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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Introduction - The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT">
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<meta name="citation_title" content="Introduction">
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<meta name="citation_date" content="2025/02">
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<meta name="citation_author" content="Kymberley Carter">
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<meta name="citation_author" content="Evangelia Williams">
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<meta name="citation_author" content="Timothy Tree">
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<meta name="DC.Title" content="Introduction">
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<meta name="DC.Contributor" content="Wai-Yee Cheung">
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<meta name="DC.Contributor" content="Hayley A Hutchings">
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<meta name="DC.Contributor" content="Greg Fegan">
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<meta name="DC.Contributor" content="Gail Holland">
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<meta name="DC.Contributor" content="Steve Luzio">
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<meta name="DC.Contributor" content="Gareth Dunseath">
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<meta name="DC.Contributor" content="Stephen Hiles">
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<meta name="DC.Contributor" content="Susie Marques-Jones">
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<meta name="DC.Contributor" content="John W Gregory">
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<meta name="DC.Contributor" content="Danijela Tatovic">
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<meta name="DC.Contributor" content="Peter Taylor">
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<meta name="DC.Contributor" content="Jane Bowen-Morris">
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<meta name="DC.Contributor" content="Ashish Marwaha">
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<meta name="DC.Contributor" content="Colin M Dayan">
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<meta name="og:description" content="Nearly 100 years after the discovery of insulin, over 70% of patients with type 1 diabetes (T1D) continue to have unsatisfactory glycaemic control putting them at risk of long-term complications.1 Tragically, death rates amongst adolescents have not improved in two decades.2 Despite major advances in closed-loop insulin pump therapy, much of the morbidity arises from young people failing to engage with complex therapies.">
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Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK612276_"><span class="label">Chapter 1</span><span class="title" itemprop="name">Introduction</span></h1><p class="fm-aai"><a href="#_NBK612276_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><p>Nearly 100 years after the discovery of insulin, over 70% of patients with type 1 diabetes (T1D) continue to have unsatisfactory glycaemic control putting them at risk of long-term complications.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib1"><sup>1</sup></a> Tragically, death rates amongst adolescents have not improved in two decades.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib2"><sup>2</sup></a> Despite major advances in closed-loop insulin pump therapy, much of the morbidity arises from young people failing to engage with complex therapies.</p><p>Several experimental approaches have been suggested as potential cures for established <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>, including islet cell transplantation, production of insulin-producing beta cells from stem cells and activation of endogenous beta cell regeneration, coupled with sufficient protection from immune destruction. Islet transplantation, using the Edmonton Protocol, holds promise as an effective treatment for long-term <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> patients. However, to date, transplanted islets do not maintain long-term function<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib3"><sup>3</sup></a><sup>–</sup><a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib6"><sup>6</sup></a> and therapy is limited by the lack of donor tissue and a lifelong need for potentially toxic immunosuppressive therapy.</p><p>Most individuals have 10–20% of beta cell function remaining at the time of diagnosis of <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>. Preservation of even 5% of beta cell function has been shown to lower glycated haemoglobin (<a href="/books/n/ukeme1201/g1/?report=reader#g1-def16">HbA1c</a>) by 1%, permit over 50% of people to reach target glycaemic levels, reduce hypoglycaemic risk by > 50% and reduce long-term complications by 50%.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib7"><sup>7</sup></a><sup>,</sup><a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib8"><sup>8</sup></a> Immunotherapy has the potential to preserve endogenous beta cell function and thereby improve metabolic control even in poorly compliant individuals.