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Background: Sarcopenia is a geriatric disease characterized by loss of muscle mass and strength. Although combined exercise and nutrition intervention are known to be effective for sarcopenia, clinical trials involving outpatients with sarcopenia in primary care are scarce. We describe a protocol for a trial to examine the effects of a 12-week combined exercise and nutrition intervention in Korean older adults with possible sarcopenia in community-based primary care., Methods: This multicenter, randomized, controlled trial will include 94 community-dwelling older outpatients aged 65-85 years with possible sarcopenia (47 participants in the intervention and control groups each). Resistance exercises, which incorporate concentric and eccentric exercises, will consist of an introductory phase (3 weeks: twice-weekly supervised exercise sessions and once-weekly home exercises; contraction exercises), an expanded phase (3 weeks: twice-weekly supervised exercise sessions and once-weekly home exercises; eccentric exercises), and a maintenance phase (6 weeks: once-weekly supervised exercise sessions and twice-weekly home exercises; power/eccentric exercises). Nutritional supplementation will be provided according to the nutritional status of the participants using a Mini-Nutritional Assessment. Participants will be assessed at baseline, 12 and 24 weeks, and the primary outcome will be the 5-times chair stand test results., Discussion: To the best of our knowledge, this will be the first clinical trial to evaluate the efficacy of a combined exercise and nutritional supplementation intervention in older outpatients with possible sarcopenia in community-based primary care clinics. These findings will provide new insights to clinicians regarding the long-term usability for doctors and outpatients with possible sarcopenia in community-based primary care., Trial Registration: This trial was prospectively registered at ClinicalTrials.gov on September 16, 2023 (registration number: NCT06049914)., (© 2024. The Author(s).)

Background: Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype., Methods/design: From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype., Discussion: This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype., Trial Registration: This cohort study was retrospectively registered at the Clinical Research Information Service ( KCT0005580 ) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

Background: Poor recruitment in clinical trials is well-documented. In large, multi-centre trials, communication between the coordinating centre and trial sites is essential. A commonly used communication tool is the hosting of an investigator/collaborator meeting, which offers an opportunity for sites to re-train and receive trial updates, learn from each other, share best practice and troubleshoot issues. Anecdotally, there is a perception that recruitment rates may increase after holding such a meeting. The aim of this before-and-after study was to examine any changes in recruitment after an investigator meeting., Methods: We conducted a retrospective study of nine trials at the Nottingham Clinical Trials Unit (NCTU) that were open to recruitment between 2014 and 2018. In the 8 weeks prior to the date of the investigator meeting, 82 sites (across nine trials) were open to recruitment; 60 of which attended the meeting, 22 who did not. Using meeting attendance data available in Trial Master Files (TMF) and recruitment data from randomisation datasets, we examined recruitment rates in the 8 weeks prior to and following the date of the investigator meeting., Results: For the 82 sites included, 284 participants were recruited in the 8 weeks prior to the meeting, with a further 300 participants recruited in the 8 weeks post meeting. This gives a mean change in weekly recruitment of 0.073 (- 0.129, 0.275) per site, demonstrating no statistically significant increase in recruitment after the investigator meeting. For the 60 attending sites, recruitment increased from 254 participants prior to the meeting to 271 post meeting, giving a 0.100 (- 0.160, 0.360) mean change in weekly recruitment per site, providing no evidence that recruitment rates increase following an investigator meeting., Conclusion: There is no statistical evidence to conclude that holding an investigator meeting increases recruitment in the 8 weeks following the meeting. Thus, if the meeting has been held in the belief that it will have a positive impact upon recruitment, trialists may wish to consider other evidence-based strategies known to increase recruitment rates. However, since there are a variety of reasons why an investigator meeting may be held, trialists should continue to consider this as a communication strategy with sites.

Background: Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional's skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials., Methods: A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate., Results: Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided., Conclusions: Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.

Background: Assessment of diet and physical activity and their determinants still remains a demanding task, especially when the objective is to evaluate the efficacy of lifestyle interventions. In the context of the Feel4Diabetes study (a European community based intervention study in families with school aged children and at high risk of developing diabetes), we aimed to develop questionnaires for the assessment of food-frequency and eating behaviors, and physical activity and sedentary behaviors in both parents and school-aged children and a questionnaire for overall family's energy balance-related behaviors., Methods: Questionnaires were developed to be used in 6 countries under standardized harmonization procedures and included questions regarding not only food intake and physical activity, but also questions of their determinants. A reliability study was conducted in 191 pairs of parents and their children (N = 191). Parents completed the questionnaires on two occasions, within a 1-2 week interval. Reliability was tested by the intra-class correlation coefficients (ICC) of test-retest., Results: Most of the questions in all questionnaires had excellent reliability, assessed as an ICC of > 0.810. Mean ICCs for food-frequency and eating behaviors questionnaires were 0.838 and 0.787, and for physical activity and sedentary behaviors questionnaires were 0.734 and 0.793, in adults and children respectively. Mean ICC for overall family's energy balance-related behaviors and their determinants was 0.659., Conclusion: The developed questionnaires showed acceptable reliability and may be valuable tools in the assessment of children's and parents' behaviors related to diet, physical activity, sedentary behavior and overall energy balance in school- and community-based interventions.

Feel4Diabetes (standing for: Families across Europe following a hEalthy Lifestyle for Diabetes prevention, http://feel4diabetes-study.eu/) is a school and community based intervention program, aiming to prevent type 2 diabetes (T2D) among families from vulnerable population groups, in six European countries, by promoting healthy lifestyle. In the current issue of BMC Endocrine Disorders, three reviews and three papers providing a detailed description of the methodology used to obtain measurements related to the trial conduction, as well as two papers using original data collected in the Feel4Diabetes-study are presented.

Background: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results., Methods: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations., Discussion: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Background: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO 2 -C) reduces time outside the hemoglobin oxygen saturation (SpO 2 ) target range, number and duration of hypo- and hyperoxemic episodes and caregivers' workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied., Methods: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO 2 -C (in addition to routine manual control (RMC) of FiO 2 ), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO 2 -C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO 2 -C is provided by commercially available and CE-marked ventilators with an FiO 2 -C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age., Discussion: Short-term studies on FiO 2 -C showed improved time ELGANs spent within their assigned SpO 2 target range, but effects of FiO 2 -C on clinical outcomes are yet unknown and will be addressed in the FiO 2 -C trial. This will ensure an appropriate assessment of safety and efficacy before FiO 2 -C may be implemented as standard therapy., Trial Registration: The study is registered at www.ClinicalTrials.gov: NCT03168516 , May 30, 2017.

