and Mechanism Evaluation
ISSN:	2050-4373
Published:	National Institute for Health and Care Research 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa68939

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Objective(s): To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design: Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting: Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants: Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria: Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions: Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures: Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation: 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding: Blinding of participants, investigators, laboratory and trial staff. Numbers randomised: Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment: Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed: Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome: Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells (p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms: No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations: Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions: Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work: Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration: Current Controlled Trials ISRCTN14274380.</abstract><type>Journal Article</type><journal>Efficacy and Mechanism Evaluation</journal><volume>12</volume><journalNumber>1</journalNumber><paginationStart>1</paginationStart><paginationEnd>66</paginationEnd><publisher>National Institute for Health and Care Research</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2050-4373</issnElectronic><keywords/><publishedDay>21</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-02-21</publishedDate><doi>10.3310/fqln7416</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Not Required</apcterm><funders>This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/36/01).</funders><projectreference/><lastEdited>2025-05-08T15:43:52.2809222</lastEdited><Created>2025-02-21T12:46:44.4259583</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Health Data Science</level></path><authors><author><firstname>Kym</firstname><surname>Carter</surname><orcid>0000-0003-0691-6282</orcid><order>1</order></author><author><firstname>Wai-Yee</firstname><surname>Cheung</surname><orcid>0000-0002-0915-9312</orcid><order>2</order></author><author><firstname>Hayley</firstname><surname>Hutchings</surname><orcid>0000-0003-4155-1741</orcid><order>3</order></author><author><firstname>Greg</firstname><surname>Fegan</surname><orcid>0000-0002-2663-2765</orcid><order>4</order></author><author><firstname>Gail</firstname><surname>Holland</surname><orcid>0000-0002-6924-2521</orcid><order>5</order></author><author><firstname>Steve</firstname><surname>Luzio</surname><orcid>0000-0002-7206-6530</orcid><order>6</order></author><author><firstname>Gareth</firstname><surname>Dunseath</surname><orcid>0000-0001-6022-862X</orcid><order>7</order></author><author><firstname>Stephen</firstname><surname>Hiles</surname><orcid>0000-0002-8376-4377</orcid><order>8</order></author><author><firstname>Susie</firstname><surname>Marques-Jones</surname><order>9</order></author><author><firstname>John W</firstname><surname>Gregory</surname><orcid>0000-0001-5189-3812</orcid><order>10</order></author><author><firstname>Danijela</firstname><surname>Tatovic</surname><orcid>0000-0002-3879-2686</orcid><order>11</order></author><author><firstname>Peter</firstname><surname>Taylor</surname><orcid>0000-0002-3436-422x</orcid><order>12</order></author><author><firstname>Jane</firstname><surname>Bowen-Morris</surname><orcid>0009-0003-8929-346x</orcid><order>13</order></author><author><firstname>Rachel</firstname><surname>Stenson</surname><orcid>0000-0001-9398-3576</orcid><order>14</order></author><author><firstname>Stephanie</firstname><surname>Hanna</surname><orcid>0000-0002-0821-4498</orcid><order>15</order></author><author><firstname>Zainab</firstname><surname>Mahmood</surname><orcid>0000-0001-5383-5704</orcid><order>16</order></author><author><firstname>Jennie</firstname><surname>Yang</surname><orcid>0000-0001-6171-833x</orcid><order>17</order></author><author><firstname>Evangelia</firstname><surname>Williams</surname><orcid>0009-0001-4526-112x</orcid><order>18</order></author><author><firstname>Timothy</firstname><surname>Tree</surname><orcid>0000-0002-6973-5377</orcid><order>19</order></author><author><firstname>Ashish</firstname><surname>Marwaha</surname><orcid>0000-0003-1234-0224</orcid><order>20</order></author><author><firstname>Colin M</firstname><surname>Dayan</surname><orcid>0000-0002-6557-3462</orcid><order>21</order></author><author><firstname>Ivy</firstname><surname>Cheung</surname><order>22</order></author><author><firstname>Steve</firstname><surname>Hiles</surname><order>23</order></author></authors><documents><document><filename>68939__33664__f58f01fe0b784e65a855f276c6721698.pdf</filename><originalFilename>3047149.pdf</originalFilename><uploaded>2025-02-21T13:20:26.4350339</uploaded><type>Output</type><contentLength>2486695</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Copyright © 2025 Carter et al. 