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Background Clinical trials generally each collect their own data despite routinely collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD. Methods We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013 and 2018 for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction were undertaken between January and May 2019. Results We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (about 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes. Conclusions In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined-up thinking between the registries and the regulatory authorities. Trial registration PROSPERO CRD42019123088 .

Background Traditional randomised controlled trials (RCTs) are the gold standard for evaluating the effectiveness of interventions in clinical research. Traditional RCTs however are complex, expensive and have low external validity. Registry-based randomised controlled trials (RRCTs) are an emerging alternative approach that integrates the internal validity of a traditional RCT with the external validity of a clinical registry by recruiting more real-world patients and leveraging an existing registry platform for data collection. As RRCTs are a novel research design, there is limited understanding of the RRCT landscape in Australia. This qualitative study aims to explore the RRCT landscape in Australia including current capacity and capabilities, and to identify challenges and opportunities for conducting RRCTs. Methods We conducted 30 semi-structured interviews with 18 clinician researchers, 6 research program managers and 6 research governance officers. Interviews were audio-recorded and transcribed verbatim. We analysed the data using thematic analysis. Results We identified four overarching themes: (1) understanding of the RRCT methodology concept and knowledge of Australian clinical registries and RRCT landscape; (2) enablers and barriers in the uptake and conduct of RRCTs; (3) ethics and governance requirements impacting the conduct of RRCTs and (4) recommendations for the promotion, support and implementation of RRCTs. Understanding of and ability to define an RRCT varied considerably amongst participants, as did their appreciation of the role the registry should play in supporting these trials. Lack of ongoing funding to support both registries and RRCTs, along with low awareness and minimal education around this methodology, were identified as the predominant barriers to the uptake of RRCTs in Australia. The simplicity of RRCTs, specifically their pragmatic nature and lower costs, was identified as one of their best attributes. There was consensus that inadequate funding, onerous research governance requirements and poor awareness of this methodology were currently prohibitive in enticing clinicians and researchers to conduct RRCTs. Recommendations to improve the uptake of RRCTs included establishing a sustainable funding model for both registries and RRCTs, harmonising governance requirements across jurisdictions and increasing awareness of RRCTs through education initiatives. Conclusions RRCTs in Australia are an evolving methodology with slow but steady uptake across a number of clinical disciplines. Whilst RRCTs are increasingly identified as a beneficial alternative methodology to evaluate and improve current standards of care, several barriers to effective RRCT implementation were identified. Creating greater awareness of the benefits of RRCTs across a number of stakeholders to help secure ongoing funding and addressing both registry and RRCT governance challenges are two essential steps in enhancing the uptake of RRCTs in Australia and internationally.

Background Recent studies have demonstrated a correlation between intestinal flora and the severity of myocardial infarction as well as post-myocardial infarction repair. However, few studies have investigated whether probiotics reduce mortality and improve cardiovascular outcomes in patients with acute myocardial infarction. In this study, we will conduct a randomized controlled trial (RCT) to evaluate the effect of probiotics on in-hospital mortality and the incidence of major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). Methods This is an open-label, randomized, controlled, superiority clinical trial involving 2594 adult patients who were diagnosed with acute myocardial infarction. Patients will be randomized to (1) receive bifidobacteria triple viable capsule ( Bifidobacterium longum , Lactobacillus acidophilu s, and Enterococcus faecalis ) 840 mg, twice a day, plus standard treatment strategy during the hospital stay, for a maximum of 30 days, or (2) receive the standard treatment strategy and will not take the bifidobacterium triple live capsule. The primary outcome was in-hospital all-cause mortality. Discussion The purpose of this clinical trial is to determine whether probiotics can reduce in-hospital mortality and improve prognosis in patients with AMI, and the results will provide evidence for probiotics as a complementary treatment for AMI. Trial registration Chinese Clinical Trials Registry ChiCTR2000038797. Registered on 2 October 2020.