Background: Hydroxyurea (HU) is recommended as standard practice for youth with sickle cell disease (SCD). Yet, despite its efficacy, HU adherence in adolescents and young adults is often poor. Poor medication adherence increases disease burden, healthcare cost and widens health disparities. Adolescence is a critical time to improve adherence through improved chronic disease self-management. This study aims to test the efficacy of an intervention delivered to youth/parent dyads by community health workers (CHWs), augmented by tailored text messages on HU adherence (primary outcome). Secondary outcomes are intervention sustainability, youth health-related quality of life, self-management responsibility concordance, acute hospital use and self-reported disease symptoms., Methods: Hydroxyurea Adherence for Personal Best in Sickle Cell Disease, "HABIT," is a 12 month multi-center randomized controlled trial. One hundred four youth, 10 to 18 years of age prescribed HU who meet eligibility criteria, enrolled with their parent as dyads, will be randomized 1:1 to either the HABIT intervention or to usual clinical care plus education handouts. All subjects will complete clinic visits at months 0, 2, 4, 6 (efficacy component), 9 and 12 (sustainability component) for assessment of HbF biomarker, other hematologic parameters, and to complete questionnaires. In addition, dyads assigned to the HABIT intervention will work with CHWs to identify a daily habit (e.g., brushing teeth) on which to build a HU adherence habit. Tailored daily text message reminders to support the habit will be developed by the dyad in collaboration with the CHWs and sent to parent and youth. At the 6 month visit, the intervention will end and the sustainability portion of the trial will begin. All data analyses will be based on intention to treat with all randomized subjects included in the analyses., Discussion: Prior retrospective studies demonstrate that a majority of adolescents are poorly adherent to HU. If efficacious, the HABIT intervention has the potential to improve the lives of youth with SCD., Trial Registration: Clinicaltrials.gov NCT03462511 . Registered March 6, 2018, last updated July 26, 2019.

Background: Clinical trials management can be studied using project management theory. The CYCLE pilot randomized controlled trial (RCT) was conducted to determine the feasibility of a future rehabilitation trial of early in-bed cycling in the intensive care unit (ICU). In-bed cycling is a novel intervention, not typically available in ICUs. Implementation of this intervention requires personnel with specialized clinical expertise caring for critically ill patients and use of the in-bed cycle. Our objective was to describe the implementation and conduct of our pilot RCT using a project management approach., Methods: We retrospectively reviewed activities, timelines, and personnel involved in the trial. We organized activities into four project management phases: initiation, planning, execution, and monitoring and controlling. Data sources included Methods Centre documents used for trial coordination and conduct, and the trial data set. We report descriptive statistics as counts and proportions and also medians and quartiles, and we summarize the lessons learned., Results: Seven ICUs in Canada participated in the trial. Time from research ethics board and contracts submission to first enrolment was a median (first quartile, third quartile) of 185 (146, 209) and 162 (114, 181) days, respectively. We trained 128 personnel on the CYCLE pilot RCT protocol, and 80 (63%) completed trial-related activities. Four sites required additional training after start-up due to staff turnover and leaves of absence. Over 15 months, we screened 864 patients: 256 were eligible and 66 were enrolled. Despite an 85% consent rate, 74% (190/256) of eligible patients were not randomized, largely (80% [152/190]) due to physiotherapist availability. Thirteen percent of recruitment weeks were lost due to physiotherapist staffing shortages. We highlight five key lessons learned: (1) prepare and anticipate site needs; (2) communicate regularly; (3) proactively analyse and act on process measure data; (4) develop contingency plans; (5) express appreciation to participating sites., Conclusions: Our analysis highlights the scope of relevant activities, rigorous training and monitoring, number and types of required personnel, and time required to conduct a multicentre ICU rehabilitation intervention trial. Our lessons learned can help others interested in implementing complex intervention trials, such as rehabilitation., Trial Registration: ClinicalTrials.gov, NCT02377830 . Registered prospectively on 4 March 2015.

Background: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease., Methods: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies., Discussion: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants., Trial Registration: Does not apply for this study.

Background: Sub-Saharan Africa (SSA) alone has nine out of every 10 children living with HIV globally and monitoring in this setting remains suboptimal, even as these children grow older. With scalability of antiretroviral therapy (ART), several HIV-infected children are growing towards adolescence (over 2.1 million), with the potentials to reach adulthood. However, despite an overall reduction in HIV-related mortality, there are increasing deaths among adolescents living with HIV (ADLHIV), with limited evidence for improved policy-making. Of note, strategies for adolescent transition from pediatrics to adult-healthcare are critical to ensure successful treatment response and longer life expectancy. Interestingly, with uptakes in prevention of mother-to-child transmission, challenges in ART programs, and high viremia among children in SSA, the success rate of paediatric ART might be quickly jeopardised, with possible HIV-1 drug-resistance (HIVDR) emergence, especially after years of paediatric ART exposure. Therefore, monitoring ART response in adolescents and evaluating HIVDR patterns might limit disease progression and guide on subsequent ART options for SSA ADLHIV., Objectives: Among Cameroonian ADLHIV receiving ART, we shall evaluate the rate of immunovirologic failure, acquired HIVDR-associated mutations, HIV-1 subtype distribution, genetic variability in circulating (plasma) versus archived (cellular) viral strains, and HIVDR early warning indicators (EWIs) at different time-points., Methods: A prospective and observational study will be conducted among 250 ADLHIV (10-19 years old) receiving ART in the centre region of Cameroon, and followed-up at 6 and 12 months after enrollment. Following consecutive sampling at enrolment, plasma viral load and CD4/CD8 count will be measured, and genotypic resistance testing (GRT) will be performed both in plasma and in buffy coat for participants experiencing virological failure (two consecutive viremia > = 1000 copies/ml). Plasma viral load and CD4/CD8 will be monitored for all participants at 6 and 12 months after enrolment. HIVDR-EWIs will be monitored and survival analysis performed during the 12 months follow-up. Primary outcomes are rates of virological failure, acquired-HIVDR, and mortality., Discussion: Our findings will provide evidence-based recommendations to ensure successful transition from paediatrics to adult ART regimens and highlight further needs of active ART combinations, for reduced morbidity and mortality in populations of ADLHIV within SSA.

