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Background: Chronic diseases are a significant and growing problem of our time. They impair the ability to work and increase the risk of early retirement. To support the return to work, rehabilitation services can be applied for in Germany. Currently, the application system for rehabilitation allows only a limited degree of individualisation of the treatment and is associated with a lack of multidisciplinary communication. To facilitate rehabilitation care planning, we developed a complex intervention. A digital, platform-based case management approach (intervention) will ensure multidisciplinary communication and the tailored selection of medical treatments and/or non-medical support measures. The overall objective is to assess the effectiveness of the intervention compared to treatment as usual (control condition). The German Federal Ministry of Labour and Social Affairs (BMAS) funds the RehaPro-SERVE study (grant number: 661R0053K1). Methods: This is the protocol for an investigator-initiated, pragmatic, multicentre, randomised and controlled two-arm parallel-group superiority trial with embedded qualitative process evaluation. The study will be conducted in Hesse state, Germany. N = 59 primary care physicians will be recruited and tasked with the recruitment of six eligible patients each. Eligibility criteria: age 40–60; minimum of 4-week work disability due to musculoskeletal, oncologic or psychological conditions or the post-COVID-19 syndrome within the last 6 months; at high risk for early retirement. In total, n = 352 patients will be randomised with a 1:1 allocation to intervention or control group and stratified by primary care practice using permuted blocks. The primary outcome is the number of days of sick leave during a 12-month period after the assumed completion of treatments (t1 to t2). Secondary outcomes include the number of days of sick leave (self-report), work ability, and health-related quality of life, as well as data from the qualitative process evaluation. Discussion: The results of the study will inform the design of future care services and provide valuable information on multidisciplinary case management in the context of rehabilitation care planning. The results of the qualitative process evaluation will further contribute to the understanding of facilitating and hindering factors. Trial registration: DRKS-German Clinical Trials Register, DRKS0 00242 07. Registered on 22 March 2021. [ABSTRACT FROM AUTHOR]

Background: Recruitment for neonatal clinical trials can be particularly challenging. Low enrollment rates bias the research population and decrease generalizability of findings. We identified a critical need for an intervention to improve how researchers recruit for neonatal clinical trials. Working within the US neonatal research context, we developed the Better Research Interactions for Every Family (BRIEF) Intervention, which had two overarching goals: to improve the recruitment experience for all parents, focusing on minoritized populations, and to increase participation, focusing on decreasing disparities in research participation. Methods: We used intervention mapping (IM) to guide all steps of intervention development. IM is a planning framework that provides a systematic process and detailed protocol for step-by-step decision-making for intervention development, implementation, and evaluation. Results: We performed IM's six steps. In step 1, we convened two stakeholder groups, a parent panel and an expert panel, who provided guidance through development of all BRIEF components. Through a recent systematic review, empirical data collected by our team, and consultations with the panels, we identified key determinants (barriers and facilitators) of low enrollment rates and research team members as change agents. In step 2, we iteratively refined our list of key factors to include and linked determinants of behavior changes to these performance objectives. In step 3, we chose three theories (social cognitive theory, theory of information processing, and the trans-theoretical model), methods from identified practical applications suitable for the population (research team members) and the context (busy research NICU teams). In step 4, we developed and refined the intervention components, including self-guided pre-work and a single in-person session. In step 5, we identified the Darbepoetin plus slow-release intravenous iron trial as our partner study in which to pilot BRIEF. In step 6, we developed a multi-stage evaluation plan that included five distinct levels of outcomes. Conclusions: This manuscript shares our rationale and processes for the creation of a research team member-facing intervention aiming to improve recruitment processes for neonatal clinical trials. Our approach can inform those aiming to improve recruitment for neonatal clinical trials and those who may be considering use of IM within similar contexts. [ABSTRACT FROM AUTHOR]

Background: The number of surgical trials is increasing but such trials can be complex to deliver and pose specific challenges. A multi-centre, Phase III, RCT comparing Posterior Cervical Foraminotomy versus Anterior Cervical Discectomy and Fusion in the Treatment of Cervical Brachialgia (FORVAD Trial) was unable to recruit to target. A rapid qualitative study was conducted during trial closedown to understand the experiences of healthcare professionals who participated in the FORVAD Trial, with the aim of informing future research in this area. Methods: Semi-structured interviews were conducted with 18 healthcare professionals who had participated in the FORVAD Trial. Interviews explored participants' experiences of the FORVAD trial. A rapid qualitative analysis was conducted, informed by Normalisation Process Theory. Results: Four main themes were generated in the data analysis: (1) individual vs. community equipoise; (2) trial set-up and delivery; (3) identifying and approaching patients; and (4) timing of randomisation. The objectives of the FORVAD trial made sense to participants and they supported the idea that there was clinical or collective equipoise regarding the two FORVAD interventions; however, many surgeons had treatment preferences and lacked individual equipoise. The site which had most recruitment success had adopted a more structured process for identification and recruitment of patients, whereas other sites that adopted more "ad hoc" screening strategies struggled to identify patients. Randomisation on the day of surgery caused both medico-legal and practical concerns at some sites. Conclusions: Organisation and implementation of a surgical trial in neurosurgery is complex and presents many challenges. Sites often reported low recruitment and discussed the logistical issues of conducting a complex surgical RCT. Future trials in neurosurgery may need to offer more flexibility and time during set-up to maximise opportunities for larger recruitment numbers. Rapid qualitative analysis informed by Normalisation Process Theory was able to quickly identify key issues with trial implementation so rapid qualitative analysis may be a useful approach for teams conducting qualitative research in trials. Trial registration: ISRCTN, ISRCTN reference: 10,133,661. Registered 23rd November 2018. [ABSTRACT FROM AUTHOR]

Background: Recruitment for clinical trials and large-scale studies is challenging, especially for patients with complex conditions like chronic pain. Email recruitment has the potential to increase efficiency, to reduce costs, and to improve access for underrepresented patient populations. The objective of this study was to examine the effectiveness, efficiency, and equitability of email versus postal mail recruitment for the Learning to Apply Mindfulness to Pain (LAMP) study, a three-site clinical trial of mindfulness-based interventions for chronic pain. Methods: Patients with chronic pain diagnoses were recruited from three United States Department of Veterans Affairs (VA) facilities using the VA electronic health record (EHR). Recruitment materials were sent using either postal mail (n = 7986) or email (n = 19,333). Patients in the email recruitment group were also mailed introductory postcards before any emails. Mailing addresses and email addresses were obtained from the EHR. Effectiveness was measured by the response rate of patients who logged into the secure LAMP study website. Efficiency was measured by the number of days from when the recruitment materials were sent to when patients logged into the LAMP portal as well as the estimated costs of each recruitment approach. To assess equitability, we examined whether email recruitment was less effective for underrepresented populations, based on demographic information from the EHR. Results: Effectiveness—unadjusted response rates were greater for email versus postal-mail recruitment (18.9% versus 6.3%), and adjusted response rates were over three times greater for email recruitment (RR = 3.5, 95% CI 3.1–3.8) based on a multivariable analysis controlling for age, gender, race, ethnicity, rurality, and site. Efficiency—email recruitment had a significantly lower mean response time (1 day versus 8 days) and a lower cost. Equity—email recruitment led to higher response rates for all subpopulations, including older, non-White, Hispanic, rural, and female Veterans. Conclusions: Email recruitment is an effective, efficient, and equitable way to recruit VA patients to large-scale, chronic pain clinical trials. Trial registration: Clinical Trial Registration Number: NCT04526158. Patient enrollment began on December 4, 2020. [ABSTRACT FROM AUTHOR]

