It is difficult to ensure clinical trial outcomes are defined completely in registrations, and to check outcome changes between registration and posting results. We developed a large language model (LLM)-based approach to evaluate outcome definitions and changes on ClinicalTrials.gov. Our LLM-based approach accurately identified incomplete outcomes in prospective trial registrations (sensitivity, 0.91 [95% confidence interval {CI}, 0.87–0.94]; positive predictive value [PPV], 0.98 [95% CI, 0.97–1.00]). Comparing prospective registrations with posted results, it correctly identified 96.1% of missing and 97.9% of added outcomes. It identified all outcomes with a priority change (e.g., from primary to secondary) and 99.2% without one. Sensitivity and PPV for identifying any outcome change were 0.97 (95% CI, 0.95–0.99) and 0.95 (95% CI, 0.89–0.98), respectively. Estimated costs per trial were $0.13 for o3-mini, $0.30 for GPT-4o, and $1.80 for o1. The accuracy of our approach suggests it could be used to improve registration quality and to detect outcome changes at large scale and at low cost.

This JAMA Pediatrics Patient Page describes how new guidance aiming to improve reporting of clinical trials may help young people and parents find information to make the right health care decisions for them.

Ibuprofen is first-line therapy for musculoskeletal pain. However, two-thirds of children experience inadequate pain relief with ibuprofen monotherapy, and the efficacy of additive medications for moderate to severe musculoskeletal pain is unclear. To determine whether treatment with an opioid (hydromorphone) plus ibuprofen or nonopioid (acetaminophen [paracetamol]) plus ibuprofen decreased pain scores compared with ibuprofen alone. Two randomized, double-masked, placebo-controlled trials were conducted from April 2019 to March 2023 in 6 university-affiliated, tertiary care Canadian pediatric emergency departments. Children aged 6 to 17 years presenting with a nonoperative acute limb injury (<24 hours) and a verbal numerical rating scale (vNRS) pain score of 5 or more out of 10 were enrolled. Date of final follow-up was March 22, 2023. The opioid trial randomized participants to a single oral dose of ibuprofen plus hydromorphone, ibuprofen plus acetaminophen, or ibuprofen alone. The nonopioid trial randomized participants to a single oral dose of ibuprofen plus acetaminophen or ibuprofen alone. In all groups, ibuprofen was dosed at 10 mg/kg (maximum, 600 mg). The acetaminophen dose was 15 mg/kg (maximum, 1000 mg), and the hydromorphone dose was 0.05 mg/kg (maximum, 5 mg). The primary efficacy outcome was self-reported vNRS pain score at 60 minutes post medication administration (score range, 0 [no pain] to 10 [worst pain]; minimal clinically important difference, 1.5). The primary safety end point was the proportion of children with any adverse event related to study drug administration. A total of 8098 children were screened for eligibility; 699 were randomized and 653 were included in the efficacy analyses. The opioid trial included 249 children: 110 randomized to ibuprofen plus hydromorphone, 70 to ibuprofen plus acetaminophen, and 69 to ibuprofen alone. The nonopioid trial included 450 children: 225 randomized to a single oral dose of ibuprofen plus acetaminophen and 225 randomized to ibuprofen alone. The mean (SD) age of children in the 2 trials was 11.5 (3.5) years and 47.4% were female. The mean (SD) vNRS score at recruitment was 6.4 (1.8). In pooled analyses, mean (SD) vNRS scores 60 minutes after drug administration were 4.8 (2.6) in the ibuprofen plus hydromorphone group, 4.6 (2.4) in the ibuprofen plus acetaminophen group, and 4.6 (2.3) in the ibuprofen alone group ( P = .78). Any adverse event occurred at higher rates in the ibuprofen plus hydromorphone group (28.2%) compared with the ibuprofen plus acetaminophen (6.1%) or ibuprofen alone groups (5.8%). No serious adverse events occurred. For children with acute nonoperative musculoskeletal injury, pain scores at 60 minutes after drug administration did not improve with ibuprofen plus acetaminophen or ibuprofen plus hydromorphone compared with ibuprofen alone. Adverse events were 4-fold more frequent with hydromorphone. Clinicaltrials.gov Identifier: NCT03767933

Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnostic yield and potential to influence treatment and care planning decisions, little is known about how families experience rGS in the ICU and the emotional and contextual factors influencing their testing-related decisions. We conducted semi-structured interviews with twenty-three parents of infants who consented to rGS in an ICU at two tertiary hospitals in Toronto, Ontario, Canada; all interviews took place in close proximity to the decision to pursue rGS. Parents’ experiences with rGS and the related genetics consultation demonstrated a complex interplay of emotional, pragmatic, relational, and temporal ‘sense-making’ to grasp what was happening. Overall, parents felt overwhelmed in the ICU. Some de-prioritized genetic testing compared to other aspects of care while others reflected negatively or ambivalently on rGS or felt that it was implicitly expected that they pursue it. We conclude that an rGS approach tailored to the ICU setting is needed. Consideration should be given to distributing complex decisions (such as those relating to primary vs. secondary findings) across multiple briefer visits, and alleviating decisional burden by reframing rGS as one of the many shared decisions made with families in this setting.

BACKGROUND AND OBJECTIVES:Bronchopulmonary dysplasia (BPD) is the most prevalent chronic respiratory complication of preterm birth and is associated with lifelong impairments. Multiple definitions are currently in use, creating variability in reported incidences and challenges in benchmarking. A harmonized definition is crucial for clinical care, research, and quality improvement. The objective of this international Delphi procedure was to identity key features of a BPD definition. METHODS:Health care professionals involved in neonatal clinical care and research were invited via an open electronic link to participate in a 2-round Delphi survey. A steering group disseminated the initial invitation. In round 1, participants rated 18 statements regarding BPD definition features using a 5-point Likert scale. Round 2 provided feedback from round 1, with consensus defined as greater than 70% agreement on acceptance or rejection of key features. RESULTS:Of 438 respondents, 351 (80.1%) completed both survey rounds. Although the 2001 National Institutes of Health definition was most commonly applied (66.4%), substantial variability in practice was reported. Most statements (72.2%) received median scores of 4 or 5 in the first round. Bronchopulmonary dysplasia definitions were primarily used for quality improvement (82.1%), prognostication of respiratory outcomes (81.5%), and as research outcomes (64.1%). In round 2, 13 of 18 statements achieved greater than 70% consensus. The strongest agreement emphasized that BPD definitions should be severity based, serve as benchmarks across centers, and predict long-term respiratory outcomes. CONCLUSIONS:This international Delphi procedure identified key features for defining BPD. Results highlight the need for a harmonized, severity-based classification predictive of long-term outcomes and supporting consistency in clinical care, research, and benchmarking.

Paediatric randomised controlled trials (RCTs) are key to evaluating new and existing interventions that can improve health outcomes in newborns, infants, children, and adolescents (aged 0-19 years). Well reported RCT protocols facilitate the planning and implementation of trials that generate high quality, reproducible evidence, and strengthen the foundations of paediatric healthcare decisions and ultimately improve patient outcomes. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement contains a checklist of essential reporting items and an explanation and elaboration paper. However, SPIRIT 2025 does not consider important elements that are unique to paediatric RCT protocols. As a paediatric extension to SPIRIT, we developed the SPIRIT-Children and Adolescents (SPIRIT-C) 2026 checklist, which this explanation and elaboration paper accompanies. We adopted a group writing approach to prepare this explanation and elaboration paper, and involved key partners with lived experience relevant to paediatric clinical trials, including family caregivers, trialists, child health researchers, clinicians, journal editors, and methodologists. This explanation and elaboration paper presents examples, explanations, and key elements for the 17 new SPIRIT-C 2026 reporting items; paediatric considerations with good reporting examples for six SPIRIT 2025 items; and a glossary. This paper also promotes the reporting of methodological rigor, patient safety, promotes a patient oriented approach, and facilitates the generation of high quality, reproducible trial evidence that will strengthen paediatric practice and policy decisions and ultimately improve patient outcomes.