Background The advantages of laparoscopic left-sided hepatectomy (LLH) for treating hepatolithiasis in terms of the time to postoperative length of hospital stay (LOS), morbidity, long-term abdominal wall hernias, hospital costs, residual stone rate, and recurrence of calculus have not been confirmed by a randomized controlled trial. The aim of this trial is to compare the safety and effectiveness of LLH with open left-sided hepatectomy (OLH) for the treatment of hepatolithiasis. Methods Patients with hepatolithiasis eligible for left-sided hepatectomy will be recruited. The experimental design will produce two randomized arms (laparoscopic and open hepatectomy) at a 1:1 ratio and a prospective registry. All patients will undergo surgery in the setting of an enhanced recovery after surgery (ERAS) programme. The prospective registry will be based on patients who cannot be randomized because of the explicit treatment preference of the patient or surgeon or because of ineligibility (not meeting the inclusion and exclusion criteria) for randomization in this trial. The primary outcome is the LOS. The secondary outcomes are percentage readmission, morbidity, mortality, hospital costs, long-term incidence of incisional hernias, residual stone rate, and recurrence of calculus. It will be assumed that, in patients undergoing LLH, the length of hospital stay will be reduced by 1 day. A sample size of 86 patients in each randomization arm has been calculated as sufficient to detect a 1-day reduction in LOS [90% power and α  = 0.05 (two-tailed)]. The trial is a randomized controlled trial that will provide evidence for the merits of laparoscopic surgery in patients undergoing liver resection within an ERAS programme. Conclusions Although the outcomes of LLH have been proven to be comparable to those of OLH in retrospective studies, the use of LLH remains restricted, partly due to the lack of short- and long-term informative RCTs pertaining to patients with hepatolithiasis in ERAS programmes. To evaluate the surgical and long-term outcomes of LLH, we will perform a prospective RCT to compare LLH with OLH for hepatolithiasis within an ERAS programme. Trial registration ClinicalTrials.gov NCT03958825. Registered on 21 May 2019.

Background Many technology companies, including Airbnb, Amazon, Booking.com , eBay, Facebook, Google, LinkedIn, Lyft, Microsoft, Netflix, Twitter, Uber, and Yahoo!/Oath, run online randomized controlled experiments at scale, namely hundreds of concurrent controlled experiments on millions of users each, commonly referred to as A/B tests. Originally derived from the same statistical roots, randomized controlled trials (RCTs) in medicine are now criticized for being expensive and difficult, while in technology, the marginal cost of such experiments is approaching zero and the value for data-driven decision-making is broadly recognized. Methods and results This is an overview of key scaling lessons learned in the technology field. They include (1) a focus on metrics, an overall evaluation criterion and thousands of metrics for insights and debugging, automatically computed for every experiment; (2) quick release cycles with automated ramp-up and shut-down that afford agile and safe experimentation, leading to consistent incremental progress over time; and (3) a culture of ‘test everything’ because most ideas fail and tiny changes sometimes show surprising outcomes worth millions of dollars annually. Technological advances, online interactions, and the availability of large-scale data allowed technology companies to take the science of RCTs and use them as online randomized controlled experiments at large scale with hundreds of such concurrent experiments running on any given day on a wide range of software products, be they web sites, mobile applications, or desktop applications. Rather than hindering innovation, these experiments enabled accelerated innovation with clear improvements to key metrics, including user experience and revenue. As healthcare increases interactions with patients utilizing these modern channels of web sites and digital health applications, many of the lessons apply. The most innovative technological field has recognized that systematic series of randomized trials with numerous failures of the most promising ideas leads to sustainable improvement. Conclusion While there are many differences between technology and medicine, it is worth considering whether and how similar designs can be applied via simple RCTs that focus on healthcare decision-making or service delivery. Changes – small and large – should undergo continuous and repeated evaluations in randomized trials and learning from their results will enable accelerated healthcare improvements.

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

Background The incidence of colorectal cancer among the middle-aged and elderly is gradually increasing in China. Colonoscopy is an effective method for the early diagnosis of colorectal cancer, and bowel preparation is one of many important factors affecting colonoscopy. Although there are many studies on intestinal cleansers, the results are not ideal. There is evidence that hemp seed oil has certain potential effects in intestinal cleansing, but prospective studies on this topic are still lacking. Methods This is a randomized, double-blind, single-center clinical study. We randomly assigned 690 participants to groups each administered 3 L of polyethylene glycol (PEG), 30 mL of hemp seed oil and 2 L of PEG, or 30 mL of hempseed oil, 2 L of PEG, and 1000 mL of 5% sugar brine. The Boston Bowel Preparation Scale was considered the primary outcome measure. We evaluated the interval between consumption of bowel preparation and first bowel movement. Secondary indicators included the time of cecal intubation, detection rate of polyps and adenomas, willingness to repeat the same bowel preparation, whether the protocol was tolerated, and whether there were adverse reactions during bowel preparation and were evaluated after counting the total number of bowel movements. Discussion This study aimed to test the hypothesis that hemp seed oil (30 mL) increases the quality of bowel preparation and reduces the amount of PEG. Previously, we found that its combination with 5% sugar brine can reduce the occurrence of adverse reactions. Trial registration Chinese Clinical Trial Registry ChiCTR2200057626. Prospectively registered on March 15, 2022