Background: Multicentre randomised trials provide some of the key evidence underpinning healthcare practice around the world. They are also hard work and generally expensive. Some of this work and expense are devoted to sites that fail to recruit as many participants as expected. Methods to identify sites that will recruit to target would be helpful., Methods: We asked trial managers at the Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen to predict whether a site would recruit to target. Predictions were made after a site initiation visit and were collected on a form comprising a simple 'Yes/No' prediction and a reason for the prediction. We did not provide guidance as to what trial managers might want to think about when making predictions. After a minimum of eight months of recruitment at each site for which a prediction had been made, all trial mangers in CHaRT were invited to a group discussion where predictions were presented together with sites' actual recruitment performance over that period. Individual trial managers reflected on their predictions and there was a general discussion about predicting site recruitment. The prediction reasons from the forms and the content of the group discussion were used to identify features linked to correct predictions of recruitment failure., Results: Ten trial managers made predictions for 56 site visits recruiting to eight trials. Trial managers' sensitivity was 82% and their specificity was 32%, correctly identifying 65% of sites that would hit their recruitment target and 54% of those that did not. Eight 'red flags' for recruitment failure were identified: previous poor site performance; slow approvals process; strong staff/patient preferences; the site recruitment target; the trial protocol and its implementation at the site; lack of staff engagement; lack of research experience among site staff; and busy site staff. We used these red flags to develop a guided prediction form., Conclusions: Trial managers' unguided recruitment predictions were not bad but were not good enough for decision-making. We have developed a modified prediction form that includes eight flags to consider before making a prediction. We encourage anyone interested in contributing to its evaluation to contact us.

Background: National leaders recommend documenting social determinants of health and actions taken to address social determinants of health in electronic health records, and a growing body of evidence suggests the health benefits of doing so. However, little evidence exists to guide implementation of social determinants of health documentation/action., Methods: This paper describes a 5-year, mixed-methods, stepped-wedge trial with realist evaluation, designed to test the impact of providing 30 community health centers with step-by-step guidance on implementing electronic health record-based social determinants of health documentation. This guidance will entail 6 months of tailored support from an interdisciplinary team, including training and technical assistance. We will report on tailored support provided at each of five implementation steps; impact of tailored implementation support; a method for tracking such tailoring; and context-specific pathways through which these tailored strategies effect change. We will track the competencies and resources needed to support the study clinics' implementation efforts., Discussion: Results will inform how to tailor implementation strategies to meet local needs in real-world practice settings. Secondary analyses will assess impacts of social determinants of health documentation and referral-making on diabetes outcomes. By learning whether and how scalable, tailored implementation strategies help community health centers adopt social determinants of health documentation and action, this study will yield timely guidance to primary care providers. We are not aware of previous studies exploring implementation strategies that support adoption of social determinants of action using electronic health and interventions, despite the pressing need for such guidance., Trial Registration: clinicaltrials.gov, NCT03607617 , registration date: 7/31/2018-retrospectively registered.

Background: Most people who make the transition to renal replacement therapy (RRT) are treated with a fixed dose thrice-weekly hemodialysis réegimen, without considering their residual kidney function (RKF). Recent papers inform us that incremental hemodialysis is associated with preservation of RKF, whenever compared with conventional hemodialysis. The objective of the present controlled randomized trial (RCT) is to determine if start HD with one sessions per week (1-Wk/HD), it is associated with better patient survival and other safety parameters., Methods/design: IHDIP is a multicenter RCT experimental open trial. It is randomized in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 incident patients older than 18 years, with a RRF of ≥4 ml/min/1.73 m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with incremental HD (1-Wk/HD). The control group includes 76 patients who will start with thrice-weekly hemodialysis régimen. The primary outcome is assessing the survival rate, while the secondary outcomes are the morbidity rate, the clinical parameters, the quality of life and the efficiency., Discussion: This study will enable to know the number of sessions a patient should receive when starting HD, depending on his RRF. The potentially important clinical and financial implications of incremental hemodialysis warrant this RCT., Trial Registration: U.S. National Institutes of Health, ClinicalTrials.gov . Number: NCT03239808 , completed 13/04/2017., Sponsor: Foundation for Training and Research of Health Professionals of Extremadura.

Background: Large multicentre trials are complex and expensive projects. A key factor for their successful planning and delivery is how well sites meet their targets in recruiting and retaining participants, and in collecting high-quality, complete data in a timely manner. Collecting and monitoring easily accessible data relevant to performance of sites has the potential to improve trial management efficiency. The aim of this systematic review was to identify metrics that have either been proposed or used for monitoring site performance in multicentre trials., Methods: We searched the Cochrane Library, five biomedical bibliographic databases (CINAHL, EMBASE, Medline, PsychINFO and SCOPUS) and Google Scholar for studies describing ways of monitoring or measuring individual site performance in multicentre randomised trials. Records identified were screened for eligibility. For included studies, data on study content were extracted independently by two reviewers, and disagreements resolved by discussion., Results: After removing duplicate citations, we identified 3188 records. Of these, 21 were eligible for inclusion and yielded 117 performance metrics. The median number of metrics reported per paper was 8, range 1-16. Metrics broadly fell into six categories: site potential; recruitment; retention; data collection; trial conduct and trial safety., Conclusions: This review identifies a list of metrics to monitor site performance within multicentre randomised trials. Those that would be easy to collect, and for which monitoring might trigger actions to mitigate problems at site level, merit further evaluation.

Background: Site performance is key to the success of large multicentre randomised trials. A standardised set of clear and accessible summaries of site performance could facilitate the timely identification and resolution of potential problems, minimising their impact. The aim of this study was to identify and agree a core set of key performance metrics for managing multicentre randomised trials., Methods: We used a mixed methods approach to identify potential metrics and to achieve consensus about the final set, adapting methods that are recommended by the COMET Initiative for developing core outcome sets in health care. We used performance metrics identified from our systematic search and focus groups to create an online Delphi survey. We invited respondents to score each metric for inclusion in the final core set, over three survey rounds. Metrics scored as critical by ≥70% and unimportant by <15% of respondents were taken forward to a consensus meeting of representatives from key UK-based stakeholders. Participants in the consensus meeting discussed and voted on each metric, using anonymous electronic voting. Metrics with >50% of participants voting for inclusion were retained., Results: Round 1 of the Delphi survey presented 28 performance metrics, and a further six were added in round 2. Of 294 UK-based stakeholders who registered for the Delphi survey, 211 completed all three rounds. At the consensus meeting, 17 metrics were discussed and voted on: 15 metrics were retained following survey round 3, plus two others that were preferred by consensus meeting participants. Consensus was reached on a final core set of eight performance metrics in three domains: (1) recruitment and retention, (2) data quality and (3) protocol compliance. A simple tool for visual reporting of the metrics is available from the Nottingham Clinical Trials Unit website., Conclusions: We have established a core set of metrics for measuring the performance of sites in multicentre randomised trials. These metrics could improve trial conduct by enabling researchers to identify and address problems before trials are adversely affected. Future work could evaluate the effectiveness of using the metrics and reporting tool.