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib9"><sup>9</sup></a><sup>–</sup><a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib11"><sup>11</sup></a></p><p>Novel low-risk targeted biologic therapies are widely used in other autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis, but no treatment is yet licensed for use in new-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>. There is an urgent need to identify which agents will work in <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> and bring these into clinical practice.</p><p>We tested a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta cells in the pancreas at the time of diagnosis. Among the many molecular candidates for inhibition in this complex disease, we chose to simultaneously target two major autoimmune cytokine pathways, interleukin (IL)-12/interferon-gamma (IFN-γ) and IL-23/IL-17, for which extensive evidence exists to implicate their role in beta cell destruction. The drug tested, ustekinumab (STELARA<sup>®</sup>), binds and inhibits the p40 molecular subunits of both IL-12 and IL-23, thus blocking their action in inducing pathogenic CD4 T helper 1 (Th1) and Th17 T-cell subsets.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib12"><sup>12</sup></a></p><p>Ustekinumab is licenced in the UK for the treatment of psoriasis in children and adults, psoriatic arthritis in adults and Crohn’s disease in adults. In a 1-year study of 110 adolescent patients, ustekinumab at the standard dose improved plaque psoriasis with no unexpected adverse effects,<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib13"><sup>13</sup></a> which led to its licencing for the use in adolescents (> 12 years of age) with psoriasis. Another pilot study indicated its potential efficacy in inflammatory bowel disease in the paediatric population.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib14"><sup>14</sup></a></p><div id="s1-1"><h2 id="_s1-1_">Scientific background and rationale</h2><p>We proposed that for <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>, permanent or long-term interruption of T-cell-mediated, autoimmune beta cell destruction at the time of clinical presentation will preserve sufficient beta cells so that physiological insulin secretion may be maintained. This concept is based on preliminary data generated from a model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, and from human participants with recent-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>. The approach is feasible because functional beta cells remain present within islets at the time of disease presentation. The surviving beta cells account for the numerous observations of endogenous insulin production during the so-called ‘honeymoon period’, which occurs shortly after metabolic stabilisation of newly diagnosed patients. We predicted that simultaneous inhibition of two pro-inflammatory pathways, which are mediated by T cells that secrete IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a>, will halt or reverse disease in participants with recent-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>. Agents to facilitate this approach were in clinical use: for example, ustekinumab, a humanised monoclonal antibody that targets these two pathways, has been approved for the treatment of psoriasis in North America and the UK since 2009.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib15"><sup>15</sup></a> Ustekinumab is highly effective and safe in the treatment of psoriasis, a disease whose pathogenesis depends upon both <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> and IL-17.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib16"><sup>16</sup></a><sup>,</sup><a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib17"><sup>17</sup></a></p><p>Animal studies have implicated the IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> pathways in the pathogenesis of autoimmune diabetes. In diabetes-prone BioBreeding rats, the potentially pathogenic Th17 cell population increases in the first months of age, but the proportion and function of T regulatory cells do not change. In <a href="/books/n/ukeme1201/g1/?report=reader#g1-def30">NOD</a> mice, inhibition of IL-17, through the use of blocking antibodies, delays disease onset. However, when beta cell-specific CD4+ T cells from T-cell receptor-transgenic BDC2.5 <a href="/books/n/ukeme1201/g1/?report=reader#g1-def30">NOD</a> mice are polarised to a Th17 phenotype, and then transferred to non-diabetic NOD-severe combined immunodeficiency recipients, the cells accelerate diabetes <i>only after</i> differentiating to a Th1-like phenotype.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib18"><sup>18</sup></a><sup>,</sup><a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib19"><sup>19</sup></a> This complementary pathogenic role of <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> has also been suggested by experiments in which antigen-specific Tc17 cells that targeted haemagglutinin on pancreatic beta cells were able to induce diabetes <i>only when</i> co-transferred with diabetogenic CD4+ T cells that secrete IL-12 (presumably allowing Tc17 conversion to an IFN-γ-secreting phenotype). A very recent and definitive study in <a href="/books/n/ukeme1201/g1/?report=reader#g1-def30">NOD</a> mice has shown that genetic ablation (knock out) of both the <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> receptor and IL-17 is required to prevent the onset of <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib20"><sup>20</sup></a> These data are consistent with a synergistic pathogenic effect between IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a>, as the effect of disabling of both pathways is much stronger than knocking out either pathway alone. Finally, treatment of <a href="/books/n/ukeme1201/g1/?report=reader#g1-def30">NOD</a> mice with neutralising antibodies to the p40 subunit of IL-12/IL-23 (C17.8, a murine equivalent to ustekinumab) suppresses insulitis and prevents disease.