Randomized controlled trials (RCTs) in children and adolescents provide evidence for patients, families, researchers, clinicians, regulators, funders, policymakers, and other interest holders to inform decisions about health care interventions and improve outcomes for young patients and their families. To critically evaluate, interpret, and apply trial results, readers require access to a complete and transparent report of what was planned, done, and found, taking unique considerations specific to children and adolescents into account. Harmonized guidance based on evidence and consensus is needed to optimize standardized reporting and reduce research waste in pediatric RCTs. To develop a pediatric reporting guideline extension to the Consolidated Standards of Reporting Trials (CONSORT) 2025 guideline, CONSORT–Children and Adolescents (CONSORT-C) 2026, that supports comprehensive reporting and enhances the transparency, reproducibility, accuracy, and utility of published pediatric RCT reports. The Enhancing the Quality of Transparency of Health Research (EQUATOR) Network’s published framework primarily informed the development of CONSORT-C 2026. A literature review was conducted to generate a list of candidate reporting items. To obtain direct input from young people and family caregivers throughout the project, a Youth Advisory Group and a Family Caregiver Advisory Group were formed. An international Delphi study with a priori consensus thresholds, consensus meeting, group writing of the explanation and elaboration paper, and pilot testing were conducted. Harmonized guidance based on evidence and consensus is needed to optimize standardized reporting and reduce research waste in pediatric RCTs. As an extension to the CONSORT 2025 statement, the CONSORT-C 2026 reporting guideline aims to improve the quality and completeness of reporting of pediatric RCTs that involve participants aged 0 to 19 years. The new CONSORT-C 2026 guideline is an extension to the updated CONSORT 2025 statement and adds reporting items applicable to pediatric RCT reports involving children and adolescents aged 0 to 19 years. Developed in partnership with young people (aged 10-24 years) and family caregivers, CONSORT-C 2026 comprises 13 new items recommended to be reported in pediatric RCT reports in addition to the CONSORT 2025 items. The 13 new reporting items include 1 youth-generated and 6 youth-endorsed items. CONSORT-C 2026 can be considered a minimum set of reporting items applicable to pediatric RCT reports reflecting the priorities of clinicians, researchers, young people, family caregivers, and other interest holders. Widespread implementation and uptake of CONSORT-C 2026 should optimize the usability of trial results for these populations, improve the reproducibility of trial results, and reduce research waste.

Appropriately designed, conducted, and reported randomised controlled trials (RCTs) in children and adolescents inform treatment and health-care decisions made by young people, families, researchers, clinicians, regulators, funders, policy makers, and other interest holders. To critically evaluate, interpret, and apply trial results, readers require access to a complete and transparent report of what was planned, done, and found, taking unique considerations specific to children and adolescents into account. Harmonised guidance based on evidence and consensus is needed to optimise standardised reporting and reduce research waste in paediatric RCTs. As an extension to the Consolidated Standards of Reporting Trials (CONSORT) 2025 statement, the CONSORT-Children and Adolescents (CONSORT-C) 2026 reporting guideline aims to improve the quality and completeness of reporting of paediatric RCTs that involve participants aged 0-19 years. The Enhancing the Quality of Transparency of Health Research (EQUATOR) Network's published framework primarily informed the development of CONSORT-C 2026. A literature review was conducted to generate a list of candidate reporting items. To obtain direct input from young people and family caregivers throughout the project, a Youth Advisory Group and a Family Caregiver Advisory Group were formed. An international Delphi study with a priori consensus thresholds, consensus meeting, group writing of the explanation and elaboration paper, and pilot testing were conducted. CONSORT-C 2026 consists of a checklist with 13 new reporting items, including one youth-generated and six youth-endorsed items; the accompanying explanation and elaboration paper explains all items and offers examples of good reporting. CONSORT-C 2026 can be considered a minimum set of reporting items applicable to paediatric RCT reports reflecting the priorities of clinicians, researchers, young people, family caregivers, and other interest holders. Widespread implementation and uptake of CONSORT-C 2026 should optimise the usability of trial results for these populations, improve the reproducibility of trial results, and reduce research waste.