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spelling	2025-05-08T15:43:52.2809222 v2 68939 2025-02-21 The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT 1b1870c5c1ec66eed0bf209e50a6ee25 0000-0003-0691-6282 Kym Carter Kym Carter true false bdf5d5f154d339dd92bb25884b7c3652 0000-0003-4155-1741 Hayley Hutchings Hayley Hutchings true false b9f3a8bf7478db012c8856b7bbbc7597 0000-0002-6924-2521 Gail Holland Gail Holland true false 01491e1cd582746a654fad9addf0de16 0000-0002-7206-6530 Steve Luzio Steve Luzio true false fccbba9edcaee08a839a3c5cff8cbe19 0000-0001-6022-862X Gareth Dunseath Gareth Dunseath true false a9142ffd398f89eff40ada503e315639 Ivy Cheung Ivy Cheung true false 5ecd70f8c0f27219f84a7f297d99b22b Steve Hiles Steve Hiles true false 2025-02-21 MEDS Background: Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s): To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design: Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting: Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants: Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria: Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions: Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures: Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation: 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding: Blinding of participants, investigators, laboratory and trial staff. Numbers randomised: Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment: Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed: Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome: Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells (p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms: No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations: Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions: Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work: Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration: Current Controlled Trials ISRCTN14274380. Journal Article Efficacy and Mechanism Evaluation 12 1 1 66 National Institute for Health and Care Research 2050-4373 21 2 2025 2025-02-21 10.3310/fqln7416 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Not Required This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/36/01). 2025-05-08T15:43:52.2809222 2025-02-21T12:46:44.4259583 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Health Data Science Kym Carter 0000-0003-0691-6282 1 Wai-Yee Cheung 0000-0002-0915-9312 2 Hayley Hutchings 0000-0003-4155-1741 3 Greg Fegan 0000-0002-2663-2765 4 Gail Holland 0000-0002-6924-2521 5 Steve Luzio 0000-0002-7206-6530 6 Gareth Dunseath 0000-0001-6022-862X 7 Stephen Hiles 0000-0002-8376-4377 8 Susie Marques-Jones 9 John W Gregory 0000-0001-5189-3812 10 Danijela Tatovic 0000-0002-3879-2686 11 Peter Taylor 0000-0002-3436-422x 12 Jane Bowen-Morris 0009-0003-8929-346x 13 Rachel Stenson 0000-0001-9398-3576 14 Stephanie Hanna 0000-0002-0821-4498 15 Zainab Mahmood 0000-0001-5383-5704 16 Jennie Yang 0000-0001-6171-833x 17 Evangelia Williams 0009-0001-4526-112x 18 Timothy Tree 0000-0002-6973-5377 19 Ashish Marwaha 0000-0003-1234-0224 20 Colin M Dayan 0000-0002-6557-3462 21 Ivy Cheung 22 Steve Hiles 23 68939__33664__f58f01fe0b784e65a855f276c6721698.pdf 3047149.pdf 2025-02-21T13:20:26.4350339 Output 2486695 application/pdf Version of Record true Copyright © 2025 Carter et al. This work was produced by Carter et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence. true eng https://creativecommons.org/licenses/by/4.0/
title	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
spellingShingle	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT Kym Carter Hayley Hutchings Gail Holland Steve Luzio Gareth Dunseath Ivy Cheung Steve Hiles
title_short	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
title_full	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
title_fullStr	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
title_full_unstemmed	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
title_sort	The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT
author_id_str_mv	1b1870c5c1ec66eed0bf209e50a6ee25 bdf5d5f154d339dd92bb25884b7c3652 b9f3a8bf7478db012c8856b7bbbc7597 01491e1cd582746a654fad9addf0de16 fccbba9edcaee08a839a3c5cff8cbe19 a9142ffd398f89eff40ada503e315639 5ecd70f8c0f27219f84a7f297d99b22b
author_id_fullname_str_mv	1b1870c5c1ec66eed0bf209e50a6ee25_*_Kym Carter bdf5d5f154d339dd92bb25884b7c3652__Hayley Hutchings b9f3a8bf7478db012c8856b7bbbc7597__Gail Holland 01491e1cd582746a654fad9addf0de16__Steve Luzio fccbba9edcaee08a839a3c5cff8cbe19__Gareth Dunseath a9142ffd398f89eff40ada503e315639__Ivy Cheung 5ecd70f8c0f27219f84a7f297d99b22b_**_Steve Hiles
