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Provisions for post-trial care {30} | Not applicable—as there is no intervention directly to participants. The intervention, additional hospital cleaning, carries no additional risk to participants. | PMC9944767 | ||
Outcomes {12} | SECONDARY | The primary outcome is the proportion of inpatients aged ≥ 18 years old with a HAI as measured by a HAI point prevalence study (PPS). The secondary outcomes are the thoroughness of cleaning as being the proportion of dots that were completely removed, as measured by the FM gel and ultraviolet light system, and the cost-effectiveness of the intervention compared with routine cleaning. | PMC9944767 | |
Sample size {14} | HAI infection, FM | The participant timeline is shown in Fig. Timeline for enrolment, interventions and assessments of the study. FM fluorescent markers, HAI healthcare-associated infectionThe study design ensures a sample size sufficient to detect a relative reduction of at least 35% in total HAI infection, with a baseline point prevalence of 11%. It is powered at 80%, based on a two-sided 5% significance level with an inter-cluster correlation of 0.3 and coefficient of variation of 0.65—allowing for variation in cluster size. A stepped wedge sample size formula was used, considering the number and size of clusters and the time period. The required cluster size is 132 (66 per ward), achieved with two wards forming clusters and three fortnightly PPS each time period ( | PMC9944767 | |
Recruitment {15} | DISEASE | In alignment with past approaches in Australia and the European Centre for Disease Prevention and Control protocol, all patients admitted to the ward before or at 08:00 h on the first survey day and not discharged from the ward at the time of the survey will be eligible and will be evaluated for a HAI. Patients transferred in or out after 08:00 h will not be included. Patients will be excluded if they are under 18 years of age or are due to have same-day treatment or surgery. | PMC9944767 | |
Assignment of interventions: allocation | PMC9944767 | |||
Sequence generation {16a} | FM | There will be two wards allocated to each cluster. The allocation of when each cluster will commence the intervention will be randomised using Microsoft Excel. This will be undertaken by the study statistician, not involved in data collection or the determination of outcomes. The equipment to be tested in the FM audit will be randomised using Microsoft Excel to ensure a variety of shared medical equipment is audited. This will be undertaken by one member of the research team, not involved in data collection or the determination of outcomes. | PMC9944767 | |
Concealment mechanism {16b} | Once randomisation has occurred and each ward is allocated into a cluster, this information will be kept by the person undertaking randomisation on their own (work) computer. This allocation will not be available to the participating wards or PSAs or those involved in data collection. Each participating ward and PSAs will be informed of the cluster allocation 2 weeks prior to the commencement of the intervention of that cluster. This concealment process will be undertaken by the person undertaking the randomisation informing the trial coordinator of the allocation, as per the timing above. The trial coordinator will then inform the ward and PSAs. | PMC9944767 | ||
Implementation {16c} | The allocation sequence will be generated by the study statistician and each ward will be randomly assigned to a cluster. As each cluster enters the intervention phase, the trial coordinator will facilitate PSA training sessions and auditing feedback. | PMC9944767 | ||
Assignment of interventions: blinding | PMC9944767 | |||
Who will be blinded {17a} | FM | The researcher collecting the data on the primary outcome (HAI data) will be blinded to the intervention (i.e. knowing whether the ward is an intervention or control ward). Similarly, the researcher collecting FM audit data will be blinded to the intervention. Results of the audit process will not be made available to wards in the control phase of the study. | PMC9944767 | |
Procedure for unblinding if needed {17b} | Once data collection and statistical analysis have been finalised, the interventions can be unblinded for the purpose of interpreting the data. | PMC9944767 | ||
Data collection and management | PMC9944767 | |||
Plans for assessment and collection of outcomes {18a} | infection | INFECTION, PATHOLOGY | A data extraction tool has been developed and piloted in REDCap®. This tool was adapted from a previous multi-centre point prevalence study (1). The researcher responsible for collecting the data will be trained in the use of the survey instrument to extract relevant data pertaining to the intervention and relevant outcomes. After reviewing medical records, pathology and microbiology databases, the researcher will determine if the patient has a HAI. The determination of a HAI will be undertaken through an algorithm applying the HAI definitions in the ECDC protocol (16). Data on each HAI identified will be consistent with the ECDC protocol. The attribution of a HAI to a ward will be determined through the use of a 48-h time frame, i.e. the infection symptom onset must occur > 48 h after admission to the ward, for it to be attributable to the ward. If a patient is transferred to a ward and a HAI is identified within 48 h of transfer, it will be attributed to the previous ward. An interrater reliability assessment will be independently undertaken to validate the accuracy of HAI determinations (1). | PMC9944767 |