Background: Distressing symptoms are common in advanced cancer. Medicinal cannabinoids are commonly prescribed for a variety of symptoms. There is little evidence to support their use for most indications in palliative care. This study aims to assess a 1:20 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom distress in patients with advanced cancer undergoing palliative care. Methods and design: One hundred and fifty participants will be recruited across multiple sites in Queensland, Australia. A teletrial model will facilitate the recruitment of patients outside of major metropolitan areas. The study is a pragmatic, multicenter, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:20 THC/CBD medicinal cannabinoid preparation (10 mg THC:200 mg CBD/mL). It will compare the efficacy and safety outcomes of a titrated dose range of 2.5 mg THC/50mgCBD to 30 mg THC/600 mg CBD per day against a placebo. There is a 2-week patient-determined titration phase, to reach a dose that achieves symptom relief or intolerable side effects, with a further 2 weeks of assessment on the final dose. The primary objective is to assess the effect of escalating doses of a 1:20 THC/CBD medicinal cannabinoid preparation against placebo on change in total symptom distress score, with secondary objectives including establishing a patient-determined effective dose, the effect on sleep quality and overall quality of life. Some patients will be enrolled in a sub-study which will more rigorously evaluate the effect on sleep. Discussion: MedCan-3 is a high-quality, adequately powered, placebo-controlled trial which will help demonstrate the utility of a THC:CBD 1:20 oral medicinal cannabis product in reducing total symptom distress in this population. Secondary outcomes may lead to new hypotheses regarding medicinal cannabis' role in particular symptoms or in particular cancers. The sleep sub-study will test the feasibility of using actigraphy and the Insomnia Severity Index (ISI) in this cohort. This will be the first large-scale palliative care randomised clinical trial to utilise the teletrial model in Australia. If successful, this will have significant implications for trial access for rural and remote patients in Australia and internationally. Trial registration: ANZCTR ACTRN12622000083796. Protocol number 001/20. Registered on 21 January 2022. Recruitment started on 8 August 2022. [ABSTRACT FROM AUTHOR]

This document discusses the impact of carbon emissions on clinical trials and explores the carbon-relevant factors that influence participants' decisions to join and remain in trials. The study found that factors such as trial supplies and equipment, CTU emissions, trial-specific patient assessments, meetings and travel, and trial setup were the most frequently identified carbon-relevant factors. However, there was limited data on the influence of carbon on trial retention. The authors suggest that future studies should directly ask participants about the influence of carbon-relevant factors and involve patient partners in trial design discussions. [Extracted from the article]

Background: As part of the German Medical Informatics Initiative, the MIRACUM project establishes data integration centers across ten German university hospitals. The embedded MIRACUM Use Case "Alerting in Care - IT Support for Patient Recruitment", aims to support the recruitment into clinical trials by automatically querying the repositories for patients satisfying eligibility criteria and presenting them as screening candidates. The objective of this study is to investigate whether the developed recruitment tool has a positive effect on study recruitment within a multi-center environment by increasing the number of participants. Its secondary objective is the measurement of organizational burden and user satisfaction of the provided IT solution. Methods: The study uses an Interrupted Time Series Design with a duration of 15 months. All trials start in the control phase of randomized length with regular recruitment and change to the intervention phase with additional IT support. The intervention consists of the application of a recruitment-support system which uses patient data collected in general care for screening according to specific criteria. The inclusion and exclusion criteria of all selected trials are translated into a machine-readable format using the OHDSI ATLAS tool. All patient data from the data integration centers is regularly checked against these criteria. The primary outcome is the number of participants recruited per trial and week standardized by the targeted number of participants per week and the expected recruitment duration of the specific trial. Secondary outcomes are usability, usefulness, and efficacy of the recruitment support. Sample size calculation based on simple parallel group assumption can demonstrate an effect size of d=0.57 on a significance level of 5% and a power of 80% with a total number of 100 trials (10 per site). Data describing the included trials and the recruitment process is collected at each site. The primary analysis will be conducted using linear mixed models with the actual recruitment number per week and trial standardized by the expected recruitment number per week and trial as the dependent variable. Discussion: The application of an IT-supported recruitment solution developed in the MIRACUM consortium leads to an increased number of recruited participants in studies at German university hospitals. It supports employees engaged in the recruitment of trial participants and is easy to integrate in their daily work. [ABSTRACT FROM AUTHOR]

Background: The NIHR's Associate Principal Investigator (API) Scheme in the United Kingdom was expanded nationally in 2020 with the aim of training clinicians to become Principal Investigators for clinical research in the future. The HEAL-COVID adaptive platform trial is an urgent public health study registered with the API Scheme. Within eighteen months of opening, the trial had recruited almost 1200 patients with over 100 active sites. Here we describe our experiences of APIs working on the trial with two broad objectives. Firstly, we aim to explore through qualitative methods the impact that the scheme has had on the APIs' professional development. Secondly, we aim to quantify the impact that the APIs have had on the recruitment of patients into the trial. Methods: The professional backgrounds of the APIs are described from data from their application forms to the scheme. The HEAL-COVID API Network is described from records of the monthly meetings. The APIs' experiences are reviewed from data from the NIHR exit surveys at 6 months and from a reflective practice exercise at the final network meeting. Data of patient recruitment to HEAL-COVID was analysed for centres with and without APIs via a multivariate analysis. Results: Forty-two APIs were registered with the HEAL-COVID trial with a diversity of backgrounds in terms of gender, country, profession, grade and specialty. Eleven monthly network meetings took place with the dual objectives of facilitating trial activity and providing educational content. Fourteen APIs completed the NIHR survey with all reporting Good Clinical Practice completion, local promotional activity of the trial, patient recruitment and support from their respective PI. Sites with at least one API recruited over 3.5 times more patients than sites without an API (medians 4 vs 14.5, p < 0.05), independent of factors including type of hospital or number of inpatient beds. Discussion: This study adds to the growing literature that the NIHR's API Scheme is effective in meeting its objectives in providing research training to clinicians, thus building a workforce of future clinical researchers. Moreover, data from the HEAL-COVID trial shows that sites with an API are associated with higher recruitment. Overall, registering a trial with the API Scheme not only trains future clinical researchers, but it is also likely to increase the number of patients recruited (amongst other benefits), increasing the efficiency of trials and improving access for patients. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. Methods: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. Discussion: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. Trial registration: ClinicalTrials.gov NCT03800524. Registered on January 11, 2019. [ABSTRACT FROM AUTHOR]

The article discusses the importance of accurately assessing physical fitness components in physical exercise training studies for patients with inflammatory bowel disease (IBD). The authors emphasize the need for adequate patient selection based on physical fitness components to ensure optimal therapeutic potential. They also highlight the importance of monitoring the response to training and evaluating changes in physical fitness throughout and after the intervention. The article suggests using validated screening tools and assessment methods for physical fitness components and adhering to the international consensus on therapeutic exercise and training to develop high-quality exercise interventions for individuals with IBD. [Extracted from the article]

Abstract Introduction The COVID-19 pandemic impacted the operationalisation of non-COVID-19 clinical trials globally, particularly site and participant recruitment and trial success/stoppage. Trials which anticipate recruitment challenges may embed methods such as the QuinteT Recruitment Intervention (QRI) to help identify and understand the sources of challenges. Such interventions can help shed light on pandemic-related challenges. This paper reports our experience of the impact of the COVID-19 pandemic on conducting clinical trials with an embedded QRI, highlighting how the QRI aided in identifying challenges and potential solutions, particularly related to the site set-up and participant recruitment. Main body We report on 13 UK clinical trials which included a QRI. Information is from QRI data and researchers’ experience and reflections. In most trials, recruitment was lower than even the lowest anticipated rates. The flexibility of the QRI facilitated rapid data collection to understand and document, and in some instances respond to, operational challenges. Challenges were mostly logistical, pandemic-related and beyond the control of the site or central trial teams. Specifically: disrupted and variable site opening timelines —often due to local research and development (R&D) delays— shortages of staff to recruit patients; fewer eligible patients or limited access to patients; and intervention-related factors. Almost all trials were affected by pandemic-related staffing issues including redeployment, prioritisation of COVID-19 care and research, and COVID-19-related staff illness and absence. Trials of elective procedures were particularly impacted by the pandemic, which caused changes to care/recruitment pathways, deprioritisation of services, reduced clinical and surgical capacity and longer waiting lists. Attempted solutions included extra engagement with staff and R&D departments, trial protocol changes (primarily moving online) and seeking additional resourcing. Conclusion We have highlighted wide-ranging, extensive and consistent pandemic-related challenges faced by UK clinical trials, which the QRI helped to identify and, in some cases, address. Many challenges were insurmountable at individual trials or trials unit level. This overview highlights the need to streamline trial regulatory processes, address staffing crises, improve recognition of NHS research staff and for clearer, more nuanced central guidance on the prioritisation of studies and how to deal with the backlog. Pre-emptively embedding qualitative work and stakeholder consultation into trials with anticipated difficulties, moving some processes online, and flexible trial protocols may improve the resilience of trials in the current challenging context.