Importance:Ibuprofen is first-line therapy for musculoskeletal pain. However, two-thirds of children experience inadequate pain relief with ibuprofen monotherapy, and the efficacy of additive medications for moderate to severe musculoskeletal pain is unclear. Objective:To determine whether treatment with an opioid (hydromorphone) plus ibuprofen or nonopioid (acetaminophen [paracetamol]) plus ibuprofen decreased pain scores compared with ibuprofen alone. Design, Setting, and Participants:Two randomized, double-masked, placebo-controlled trials were conducted from April 2019 to March 2023 in 6 university-affiliated, tertiary care Canadian pediatric emergency departments. Children aged 6 to 17 years presenting with a nonoperative acute limb injury (<24 hours) and a verbal numerical rating scale (vNRS) pain score of 5 or more out of 10 were enrolled. Date of final follow-up was March 22, 2023. Interventions:The opioid trial randomized participants to a single oral dose of ibuprofen plus hydromorphone, ibuprofen plus acetaminophen, or ibuprofen alone. The nonopioid trial randomized participants to a single oral dose of ibuprofen plus acetaminophen or ibuprofen alone. In all groups, ibuprofen was dosed at 10 mg/kg (maximum, 600 mg). The acetaminophen dose was 15 mg/kg (maximum, 1000 mg), and the hydromorphone dose was 0.05 mg/kg (maximum, 5 mg). Main Outcomes and Measures:The primary efficacy outcome was self-reported vNRS pain score at 60 minutes post medication administration (score range, 0 [no pain] to 10 [worst pain]; minimal clinically important difference, 1.5). The primary safety end point was the proportion of children with any adverse event related to study drug administration. Results:A total of 8098 children were screened for eligibility; 699 were randomized and 653 were included in the efficacy analyses. The opioid trial included 249 children: 110 randomized to ibuprofen plus hydromorphone, 70 to ibuprofen plus acetaminophen, and 69 to ibuprofen alone. The nonopioid trial included 450 children: 225 randomized to a single oral dose of ibuprofen plus acetaminophen and 225 randomized to ibuprofen alone. The mean (SD) age of children in the 2 trials was 11.5 (3.5) years and 47.4% were female. The mean (SD) vNRS score at recruitment was 6.4 (1.8). In pooled analyses, mean (SD) vNRS scores 60 minutes after drug administration were 4.8 (2.6) in the ibuprofen plus hydromorphone group, 4.6 (2.4) in the ibuprofen plus acetaminophen group, and 4.6 (2.3) in the ibuprofen alone group (P = .78). Any adverse event occurred at higher rates in the ibuprofen plus hydromorphone group (28.2%) compared with the ibuprofen plus acetaminophen (6.1%) or ibuprofen alone groups (5.8%). No serious adverse events occurred. Conclusions and Relevance:For children with acute nonoperative musculoskeletal injury, pain scores at 60 minutes after drug administration did not improve with ibuprofen plus acetaminophen or ibuprofen plus hydromorphone compared with ibuprofen alone. Adverse events were 4-fold more frequent with hydromorphone. Trial Registration:Clinicaltrials.gov Identifier: NCT03767933.

Randomised controlled trial (RCT) protocols contain essential details needed to understand and evaluate the trial's planned aims, design, data collection methods, monitoring, data analysis, and participants' safety. However, key information is often omitted from paediatric RCT protocols, including details on dose adjustments of interventions based on age, body surface area, or weight; developmental appropriateness of trial outcome measures and processes; or strategies to minimise participants' anxiety and pain. These deficiencies impair the planning and implementation of potentially impactful trials for children and adolescents. Appropriate guidance is needed to support harmonised, comprehensive reporting of paediatric RCT protocols involving participants aged 0-19 years. The methodological framework for developing reporting guidelines published by the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network was implemented to develop a paediatric extension to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 guidelines, called SPIRIT-Children and Adolescents (SPIRIT-C) 2026. A list of candidate reporting items was generated from the literature, and a Youth Advisory Group and a Family Caregiver Advisory Group contributed essential input throughout the project. An international Delphi study with a priori consensus thresholds, a consensus meeting, group writing of the explanation and elaboration paper, and pilot testing of the draft guideline were conducted. SPIRIT-C 2026 consists of a checklist with 17 new reporting items for reporting paediatric RCT protocols; four items are youth generated and six youth endorsed. SPIRIT-C 2026 can be considered a minimum set of reporting items pertinent to paediatric RCT protocols that are relevant to various interest holders, including young people, family caregivers, researchers, paediatric trialists, ethics committees, regulators, funders, and journal editors. The accompanying explanation and elaboration paper explains all items and offers examples of good reporting. Widespread implementation and uptake of SPIRIT-C 2026 should enhance the quality and usefulness of protocols for RCTs that involve participants from birth through adolescence, and ultimately foster high-quality paediatric trials.

