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To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions. Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average. Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.

Background Recognizing the value of promoting public access to clinical trial protocols, Trials pioneered the way for their publication over a decade ago. However, despite major advances in the public accessibility of information about trial methods and results, protocol sharing remains relatively rare. Main body Protocol sharing facilitates the critical appraisal of clinical trials and helps to identify and deter the selective reporting of outcomes and analyses. Challenges to the routine availability of high quality trial protocols include the gaps in incentives and adherence mechanisms, limited venues for sharing the original and final protocol versions, and the need for mechanisms to ensure transparent and complete protocol content. Conclusions We propose recommendations for addressing key challenges to protocol sharing in order to promote routine public access to protocols for the benefit of patients and other users of evidence from clinical trials.

Clinical trials with investigator sponsors at academic sites have increased, in part due to studies involving drug repurposing, the process of identifying new uses for existing drugs that are initially conducted in patients rather than healthy participants. In contrast to industry‐ or government‐sponsored trials, investigator‐sponsored clinical studies, also known as investigator‐initiated trials, are typically conducted at one or several academic centers and are resource‐limited by finances and patient numbers. These studies can serve as crucial pilot studies to inform the design of larger, more definitive clinical trials. Drawing from the experience of working with clinical researchers in academic settings, this tutorial presents guidelines for writing clinical protocols for resource‐limited investigator‐sponsored studies that meet international standards and optimize the detection of meaningful signals or outcomes that can lead to investigation in larger well‐controlled trials.

A high‐quality protocol document is essential for the successful and efficient implementation of clinical trials, but there is no consensus on how clinical trial protocol document quality should be evaluated. We used a modified Delphi approach and cognitive interviews to develop a new protocol document quality assessment tool, the Protocol Quality Rating Tool (PQRT). We compiled a checklist of elements that should be included in a high‐quality trial protocol document and asked experts to rate the importance of each element. We developed the PQRT by describing the expected content of each element and identified essential vs. additional (bonus) content to differentiate high‐ versus low‐quality protocol documents and then organized the elements into 18 sections. We revised the PQRT based on feedback from and cognitive interviews with our protocol quality rating team. We then tested the PQRT using ten protocol documents previously approved by the Institutional Review Board. All the protocol quality raters found the tool easy to use and their scores were highly concordant for eight of ten protocol documents. We have developed and tested a simple tool to measure clinical trial protocol document quality and encourage other researchers to evaluate and validate it.

AbstractImportanceThe 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.ObjectiveTo systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial.DesignWe 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.FindingsOverall, 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 relevanceWidespread 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.

FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, oral inhibitor of FGFR1-3, has demonstrated efficacy and safety in a Phase II study of patients with previously treated locally advanced/metastatic CCA harboring fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with rearrangements (NCT03656536). The primary end point is progression-free survival; secondary end points are objective response rate, overall survival, duration of response, disease control rate, safety and quality of life. Clinical Trial Registration: NCT03656536 (ClinicalTrials.gov).