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib21"><sup>21</sup></a></p><p>It has been shown that peripheral lymphocytes from children with recent-onset diabetes, in contrast to age-matched healthy controls, have an increased proportion of a subset of forkhead box P3+ T cells that secretes a substantial amount of IL-17. It was also observed that children with <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> have an increased number of CD8+ T cells that secrete IL-17 (Tc17 cells). These data are supported by a Finnish study showing an increase in IL-17 messenger ribonucleic acid transcription in cells from children with <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>, and by reports showing that in addition to peripheral T cells, <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> participants have an increased proportion of monocytes that secrete Th17 polarising cytokines<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib22"><sup>22</sup></a> and islet-antigen-specific Th17 cells. There is also evidence that (1) pancreatic lymph nodes from <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> patients have an expansion in Th17 cells<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib23"><sup>23</sup></a> and (2) islets from recent-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> patients express IL-17A, retinoid-related orphan receptor C (the human, lineage-defining IL-17 transcription factor) and IL-22.<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib24"><sup>24</sup></a></p><p>These observations suggest that IL-17 and IL-12/IFN-γ-driven responses together have an enhanced pathogenic role in <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>. Our overarching hypothesis was that interrupting the IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> axes in individuals with recent-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> would halt or slow down the autoimmune destruction of beta cells sufficient to permit beta cell preservation and maintain residual physiological insulin secretion. Given the therapeutic success of biologics that target immune molecules in other autoimmune and inflammatory diseases, and the evidence that IL-17 and IFN-γ-producing cells are pathogenic to beta cells, we proposed that drugs already approved for use in humans (e.g. ustekinumab) may be beneficial for the treatment of <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>.</p></div><div id="s1-2"><h2 id="_s1-2_">Potential risks and benefits of the trial</h2><p>Trial participants were given ustekinumab or the control treatment (saline) subcutaneously (SC) in an enhanced dose (compared to the standard psoriasis dosing regimen) depending on the body weight: 2 mg/kg (if they weigh ≤ 40 kg) or 90 mg (if they weigh > 40 kg) at weeks 0, 4 and 12 weeks and subsequently every 8 weeks up to week 44.</p><p>This dosing frequency and route of administration have already been proven safe in adolescents with psoriasis<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib13"><sup>13</sup></a> and the proposed higher dose has been approved for use in a study of ustekinumab in adolescents with Crohn’s disease (ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/show/NCT02968108" title="Study NCT02968108" ref="pagearea=body&targetsite=external&targetcat=link&targettype=clinical-trial">NCT02968108</a>). In addition, preliminary data are available from the Canadian UST1D trial of ustekinumab in young adults (20 participants) with new-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> (within 100 days from diagnosis).<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib25"><sup>25</sup></a> No serious adverse events (SAEs) related to the investigational medicinal product (IMP) were noted. The most stable C-peptide levels were seen in the 90-mg group that received five doses throughout the study (loading dose at 0 and 4 weeks followed by additional three doses every 12 weeks).</p><p>The trial <a href="/books/n/ukeme1201/g1/?report=reader#g1-def21">IMP</a> will initially be administered at a clinical research facility at each site and drug recipients will remain in the unit for at least 1 hour after the first injection to ensure no immediate serious adverse effects (local or systemic allergic reactions). If none are detected after the first dose, participants will be suitable for home administration as per the dosing schedule (doses 4, 6 and 7).</p><p>Ustekinumab has undergone extensive Phase I–IV testing in adults with psoriasis vulgaris. In the 1-year Cancer Detection by Multiparametric Ultrasound of the prostate study of 110 adolescent patients, ustekinumab at the standard dose improved plaque psoriasis with no unexpected adverse effects,<a href="/books/n/ukeme1201/ref1/?report=reader#ref1-bib13"><sup>13</sup></a> which led to its licencing for use in adolescents (> 12 years of age) with psoriasis.</p><p>In alignment with UK categories, this trial was categorised as: Type B – somewhat higher than the risk of standard medical care.</p></div><div id="s1-3"><h2 id="_s1-3_">Objectives</h2><p>Our overarching hypothesis was that interrupting the IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> axes in individuals with recent-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a> will halt or slow down the autoimmune destruction of beta cells sufficient to permit beta cell preservation and maintain residual physiological insulin secretion.