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes., Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497)., Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes)., Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes., Trial Registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 ).

Background: Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high-quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET)., Methods: Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis., Results: Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes., Conclusion: Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study., Trial Registration: Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011.

Background: Transition from distinct Child and Adolescent Mental Health (CAMHS) to Adult Mental Health Services (AMHS) is beset with multitude of problems affecting continuity of care for young people with mental health needs. Transition-related discontinuity of care is a major health, socioeconomic and societal challenge globally. The overall aim of the Managing the Link and Strengthening Transition from Child to Adult Mental Health Care in Europe (MILESTONE) project (2014-19) is to improve transition from CAMHS to AMHS in diverse healthcare settings across Europe. MILESTONE focuses on current service provision in Europe, new transition-related measures, long term outcomes of young people leaving CAMHS, improving transitional care through 'managed transition', ethics of transitioning and the training of health care professionals., Methods: Data will be collected via systematic literature reviews, pan-European surveys, and focus groups with service providers, users and carers, and members of youth advocacy and mental health advocacy groups. A prospective cohort study will be conducted with a nested cluster randomised controlled trial in eight European Union (EU) countries (Belgium, Croatia, France, Germany, Ireland, Italy, Netherlands, UK) involving over 1000 CAMHS users, their carers, and clinicians., Discussion: Improving transitional care can facilitate not only recovery but also mental health promotion and mental illness prevention for young people. MILESTONE will provide evidence of the organisational structures and processes influencing transition at the service interface across differing healthcare models in Europe and longitudinal outcomes for young people leaving CAMHS, solutions for improving transitional care in a cost-effective manner, training modules for clinicians, and commissioning and policy guidelines for service providers and policy makers., Trial Registration: "MILESTONE study" registration: ISRCTN ISRCTN83240263 Registered 23 July 2015; ClinicalTrials.gov NCT03013595 Registered 6 January 2017.

Background: There is consistent evidence from observational studies of an association between occupational lifting and carrying of heavy loads and the diagnosis of hip osteoarthritis. However, due to the heterogeneity of exposure estimates considered in single studies, a dose-response relationship between cumulative physical workload and hip osteoarthritis could not be determined so far., Methods: This study aimed to analyze the dose-response relationship between cumulative physical workload and hip osteoarthritis by replacing the exposure categories of the included studies with cumulative exposure values of an external reference population. Our meta-regression analysis was based on a recently conducted systematic review (Bergmann A, Bolm-Audorff U, Krone D, Seidler A, Liebers F, Haerting J, Freiberg A, Unverzagt S, Dtsch Arztebl Int 114:581-8, 2017). The main analysis of our meta-regression comprised six case-control studies for men and five for women. The population control subjects of a German multicentre case-control study (Seidler A, Bergmann A, Jäger M, Ellegast R, Ditchen D, Elsner G, Grifka J, Haerting J, Hofmann F, Linhardt O, Luttmann A, Michaelis M, Petereit-Haack G, Schumann B, Bolm-Audorff U, BMC Musculoskelet Disord 10:48, 2009) served as the reference population. Based on the sex-specific cumulative exposure percentiles of the reference population, we assigned exposure values to each category of the included studies using three different cumulative exposure parameters. To estimate the doubling dose (the amount of physical workload to double the risk of hip osteoarthritis) on the basis of all available case-control-studies, meta-regression analyses were conducted based on the linear association between exposure values of the reference population and the logarithm of reported odds ratios (ORs) from the included studies., Results: In men, the risk to develop hip osteoarthritis was increased by an OR of 1.98 (95% CI 1.20-3.29) per 10,000 tons of weights ≥20 kg handled, 2.08 (95% CI 1.22-3.53) per 10,000 tons handled > 10 times per day and 8.64 (95% CI 1.87-39.91) per 10 6 operations. These estimations result in doubling dosages of 10,100 tons of weights ≥20 kg handled, 9500 tons ≥20 kg handled > 10 times per day and 321,400 operations of weights ≥20 kg. There was no linear association between manual handling of weights at work and risk to develop hip osteoarthritis in women., Conclusions: Under specific conditions, the application of an external reference population allows for the derivation of a dose-response relationship despite high exposure heterogeneities in the pooled studies.

Background: The PACE Plus trial was a multi-center, double-blinded, superiority randomized controlled trial (RCT) conducted in patients from Dutch general practice to investigate the efficacy of paracetamol and NSAIDs in acute non-specific low back pain (LBP). Because insufficient numbers of patients could be recruited (only four out of the required 800 patients could be recruited over a period of 6 months), the trial was prematurely terminated in February 2017, 6 months after the start of recruitment. This article aims to transparently communicate the discontinuation of PACE Plus and to make recommendations for future studies., Methods: General Practitioners (GPs) from 36 participating practices received a one-question survey in which they were asked to give the three most important factors that in their opinion contributed to failure of patient recruitment., Results: GPs of 33 out of 36 (92%) participating practices sent a response. A total of 81 factors were reported. These have been categorized into patient factors (26 out of 81 comments, 32%), GP factors (39 out of 81 comments, 48%) and research factors (16 out of 81 comments, 20%)., Discussion: Patient recruitment in the PACE Plus trial may have failed due to inefficient medication distribution, recruitment of incident rather than prevalent cases, a design that was too complicated, adequate self-management of LBP, patient expectations different from the trial's scope and lack of time of participating GPs. Substantial differences in design may explain why the preceding PACE trial did manage to successfully complete patient recruitment., Conclusion: Although the PACE Plus trial was terminated as a result of insufficient patient inclusion, the research questions addressed in this trial remain relevant but unanswered. We hope that lessons learned from the discontinuation of PACE Plus and corresponding recommendations may be helpful in the design of upcoming research projects in LBP in general practice., Trial Registration: Dutch Trial Registration NTR6089, registered September 14th 2016.