Background The use of electronic patient records for assessing outcomes in clinical trials is a methodological strategy intended to drive faster and more cost-efficient acquisition of results. The aim of this manuscript was to outline the data collection and management considerations of a maternity and perinatal clinical trial using data from electronic patient records, exemplifying the DESiGN Trial as a case study. Methods The DESiGN Trial is a cluster randomised control trial assessing the effect of a complex intervention versus standard care for identifying small for gestational age foetuses. Data on maternal/perinatal characteristics and outcomes including infants admitted to neonatal care, parameters from foetal ultrasound and details of hospital activity for health-economic evaluation were collected at two time points from four types of electronic patient records held in 22 different electronic record systems at the 13 research clusters. Data were pseudonymised on site using a bespoke Microsoft Excel macro and securely transferred to the central data store. Data quality checks were undertaken. Rules for data harmonisation of the raw data were developed and a data dictionary produced, along with rules and assumptions for data linkage of the datasets. The dictionary included descriptions of the rationale and assumptions for data harmonisation and quality checks. Results Data were collected on 182,052 babies from 178,350 pregnancies in 165,397 unique women. Data availability and completeness varied across research sites; each of eight variables which were key to calculation of the primary outcome were completely missing in median 3 (range 1–4) clusters at the time of the first data download. This improved by the second data download following clarification of instructions to the research sites (each of the eight key variables were completely missing in median 1 (range 0–1) cluster at the second time point). Common data management challenges were harmonising a single variable from multiple sources and categorising free-text data, solutions were developed for this trial. Conclusions Conduct of clinical trials which use electronic patient records for the assessment of outcomes can be time and cost-effective but still requires appropriate time and resources to maximise data quality. A difficulty for pregnancy and perinatal research in the UK is the wide variety of different systems used to collect patient data across maternity units. In this manuscript, we describe how we managed this and provide a detailed data dictionary covering the harmonisation of variable names and values that will be helpful for other researchers working with these data. Trial registration Primary registry and trial identifying number: ISRCTN 67698474. Registered on 02/11/16.

Background Our previous randomized controlled trial (RCT) have demonstrated that intermittent Pringle’s maneuver (IPM) with a 25-min ischemic interval can be applied safely and efficiently in open or laparoscopic hepatectomy in patients with hepatocellular carcinoma (HCC) patients. But prolonging the hepatic inflow blocking time will inevitably aggravate the ischemia-reperfusion injury (IRI) caused by systemic response. This RCT aims to evaluate the effect of administration of dexamethasone versus placebo before clamping the hilar pedicle on postoperative liver function, inflammatory response, and perioperative outcomes among HCC patients undergoing liver resection with 25-min hepatic inflow occlusion. Methods and analysis This will be a randomized, dual-arm, parallel-group, double-blinded trial. All eligible and consecutive patients are coming from a regional medical center who are diagnosed with HCC and underwent radical R0/R1 resection. All participates are randomly allocated in dexamethasone group or placebo group. All surgeons, anesthesiologists, and outcome assessors will be blinded to allocation status. Primary endpoints are transaminase-based postoperative hepatic injury on seven consecutive days after surgery and assessed by their peak values as well as area under the curve (AUC) of the postoperative course of aminotransferases. Secondary endpoints are postoperative total bilirubin (TBil), coagulation function, inflammatory cytokines and their respective peaks, intraoperative blood loss, postoperative hospital stay, morbidity, and mortality. The above parameters will be compared using the corresponding statistical approach. Subgroup analysis will be performed according to the liver cirrhosis and major hepatectomy. Discussion Based on our previous study, we will explore further the effect of glucocorticoid administration on attenuating the surgical stress response in order to follow securely 25-min hepatic inflow occlusion. Therefore, the trial protocol is reasonable and the results of the trial may be clinically significant. Trial registration This trial was registered on 3 December 2022, in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR2200066381. The protocol version is V1.0 (20221104).

Background It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative ( http://www.comet-initiative.org/ . Accessed 3 Apr 2020) supports and encourages the development and use of ‘core outcome sets’ (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this. Methods We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study. Results There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR. Conclusions This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.