BACKGROUND AND OBJECTIVES:The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension for scoping reviews (ScRs) (PRISMA-ScR) was published in 2018 to provide reporting guidance. A substantial increase in published ScRs in recent years coupled with the omission or lack of engagement of interest-holders, including patients and public partners, as research partners throughout its development necessitate updating PRISMA-ScR. Important methodological advancements have emerged since PRISMA-ScR 2018, including automation and data extraction, which need to be incorporated into this update and reflected in new reporting items. Aligned with PRISMA 2020, this ScR underpins the update by identifying potential new reporting items for consideration from recent studies related to reporting guidance and the evaluation of reporting completeness in ScRs. METHODS:The protocol for this review was published and registered with the Open Science Framework and in a peer-reviewed journal. We conducted database searches in MEDLINE, Embase, and Cochrane Methodology Register and gray literature searches guided by the Canada's Drug Agency Gray Matters tool. Retrieved sources were screened in duplicate to assess eligibility. Included studies underwent data extraction with one extractor and one verifier. We summarized results and proposed additional PRISMA-ScR reporting items. RESULTS:Of the 8265 records screened, 43 unique documents (13 overviews of ScRs and 30 guidance documents) were included and extracted. Thirty-seven potential reporting items for ScRs were identified; these will be evaluated in a subsequent Delphi survey to inform the PRISMA-ScR update. The most common additional items were related to objectives (67.4%), eligibility criteria (62.8%), search strategy (51.2%), data collection process (53.5%), and results of synthesis (51.2%). Newly identified items included reporting the inclusion criteria using a suitable framework (e.g., Population, Concept, and Context), reporting protocol deviations in the final ScR, and visually presenting results along with relevant text to support the visuals. CONCLUSION:This ScR highlights gaps in existing PRISMA-ScR reporting guidance and provides additional reporting items for consideration and potential inclusion in an updated guideline. When aligned with the latest methodological advancements and involving interest-holders, including patients and public partners, the updated guideline will enhance the transparency and robustness of ScRs. PLAIN LANGUAGE SUMMARY:The goal of this project is to update the reporting guideline for ScRs. The reporting guideline is called PRISMA-ScR. ScRs collect and summarize information from many studies addressing a broad research question. They are useful because they help researchers see what is already known. They also find gaps in knowledge and inform what research should be conducted next. ScRs also help health-care workers, leaders, and policy makers make informed decisions. PRISMA-ScR is a guide to help researchers clearly explain the methods they used to conduct their ScR. Clear reporting of the methods used is important so readers can judge the quality of the review and know if they can be confident in the results. It allows other researchers to repeat the study to check if the results are reliable. Health professionals also use the information to guide patient care and healthcare planning. An update to PRISMA-ScR is needed for several reasons. 1. ScRs are not always reported in a clear or consistent way. This can make them hard to understand or use. 2. The original guideline from 2018 did not include patients or public partners. In this project, patients and public partners are involved throughout the entire process. Their experiences and perspectives help make the guideline more useful and relevant. 3. New methods for doing ScRs have been developed since 2018. The guideline needs to reflect these changes. To support the guidance update, researchers looked at current guidelines. They also completed a new ScR. They found 47 research papers that suggested 37 new reporting items. These items suggest there may be gaps in the existing guidelines. As a result, the new reporting items will be considered as part of the PRISMA-ScR update.

PURPOSE:Use of genomic sequencing (GS) in neonatal intensive care units (NICUs) has increased with improved diagnostic yield. However, uncertainty persists regarding when and for whom GS is most useful. Because a standardized approach to assessing utility is lacking, we developed a novel version of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE) to quantify the utility of GS in NICUs. METHODS:Informed by a scoping review, we developed a draft C-GUIDE NICU tool to quantify utility, which underwent iterative revisions through feedback from clinician interviews and questionnaires on item relevance, comprehensibility, and comprehensiveness. We finalized the expert-informed C-GUIDE NICU using an international Delphi consensus process. RESULTS:Scoping review (n = 25 articles) and interviews (n = 21) revealed key themes of utility. Guided by qualitative feedback and item scoring, C-GUIDE was iteratively reduced to include 21, 18, and 14 items. The Delphi consensus process with 22 experts achieved item consensus and stability, yielding a final 10-item tool. CONCLUSION:Using a rigorous process, we developed a consensus-based standardized method for capturing the clinical utility of GS in NICUs. C-GUIDE NICU can be used by clinicians, researchers, and payers to assess GS value to patient care and will be available for licensed use following reliability and validity testing.

Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (eg, personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.