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: The objective of this analysis is to evaluate the necessity of large clinical trials using FLOW trial data., Methods: The FLOW pilot study and definitive trial were factorial trials evaluating the effect of different irrigation solutions and pressures on re-operation. To explore treatment effects over time, we analyzed data from the pilot and definitive trial in increments of 250 patients until the final sample size of 2447 patients was reached. At each increment we calculated the relative risk (RR) and associated 95% confidence interval (CI) for the treatment effect, and compared the results that would have been reported at the smaller enrolments with those seen in the final, adequately powered study., Results: The pilot study analysis of 89 patients and initial incremental enrolments in the FLOW definitive trial favored low pressure compared to high pressure (RR: 1.50, 95% CI: 0.75-3.04; RR: 1.39, 95% CI: 0.60-3.23, respectively), which is in contradiction to the final enrolment, which found no difference between high and low pressure (RR: 1.04, 95% CI: 0.81-1.33). In the soap versus saline comparison, the FLOW pilot study suggested that re-operation rate was similar in both the soap and saline groups (RR: 0.98, 95% CI: 0.50-1.92), whereas the FLOW definitive trial found that the re-operation rate was higher in the soap treatment arm (RR: 1.28, 95% CI: 1.04-1.57)., Conclusions: Our findings suggest that studies with smaller sample sizes would have led to erroneous conclusions in the management of open fracture wounds., Trial Registration: NCT01069315 (FLOW Pilot Study) Date of Registration: February 17, 2010, NCT00788398 (FLOW Definitive Trial) Date of Registration: November 10, 2008.

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer., Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy., Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.

Background: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions., Methods: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics., Findings: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff., Conclusion: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Background: Analyses of multicenter studies often need to account for center clustering to ensure valid inference. For binary outcomes, it is particularly challenging to properly adjust for center when the number of centers or total sample size is small, or when there are few events per center. Our objective was to evaluate the performance of generalized estimating equation (GEE) log-binomial and Poisson models, generalized linear mixed models (GLMMs) assuming binomial and Poisson distributions, and a Bayesian binomial GLMM to account for center effect in these scenarios., Methods: We conducted a simulation study with few centers (≤30) and 50 or fewer subjects per center, using both a randomized controlled trial and an observational study design to estimate relative risk. We compared the GEE and GLMM models with a log-binomial model without adjustment for clustering in terms of bias, root mean square error (RMSE), and coverage. For the Bayesian GLMM, we used informative neutral priors that are skeptical of large treatment effects that are almost never observed in studies of medical interventions., Results: All frequentist methods exhibited little bias, and the RMSE was very similar across the models. The binomial GLMM had poor convergence rates, ranging from 27% to 85%, but performed well otherwise. The results show that both GEE models need to use small sample corrections for robust SEs to achieve proper coverage of 95% CIs. The Bayesian GLMM had similar convergence rates but resulted in slightly more biased estimates for the smallest sample sizes. However, it had the smallest RMSE and good coverage across all scenarios. These results were very similar for both study designs., Conclusions: For the analyses of multicenter studies with a binary outcome and few centers, we recommend adjustment for center with either a GEE log-binomial or Poisson model with appropriate small sample corrections or a Bayesian binomial GLMM with informative priors.

Background: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs., Methods: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy., Participants: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed., Results: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful., Conclusions: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research., Trial Registration: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012.

Background: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers., Methods: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project., Results: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential., Conclusions: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

Background: Clinical trial globalization is a major trend for industry-sponsored clinical trials. There has been a shift in clinical trial sites towards emerging regions of Eastern Europe, Latin America, Asia, the Middle East, and Africa. Our study objectives were to evaluate the current characteristics of clinical trials and to find out the associated multiple factors which could explain clinical trial globalization and its implications for clinical trial globalization in 2011-2013., Methods: The data elements of "phase," "recruitment status," "type of sponsor," "age groups," and "design of trial" from 30 countries were extracted from the ClinicalTrials.gov website. Ten continental representative countries including the USA were selected and the design elements were compared to those of the USA. Factors associated with trial site distribution were chosen for a multilinear regression analysis., Results: The USA, Germany, France, Canada, and United Kingdom were the "top five" countries which frequently held clinical trials. The design elements from nine continental representative countries were quite different from those of the USA; phase 1 trials were more prevalent in India (OR 1.517, p < 0.001) while phase 3 trials were much more prevalent in all nine representative countries than in the USA. A larger number of "child" age group trials was performed in Poland (OR 1.852, p < 0.001), Israel (OR 1.546, p = 0.005), and South Africa (OR 1.963, p < 0.001) than in the USA. Multivariate analysis showed that health care expenditure per capita, Economic Freedom Index, Human Capital Index, and Intellectual Property Rights Index could explain the variance of regional distribution of clinical trials by 63.6%., Conclusions: The globalization of clinical trials in the emerging regions of Asia, South Africa, and Eastern Europe developed in parallel with the factors of economic drive, population for recruitment, and regulatory constraints.

Background: The stepped wedge cluster randomised trial (SW-CRT) is increasingly being used to evaluate policy or service delivery interventions. However, there is a dearth of trials literature addressing analytical approaches to the SW-CRT. Perhaps as a result, a significant number of published trials have major methodological shortcomings, including failure to adjust for secular trends at the analysis stage. Furthermore, the commonly used analytical framework proposed by Hussey and Hughes makes several assumptions., Methods: We highlight the assumptions implicit in the basic SW-CRT analytical model proposed by Hussey and Hughes. We consider how simple modifications of the basic model, using both random and fixed effects, can be used to accommodate deviations from the underlying assumptions. We consider the implications of these modifications for the intracluster correlation coefficients. In a case study, the importance of adjusting for the secular trend is illustrated., Results: The basic SW-CRT model includes a fixed effect for time, implying a common underlying secular trend across steps and clusters. It also includes a single term for treatment, implying a constant shift in this trend under the treatment. When these assumptions are not realistic, simple modifications can be implemented to allow the secular trend to vary across clusters and the treatment effect to vary across clusters or time. In our case study, the naïve treatment effect estimate (adjusted for clustering but unadjusted for time) suggests a beneficial effect. However, after adjusting for the underlying secular trend, we demonstrate a reversal of the treatment effect., Conclusion: Due to the inherent confounding of the treatment effect with time, analysis of a SW-CRT should always account for secular trends or risk-biased estimates of the treatment effect. Furthermore, the basic model proposed by Hussey and Hughes makes a number of important assumptions. Consideration needs to be given to the appropriate model choice at the analysis stage. We provide a Stata code to implement the proposed analyses in the illustrative case study.