While randomized controlled trials are essential to health research, many of these trials fail to recruit enough participants. Approaching recruitment through the lens of behavioral science can help trialists to understand influences on the decision to participate and use them to increase recruitment. Although this approach is promising, the use of behavioral influences during recruitment is in tension with the ethical principle of respect for persons, as at least some of these influences could be used to manipulate potential participants. In this paper, we examine this tension by discussing two types of behavioral influences: one example involves physician recommendations, and the other involves framing of information to exploit cognitive biases. We argue that despite the apparent tension with ethical principles, influencing trial participants through behavior change strategies can be ethically acceptable. However, we argue that trialists have a positive obligation to analyze their recruitment strategies for behavioral influences and disclose these upfront to the research ethics committee. But we also acknowledge that since neither trialists nor ethics committees are presently well equipped to perform these analyses, additional resources and guidance are needed. We close by outlining a path toward the development of such guidance. [ABSTRACT FROM AUTHOR]

Background: The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. Methods: Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. Results: Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. Conclusions: Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. Trial registration: ISRCTN27544579, prospectively registered on 22 May 2014 [ABSTRACT FROM AUTHOR]

Background: Clinical research nurses are a key part of the clinical trial team but typically get involved later in the trial, usually during recruitment. The purpose of our study was to establish if CRNs who read the trial protocol can predict the performance of the trial. Methods: We randomly selected 18 trial protocols with three statuses, terminated, withdrawn, and completed, from ClinicalTrials.gov, between 2014 and 2018 inclusive. We gave the protocols to five CRNs, asked them to make a judgement and provide a reason for that judgement (via a 12-item questionnaire) on the status of the trial (terminated, withdrawn or completed), if the trial met its recruitment target, if it recruited on time, and if it retained its participants. We also asked if it was likely a CRN was involved in the design of the trial. The CRNs were blinded to the study outcomes, did not receive any training on how to read a protocol and were prohibited from using/abstained from using the internet while completing the task. Results: Twenty-three questionnaires on 23 trial protocols (18 different trials) were completed by 5 CRNs. The CRNs correctly predicted the trial status 48%, 95% CI: 29–67% (11/23) of the time; successful/unsuccessful recruitment 74%, 95% CI: 54–87% (17/23) of the time; on-time recruitment 70%, 95% CI: 49–84% (16/23) of the time; and participant retention 52%, 95% CI: 33–71% (12/23). CRNs identified 100% (sensitivity) of sites that hit their target and 63%, 95% CI: 36–84% (specificity) of sites that missed their target. Conclusions: CRNs are very good judges of trial recruitment and site performance issues and are a vital part of the clinical trial team. Taken with the ESP (Estimating Site Performance) study, we have made a strong case for broadening the trial team at the trial design stage. Early engagement of a broad skillset can potentially offset problems of recruitment, retention and trial failure. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 pandemic impacted the operationalisation of non-COVID-19 clinical trials globally, particularly site and participant recruitment and trial success/stoppage. Trials which anticipate recruitment challenges may embed methods such as the QuinteT Recruitment Intervention (QRI) to help identify and understand the sources of challenges. Such interventions can help shed light on pandemic-related challenges. This paper reports our experience of the impact of the COVID-19 pandemic on conducting clinical trials with an embedded QRI, highlighting how the QRI aided in identifying challenges and potential solutions, particularly related to the site set-up and participant recruitment. Main body: We report on 13 UK clinical trials which included a QRI. Information is from QRI data and researchers' experience and reflections. In most trials, recruitment was lower than even the lowest anticipated rates. The flexibility of the QRI facilitated rapid data collection to understand and document, and in some instances respond to, operational challenges. Challenges were mostly logistical, pandemic-related and beyond the control of the site or central trial teams. Specifically: disrupted and variable site opening timelines —often due to local research and development (R&D) delays— shortages of staff to recruit patients; fewer eligible patients or limited access to patients; and intervention-related factors. Almost all trials were affected by pandemic-related staffing issues including redeployment, prioritisation of COVID-19 care and research, and COVID-19-related staff illness and absence. Trials of elective procedures were particularly impacted by the pandemic, which caused changes to care/recruitment pathways, deprioritisation of services, reduced clinical and surgical capacity and longer waiting lists. Attempted solutions included extra engagement with staff and R&D departments, trial protocol changes (primarily moving online) and seeking additional resourcing. Conclusion: We have highlighted wide-ranging, extensive and consistent pandemic-related challenges faced by UK clinical trials, which the QRI helped to identify and, in some cases, address. Many challenges were insurmountable at individual trials or trials unit level. This overview highlights the need to streamline trial regulatory processes, address staffing crises, improve recognition of NHS research staff and for clearer, more nuanced central guidance on the prioritisation of studies and how to deal with the backlog. Pre-emptively embedding qualitative work and stakeholder consultation into trials with anticipated difficulties, moving some processes online, and flexible trial protocols may improve the resilience of trials in the current challenging context. [ABSTRACT FROM AUTHOR]

Background: Recruitment of participants is crucial to the success of randomised control trials (RCTs) but can be challenging and expensive. Current research on trial efficiency is often focused at the patient-level with an emphasis on effective recruitment strategies. Less is known about selection of study sites to optimise recruitment. We examine site-level factors that are associated with patient recruitment and cost efficiency using data from an RCT conducted across 25 general practices (GP) in Victoria, Australia. Methods: Data on number of participants screened, excluded, eligible, recruited, and randomised from each study site were extracted from a clinical trial. Details regarding site characteristics, recruitment practices, and staff time commitment were collected using a three-part survey. The key outcomes assessed were recruitment efficiency (ratio of screened to randomised), average time, and cost for each participant recruited and randomised. To identify practice-level factors associated with efficient recruitment and lower cost, outcomes were dichotomised (25th percentile vs others) and each practice-level factor assessed against the outcomes to determine its association. Results: Across 25 GP study sites, 1968 participants were screened of which 299 (15.2%) were recruited and randomised. The mean recruitment efficiency was 7.2, varying from 1.4 to 19.8 across sites. The strongest factor associated with efficiency was assigning clinical staff to identify potential participants (57.14% vs. 22.2%). The more efficient sites were smaller practices and were more likely to be rural locations and in areas of lower socioeconomic status. The average time used for recruitment was 3.7 h (SD2.4) per patient randomised. The mean cost per patient randomised was $277 (SD161), and this varied from $74 to $797 across sites. The sites identified with the 25% lowest recruitment cost (n = 7) were more experienced in research participation and had high levels of nurse and/or administrative support. Conclusion: Despite the small sample size, this study quantified the time and cost used to recruit patients and provides helpful indications of site-level characteristics that can help improve feasibility and efficiency of conducting RCT in GP settings. Characteristics indicative of high levels of support for research and rural practices, which often tends to be overlooked, were observed to be more efficient in recruiting. [ABSTRACT FROM AUTHOR]

Background: Induction of labour (IOL) at 39 weeks has been shown to decrease maternal and neonatal adverse outcomes. Given the growing demand for 39-week IOL, it is imperative that effective methods be assessed for induction in the outpatient setting. The aim of this study is to answer the clinical question as to whether Dilapan-S® vs Propess® as a method of cervical ripening is non-inferior in the outpatient setting at 39 weeks and to ascertain whether Dilapan-S® 12 h is non-inferior to Dilapan-S® 24 h. Methods: This study is an open-label parallel group single-centre randomised trial. Participants are normal risk nulliparous women who have no pregnancy-related or medical contraindication to IOL. Women will be randomised to one of three induction groups—Dilapan-S® (12-h insertion or 24-h insertion) or Propess. Induction will be initiated between 39+0 and 39+4 weeks' gestation and participants will return home for either 12 or 24 h. They will be readmitted 12/24 h later in order to continue with induction of labour. Patient recruitment will take place over 30 months within a single centre. The study will recruit a maximum 109 women for each study arm. Total duration of participants' involvement in the trial will be 8 weeks to allow for postpartum follow-up. Discussion: This study will definitively answer whether Dilapan-S is non-inferior to Propess® as a method of induction of labour in the outpatient setting and whether cervical ripening with Dilapan-S over a 12-h timeframe is non-inferior to cervical ripening with Dilapan-S over a 24-h timeframe. Trial registration: EudraCT Number 2019-004697-25 Registered 14 September 2020 [ABSTRACT FROM AUTHOR]