Abstract Objective This article describes a scalable, performant, sustainable global network of electronic health record data for biomedical and clinical research. Materials and Methods TriNetX has created a technology platform characterized by a conservative security and governance model that facilitates collaboration and cooperation between industry participants, such as pharmaceutical companies and contract research organizations, and academic and community-based healthcare organizations (HCOs). HCOs participate on the network in return for access to a suite of analytics capabilities, large networks of de-identified data, and more sponsored trial opportunities. Industry participants provide the financial resources to support, expand, and improve the technology platform in return for access to network data, which provides increased efficiencies in clinical trial design and deployment. Results TriNetX is a growing global network, expanding from 55 HCOs and 7 countries in 2017 to over 220 HCOs and 30 countries in 2022. Over 19 000 sponsored clinical trial opportunities have been initiated through the TriNetX network. There have been over 350 peer-reviewed scientific publications based on the network’s data. Conclusions The continued growth of the TriNetX network and its yield of clinical trial collaborations and published studies indicates that this academic-industry structure is a safe, proven, sustainable path for building and maintaining research-centric data networks. Lay Summary This article describes a network—a series of interconnected data repositories—where clinical data about patients is stored after being extracted from electronic health record systems. The data on this network are meant to be used by researchers working in healthcare institutions as well as the life sciences industry. This network aims to make it easier, faster, and cheaper to find patients for recruitment into clinical trials and to conduct research using the clinical data. This network is being developed and maintained by a commercial company TriNetX, LLC. It is growing rapidly, expanding from 55 healthcare organizations and 7 countries in 2017 to over 220 healthcare organizations and 30 countries in 2022. The privacy and security of patient as well as member organizations’ data are of paramount concern. TriNetX takes a very conservative stand with respect to privacy protection and data governance. The data on this network have been used extensively for research and there’s currently over 350 peer-reviewed scientific publications based on the network’s data. The continued growth of the TriNetX network demonstrates that this approach to clinical data sharing is a safe, proven, and sustainable path for supporting the data needs of healthcare and life sciences researchers.

Background: Most patients with diabetic kidney disease (DKD) experience disease progression despite receiving standard care therapy. Oxidative stress is associated with DKD severity and risk of progression, but currently approved therapies do not directly attenuate the pathologic consequences of oxidative stress. GS-4997 is a once daily, oral molecule that inhibits Apoptosis Signal-regulating Kinase 1 (ASK1), which is a key mediator of the deleterious effects of oxidative stress. Methods: We describe the rationale and design of a Phase 2 placebo-controlled clinical trial investigating the effects of GS-4997 in patients with T2DM and stage 3/4 DKD receiving standard of care therapy. Approximately, 300 subjects will be randomized in a stratified manner, based on the estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio, to one of four arms in this dose-ranging study. The primary endpoint is change in eGFR at 48 weeks, and the key secondary endpoint is change in albuminuria. Conclusion: Guided by the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods, the decisions made for this Phase 2 study regarding delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design.

Making protocols of randomized clinical trials (RCTs) publicly available is important for the trustworthiness and quality of medical research. In a previous study assessing 326 RCTs with ethical approval in 2012, only 36% had a publicly available protocol. We aimed to generate current evidence on the availability of RCT protocols and to evaluate changes over time. Using a representative sample of RCTs approved in 2016 in Switzerland, Canada, Germany, and the United Kingdom, we investigated the number of available protocols by searching PubMed, Google Scholar, trial registries, and Google. Up to June 2024, we systematically searched for (i) protocols available as peer-reviewed publications, (ii) protocols attached to trial registries, and (iii) protocols shared with result publications of RCTs. We used multivariable logistic regression to examine the association of protocol availability with trial characteristics such as sample size, drug vs nondrug interventions, multicenter vs single-center status, and RCT approval in 2016 vs 2012. Of the 347 included RCTs, 228 (66%) had an available protocol. Forty-three percent (150/347) of the protocols were available as files on trial registries, 26% (91/347) as supplementary material to result publication, and 23% (81/347) as peer-reviewed publications. Protocol availability improved over time in industry trials (83.4% in 2016 vs 34.6% in 2012). Protocol availability for nonindustry trials remained low (46.4% 2016 vs 38.1% 2012). Multicenter trials (206/256; 77.7% vs single-center trials 22/82; 26.8%) and larger sample size (>500 participants 68/77; 88.3%, 100-500 participants 131/191; 68.6%, <100 participants 29/79; 36.7%) showed higher protocol availability. The availability of protocols increased in RCTs approved in 2016 compared to RCTs from 2012. This was mainly driven by industry sponsored trials. Efforts to further improve protocol availability should be continued, especially in nonindustry sponsored RCTs. [Display omitted] •Meta-research on the frequency of publicly available protocols of randomized trials.•Two-thirds of the randomized-trials approved in 2016 had an available protocol.•This is a strong improvement compared to trials approved in 2012.•Increase mainly driven by improved protocol availability in industry-sponsored trials.