Plans to promote participant retention and complete follow-up {18b} | Not applicable—as patients are not recruited and there is no patient follow-up in this study. | PMC9944767 | ||
Data management {19} | The data which will be obtained from patients’ hospital medical record will be non-identifiable and there are clear processes in place to ensure that the privacy of data is maintained. These processes include appropriate storage of data in password-protected files and the destruction of these data after completion of the study. The data will be kept for a period of 5 years from the point of any publication relating to the research. | PMC9944767 | ||
Confidentiality {27} | No identifiable data is collected. The project is supervised and overseen by a clinician, registered with the Australian Health Practitioner Regulation Authority. | PMC9944767 | ||
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | There will be no biological specimens tested in this study. | PMC9944767 | ||
Statistical methods | PMC9944767 | |||
Statistical methods for primary and secondary outcomes {20a} | PMC9944767 | |||
Primary outcome analysis | RSV, pneumonia, viral respiratory infections, generalised, bloodstream infections | BLOODSTREAM INFECTION, PNEUMONIA, URINARY TRACT INFECTIONS, SURGICAL SITE INFECTION, VIRAL RESPIRATORY INFECTION, INFLUENZA | The primary outcome is defined as the total fortnightly rates of HAI identified. The primary outcome will be analysed by a generalised linear mixed model (GLMM) with a logit link function, where the dependent variable is defined as will be used, to estimate changes in fortnightly cases of HAI. To standardise rates, the fortnightly numbers of HAIs identified (combined, all types of HAIs) will be divided by the number of at-risk patients. Models will have a random intercept for each ward to control for baseline differences. Fixed effects will include the intervention and study time in weeks and fixed effects for the intervention and study time. Study time will be modelled as a categorical fixed effect; inclusion as a linear fixed effect will also be tested. Models will have a random intercept for each ward to control for baseline differences between wards, and a linear fixed effect to control for unrelated changes over time. Intervention effectiveness will be represented in the model as a binary independent variable that will for the intervention switched from ‘no’ (0) to ‘yes’ (1) 1 week after the start of the intervention period. This will account for a delay in the intervention effect, as wards become familiarised with the enhanced cleaning procedures. Model estimates will be reported as odds ratios with 95% confidence.We will undertake sensitivity analyses to determine the possibility of a delayed intervention effect of longer than 1 week, the influence of each ward on model estimates and the effect of the intervention on the most common and serious HAIs—pneumonia, urinary tract infections, bloodstream infections and surgical site infection. The delayed intervention effect will be modelled at 2 and 4 weeks after each ward’s intervention start date. The influence of each ward will be examined using a leave-one-ward-out analysis examining changes to the intervention effect and Cook’s distances.Additional analyses will consider alternative model specifications if the proposed GLMM does not converge or provides an inadequate fit to the data. Planned alternatives will be testing of different link functions (identity, log), changing the distribution for the dependent variable from binomial to beta-binomial to account for over-dispersion, and the use of generalised estimating equations in place of a GLMM.To reduce the effect of confounders due to seasonality, viral respiratory infections (RSV, COVID-19, influenza) will be removed for the purpose of primary analysis. In addition, any HAI data related to an outbreak will be excluded from primary analysis. The study period is aligned to span over three full seasons (autumn, winter, spring), with the study midpoint corresponding to the usual epidemiological peak for respiratory infection in the region. Additionally, the use of historical coding data can identify underlying trends over recent years. | PMC9944767 |
Secondary outcome analysis | PMC9944767 | |||
FM