Background: A common challenge for randomised controlled trials (RCTs) is recruiting enough participants to be adequately powered to answer the research question. Recruitment has been set as a priority research area in trials to improve recruitment and thereby reduce wasted resources in conducted trials that fail to recruit sufficiently. Methods: We conducted a systematic mixed studies review to identify the factors associated with recruitment to RCTs in general practice. On September 8, 2020, English language studies were identified from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and CENTRAL databases for published studies. NTIS and OpenGrey were searched for grey literature, and BMC Trials was hand searched. A narrative synthesis was conducted for qualitative studies and a thematic synthesis for qualitative studies. Results: Thirty-seven studies met the inclusion criteria. These were of different study types (10 cross-sectional, 5 non-randomised studies of interventions, 2 RCTs, 10 qualitative and 10 mixed methods). The highest proportion was conducted in the UK (48%). The study quality was generally poor with 24 (65%) studies having major concerns. A complex combination of patient, practitioner or practice factors, and patient, practitioner or practice recruitment were assessed to determine the possible associations. There were more studies of patients than of practices or practitioners. Conclusions: For practitioners and patients alike, a trial that is clinically relevant is critical in influencing participation. Competing demands are given as an important reason for declining participation. There are concerns about randomisation relating to its impact on shared decision-making and not knowing which treatment will be assigned. Patients make decisions about whether they are a candidate for the trial even when they objectively fulfil the eligibility criteria. General practice processes, such as difficulties arranging appointments, can hinder recruitment, and a strong pre-existing doctor-patient relationship can improve recruitment. For clinicians, the wish to contribute to the research enterprise itself is seldom an important reason for participating, though clinicians reported being motivated to participate when the research could improve their clinical practice. One of the few experimental findings was that opportunistic recruitment resulted in significantly faster recruitment compared to systematic recruitment. These factors have clear implications for trial design. Methodologically, recruitment research of practices and practitioners should have increased priority. Higher quality studies of recruitment are required to find out what actually works rather than what might work. Trial registration: PROSPERO CRD42018100695. Registered on 03 July 2018. [ABSTRACT FROM AUTHOR]

Background: In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity Main body: In this paper, we critically reflect upon the factors which impacted recruitment to the pilot phase of a phase IV unblinded, randomised controlled 3×2 factorial trial examining the effectiveness of two antiseizure medications (ASMs) and a sleep behaviour intervention in children with Rolandic epilepsy. We consider the processes established to support recruitment, public and patient involvement and engagement (PPIE), site induction, our oversight of recruitment targets and figures, and the actions we took to help us understand why we failed to recruit sufficient children to continue to the substantive trial phase. The key lessons learned were about parent preference, children's involvement and collaboration in decision-making, potential and alternative trial designs, and elicitation of stated preferences pre-trial design. Despite pre-funding PPIE during the trial design phase, we failed to anticipate the scale of parental treatment preference for or against antiseizure medication (ASMs) and consequent unwillingness to be randomised. Future studies should ensure more detailed and in-depth consultation to ascertain parent and/or patient preferences. More intense engagement with parents and children exploring their ideas about treatment preferences could, perhaps, have helped predict some recruitment issues. Infrequent seizures or screening children close to natural remission were possible explanations for non-consent. It is possible some clinicians were unintentionally unable to convey clinical equipoise influencing parental decision against participation. We wanted children to be involved in decisions about trial participation. However, despite having tailored written and video information to explain the trial to children we do not know whether these materials were viewed in each consent conversation or how much input children had towards parents' decisions to participate. Novel methods such as parent/patient preference trials and/or discrete choice experiments may be the way forward. Conclusion: The importance of diligent consultation, the consideration of novel methods such as parent/patient preference trials and/or discrete choice experiments in studies examining the effectiveness of ASMs versus no-ASMs cannot be overemphasised even in the presence of widespread clinician equipoise. [ABSTRACT FROM AUTHOR]

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13063-021-05965-4. [ABSTRACT FROM AUTHOR]

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Background: Despite substantial awareness that certain groups (e.g. ethnic minorities) are under-represented and under-served in trials, limited progress has been made in addressing this. As well as a public service and ethical duty to recruit and engage under-served groups in relevant research, importantly, there are clear scientific benefits, for example, increased generalisability. The key aims of the current study were to explore the following: general barriers and facilitators to enhancing the recruitment of under-served groups into trials, the usability and value of a specific tool (INCLUDE Ethnicity Framework) to support engagement and recruitment of under-served groups, and ways of engaging diverse patient, public and community involvement and engagement (PCIE) groups.Methods: Firstly, researchers completed a brief survey in relation to a specific trial in which they were involved (N = 182, 38% response rate). A second stage involved sampling survey respondents and asking them to complete the INCLUDE Ethnicity Framework and then a remote semi-structured interview (N = 15). Qualitative data were analysed using thematic analysis. Finally, we conducted a consultation process with PCIE contributors primarily to develop guidelines for discussing the INCLUDE Ethnicity Framework with PCIE representatives.Results: Researchers recognised the importance of increasing engagement and recruitment of under-served groups within trials, but varied in their knowledge, ability and commitment to implementation in practice. The INCLUDE Ethnicity Framework was described by some as raising their awareness of how inclusion could be improved. Respondents highlighted a need for shared resources and wider structural change to facilitate such engagement. PCIE was identified, in the survey and interviews, as the most common method of trying to improve recruitment of under-served groups. However, researchers also commonly highlighted that PCIE groups were sometimes not very diverse.Conclusions: There is a need for researchers to consider the funding and time resources required for diverse and inclusive recruitment to trials and for funders to enable this. The INCLUDE Ethnicity Framework can help to raise awareness of inclusion challenges. This study indicates that it is important to take proactive steps to involve relevant under-served groups in PCIE and practical suggestions are made to facilitate this. [ABSTRACT FROM AUTHOR]

Background: The benefits of randomised trials are not shared equally, and people from ethnic minority groups are a key constituency under-served by clinical research and clinical care. The STRIDE project aimed to give trialists practical information about how to decide which ethnic groups should be in their trials, and at what proportion., Methods: We considered trials in six clinical areas: cancer, cardiovascular, diabetes, maternal health, mental health, and smoking cessation. We created a summary for each, including participants-intervention-comparators-outcomes, and data on disease prevalence by ethnicity. These were discussed with panels with clinical expertise, trial and methodology expertise, lived experience, funding, and experience of working with and on behalf of ethnic communities. For each trial, we asked panel members to decide which ethnic groups should have been involved and at what proportion., Results: We discussed 23 trials with 40 individual panel members. Panels found our questions difficult to answer. The lack of publicly available data on prevalence by ethnicity was central to this. Where data were available, decision-making was easier but not simple. The discussions led to eight STRIDE recommendations. We recommend that discussions involve diverse teams and that discussions need time, with access to the best available data. In the absence of data or consensus, we recommend the adoption of 'default' minimum rates of inclusion, with oversampling considered. These discussions should inform site selection, and the practical challenges of recruitment and retention should not determine which groups are to be included. We also suggest five policy initiatives to support implementation of the recommendations. Broadly, these are (1) funders need to signal that ethnic diversity is expected, (2) trial teams need access to better data, (3) funders and others need to signal that ethnic diversity means better science, (4) more funding is needed for evaluation, and (5) Good Clinical Practice training should cover ethnic diversity., Conclusions: Agreeing targets for which ethnic groups to involve in a trial is essential but difficult. Our eight recommendations could help to make trials more ethnically diverse if followed, and we suggest five policy initiatives that would create a supportive environment for their implementation., Competing Interests: Declarations Ethics approval and consent to participate Ethics approval was not required for this work. Members of the public who took part did so as patient and public partners helping to drive and shape the work, not as research participants. Consent for publication Not applicable for this article. Competing interests KK is Director for Centre for Ethnic Health Research, University of Leicester, UK. ST is an Editor-in-Chief of Trials. All other authors declare no competing interests., (© 2024. The Author(s).)

