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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.

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.

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.

Patient-reported outcomes (PROs) provide crucial information for evaluating health-care interventions, but previous research in specific disease areas suggested infrequent use and incomplete reporting of PROs. We examined the prevalence and characteristics of PROs in randomized clinical trial (RCT) protocols across medical fields, their reporting quality, and the consistency between PROs specified in trial protocols and subsequent reporting in trial publications. We included 237 RCT protocols approved in 2012 and 251 approved in 2016, by ethics committees in Switzerland, Germany, and Canada. We systematically searched for corresponding peer-reviewed results publications and results on trial registries. Pairs of reviewers independently extracted characteristics of RCT protocols, PROs specified in protocols and reported in corresponding results publications, and assessed the reporting quality of RCTs with a PRO as the primary outcome using the Consolidated Standards of Reporting Trials–patient-reported outcome (CONSORTs-PRO) extension. Out of 488 included RCT protocols, 147 (30%) did not report use of a PRO; 97 (20%) specified a PRO as the primary outcome and an additional 244 (50%) as a secondary outcome. The prevalence of PROs varied substantially across medical fields, ranging from 100% in rheumatology and psychiatry to about one-third in cardiology and anesthesiology. At 8–10 years after RCT approval, results were available for 264 of the 341 (77%) trial protocols that prespecified PROs. Forty-four percent of the published trials (115/264) reported all PROs as defined in the protocol, 21% (55/264) did not report any prespecified PROs, and 36% (94/264) reported more, fewer, or different PROs than those prespecified. These findings were consistent between trial protocols approved in 2012 and 2016. Among 63 peer-reviewed RCT publications that reported a PRO as their primary outcome, reporting quality was often inadequate, with seven of 13 CONSORT-PRO items. Less than half of RCT protocols with planned PROs reported them as specified in corresponding published results, suggesting outcome reporting bias, and PRO reporting quality was often deficient. These limitations complicate informed decision-making between patients and health-care providers, as well as the development of evidence-based clinical practice guidelines. •One-third of the trial protocols did not consider patient-reported outcomes (PROs).•Prevalence of PROs in protocols varied substantially across medical fields.•In trial result publications, 21% failed to report any prespecified PROs.•36% of result publications reported more, less, or different PROs than protocols.•The reporting quality of PROs in trial publications was often deficient.

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.

Background To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. Methods We had access to RCT study protocols that received ethical approval in the UK in 2012 ( n =103) and 2016 ( n =108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. Results The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6–69.2%) in 2012 to a median of 72.5% (IQR, 65.3–78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1–69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5–67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2–79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6–76.3%). Conclusions The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.

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.

Background Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain. Objectives and methods Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs. Discussion The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.

Background Employers express a need for support to facilitate the return to work (RTW) process of employees with cancer. We have developed the MiLES intervention, an online toolbox targeting employers during the RTW of employees with cancer. To evaluate the MiLES intervention, we propose the design of a pilot randomised controlled trial (RCT). The aim of this pilot is to determine whether a future RCT to study the effectiveness of this intervention on successful RTW of employees with cancer is feasible. Secondary aims are to obtain preliminary results on the effectiveness of the intervention and to determine the sample size needed in a future definitive RCT. Methods A pilot RCT with a 6-month follow-up will be conducted. Using medical specialists at Dutch hospitals, we aim to enrol 90 participants diagnosed with cancer (<2 years earlier) aged 18–63 years who are in paid employment with an employer and who are currently sick-listed or partly sick-listed for <1 year. Participants randomised to the intervention group will be asked to inform their employer about the online toolbox supporting employers during the RTW process of employees with cancer. Participants in the control group will receive ‘care as usual’ from their employer. All measures will be assessed at the level of the employee using questionnaires at baseline and after 3 and 6 months of follow-up. The feasibility of a future RCT will be determined using criteria concerning method-related uncertainties and acceptability of the study protocol. The primary effect measure will be successful RTW (that is, RTW perceived as being successful by the cancer survivor themselves). This effect measure will be used to perform the sample size calculation for a future definitive RCT. Discussion The design is proposed to determine the feasibility to study the effectiveness of the MiLES intervention targeting employers on the successful RTW of employees diagnosed with cancer. This pilot RCT can increase the probability of a successful future definitive RCT on the effectiveness of the intervention and potentially obviate the need to carry out an unfeasible and resource-intensive study. Trial registration Dutch Trial Register (NTR): NL6758 , NTR7627 . Registered on 30 October 2018.

Post-COVID-19 Syndrome (PCS) includes neurological manifestations, especially fatigue and cognitive deficits. Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation are discussed as potential pathophysiological mechanisms. The post-corona-virus immune treatment (PoCoVIT) trial is a phase 2a randomized, controlled, double-blind trial designed to evaluate the effect of methylprednisolone versus placebo on cognitive impairment in PCS. This trial is designed based on the hypothesised autoimmunological pathogenesis and positive aberrations, employing a series of off-label applications. Recruitment criteria include a diagnosis of PCS, a minimum age of 18 years and self-reported cognitive deficits at screening. A total of 418 participants will be randomly assigned to either verum or placebo intervention in the first phase of the trial. The trial will consist of a first trial phase intervention with methylprednisolone versus placebo for six weeks, followed by a six-week treatment interruption period. Subsequently, an open second phase will offer methylprednisolone to all participants for six weeks. Outpatient follow-up visits will take place two weeks after each trial medication cessation. The third and final follow-up, at week 52, will be conducted through a telephone interview. The primary outcome measures an intra-patient change of 15 or more points in the memory satisfaction subscale of the Multifactorial Memory Questionnaire (MMQ) from baseline to follow-up 1 (week 8). Key secondary outcomes include long-term intra-patient changes in memory satisfaction from baseline to follow-up 2 (week 20), changes in other MMQ subscales (follow-up 1 and 2), and changes in neuropsychological and cognitive scores, along with assessments through questionnaires focusing on quality of life, fatigue, and mood over the same periods. Exploratory outcomes involve molecular biomarkers variations in serum and cerebrospinal fluid, as well as structural and functional brain magnetic resonance imaging (MRI) parameters changes related to cognition. This trial aims to contribute novel evidence for treating patients with PCS, with a primary focus on those manifesting cognitive deficits. By doing so, it may enhance comprehension of the underlying pathophysiological mechanisms, thereby facilitating biomarker research to advance our understanding and treatment of patients with PCS.