audits | We will analyse data from fortnightly cleaning audits using a binomial generalised linear mixed model with a logit link function on the proportion of equipment that were deemed ‘cleaned’. A random intercept will be included for each ward. The effect of the intervention will be tested in three ways: a binary intervention effect, to model an immediate improvement in cleaning; a linear intervention effect, defined as weeks after each ward’s intervention start date, to model a more gradual improvement over time; and a combined binary–linear intervention effect. As per the analysis of the primary outcome, the intervention effect will switch from ‘no’ to ‘yes’ 1 week after the start of the intervention period. | PMC9944767 | ||
Cost-effectiveness | ’ | The costs of adopting the intervention will be prospectively collected from hospital records, such as the cost of cleaning consumables. Excess length-of-stay estimates will be sourced from studies identified by systematic reviews to estimate the value of bed days saved. The cost-effectiveness of the intervention will be evaluated from the perspective of the hospital decision-maker. Cost-effectiveness will be summarised by the incremental cost-effectiveness ratio and net monetary benefit, which offer different summaries of the change in costs versus health benefits. Modelled changes in the primary outcome (HAIs) will be used to estimate changes in health benefits from cases prevented by the intervention, as quality-adjusted life year (QALY). Probabilistic sensitivity analysis will be undertaken to account for uncertainty in model parameters and its impact on cost-effectiveness outcomes.Uncertainties in parameter estimates will be captured using appropriate statistical distributions to describe the variability. The fitted distributions will be subject to random re-samples simulated 10,000 times. The distributions of all prior parameters are used to estimate the posterior distributions of ‘change to costs’ and ‘change to QALY’ outcomes. The decision will be informed by plotting cost-effectiveness acceptability curves with threshold values between zero and 100,000 per QALY gained and using the net monetary benefits framework. These approaches are semi-Bayesian and appropriately account for all parameter uncertainty for the adoption decisions. | PMC9944767 | |
Interim analyses {21b} | There will be no interim analysis as we do not expect there to be any negative effects from this study. | PMC9944767 | ||
Methods for additional analyses (e.g. subgroup analyses) {20b} | Not applicable—there are no subgroup analyses planned. | PMC9944767 | ||
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | SECONDARY | Statistical analyses will be performed as intention-to-treat, in accordance with the published protocol. For the specified study design, the intention-to-treat analysis will assume cluster transitions from control to intervention according to randomised sequence allocation and include all patients who meet the study inclusion criteria.Missing data will be handled by complete case analysis. Given the use of standardised data collection instruments and protocols, missing data on primary and secondary outcomes is expected to be low. Any deviations from the protocol will be documented and reported in planned research outputs. | PMC9944767 | |
Plans to give access to the full protocol, participant-level data and statistical code {31c} | Fully de-identified data sets and statistical codes will only be available by contacting a chief investigator and providing the appropriate ethical approvals. | PMC9944767 | ||
Oversight and monitoring | PMC9944767 | |||
Composition of the coordinating centre and trial steering committee {5d} | The project consists of a management and steering committee. The management committee (coordinating centre) will oversee the day-to-day running of the trial and decide on the operational elements of the trial. Members of the coordinating centre are two chief investigators and the trial coordinator. The steering committee will meet as required to provide oversight of the study. The steering committee will have accountability and responsibility for the project, including progress towards completion of agreed project activities (milestones/ deliverables), risks arising and how these are being managed to ensure project outcomes, and research reports. The steering committee consists of all chief investigators and the trial coordinator. Associate investigators are non-voting members of the Steering Committee. | PMC9944767 | ||
Composition of the data monitoring committee, its role and reporting structure {21a} | The study does not have a data monitoring committee. The intervention is an enhancement of existing health services delivery (cleaning) with no anticipated risks. There is no planned interim analysis. | PMC9944767 | ||
Adverse event reporting and harms {22} | ADVERSE EVENTS, ADVERSE EVENT | The trial coordinator is responsible for ensuring that all adverse events observed by the investigator/s, study team or reported by sites are collected and recorded in the source documents. The trial coordinator will notify the approving ethics committee of serious adverse events occurring at any of the sites. Adverse events could require reporting as per hospital-specific policy. | PMC9944767 | |