Background: Trials of complex interventions are associated with high costs and burdens in terms of paperwork, management, data collection, validation, and intervention fidelity assessment occurring across multiple sites. Traditional data collection methods rely on paper-based forms, where processing can be time-consuming and error rates high. Electronic source data collection can potentially address many of these inefficiencies, but has not routinely been used in complex intervention trials. Here we present the use of an on-line system for managing all aspects of data handling and for the monitoring of trial processes in a multicentre trial of a complex intervention. We custom built a web-accessible software application for the delivery of ENGAGE-HD, a multicentre trial of a complex physical therapy intervention. The software incorporated functionality for participant randomisation, data collection and assessment of intervention fidelity. It was accessible to multiple users with differing levels of access depending on required usage or to maintain blinding. Each site was supplied with a 4G-enabled iPad for accessing the system. The impact of this system was quantified through review of data quality and collation of feedback from site coordinators and assessors through structured process interviews., Results: The custom-built system was an efficient tool for collecting data and managing trial processes. Although the set-up time required was significant, using the system resulted in an overall data completion rate of 98.5% with a data query rate of 0.1%, the majority of which were resolved in under a week. Feedback from research staff indicated that the system was highly acceptable for use in a research environment. This was a reflection of the portability and accessibility of the system when using the iPad and its usefulness in aiding accurate data collection, intervention fidelity and general administration., Conclusions: A combination of commercially available hardware and a bespoke online database designed to support data collection, intervention fidelity and trial progress provides a viable option for streamlining trial processes in a multicentre complex intervention trial. There is scope to further extend the system to cater for larger trials and add further functionality such as automatic reporting facilities and participant management support., Trial Registration: ISRCTN65378754 , registered on 13 March 2014.

Background: Subject recruitment for medical research is challenging. Slow patient accrual leads to increased costs and delays in treatment advances. Researchers need reliable tools to manage and predict the accrual rate. The previously developed Bayesian method integrates researchers' experience on former trials and data from an ongoing study, providing a reliable prediction of accrual rate for clinical studies., Methods: In this paper, we present a user-friendly graphical user interface program developed in R. A closed-form solution for the total subjects that can be recruited within a fixed time is derived. We also present a built-in Android system using Java for web browsers and mobile devices., Results: Using the accrual software, we re-evaluated the Veteran Affairs Cooperative Studies Program 558- ROBOTICS study. The application of the software in monitoring and management of recruitment is illustrated for different stages of the trial., Conclusions: This developed accrual software provides a more convenient platform for estimation and prediction of the accrual process.

Background: Electromagnetic navigation bronchoscopy (ENB) procedures allow physicians to access peripheral lung lesions beyond the reach of conventional bronchoscopy. However, published research is primarily limited to small, single-center studies using previous-generation ENB software. The impact of user experience, patient factors, and lesion/procedural characteristics remains largely unexplored in a large, multicenter study., Methods/design: NAVIGATE (Clinical Evaluation of superDimension™ Navigation System for Electromagnetic Navigation Bronchoscopy) is a prospective, multicenter, global, cohort study. The study aims to enroll up to 2,500 consecutive subjects presenting for evaluation of lung lesions utilizing the ENB procedure at up to 75 clinical sites in the United States, Europe, and Asia. Subjects will be assessed at baseline, at the time of procedure, and at 1, 12, and 24 months post-procedure. The pre-test probability of malignancy will be determined for peripheral lung nodules. Endpoints include procedure-related adverse events, including pneumothorax, bronchopulmonary hemorrhage, and respiratory failure, as well as quality of life, and subject satisfaction. Diagnostic yield and accuracy, repeat biopsy rate, tissue adequacy for genetic testing, and stage at diagnosis will be reported for biopsy procedures. Complementary technologies, such as fluoroscopy and endobronchial ultrasound, will be explored. Success rates of fiducial marker placement, dye marking, and lymph node biopsies will be captured when applicable. Subgroup analyses based on geography, demographics, investigator experience, and lesion and procedure characteristics are planned., Discussion: Study enrollment began in April 2015. As of February 19, 2016, 500 subjects had been enrolled at 23 clinical sites with enrollment ongoing. NAVIGATE will be the largest prospective, multicenter clinical study on ENB procedures to date and will provide real-world experience data on the utility of the ENB procedure in a broad range of clinical scenarios., Trial Registration: ClinicalTrials.gov NCT02410837 . Registered 31 March 2015.

Background: There is an increasing interest worldwide to ensure evidence-informed health policymaking as a means to improve health systems performance. There is a need to engage policymakers in collaborative approaches to generate and use knowledge in real world settings. To address this gap, we implemented two interventions based on iterative exchanges between researchers and policymakers/implementers. This article aims to reflect on the implementation and impact of these multi-site evidence-to-policy approaches implemented in low-resource settings., Methods: The first approach was implemented in Mexico and Nicaragua and focused on implementation research facilitated by communities of practice (CoP) among maternal health stakeholders. We conducted a process evaluation of the CoPs and assessed the professionals' abilities to acquire, analyse, adapt and apply research. The second approach, called the Policy BUilding Demand for evidence in Decision making through Interaction and Enhancing Skills (Policy BUDDIES), was implemented in South Africa and Cameroon. The intervention put forth a 'buddying' process to enhance demand and use of systematic reviews by sub-national policymakers. The Policy BUDDIES initiative was assessed using a mixed-methods realist evaluation design., Results: In Mexico, the implementation research supported by CoPs triggered monitoring by local health organizations of the quality of maternal healthcare programs. Health programme personnel involved in CoPs in Mexico and Nicaragua reported improved capacities to identify and use evidence in solving implementation problems. In South Africa, Policy BUDDIES informed a policy framework for medication adherence for chronic diseases, including both HIV and non-communicable diseases. Policymakers engaged in the buddying process reported an enhanced recognition of the value of research, and greater demand for policy-relevant knowledge., Conclusions: The collaborative evidence-to-policy approaches underline the importance of iterations and continuity in the engagement of researchers and policymakers/programme managers, in order to account for swift evolutions in health policy planning and implementation. In developing and supporting evidence-to-policy interventions, due consideration should be given to fit-for-purpose approaches, as different needs in policymaking cycles require adapted processes and knowledge. Greater consideration should be provided to approaches embedding the use of research in real-world policymaking, better suited to the complex adaptive nature of health systems.