</p><div id="s1-3-1"><h3>Primary objective</h3><p>To determine the efficacy of ustekinumab for preserving Mixed Meal Tolerance Test (MMTT) stimulated 2-hour C-peptide area under the curve (AUC) at week 52 as compared to the control treatment in children and adolescents aged 12–18 years with new-onset <a href="/books/n/ukeme1201/g1/?report=reader#g1-def48">T1D</a>.</p></div><div id="s1-3-2"><h3>Secondary objectives</h3><ol><li class="half_rhythm"><div>To determine the efficacy of ustekinumab [dose: 2 mg/kg (≤ 40 kg); 90 mg (> 40 kg)] in eliciting a metabolic response to treatment defined as <a href="/books/n/ukeme1201/g1/?report=reader#g1-def16">HbA1c</a> ≤ 48 mmol/mol and mean daily insulin use < 0.5 IU/kg/day.</div></li><li class="half_rhythm"><div>To investigate additional efficacy (metabolic) end points including <a href="/books/n/ukeme1201/g1/?report=reader#g1-def28">MMTT</a> C-peptide <a href="/books/n/ukeme1201/g1/?report=reader#g1-def6">AUC</a> at week 28, <a href="/books/n/ukeme1201/g1/?report=reader#g1-def16">HbA1c</a> and insulin use measurements at weeks 12, 28 and 52.</div></li><li class="half_rhythm"><div>To compare alternative metabolic end-point assays to <a href="/books/n/ukeme1201/g1/?report=reader#g1-def28">MMTT</a>, including glycaemic variability in glucose monitoring and hypoglycaemia rates.</div></li><li class="half_rhythm"><div>To determine safety of ustekinumab [dose: 2 mg/kg (≤ 40 kg); 90 mg (> 40 kg)] in this patient group including rate, frequency and severity of all adverse events (AEs).</div></li><li class="half_rhythm"><div>To compare between treatment arms and across the course of treatment the age-appropriate participant-reported outcome measures (PROMs) scores completed by participants and parents.</div></li></ol></div><div id="s1-3-3"><h3>Tertiary objectives</h3><ol><li class="half_rhythm"><div>To investigate alternative ways of measuring islet activity other than <a href="/books/n/ukeme1201/g1/?report=reader#g1-def28">MMTT</a> C-peptide including <a href="/books/n/ukeme1201/g1/?report=reader#g1-def28">MMTT</a> urine C-peptide/creatinine ratio (UCPCR), <i>dried blood spot (DBS) measurements for C-peptide and fasting, post-meal proinsulin/C-peptide ratio, glucagon and somatostatin levels and fasting and post-meal plasma PI/C-peptide ratio.</i></div></li><li class="half_rhythm"><div>To determine changes in relevant immune mechanistic parameters including flow cytometry immune phenotyping of all IL-17 and IFN-γ-secreting T-cell subsets, FluoroSpot analysis for IL-17 and <a href="/books/n/ukeme1201/g1/?report=reader#g1-def19">IFN-γ</a> secretion in response to antigens for CD4+ T cells and <i>islet-derived serum cell-free DNA.</i></div></li><li class="half_rhythm"><div>
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<i>To measure ustekinumab serum levels to assess pharmacokinetics and compliance.</i>
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</div></li><li class="half_rhythm"><div>To explore the association of C-peptide changes with age-appropriate <a href="/books/n/ukeme1201/g1/?report=reader#g1-def37">PROMs</a> including the Hypoglycaemia Fear Survey (HypoFear), Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Paediatric Quality of Life Inventory (PedsQL) questionnaires.</div></li><li class="half_rhythm"><div>To compare participant and parent/carer proxy completed <a href="/books/n/ukeme1201/g1/?report=reader#g1-def37">PROMs</a>.</div></li><li class="half_rhythm"><div>
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<i>To investigate longer-term effects of ustekinumab on glycaemic control including insulin usage, severe hypoglycaemic events, <a href="/books/n/ukeme1201/g1/?report=reader#g1-def16">HbA1c</a>, C-peptide and continuous glucose monitoring (CGM) data (remote data collection to week 104).</i>
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</div></li><li class="half_rhythm"><div>To determine whether any participants had COVID-19 during their time in the trial and to ascertain whether it had any effects.</div></li></ol><p>Note: The objectives listed in italics were supported by funders other than National Institute for Health and Care Research (NIHR) as part of separate projects and not all data from these are listed in this report.</p></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK612276_pubdet_">Publication Details</h2><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 2025 Carter <i>et al</i>.<p class="small">This work was produced by Carter <i>et al</i>. 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, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: <a href="https://creativecommons.org/licenses/by/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">https://creativecommons.org/licenses/by/4.0/</a>. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.</p></div></div><h3>Publisher</h3><p><a href="http://www.journalslibrary.nihr.ac.uk/eme" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Institute for Health and Care Research</a>, Southampton (UK)</p><h3>NLM Citation</h3><p>Carter K, Cheung WY, Hutchings HA, et al. The efficacy and safety of ustekinumab in adolescents newly diagnosed with type 1 diabetes: the USTEK1D RCT. Southampton (UK): National Institute for Health and Care Research; 2025 Feb. (Efficacy and Mechanism Evaluation, No. 12.01.) Chapter 1, Introduction.<span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/ukeme1201/abs3/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/ukeme1201/s2/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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