Frequency and plans for auditing trial conduct {23} | The HREC granting approval for this study may conduct an external audit at any point in the trial. The steering committee will be responsible for monitoring risks and the progress of the trial. | PMC9944767 | ||
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} | Where there are any ethical amendments to the trial protocol, approval will be sought from the approving HREC. Similarly, important protocol modification will be updated on the Australian and New Zealand Clinical Trial registry. | PMC9944767 | ||
Dissemination plans {31a} | The investigators will implement a dissemination plan that will include key communication strategies for all stakeholders, an open-access publication plan, authorship requirements and publication standards that align with NHMRC Australian Code for the Responsible Conduct of Research ( | PMC9944767 | ||
Discussion | infection | INFECTION | The CLEEN study is a large cluster randomised controlled trial conducted in an Australian tertiary hospital. The study represents the first randomised controlled study in the world to provide level 1 evidence on the impact of additional cleaning of shared equipment on rates of HAIs (5). The advantages of the study design include a simple and feasible intervention, with strategies built in to ensure adherence and fidelity. Unlike pragmatic trial designs, which may use existing resources of PSAs, we are able to ensure that the intervention is delivered through additional resources being provided specifically for the purpose of delivering the intervention. The stepped wedge design is another strength of the research design, as each ward will act as its own control. This negates issues associated with differing patient case mix, individual ward culture, operational issues and local practices. This study will provide evidence to inform the development of a future service delivery model, national guidelines and local policy with respect to roles and responsibilities and the importance of cleaning of shared medical equipment.Limitations to the study may include issues such as hospital changes in policy or practice that may influence the outcomes being observed. However, the hospital is committed to ensuring that there will be no significant changes to the hospital cleaning policy during the trial period unless absolutely necessary. Other aspects of infection prevention control policy such as hand hygiene and antimicrobial usage will be monitored, and we will be able to document/identify changes in other policies that may influence the outcomes of this study. Further potential disadvantages of the trial may include that the intervention will only be delivered 5 days of 7, due to physical and financial constraints. Given the intervention is being delivered over the vast majority of the working week, the burden and risk in the environment will still likely be significantly reduced. Environmental swabbing of the environment was considered; however, due to poor positive predictive value, it was not included in the current study design (17). In a related study in the same participating hospital, we intend to use targeted whole genome sequencing to evaluate potential transmission pathways through shared medical equipment. | PMC9944767 |
Trial status | RECRUITMENT | The trial protocol V1.1. is the current and approved version as of 21 September 2022. Hospital recruitment is completed, including all required ethical approvals. Data collection will begin in March 2023 with an expected end date for data collection in November 2023.
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Acknowledgements | Not applicable. | PMC9944767 | ||
Authors’ contributions {31b} | DB, NW | AC is a chief investigator who helped develop the protocol and revised the manuscript. AS is a chief investigator who helped develop the protocol and revised the manuscript. BM is the lead and chief investigator who conceived the study, led the proposal and protocol development and revised the manuscript. DB is a chief investigator who helped develop the protocol and revised the manuscript. GO is an associate investigator who helped develop the protocol and revised the manuscript. JK is an associate investigator who helped develop the protocol and revised the manuscript. KB is the trial coordinator who drafted and revised the manuscript. KG is an associate investigator who helped develop the protocol and revised the manuscript. MA is an associate investigator and site lead who helped develop the protocol and revised the manuscript. MK is an associate investigator who helped develop the protocol and revised the manuscript. NW is a chief investigator who helped to develop the protocol methodology and statistical analysis and revised the manuscript. PR is a chief investigator who designed the protocol methodology and revised the manuscript. PT is a chief investigator and project manager who revised the manuscript. The authors read and approved the final manuscript.
