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Abstract Background Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback. Results The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

Summary: Background: Type 1 diabetes is a complex heterogenous autoimmune disease without therapeutic interventions available to prevent or reverse the disease. This study aimed to identify transcriptional changes associated with the disease progression in patients with recent-onset type 1 diabetes. Methods: Whole-blood samples were collected as part of the INNODIA study at baseline and 12 months after diagnosis of type 1 diabetes. We used linear mixed-effects modelling on RNA-seq data to identify genes associated with age, sex, or disease progression. Cell-type proportions were estimated from the RNA-seq data using computational deconvolution. Associations to clinical variables were estimated using Pearson's or point-biserial correlation for continuous and dichotomous variables, respectively, using only complete pairs of observations. Findings: We found that genes and pathways related to innate immunity were downregulated during the first year after diagnosis. Significant associations of the gene expression changes were found with ZnT8A autoantibody positivity. Rate of change in the expression of 16 genes between baseline and 12 months was found to predict the decline in C-peptide at 24 months. Interestingly and consistent with earlier reports, increased B cell levels and decreased neutrophil levels were associated with the rapid progression. Interpretation: There is considerable individual variation in the rate of progression from appearance of type 1 diabetes-specific autoantibodies to clinical disease. Patient stratification and prediction of disease progression can help in developing more personalised therapeutic strategies for different disease endotypes. Funding: A full list of funding bodies can be found under Acknowledgments.

Introduction Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysis A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and dissemination This project was approved by ICR’s Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration details SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.