Background: With the increase of clinical trial costs during the last decades, the design of feasibility studies has become an essential process to reduce avoidable and costly protocol amendments. This design includes timelines, targeted sites and budget, together with a list of eligibility criteria that potential participants need to match. The present work was designed to assess the value of obtaining potential study participant counts using an automated patient count cohort system for large multi-country and multi-site trials: the Electronic Health Records for Clinical Research (EHR4CR) system., Methods: The evaluation focuses on the accuracy of the patient counts and the time invested to obtain these using the EHR4CR platform compared to the current questionnaire based process. This evaluation will assess the patient counts from ten clinical trials at two different sites. In order to assess the accuracy of the results, the numbers obtained following the two processes need to be compared to a baseline number, the "alloyed" gold standard, which was produced by a manual check of patient records., Results: The patient counts obtained using the EHR4CR system were in three evaluated trials more accurate than the ones obtained following the current process whereas in six other trials the current process counts were more accurate. In two of the trials both of the processes had counts within the gold standard's confidence interval. In terms of efficiency the EHR4CR protocol feasibility system proved to save approximately seven calendar days in the process of obtaining patient counts compared to the current manual process., Conclusions: At the current stage, electronic health record data sources need to be enhanced with better structured data so that these can be re-used for research purposes. With this kind of data, systems such as the EHR4CR are able to provide accurate objective patient counts in a more efficient way than the current methods. Additional research using both structured and unstructured data search technology is needed to assess the value of unstructured data and to compare the amount of efforts needed for data preparation.

Background: Comprehensive rehabilitation, involving health professionals from various disciplines, is widely used as an adjunct to pharmacological and surgical treatment in people with rheumatic diseases. However, the evidence for the clinical- and cost-effectiveness of such interventions is limited, and the majority of those who receive rehabilitation are back to their initial health status six to 12 months after discharge., Methods/design: To evaluate the goal attainment, health effects and cost-effectiveness of a new rehabilitation programme compared to current traditional rehabilitation programmes for people with rheumatic diseases, a stepped-wedge cluster randomized trial will be performed. Patients admitted for rehabilitation at six centres in the south-eastern part of Norway will be invited to participate. In the trial, six participating centres will switch from a control (current rehabilitation programme) to an intervention phase (the new rehabilitation programme) in a randomized order. Supported by recent research, the new programme will be a supplement to the existing programme at each centre, and will comprise four elements designed to enhance and support lifestyle changes introduced in the rehabilitation period: structured goal-planning, motivational interviewing, a self-help booklet and four follow-up telephone calls during the first five months following discharge. The primary outcome will be health-related quality of life and goal attainment, as measured by the Patient Generated Index directly before and after the rehabilitation stay, as well as after six and 12 months. Secondary outcomes will include self-reported pain, fatigue, a global assessment of disease activity and motivation for change (measured on 11-point numeric ratings scales), health-related quality of life as measured by the Short Form 36 Health Survey (SF-36) and utility assessed by the SF6D utility index.The main analysis will be on an intention to treat basis and will assess the clinical- and cost-effectiveness of the structured goal planning and tailored follow-up rehabilitation programme for patients with rheumatic diseases., Discussion: The findings will constitute an important contribution to more cost-effective- and evidence-based rehabilitation services for people with rheumatic diseases., Trial Registration: ISRCTN91433175.

Background: Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA)., Methods/design: CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-α inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naïve and biologic experienced)., Discussion: The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA.

Background: Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic., Methods: We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial., Results: We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative., Conclusions: By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

Background: Cluster randomized trials are increasingly being used in healthcare evaluation to show the effectiveness of a specific intervention. Care pathways (CPs) are becoming a popular tool to improve the quality of health-care services provided to heart failure patients. In order to perform a well-designed cluster randomized trial to demonstrate the effectiveness of Usual care (UC) and CP in heart failure treatment, the intraclass correlation coefficient (ICC) should be available before conducting a trial to estimate the required sample size. This study reports ICCs for both demographical and outcome variables from cluster randomized trials of heart failure patients in UC and care pathways., Methods: To calculate the degree of within-cluster dependence, the ICC and associated 95% confidence interval were calculated by a method based on analysis of variance. All analyses were performed in R software version 2.15.1., Results: ICCs for baseline characteristics ranged from 0.025 to 0.058. The median value and interquartile range was 0.043 [0.026-0.052] for ICCs of baseline characteristics. Among baseline characteristics, the highest ICCs were found for admission by referral or admission from home (ICC = 0.058) and the disease severity at admission (ICC = 0.046). Corresponding ICCs for appropriateness of the stay, length of stay and hospitalization cost were 0.069, 0.063, and 0.001 in CP group and 0.203, 0.020, 0.046 for usual care, respectively., Conclusion: Reported values of ICCs from present care pathway trial and UC results for some common outcomes will be helpful for estimating sample size in future clustered randomized heart failure trials, in particular for the evaluation of care pathways.

Background: It is often desirable to account for centre-effects in the analysis of multicentre randomised trials, however it is unclear which analysis methods are best in trials with a binary outcome., Methods: We compared the performance of four methods of analysis (fixed-effects models, random-effects models, generalised estimating equations (GEE), and Mantel-Haenszel) using a re-analysis of a previously reported randomised trial (MIST2) and a large simulation study., Results: The re-analysis of MIST2 found that fixed-effects and Mantel-Haenszel led to many patients being dropped from the analysis due to over-stratification (up to 69% dropped for Mantel-Haenszel, and up to 33% dropped for fixed-effects). Conversely, random-effects and GEE included all patients in the analysis, however GEE did not reach convergence. Estimated treatment effects and p-values were highly variable across different analysis methods.The simulation study found that most methods of analysis performed well with a small number of centres. With a large number of centres, fixed-effects led to biased estimates and inflated type I error rates in many situations, and Mantel-Haenszel lost power compared to other analysis methods in some situations. Conversely, both random-effects and GEE gave nominal type I error rates and good power across all scenarios, and were usually as good as or better than either fixed-effects or Mantel-Haenszel. However, this was only true for GEEs with non-robust standard errors (SEs); using a robust 'sandwich' estimator led to inflated type I error rates across most scenarios., Conclusions: With a small number of centres, we recommend the use of fixed-effects, random-effects, or GEE with non-robust SEs. Random-effects and GEE with non-robust SEs should be used with a moderate or large number of centres.

Background: Sensitivity analyses are an important tool for understanding the extent to which the results of randomised trials depend upon the assumptions of the analysis. There is currently no guidance governing the choice of sensitivity analyses., Discussion: We provide a principled approach to choosing sensitivity analyses through the consideration of the following questions: 1) Does the proposed sensitivity analysis address the same question as the primary analysis? 2) Is it possible for the proposed sensitivity analysis to return a different result to the primary analysis? 3) If the results do differ, is there any uncertainty as to which will be believed? Answering all of these questions in the affirmative will help researchers to identify relevant sensitivity analyses. Treating analyses as sensitivity analyses when one or more of the answers are negative can be misleading and confuse the interpretation of studies. The value of these questions is illustrated with several examples., Summary: By removing unreasonable analyses that might have been performed, these questions will lead to relevant sensitivity analyses, which help to assess the robustness of trial results.