| PMC9944767 | |
Authors’ information | Not applicable | PMC9944767 | ||
Funding {4} | MITCHELL | This project is funded by a National Health and Medical Research Council Emerging Leadership Investigator grant (Prof Brett Mitchell, (GNT2008392)) and administered by Avondale University. AJS is supported by an Australian National Health and Medical Research Council Early Career Fellowships (GNT1141398).Industry partners GAMA Health Care may provide tools to support data collection and education. They have no role in the study design, implementation, analyses, interpretation or publications. | PMC9944767 | |
Availability of data and materials {29} | Details about the study will be posted on information boards in the participating hospital. Standard operating procedures for cleaning specific items of shared medical equipment will be developed and subsequently explained at the in-service (if they are not already in existence at the hospital). These will also be readily available for staff for future reference as needed. Availability of data may be available upon reasonable request, by contacting a chief investigator and providing the appropriate ethical approvals. | PMC9944767 | ||
Declarations | PMC9944767 | |||
Ethics approval and consent to participate {24} | This trial has ethical approval from the Hunter New England Local Health District (2022/ETH01780) and governance approval from the Central Coast Local Health District (2022/STE02925). | PMC9944767 | ||
Consent for publication {32} | Not applicable. | PMC9944767 | ||
Competing interests {28} | The authors declare that they have no competing interests. | PMC9944767 | ||
References | PMC9944767 | |||
Introduction | arrhythmias, arrhythmia, syncope | ARRHYTHMIAS, RECURRENCE, ARRHYTHMIA | Diagnosing underlying arrhythmia in emergency department (ED) syncope patients is difficult. There is a evidence that diagnostic yield for detecting underlying arrhythmia is highest when cardiac monitoring devices are applied early, ideally at the index visit. This strategy has the potential to change current syncope management from low diagnostic yield Holter to higher yield ambulatory monitoring, reduce episodes of syncope, reduce risk of recurrence and its potential serious consequences, reduce hospital admissions, reduce overall health costs and increase quality of life by allowing earlier diagnosis, treatment and exclusion of clinically important arrhythmias. | PMC9950891 |
Methods and analyses | syncope | This is a UK open prospective parallel group multicentre randomised controlled trial of an immediate 14-day ambulatory patch heart monitor vs standard care in 2234 patients presenting acutely with unexplained syncope. Our patient focused primary endpoint will be number of episodes of syncope at 1 year. Health economic evaluation will estimate the incremental cost per syncope episode avoided and quality-adjusted life year gained. | PMC9950891 | |
Ethics and dissemination | Informed consent for participation will be sought. The ASPIRED trial received a favourable ethical opinion from South East Scotland Research Ethics Committee 01 (21/SS/0073). Results will be disseminated via scientific publication, lay summary and visual abstract. | PMC9950891 | ||
Trial registration number | ISRCTN 10278811. | PMC9950891 | ||
STRENGTHS AND LIMITATIONS OF THIS STUDY | syncope | The ASPIRED trial uses non-blinded randomisation to compare immediate enhanced ambulatory ECG monitoring versus standard monitoring in acute unexplained syncope patients.The primary outcome measure is a patient focussed measure very relevant to the population of patients who suffer syncope.We are using health economic analysis and a separate embedded qualitative study to assess the wider implications of using immediate enhanced ambulatory ECG monitoring in this population.In contrast to the few published studies on ambulatory monitoring in syncope patients which are generally single centred, without any comparative group and with heterogeneous patient populations and device capabilities, this study is multicentred and includes a standard care group. | PMC9950891 | |
Introduction | PMC9950891 | |||