Background: Among the most powerful barriers to broader inclusion of diverse participants in clinical trials are social determinants of health, trustworthiness of health care providers and research institutions, and competing pressures on potential participants. Nevertheless, current tools to assess organizational capabilities for clinical trial diversity focus primarily on trial infrastructure, rely solely on quantitative self-reported data, and lack meaningful assessment of capabilities related to community engagement., Methods: The Equitable Breakthroughs in Medicine (EQBMED) initiative developed a holistic, collaborative, site-driven formative model and accompanying assessment to catalog sites' current capabilities and identify opportunities for growth in both conducting industry-sponsored clinical trials and enriching diversity of those trials. The model builds upon prior work and reflects unification of two historically distinct components-research operations and community engagement-since sustainable clinical trial diversity efforts must overcome these silos. Here we present the methodology we used to develop the model and accompanying assessment, describe how findings can support clinical trial diversity efforts, and report findings from early field testing at three U.S. sites., Results: The first three sites were diverse in size (e.g., < 250-1 K beds), with varying levels of clinical trial capabilities and community engagement. The maturity assessment laid the foundation for sites to identify and prioritize key areas to advance clinical trial diversity capabilities, and each has made tangible progress. In parallel to completing the assessment with these early sites to understand their maturity and set actionable goals, we also collected their feedback on content validity (e.g., clarity, comprehensiveness, terminology) and feasibility (e.g., ability to collect needed information and data, time required). We describe refinements made to improve the assessment and streamline the process. The EQBMED program will deploy the assessment across various site types (e.g., FQHCs, safety net hospitals) and make further refinements as warranted., Conclusions: Strategic investment in clinical trial diversity requires structured assessment of site maturity as a starting point for collaborative action. We propose the EQBMED maturity model as a first step toward informing efforts to increase representation of diverse populations in clinical research., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Poor patient accrual can delay reporting of clinical trials and, consequently, the development of new treatments. For reducing the risk of additional resource requirements, a method for setting planned accrual periods with minimal deviation from the actual accrual periods is desirable. Risk factors for poor patient accrual and the appropriate method of estimating the required accrual period for timely completion of clinical trials were evaluated using the data of trials conducted by the Japan Clinical Oncology Group., Methods: The study included 199 trials that started patient accrual between January 1, 1990, and June 30, 2021. The explanatory variables included factors that could be evaluated prior to trial commencement. We also evaluated whether the estimation methods for accrual pace could lead to completion within the planned accrual period., Results: Approximately 23.6% of trials were completed within the planned accrual period. The risk factors for trial extension included planned accrual periods > 3 years (reference group: ≤ 3 years, odds ratio [OR] 0.37, 95% confidence interval [CI]: 0.15-0.92, P = 0.033) and stratified trial design (reference group: nonrandomized phase II trials, nonrandomized phase III trial [OR: 3.28, 95% CI: 0.99-10.9, P = 0.051], randomized phase II trial [OR: 3.91, 95% CI: 0.75-20.30, P = 0.105], and randomized phase III trial [OR: 9.29, 95% CI: 3.39-25.40, P < 0.001]). The method of estimating the accrual pace based on past clinical trials facilitated timely completion of the trial (OR: 3.51; 95% CI: 1.73-7.10, P < 0.001), unlike the estimation method based on survey evaluation of the accrual pace for participating institutions (OR: 1.12, 95% CI: 0.56-2.26, P = 0.751). Furthermore, the discrepancy between planned and actual accrual periods was minimal when using the methods of considering the accrual pace of past clinical trials., Conclusions: Considering the accrual pace of past clinical trials is useful for estimating the required accrual period if data from past trials are available. When conducting a survey, it is necessary to be cautious of overestimating the cases at each facility., (© 2024. The Author(s).)

Background: Low English language literacy is a common barrier to participation in clinical trials. Patient information leaflets (PILs) used in clinical trials are often lengthy, complex and have poor readability; this is a persistent and prevalent problem common to trials across the world. Simplifying the information provided in PILs can lead to improved understanding, comprehension and knowledge. The aim of this project was to develop recommendations for developing accessible PILs for clinical trials through a literature review of published and grey literature and co-working with marginalised communities, patients, and health and social care charities., Methods: A literature review of MEDLINE, Embase and online resources was conducted, and recommendations for developing accessible PILs were extracted from eligible published and grey literature. Grey literature which contained insights into more inclusive forms of communication was also identified and summarised. Meetings were held with two racially marginalised community groups, two groups involving autistic adults and/or adults with learning difficulties and a patient advisory group. Examples of accessible PILs were shared and discussions held about the content and format of the PILs and suggestions for changes/improvements. National Voices, a coalition of health and social care charities in England, held a national online workshop with charities and lived experience partners. Recommendations identified from the multiple sources were coded, collated and refined to develop an overarching framework of recommendations., Results: The framework consists of 74 recommendations for developing accessible PILs for clinical trials. Recommendations cover the five topics of formatting, information presentation, writing style, content and accessibility., Conclusions: This project has developed a comprehensive framework of recommendations to guide researchers in the development of accessible PILs for clinical trials. Findings from previous research and from co-working with marginalised communities, patients and health and social care charities were collated to ensure that a diverse range of voices and experiences informed the framework. These recommendations aim to support researchers to develop better study information to reduce English language literacy as a barrier to participation in clinical trials., (© 2024. The Author(s).)

Background: Obstetric Bleeding Study UK (OBS UK) (award ID: 152057) is a National Institute for Health and Care Research (NIHR)-funded stepped wedge cluster randomised controlled trial of a complex intervention for postpartum haemorrhage. This was developed in Wales and evaluated in a feasibility study, with improvements in maternal outcomes observed. Generalisability of the findings is limited by lack of control data and limited ethnic diversity in the Welsh obstetric patient population compared to the United Kingdom (UK): 94% of the Welsh population identifies as White, versus 82% in the UK. Non-White ethnicity and socioeconomic deprivation are linked to increased risk of adverse maternal outcomes. Traditionally, decisions regarding site selection are based on desire to complete trials on target in 'tried and tested' research active institutions. To ensure widespread applicability of the results and investigate the impact of ethnicity and social deprivation on trial outcomes, maternity units were recruited that represent the ethnic diversity and social deprivation profiles of the UK., Method: Using routinely collected, publicly available data, an interactive dashboard was developed that demonstrates the demographics of the population served by each maternity unit in the UK, to inform site recruitment. Data on births per year, ethnic and socioeconomic group of the population for each maternity unit, across the UK, were integrated into the dashboard., Results: The dashboard demonstrates that OBS UK trial sites reflect the ethnic and socioeconomic diversity of the UK (study vs UK population ethnicity: White 79.2% vs 81.7%, Asian 10.5% vs 9.3%, Black 4.7% vs 4.0%, Mixed 2.5% vs 2.9%, Other 3.0% vs 2.1%) with variation in site demography, size and location. Missing data varied across sites and nations and is presented., Conclusion: The NIHR equality, diversity and inclusion strategy states studies must widen participation, facilitating individuals from all backgrounds to engage. The development of this novel interactive dashboard demonstrates an innovative way of achieving this. National Health Service (NHS) maternity researchers should consider using this tool to enhance diversity in research, address health disparities and improve generalisability of findings. This approach could be applied to healthcare settings beyond maternity care and across different global populations., Trial Registration: ISRCTN 17679951. Registered on August 30, 2023., (© 2024. The Author(s).)

Background: Ensuring diversity in clinical trials can be a challenge, which may be exacerbated when recruiting vulnerable populations, such as participants with mental health illness. As recruitment continues to be the major cause of trial delays, researchers are turning to online recruitment strategies, e.g. social media, to reach a wider population and reduce recruitment time and costs. There is mixed evidence for the use of online recruitment strategies; therefore, the REcruitment in Mental health trials: broadening the 'net', opportunities for INclusivity through online methoDs (RE-MIND) study aimed to identify evidence and provide guidance for use of online strategies in recruitment to mental health trials, with a focus on whether online strategies can enhance inclusivity. This commentary, as part of the RE-MIND study, focusses on providing recommendations for recruitment strategy selection in future research with the aim to improve trial efficiency. A mixed-methods approach was employed involving three work packages: (I) an evidence review of a cohort of 97 recently published randomised controlled trials/feasibility or pilot studies in mental health to assess the impact of online versus offline recruitment; (II) a qualitative study investigating the experiences of n = 23 key stakeholders on use of an online recruitment approach in mental health clinical trials; (III) combining the results of WP1 and WP2 to produce recommendations on the use of an online recruitment strategy in mental health clinical trials. The findings from WP1 and 2 have been published elsewhere; this commentary represents the results of the third work package., Conclusion: For external validity, clinical trial participants should reflect the populations that will ultimately receive the interventions being tested, if proven effective. To guide researchers on their options for inclusive recruitment strategies, we have developed a list of considerations and practical recommendations on how to maximise the use of online recruitment methods., (© 2024. The Author(s).)