Background: Comparison of outcomes between populations or centres may be confounded by any casemix differences and standardisation is carried out to avoid this. However, when the casemix adjustment models are large and complex, direct standardisation has been described as "practically impossible", and indirect standardisation may lead to unfair comparisons. We propose a new method of directly standardising for risk rather than standardising for casemix which overcomes these problems., Methods: Using a casemix model which is the same model as would be used in indirect standardisation, the risk in individuals is estimated. Risk categories are defined, and event rates in each category for each centre to be compared are calculated. A weighted sum of the risk category specific event rates is then calculated. We have illustrated this method using data on 6 million admissions to 146 hospitals in England in 2007/8 and an existing model with over 5000 casemix combinations, and a second dataset of 18,668 adult emergency admissions to 9 centres in the UK and overseas and a published model with over 20,000 casemix combinations and a continuous covariate., Results: Substantial differences between conventional directly casemix standardised rates and rates from direct risk standardisation (DRS) were found. Results based on DRS were very similar to Standardised Mortality Ratios (SMRs) obtained from indirect standardisation, with similar standard errors., Conclusions: Direct risk standardisation using our proposed method is as straightforward as using conventional direct or indirect standardisation, always enables fair comparisons of performance to be made, can use continuous casemix covariates, and was found in our examples to have similar standard errors to the SMR. It should be preferred when there is a risk that conventional direct or indirect standardisation will lead to unfair comparisons.

Background: In multicenter studies, center-specific variations in measurements may arise for various reasons, such as low interrater reliability, differences in equipment, deviations from the protocol, sociocultural characteristics, and differences in patient populations due to e.g. local referral patterns. The aim of this research is to derive measures for the degree of clustering. We present a method to detect heavily clustered variables and to identify physicians with outlying measurements., Methods: We use regression models with fixed effects to account for patient case-mix and a random cluster intercept to study clustering by physicians. We propose to use the residual intraclass correlation (RICC), the proportion of residual variance that is situated at the cluster level, to detect variables that are influenced by clustering. An RICC of 0 indicates that the variance in the measurements is not due to variation between clusters. We further suggest, where appropriate, to evaluate RICC in combination with R2, the proportion of variance that is explained by the fixed effects. Variables with a high R2 may have benefits that outweigh the disadvantages of clustering in terms of statistical analysis. We apply the proposed methods to a dataset collected for the development of models for ovarian tumor diagnosis. We study the variability in 18 tumor characteristics collected through ultrasound examination, 4 patient characteristics, and the serum marker CA-125 measured by 40 physicians on 2407 patients., Results: The RICC showed large variation between variables: from 2.2% for age to 25.1% for the amount of fluid in the pouch of Douglas. Seven variables had an RICC above 15%, indicating that a considerable part of the variance is due to systematic differences at the physician level, rather than random differences at the patient level. Accounting for differences in ultrasound machine quality reduced the RICC for a number of blood flow measurements., Conclusions: We recommend that the degree of data clustering is addressed during the monitoring and analysis of multicenter studies. The RICC is a useful tool that expresses the degree of clustering as a percentage. Specific applications are data quality monitoring and variable screening prior to the development of a prediction model.

Background: For a randomized trial, the primary publication is usually the one which reports the results of the primary outcome and provides consolidated data from all study centers. Other aspects of a randomized trial's findings (that is, non-primary results) are often reported in subsequent publications., Methods: We carried out a cross-sectional review of the characteristics and type of information reported in non-primary reports (n = 69) of randomized trials (indexed in PubMed core clinical journals in 2009) and whether they report pre-specified or exploratory analyses. We also compared consistency of information in non-primary publications with that reported in the primary publication., Results: The majority (n = 56; 81%) of non-primary publications were large, multicenter trials, published in specialty journals. Most reported subgroup analyses (n = 27; 39%), analyzing a specific subgroup of patients from the randomized trial, or reported on secondary outcomes (n = 29; 42%); 19% (n = 13) reported extended follow-up. Less than half reported details of trial registration (n = 30; 43%) or the trial protocol (n = 27; 39%) and in 41% (n = 28) it was unclear from reading the abstract that the report was not the primary publication for the trial. Non-primary publications often analyzed and reported multiple different outcomes (16% reported >20 outcomes) and in 10% (n = 7) it was unclear how many outcomes had actually been assessed; in 42% (n = 29) it was unclear whether the analyses reported were pre-specified or exploratory. Only 39% (n = 27) of non-primary publications described the primary outcome of the randomized trial, 6% (n = 4) reported its numerical results and 9% (n = 6) details of how participants were randomized., Conclusion: Non-primary publications often lack important information about the randomized trial and the type of analyses conducted and whether these were pre-specified or exploratory to enable readers to accurately identify and assess the validity and reliably of the study findings. We provide recommendations for what information authors should include in non-primary reports of randomized trials.

Background: Randomised controlled trials (RCTs) are the gold standard assessment for health technologies. A key aspect of the design of any clinical trial is the target sample size. However, many publicly-funded trials fail to reach their target sample size. This study seeks to assess the current state of recruitment success and grant extensions in trials funded by the Health Technology Assessment (HTA) program and the UK Medical Research Council (MRC)., Methods: Data were gathered from two sources: the National Institute for Health Research (NIHR) HTA Journal Archive and the MRC subset of the International Standard Randomised Controlled Trial Number (ISRCTN) register. A total of 440 trials recruiting between 2002 and 2008 were assessed for eligibility, of which 73 met the inclusion criteria. Where data were unavailable from the reports, members of the trial team were contacted to ensure completeness., Results: Over half (55%) of trials recruited their originally specified target sample size, with over three-quarters (78%) recruiting 80% of their target. There was no evidence of this improving over the time of the assessment. Nearly half (45%) of trials received an extension of some kind. Those that did were no more likely to successfully recruit. Trials with 80% power were less likely to successfully recruit compared to studies with 90% power., Conclusions: While recruitment appears to have improved since 1994 to 2002, publicly-funded trials in the UK still struggle to recruit to their target sample size, and both time and financial extensions are often requested. Strategies to cope with such problems should be more widely applied. It is recommended that where possible studies are planned with 90% power.

Background: The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas β-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients., Methods/design: This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L., Discussion: This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM., Trial Registration: ChiCTR-TRC-12002546.