Background and rationale | arrhythmia, heart disease, syncope, Syncope, cardiac arrhythmia, neurocardiogenic, cardiac disease | RECURRENCE, ARRHYTHMIA, HEART DISEASE, SIMPLE FAINT, CARDIAC ARRHYTHMIA, CARDIAC DISEASE, POSTURAL HYPOTENSION | Syncope (or blackout) is common; 650 000 patients present to UK emergency departments (EDs) every year. The three underlying causes are neurocardiogenic (including simple faint), postural hypotension (blood pressure fall on standing) and cardiac disease (structural heart disease or cardiac arrhythmia). Diagnosis is difficult and is not made in around 50% of patients after assessment.The difficulty in the ED is to differentiate between the causes of syncope and identify patients at higher risk. This can be complicated as many patients have fully recovered on ED arrival and their examination and presenting ECG may both be normal. The current method for establishing cardiac arrhythmia as the cause of syncope rests on correlating the arrhythmia with symptoms. The lack of efficacy and availability of commonly used monitoring devices means most high and medium risk patients are admitted to the hospital for observation and telemetry (if available), with escalating costs.In general, syncope reoccurs in around 50% of patients within a year. Recurring episodes increase hospital admissions, health costs and importantly reduce the quality of life of patients. While there is a wide variation in the literature with respect to the number of syncope episodes and recurrence rates pretreatment and post-treatmentThere is evidence that the diagnostic yield for detecting underlying arrhythmia is highest when cardiac monitoring devices are applied early after syncope, ideally at the index visitThe ASPIRED RCT will compare a novel ambulatory cardiac monitoring device with standard practice in syncope patients. We hypothesise that applying cardiac monitoring early after syncope at the index visit is the optimum strategy to detect, diagnose, treat and exclude underlying cardiac arrhythmia. | PMC9950891 |
Study objectives | PMC9950891 | |||
Primary | syncope | To determine whether immediate, enhanced (14 days) ambulatory ECG monitoring decreases the number of self-reported episodes of syncope at 1 year compared with standard care monitoring in acute unexplained syncope patients. | PMC9950891 | |
Secondary | death, syncope, cardiac arrhythmia | RECURRENCE, CARDIAC ARRHYTHMIA | To determine whether immediate, enhanced (14 days) ambulatory ECG monitoring in acute unexplained syncope patients can:Decrease the number of episodes of self-reported syncope at 90 days, and 2 years compared with standard care monitoring.Decrease the time to detection of clinically significant cardiac arrhythmia compared with standard care monitoring.Increase the rate of detection of clinically significant cardiac arrhythmia at 90 days and 1 year compared with standard care monitoring.Increase the rate of ECG/symptom correlation at 90 days and 1 year compared with standard care monitoring.Demonstrate cost-effectiveness compared with standard care monitoring.Decrease the number of episodes of syncope identified in the medical records at 90 days, 1 and 2 years compared with standard care monitoring.Decrease the index hospital admission rate and duration of hospital stay compared with standard care monitoring.Decrease 90 days, 1-year and 2-year syncope recurrence rates (identified in the medical records and self-reported) compared with standard care monitoring.Increase patient satisfaction compared with standard care monitoring.Decrease the rate of 30 day, 1-year and 2-year all-cause death compared with standard care monitoring.In the intervention group, by reporting the timing of detection of clinically significant cardiac arrhythmia what is the optimum duration of acute ambulatory ECG monitoring.Increase the affect rate of diagnostic testing and therapeutic intervention. | PMC9950891 |
Methods and analysis | PMC9950891 | |||
Study design | syncope | This is a UK open prospective parallel group multicentre RCT of an immediate 14-day ambulatory patch heart monitor versus standard care monitoring in 2234 participants presenting acutely with unexplained syncope. The patient focused primary endpoint will be number of episodes of syncope at 1 year (Study summary in PICO formatAMU, acute medicine unit; ED, emergency department. | PMC9950891 | |
Study eligibility | syncope, Syncope, TLOC, transient loss of consciousness, thirty-four | Two thousand two hundred and thirty-four adult (16 years or older) participants presenting acutely to UK hospitals with syncope remaining unexplained after initial ED or acute medicine unit (AMU) assessment will be enrolled. Syncope will be defined as transient loss of consciousness (TLOC) with inability to maintain postural tone and immediate complete spontaneous recovery without medical intervention | PMC9950891 | |
Inclusion criteria | syncope, Syncope | Syncope remains unexplained after initial ED/AMU assessment.Aged ≥16 years.Patient has capacity.Local resident (ie, resident within local health board so will not be lost to medical record follow-up).<5 self-reported episodes of syncope in the previous month. | PMC9950891 | |