Background: Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease.Methods: Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015-2016 and 2018-2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment.Results: In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART.Conclusions: Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design.Trial Registration: MS-SMART: NCT01910259 ; registered July 2013 and MS-STAT2: NCT03387670 ; registered Jan 2018. [ABSTRACT FROM AUTHOR]

Background: Many randomised controlled trials (RCTs) struggle to recruit, despite valiant efforts. The QRI (QuinteT Recruitment Intervention) uses innovative research methods to optimise recruitment by revealing previously hidden barriers related to the perceptions and experiences of recruiters and patients, and targeting remedial actions. It was designed to be integrated with RCTs anticipating difficulties at the outset. A new version of the intervention (QRI-Two) was developed for RCTs already underway with enrolment shortfalls.Methods: QRIs in 12 RCTs with enrolment shortfalls during 2007-2017 were reviewed to document which of the research methods used could be rapidly applied to successfully identify recruitment barriers. These methods were then included in the new streamlined QRI-Two intervention which was applied in 20 RCTs in the USA and Europe during 2018-2019. The feasibility of the QRI-Two was investigated, recruitment barriers and proposed remedial actions were documented, and the QRI-Two protocol was finalised.Results: The review of QRIs from 2007 to 2017 showed that previously unrecognised recruitment barriers could be identified but data collection for the full QRI required time and resources usually unavailable to ongoing RCTs. The streamlined QRI-Two focussed on analysis of screening/accrual data and RCT documents (protocol, patient-information), with discussion of newly diagnosed barriers and potential remedial actions in a workshop with the RCT team. Four RCTs confirmed the feasibility of the rapid application of the QRI-Two. When the QRI-Two was applied to 14 RCTs underway with enrolment shortfalls, an array of previously unknown/underestimated recruitment barriers related to issues such as equipoise, intervention preferences, or study presentation was identified, with new insights into losses of eligible patients along the recruitment pathway. The QRI-Two workshop enabled discussion of the newly diagnosed barriers and potential remedial actions to improve recruitment in collaboration with the RCT team. As expected, the QRI-Two performed less well in six RCTs at the start-up stage before commencing enrolment.Conclusions: The QRI-Two can be applied rapidly, diagnose previously unrecognised recruitment barriers, and suggest remedial actions in RCTs underway with enrolment shortfalls, providing opportunities for RCT teams to develop targeted actions to improve recruitment. The effectiveness of the QRI-Two in improving recruitment requires further evaluation. [ABSTRACT FROM AUTHOR]

Background: The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017.Methods: All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs.Results: HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised. Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment.Conclusion: The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies.Trial Registration: ClinicalTrials.gov ; registration number NCT01506986 . Registered on 10 Jan 2012. [ABSTRACT FROM AUTHOR]

Introduction: Organizing and executing a large clinical trial is a complex process, and often recruitment targets are not met. We describe the organization of the Levodopa in the Early Parkinson's disease (LEAP) trial and the results of an external assessment of the recruitment process.Methods: Several strategies were used to ensure that recruitment for the trial was effective and efficient. We analyzed the patterns in referrals, inclusions, and non-inclusions to investigate whether there were bottlenecks in the referral and inclusion process. For the external assessment of the recruitment process, the QuinteT Recruitment Intervention (QRI-Two) was used retrospectively, focusing on finding possible issues impeding recruitment that are less easily recognized.Results: Recruitment took 57 months, which was 27 months longer than initially expected. 6.8% of the estimated eligible patients in the Netherlands were included. The number of referrals differed widely between participating centers and regions in the Netherlands, with the region of the principal study center having the most referrals. Reasons of exclusion varied across regions, as in some regions more patients already started, wanted to start, or did not want to start with Parkinson medication compared to other regions.Discussion: Executing a large, investigator-initiated clinical trial on a limited budget still remains possible by focusing on minimizing administrative and organizational procedures. Our study suggests that centers with closer institutional ties to a principal study center tend to have a higher referral rate. The review of the LEAP trial recruitment strategies and data using the QRI-Two suggested that the variations in referrals and reasons of non-inclusion could indicate the presence of issues related to clinical equipoise, patient eligibility, or study presentation. Integrating a recruitment intervention could have explored issues with study presentation and equipoise that might have increased recruitment efficiency.Trial Registration: ISRCTN ISRCTN30518857 . The registration was initiated on 02/08/2011 and finalized on 25/08/2011. Recruitment started on 17/08/2011, after the initiation of public registration. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses) is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment. This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within approximately 24-48 h of their test result.Methods: A multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (approximately within 24-48 h of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology.Results: Prior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1013 recruits to PRINCIPLE at the start of October 2020 to 2802 recruits by 20 December 2020. Whilst procedural caveats were identified by the public consultation, out of 2639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached.Conclusions: This paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness. This approach increased recruitment and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions.Trial Registration: PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research. EudraCT number: 2020-001209-22 . 26/03/2020 ISRCTN registry: ISRCTN86534580 . 20/03/2020 REC number: 20/SC/058 IRAS number: 281958. [ABSTRACT FROM AUTHOR]

Background: Addressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context.Methods: We conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data.Results: Health system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations.Conclusions: This qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments. [ABSTRACT FROM AUTHOR]

Background: Lower than expected recruitment and retention rates are common challenges in parenting trials-particularly for community-based trials targeting parents of young children that rely on face-to-face recruitment by frontline workers. Recruitment requires parental informed consent, yet information sheets have been criticized for being lengthy and complex, and particularly challenging for parents with low literacy. Recent innovations include 'talking head' information videos. This paper aims to explore parent perceptions of using a 'talking head' video to support informed consent, recruitment, and retention procedures in parenting trials.Methods: We conducted semi-structured interviews with a sample of 24 mothers recruited after their final follow-ups in two different parenting trials in Denmark. Before consenting to participate in the trials, parents were invited to view a video of a member of the study team giving information about the study, and again before the interviews for the current study. The audio data was transcribed and thematic analysis was conducted.Results: We identified three overarching themes: (1) general impression of the video, (2) thoughts on participation in research, and (3) recruitment and retention. Participants were generally positive in their appraisal of the two talking head informational videos. We found that participants felt that a mix of paper-based and video-based sources of information would enable them to make an informed choice about whether to participate in a research study. We also found that a professionally produced video featuring a key member of the study team produced a feeling of commitment to the study that could impact retention rates.Conclusions: Informational videos are acceptable to parents; however, co-production or participant/patient involvement in the development of such videos is recommended. Informational videos may not increase recruitment but have the potential for improving retention. Key design recommendations are to ensure a 'professional' look to the video, to supplement videos with paper-based information, to keep the length to < 3 min, and for the 'talking head' part to feature a key member of the study team. [ABSTRACT FROM AUTHOR]

Introduction: ASCEND PLUS is a randomised controlled trial assessing the effects of oral semaglutide on the primary prevention of cardiovascular events in around 20,000 individuals with type 2 diabetes in the UK. The trial's innovative design includes a decentralised direct-to-participant invitation, recruitment, and follow-up model, relying on self-completion of online forms or telephone or video calls with research nurses, with no physical sites. Extensive patient and public involvement and engagement (PPIE) was essential to the design and conduct of ASCEND PLUS., Aim: To report the process and conduct of PPIE activity in ASCEND PLUS, evaluate effects on trial design, reflect critically on successes and aspects that could have been improved, and identify themes and learning relevant to implementation of PPIE in future trials., Methods: PPIE activity was coordinated centrally and included six PPIE focus groups and creation of an ASCEND PLUS public advisory group (PAG) during the design phase. Recruitment to these groups was carefully considered to ensure diversity and inclusion, largely consisting of adults living with type 2 diabetes from across the UK. Two members of the PAG also joined the trial Steering Committee. Steering Committee meetings, focus groups, and PAG meetings were conducted online, with two hybrid workshops to discuss PPIE activity and aspects of the trial., Results: PPIE activity was critical to shaping the design and conduct of ASCEND PLUS. Key examples included supporting choice for participants to either complete the screening/consent process independently online, or during a telephone or video call interview with a research nurse. A concise 'initial information leaflet' was developed to be sent with the initial invitations, with the 'full' information leaflet sent later to those interested in joining the trial. The PAG reviewed the content and format of participant- and public-facing materials, including written documents, online screening forms, animated videos, and the trial website, to aid clarity and accessibility, and provided input into the choice of instruments to assess quality of life., Conclusions: PPIE is integral in ASCEND PLUS and will continue throughout the trial. This involvement has been critical to optimising the trial design, successfully obtaining regulatory and ethical approval, and conducting the trial., (© 2024. The Author(s).)