Bronchiolitis is a common lung infection that affects infants and young children. While most children can be treated at home, some require hospitalisation where supportive care, such as fluids and oxygen, is the suggested treatment. Bronchiolitis is the leading cause of infant hospitalisation in developed countries and exerts a significant burden on the healthcare system. The aim of the Bronchiolitis in Infants Placebo Versus Epinephrine and Dexamethasone (BIPED) study is to evaluate the effects of a combination of epinephrine and dexamethasone, given during initial presentation at the emergency department, on hospitalisation for bronchiolitis. This article outlines the statistical analysis plan (SAP) for the BIPED study. The BIPED study is a Phase III, multi-centre, randomised, controlled, double-blinded superiority, placebo-controlled trial to determine whether the combination of epinephrine and dexamethasone is successful in reducing hospitalisation for bronchiolitis up to 7 days following presentation at an emergency department with bronchiolitis. The secondary outcomes include hospital admissions for bronchiolitis at the emergency department enrolment visit, and all-cause hospital admissions, health care provider visits and health care-related costs in the 21 days following enrolment. The safety outcomes are gastrointestinal bleeding, serious bacterial infection, severe varicella and death. The BIPED study will provide evidence on whether a combination of epinephrine and dexamethasone reduces hospitalisation in infants following presentation to the emergency department with bronchiolitis. These data will be analyzed using this SAP, submitted before the data became available for analysis, to reduce the risk of bias in our reported outcomes. ClinicalTrials.gov NCT03567473. Registered on June 25, 2018.

IMPORTANCE:The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. OBJECTIVE:To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. DESIGN:We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. FINDINGS:Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE:Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.

Systematic reviews of outcome measurement instruments (OMIs) are an important tool to guide the selection of OMIs for research and clinical practice. However, presenting the large amount of complex data pertaining both to the quality of each study (i.e., risk of bias) as well as the quality of the instrument (i.e., measurement properties), along with the underpinning certainty of evidence, is challenging. Here, we aim to provide guidance on optimizing data presentation in OMI systematic reviews, specifically focusing on patient-reported outcome measures (PROMs). A multidisciplinary team of experts in OMI systematic reviews, research reporting, and data visualization built on existing table templates from OMERACT and the COSMIN initiative, to align with reporting items in a recently developed reporting guideline for systematic reviews of OMIs: PRISMA-COSMIN for OMIs 2024. To enhance clarity and usability, we applied data visualization principles by reducing non-essential elements and improving interpretability through structured layouts and concise explanatory text. We present eight templates for reporting PROM systematic review results: three pertain to PROM characteristics, two to studies’ characteristics, two to the evaluation of measurement properties, and one to the summary of findings. We also provide recommendations on whether to include these templates in the review’s main manuscript or in the supplementary materials. Word versions of these templates can be downloaded from www.prisma-cosmin.ca and www.cosmin.nl . Templates complementing the PRISMA-COSMIN for OMIs 2024 reporting guidance can be used to standardize and enhance the clarity and usefulness of OMI systematic reviews focusing on PROMs. They comprise a comprehensive set of tools to effectively report OMI systematic reviews, in service of end-users who are selecting OMIs.

Introduction Infants with hypoxic-ischaemic encephalopathy (HIE) are at a high risk for neurodevelopmental impairment, and adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognised as a neurorestorative agent, but, to date, has not been used in infants. Herein, we describe a clinical trial of the safety, feasibility and pharmacokinetics of metformin in infants with HIE. Methods and analysis In collaboration with patient and family stakeholders, we designed a pragmatic clinical trial. To determine appropriate dosing of metformin, we performed physiologically based pharmacokinetic (PBPK) modelling after scaling a published adult PBPK model of metformin to an infant population of full-term newborns to 3-month-olds. Based on this PBPK modelling and target drug exposure, we determined an optimal target dose of 32 mg/kg/day. Trial participants will complete baseline bloodwork and then receive 3 weeks of metformin at 25% of the target dose, followed by 3 weeks of metformin at 50% of the target dose. At a mid-study (6 week) visit, repeat laboratory testing will be done, followed by an additional 6 weeks of metformin at target dosing. The final study visit will include repeat labs following therapy at target dosing. At-home blood glucose monitoring will be used between study visits. Pharmacokinetics of metformin will be evaluated with bloodwork collected at study visits. The incidence of safety events and feasibility measures will be reported using descriptive statistics. Our infant PBPK model will be validated with study samples and the dose for future trials adjusted based on new knowledge about metformin PK in infants.Ethics and dissemination Approval of the Boston Children’s Hospital Research Ethics Committee will be obtained prior to study initiation. Trial oversight will be under the direction of a Data Safety Monitoring Board.Trial registration number This study has been registered at www.clinicaltrials.gov under NCT06429007.