author	Kym Carter Hayley Hutchings Gail Holland Steve Luzio Gareth Dunseath Ivy Cheung Steve Hiles
author2	Kym Carter Wai-Yee Cheung Hayley Hutchings Greg Fegan Gail Holland Steve Luzio Gareth Dunseath Stephen Hiles Susie Marques-Jones John W Gregory Danijela Tatovic Peter Taylor Jane Bowen-Morris Rachel Stenson Stephanie Hanna Zainab Mahmood Jennie Yang Evangelia Williams Timothy Tree Ashish Marwaha Colin M Dayan Ivy Cheung Steve Hiles
format	Journal article
container_title	Efficacy and Mechanism Evaluation
container_volume	12
container_issue	1
container_start_page	1
publishDate	2025
institution	Swansea University
issn	2050-4373
doi_str_mv	10.3310/fqln7416
publisher	National Institute for Health and Care Research
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Health Data Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Health Data Science
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description	Background: Type 1 diabetes is an autoimmune disease affecting over 400,000 children and adults in the United Kingdom for which currently the only available therapy is insulin. Objective(s): To determine the efficacy and safety of the monoclonal antibody ustekinumab targeting the interleukin 12/interleukin 23 immune pathway that generates T helper 1/T helper 17 T cells to slow down the autoimmune process and preserve beta cell production in type 1 diabetes. Design: Randomised, double-blind, placebo-controlled, parallel-group phase II trial. Setting: Paediatric and young adult diabetes clinics across 16 sites in the United Kingdom. Participants: Newly diagnosed with type 1 diabetes and aged 12–18 years. Eligibility criteria: Type 1 diabetes confirmed by islet autoantibody testing, within 100 days of first insulin injection, and with residual beta cell function (stimulated C-peptide level > 0.2 nmol/l). Interventions: Ustekinumab at the highest approved doses or control (saline) subcutaneously at weeks 0, 4 and 12 and subsequently every 8 weeks to week 44 (seven doses). Main outcome measures: Preservation of Mixed Meal Tolerance Test stimulated 2-hour insulin C-peptide area under the curve at week 52 as compared to control (saline) treatment by analysis of covariance adjusted for baseline parameters. Randomisation: 2 : 1 Remote computerised randomisation with minimisation by age and baseline C-peptide groups. Blinding: Blinding of participants, investigators, laboratory and trial staff. Numbers randomised: Seventy-two participants were randomised, 60% male, 18% aged 16–18 years. Recruitment: Two hundred and eight potentially eligible patients were approached, and 88 patients were screened. Four participants were lost to follow-up (6%). Four participants withdrew from the treatment but attended the primary end-point assessment. Numbers analysed: Six participants were missing baseline data for the primary analysis. The final analysable sample was n = 62. Outcome: Ustekinumab was associated with a 49% higher endogenous stimulated insulin production than control at week 52 after adjustments for baseline factors [geometric ratio of ustekinumab to control was 1.49 (95% confidence interval 1.08 to 2.06; p = 0.02)]. Secondary analyses showed no difference in C-peptide at week 28 suggesting that the effect was ‘late’ or ‘delayed’. Ancillary analysis showed a significant reduction in activated T helper 17.1 T cells (p < 0.001) in the treatment group which was associated with C-peptide preservation from week 28 to week 52. Harms: No severe adverse events were reported and there were no differences between ustekinumab and control groups in the proportion of participants overall experiencing mild (87% vs. 88%) or moderate (32% vs. 32%) events. Limitations: Sensitivity analysis showed the primary end point to be robust to exclusion of small numbers of participants with some protocol deviations and extreme values in key covariates, but not to imputation of all missing data. Conclusions: Ustekinumab appears to slow down the autoimmune process providing the first clinical trial evidence that interleukin 17-secreting T cells play a pathogenic role in type 1 diabetes. Alone, it is insufficient to halt the autoimmune process. Future work: Replication of this result is ongoing in a trial with a similar design in Canada. If confirmed, consideration may be given to testing other drugs targeting the interleukin 17 pathway, using ustekinumab in combination with other agents or using it earlier in the disease pathway (preclinical disease) since it is so well tolerated and simple to use. Study registration: Current Controlled Trials ISRCTN14274380.
published_date	2025-02-21T14:14:25Z
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score	11.089677

The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT

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