Background: Interest in and use of electronic consent (e-consent) in the conduct of academic clinical trials has increased since the COVID-19 pandemic. E-consent offers advantages including increased efficiency and accessibility, and reduced burden on site staff, which can be appealing to academic trialists anticipating challenges in recruitment to complex trial designs or with limited funding. However, there are many options to consider when using e-consent in a study protocol. This paper presents five case studies from Norwich Clinical Trials Unit, demonstrating how e-consent models can be effectively tailored to the needs of different trials. These examples illustrate the options around and benefits of e-consent, the acceptability of e-consent by participants, and the design considerations that were made during the development of the trial protocols., Case Studies: Five randomised trials are presented, selected from a range of different trial designs, disease areas, interventions, and patient populations. E-consent was either offered as an alternative to paper consent, according to participant preference, or as the sole method of consent. E-consent was generally used to facilitate remote consent in decentralised trials but was also chosen to increase efficiency and reduce burden in an emergency department setting. The technical implementation of e-consent and detailed participant procedures were tailored to the needs of the trial settings and patient populations. For example, accompanying participant information sheets were provided in paper or electronic form, and electronic signatures could be typed or drawn. Administrative data on uptake of e-consent is presented where available., Conclusion: This paper demonstrates that the operational and technical aspects of implementing e-consent in clinical trials can be influenced by the trial design, the needs and characteristics of the trial population, financial/efficiency considerations, and level of risk. E-consent is not a one-size-fits-all tool for trials, and its use should be carefully considered during the development of the trial protocol, in conjunction with patient and public involvement contributors, site staff and other trial stakeholders., (© 2024. The Author(s).)

Background: Phase 1 clinical trials involve rigorous safety monitoring to identify any adverse effects of investigational treatments. There is growing evidence that healthy volunteers recruited in these studies may differ with respect to personality traits from the general population. This, in turn, may have a significant impact on the reporting of adverse events, particularly in trials investigating psychoactive treatments, including the psychedelic substances., Main Body: This analysis stems from our combined experience as investigators in phase 1 clinical trials and conveys an experiential understanding of the impact of psychological heterogeneity on study participation, reporting of adverse events and study outcomes., Conclusion: Participant variability due to psychological characteristics is regularly overlooked in phase 1 clinical trials and may significantly impact on reporting of the adverse events. In our opinion, healthy volunteers who present for these studies should not only be defined by the absence of past or current medical and psychiatric illness but also characterised by their psychological attributes., (© 2024. Crown.)

Background: Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies., Methods: We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women's College Hospital. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial., Discussion: This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients., Trial Registration: The trial was registered prospectively on the Open Science Framework (OSF), registration #46twc, on 2023-Mar-17., (© 2024. The Author(s).)

Challenges to recruitment of family caregivers exist and are amplified when consent must occur in the context of chaotic healthcare circumstances, such as the transition from hospital to home. The onset of the COVID-19 pandemic during our randomized controlled trial provided an opportunity for a natural experiment exploring and examining different consent processes for caregiver recruitment. The purpose of this publication is to describe different recruitment processes (in-person versus virtual) and compare diversity in recruitment rates in the context of a care recipient's hospitalization. We found rates of family caregiver recruitment for in-person versus virtual were 28% and 23%, respectively (p = 0.01). Differences existed across groups with family caregivers recruited virtually being more likely to be younger, white, have greater than high school education, and not be a spouse or significant other to the care recipient, such as a child. Future work is still needed to identify the modality and timing of family caregiver recruitment to maximize rates and enhance the representativeness of the population for equitable impact., (© 2024. The Author(s).)

Equity and health equity are fundamental pillars in fostering a just and inclusive society. While equity underscores fairness in resource allocation and opportunity, health equity aims to eradicate avoidable health disparities among social groups. The concept of harms in interventions-undesirable consequences associated with the use of interventions-often varies across populations due to biological and social factors, necessitating a nuanced understanding. An equity lens reveals disparities in harm distribution, urging researchers and policymakers to address these differences in their decision-making processes. Furthermore, interventions, even well-intentioned ones, can inadvertently exacerbate disparities, emphasizing the need for comprehensive harm assessment. Integrating equity considerations in research practices and trial methodologies, through study design or through practices such as inclusive participant recruitment, is pivotal in advancing health equity. By prioritizing interventions that address disparities and ensuring inclusivity in research, we can foster a more equitable healthcare system., (© 2024. The Author(s).)

Investigators often conduct randomized controlled trials (RCTs) at multiple centers/sites when determining the effect of a treatment or an intervention. Diversifying recruitment across multiple institutions allows investigators to make recruitment go faster within a shorter timeframe and allows generalizing the study results across diverse populations. Despite having a common study protocol across multiple centers, the eligible participants may be heterogeneous, site policies and practices may vary, and the investigators' experience, training, and expertise may also vary across sites. These factors may contribute to the heterogeneity in effect estimates across centers. As a result, we usually observe some degree of heterogeneity in effect estimates across centers, despite all centers following the same study protocol. During the analysis of such a trial, investigators typically ignore center effects, but some have suggested considering centers as fixed or random effects in the model. It is not clear how considering the effects of centers, either as fixed or random effects, impacts the test of the primary hypothesis. In this article, we first review the practice of accounting for center effects in the analyses of published RCTs and illustrate the extent of heterogeneity observed in a few preexisting multicenter RCTs. To determine the impact of heterogeneity on the test of a primary hypothesis of an RCT, we considered continuous and binary outcomes and the corresponding appropriate model, namely, a simple linear regression model for a continuous outcome and a logistic regression model for the binary outcome. For each model type, we considered three methods: (a) ignore the center effect, (b) account for centers as fixed effects, or (c) account for centers as random effects. Based on simulation studies of these models, we then examine whether considering the center as a fixed or random effect in the model helps to preserve or reduce the type I and type II error rates during the analysis phase of an RCT. Finally, we outline the threshold at which center-level effects are negligible and thus negligible and provide recommendations on when it may be necessary to account for center effects during the analyses of multicenter randomized controlled trials., (© 2024. The Author(s).)

Background: Patients from socioeconomically disadvantaged backgrounds are underserved in randomised controlled trials, yet they experience a much greater burden of disease compared with patients from socioeconomically advantaged areas. It is crucial to make trials more inclusive to ensure that treatments and interventions are safe and effective in real-world contexts. Improving how information about trials is verbally communicated is an unexplored strategy to make trials more inclusive. This study examined how trials are communicated verbally, comparing consultations involving patients from the most and least socioeconomically disadvantaged areas., Methods: Secondary qualitative analysis of 55 trial consultation transcripts from 41 patients, sampled from 3 qualitative studies embedded in their respective UK multi-site, cancer-related randomised controlled trials. Patients living in the most and least socioeconomically disadvantaged areas, defined using English Indices of Multiple Deprivation decile scores, were purposively sampled. Analysis was largely thematic and drew on the constant comparison method., Results: Recruiters communicated clinical uncertainty in a similar way for patients living in different socioeconomic areas. Consultations with disadvantaged patients were, on average, half the duration of those with advantaged patients, and tended to involve recruiters providing less in-depth explanations of trial concepts, used phrasing that softened trial arm risks, and described trial processes (e.g. randomisation) using informal or metaphorical phrasing. Disadvantaged and advantaged patients differed in the concerns they expressed; disadvantaged patients voiced fewer concerns and asked fewer questions but were also less likely to be invited to do so by recruiters., Conclusion: Interactions about trials unfolded in different ways between patients living in different socioeconomic areas, likely due to both patient- and recruiter-related factors. We present considerations for recruiters when discussing trials with patients from socioeconomically disadvantaged backgrounds, aimed at enhancing trial communication. Future research should examine disadvantaged patients' and recruiters' experiences of verbal trial communication to inform guidance that addresses the needs and preferences of underserved groups., (© 2024. The Author(s).)

Background: Registry-based randomised controlled trials (rRCTs) have been described as pragmatic studies utilising patient data embedded in large-scale registries to facilitate key clinical trial procedures including recruitment, randomisation and the collection of outcome data. Whilst the practice of utilising registries to support the conduct of randomised trials is increasing, the use of the registries within rRCTs is inconsistent. The purpose of this systematic review is to explore the conduct of rRCTs using a patient registry to facilitate trial recruitment and the collection of outcome data, and to discuss the advantages and challenges of rRCTs., Methods: A systematic search of the literature was conducted using five databases from inception to June 2020: PubMed, Embase (through Ovid), CINAHL, Scopus and the Cochrane Controlled Register of Trials (CENTRAL). The search strategy comprised of MESH terms and key words related to rRCTs. Study selection was performed independently by two reviewers. A risk of bias for each study was completed. A narrative synthesis was conducted., Results: A total 47,862 titles were screened and 24 rRCTs were included. Eleven rRCTs (45.8%) used more than one registry to facilitate trial conduct. Six rRCTs (25%) randomised participants via a specific randomisation module embedded within a registry. Recruitment ranged between 209 to 106,000 participants. Advantages of rRCTs are recruitment efficiency, shorter trial times, cost effectiveness, outcome data completeness, smaller carbon footprint, lower participant burden and the ability to conduct multiple trials from the same registry. Challenges are data collection/management, quality assurance issues and the timing of informed consent., Conclusions: Optimising the design of rRCTs is dependent on the capabilities of the registry. New registries should be designed and existing registries reviewed to enable the conduct of rRCTs. At all times, data management and quality assurance of all registry data should be given key consideration. We suggest the inclusion of the term 'registry-based' in the title of all rRCT manuscripts and a clear simple breakdown of the registry-based conduct of the trial in the abstract to facilitate indexing in the major databases., (© 2024. The Author(s).)

Background: Retaining participants in randomised controlled trials (RCTs) is challenging and trial teams are often required to use strategies to ensure retention or improve it. Other than monetary incentives, there is no requirement to disclose the use of retention strategies to the participant. Additionally, not all retention strategies are developed at the planning stage, i.e. post-funding during protocol development, but some protocols include strategies for participant retention as retention is considered and planned for early in the trial planning stage. It is yet unknown if these plans are communicated in the corresponding participant information leaflets (PILs). The purpose of our study was to determine if PILs communicate plans to promote participant retention and, if so, are these outlined in the corresponding trial protocol., Methods: Ninety-two adult PILs and their 90 corresponding protocols from Clinical Trial Units (CTUs) in the UK were analysed. Directed (deductive) content analysis was used to analyse the participant retention text from the PILs. Data were presented using a narrative summary and frequencies where appropriate., Results: Plans to promote participant retention were communicated in 81.5% (n = 75/92) of PILs. Fifty-seven percent (n = 43/75) of PILs communicated plans to use "combined strategies" to promote participant retention. The most common individual retention strategy was telling the participants that data collection for the trial would be scheduled during routine care visits (16%; n = 12/75 PILs). The importance of retention and the impact that missing or deleted data (deleting data collected prior to withdrawal) has on the ability to answer the research question were explained in 6.5% (n = 6/92) and 5.4% (n = 5/92) of PILs respectively. Out of the 59 PILs and 58 matching protocols that both communicated plans to use strategies to promote participant retention, 18.6% (n = 11/59) communicated the same information, the remaining 81.4% (n = 48/59) of PILs either only partially communicated (45.8%; n = 27/59) the same information or did not communicate the same information (35.6%; n = 21/59) as the protocol with regard to the retention strategy(ies)., Conclusion: Retention strategies are frequently communicated to potential trial participants in PILs; however, the information provided often differs from the content in the corresponding protocol. Participant retention considerations are best done at the planning stage of the trial and we encourage trial teams to be consistent in the communication of these strategies in both the protocol and PIL., (© 2024. The Author(s).)

Background: The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania.Methods: The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings.Results: Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%).Conclusions: The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered. [ABSTRACT FROM AUTHOR]

Background: Botulinum neurotoxin (BoNT) is currently the best therapeutic option in the treatment for cervical dystonia (CD). Additional treatments like physiotherapy (PT) may even improve the results of the BoNT injection with type A (BoNT-A), but there are no definite recommendations. In the last few years, some studies showed tendencies for PT as an adjuvant therapy to benefit. However, high-quality studies are required.Methods: This study is a multicentre, randomized, single-blind, controlled trial to demonstrate the effectiveness of a multimodal PT program compared to a nonspecific cupping therapy, additionally to the BoNT-A therapy. Two hundred participants will be assigned into the multimodal PT plus BoNT intervention arm or the BoNT plus cupping arm using randomization. Primary endpoint is the total Score of Toronto Western Spasmodic Rating Scale (TWSTRS). Secondary endpoints are the mobility of the cervical spine (range of motion, ROM), the TWSTRS subscales, and the quality of life (measured by questionnaires: CDQ-24 and SF-36). Patients will be single-blind assessed every 3 months according to their BoNT injection treatment over a period of 9 months.Discussion: The study aims to determine the effectiveness and therefore potential benefit of an additional multimodal physiotherapy for standardized treatment with BoNT-A in patients with CD, towards the BoNT-therapy alone. This largest randomized controlled trial in this field to date is intended to generate missing evidence for therapy guidelines.Trial Registration: The study was registered in the German Clinical Study Register before the start of the patient recruitment ( DRKS00020411 ; date: 21.01.2020). [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials in surgery can be a challenge to design and conduct, especially when including a non-surgical comparison. As few as half of initiated surgical trials reach their recruitment target, and failure to recruit is cited as the most frequent reason for premature closure of surgical RCTs. The aim of this qualitative evidence synthesis was to identify and synthesise findings from qualitative studies exploring the challenges in the design and conduct of trials directly comparing surgical and non-surgical interventions.Methods: A qualitative evidence synthesis using meta-ethnography was conducted. Six electronic bibliographic databases (Medline, Central, Cinahl, Embase and PsycInfo) were searched up to the end of February 2018. Studies that explored patients' and health care professionals' experiences regarding participating in RCTs with a surgical and non-surgical comparison were included. The GRADE-CERQual framework was used to assess confidence in review findings.Results: In total, 3697 abstracts and 49 full texts were screened and 26 published studies reporting experiences of patients and healthcare professionals were included. The focus of the studies (24/26) was primarily related to the challenge of recruitment. Two studies explored reasons for non-compliance to treatment allocation following randomisation. Five themes related to the challenges to these types of trials were identified: (1) radical choice between treatments; (2) patients' discomfort with randomisation: I want the best treatment for me as an individual; (3) challenge of equipoise: patients' a priori preferences for treatment; (4) challenge of equipoise: clinicians' a priori preferences for treatment and (5) imbalanced presentation of interventions.Conclusion: The marked dichotomy between the surgical and non-surgical interventions was highlighted in this review as making recruitment to these types of trials particularly challenging. This review identified factors that increase our understanding of why patients and clinicians may find equipoise more challenging in these types of trials compared to other trial comparisons. Trialists may wish to consider exploring the balance of potential factors influencing patient and clinician preferences towards treatments before they start recruitment, to enable issues specific to a particular trial to be identified and addressed. This may enable trial teams to make more efficient considered design choices and benefit the delivery of such trials. [ABSTRACT FROM AUTHOR]

BackgroundInhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.MethodsTwo pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and