Exclusion criteria | cerebrovascular accident/transient ischaemic, TLOC.Inability, Haemorrhage, syncope, pulmonary embolus, Arrhythmia, Head trauma, vasovagal syncope | ACUTE MYOCARDIAL INFARCTION, HAEMORRHAGE, SUBARACHNOID HAEMORRHAGE, RECRUITMENT, PULMONARY EMBOLUS, EPILEPTIC SEIZURE, ARRHYTHMIA, HYPOGLYCAEMIA, VASOVAGAL SYNCOPE, POSTURAL HYPOTENSION | Obvious underlying cause after assessment.Features of vasovagal syncope (see Arrhythmia on prehospital or hospital ECG as likely cause of syncope.Postural hypotension (symptomatic postural drop >20 mm Hg AND suggestive history).Confirmed diagnosis of pulmonary embolus or acute myocardial infarction.Radiological diagnosis or clinical signs/symptoms of cerebrovascular accident/transient ischaemic attack or subarachnoid haemorrhage.Evidence of:Haemorrhage.Alcohol or illicit drugs.Epileptic seizure.Hypoglycaemia.Head trauma.Other obvious cause of syncope as presumptive cause of TLOC.Inability to consent.Previous recruitment into the study.Patient in custody or prison.Aged<16 years.Patient does not reside within local health board and will therefore be lost to medical record follow-up.Five or more self-reported episodes of syncope in previous 4 weeks.Pregnancy is not an exclusion criteria. | PMC9950891 |
Features of vasovagal/postural syncope | nausea, light-headedness, syncope, pain, cough, blood phobia, tumour, vomiting).After sudden | TUMOUR | Associated with typical symptoms of reflex syncope (eg, light-headedness, feeling of warmth, nausea, vomiting).After sudden unexpected unpleasant sight, sound, smell or pain.In association with micturition, defaecation, cough, laughter, venepuncture, blood phobia.After prolonged standing or crowded, hot places.During a meal or after eating a meal.With head rotation or pressure on carotid sinus (eg, tumour, shaving, tight collars).Associated with standing up quickly from a sitting or lying position.Long history (years) of recurrent syncope with low-risk features with the same characteristics of the current episode. | PMC9950891 |
Participant recruitment | RECRUITMENT, RECRUITMENT | Recruitment will take place in around 30–40 NHS acute tertiary and district hospitals. Schematic diagram of the study design and participant recruitment. AMU, acute medicine unit; ED, emergency department; GP, general practitioner. | PMC9950891 | |
Randomisation and interventions | syncope | RECRUITMENT, EVENT | Randomisation will be performed using a web-based randomisation service to ensure allocation concealment, managed by Edinburgh Clinical Trials Unit (ECTU). The allocation sequence will be created by an ECTU database programmer using computer-generated pseudo-random numbers. Participants will be randomised, 1:1, between the two study arms. Stratification by site will be used to ensure there will not be a significant imbalance between the number randomised to intervention and control at any site. Stratification by other site-level characteristics will not be performed.Standard care will include all care usually given to unexplained syncope patients at each participating site along with some form of standard care monitoring such as but not limited to wired inpatient telemetry, Holter style monitoring or implantable ECG recorder. The study will be conducted over 4 years. Recruitment will take place over 18 months. Intervention group participants will be fitted with a 14-day ambulatory heart monitor. All participants will be followed up for 2 years after index event. | PMC9950891 |
Outcome measures | PMC9950891 | |||
Primary endpoint | syncope | Number of self-reported episodes of syncope at 1 year. | PMC9950891 | |
Secondary endpoints | death, syncope, cardiac arrhythmia | RECURRENCE, CARDIAC ARRHYTHMIA | Within trial cost-effectiveness (cost per syncope avoided and cost per quality-adjusted life year (QALY) gained), and lifetime cost per QALY gained at (a) 1 year and (b) 2 years.Number of self-reported episodes of syncope at (a) 90 days and (b) 2 years, those identified in the medical records at (c) 90 days, (d) 1 year and (e) 2 years, and syncope recurrence rate at (f) 90 days, (g) 1 year and (h) 2 years.Index presentation hospital (a) admission rate and (b) duration of hospital stay.Patient satisfaction (measured using a patient questionnaire) at 1 year.Clinically significant cardiac arrhythmia (serious and/or symptomatic cardiac arrhythmia, (a) 30-day, (b) 1-year and (c) 2-year all-cause death.Detection of diagnostic ECG/symptom correlation (symptomatic) at (a) 90 days, (b) 1 year and (c) 2 years.Time to detect clinically significant cardiac arrhythmia (ie, time to clinician being aware).In the intervention group, duration of enhanced ambulatory ECG monitoring required to detect clinically significant cardiac arrhythmia.Number and type of diagnostic tests and therapeutic interventions at (a) 1 year and (b) 2 years. | PMC9950891 |
Definitions of clinically significant cardiac arrhythmias | Bradycardia, bradycardia, tachycardia, arrhythmias, VT, atrial flutter/fibrillation, Atrial flutter/fibrillation | SINUS PAUSE, SINUS BRADYCARDIA, SUPRAVENTRICULAR TACHYCARDIA, 3RD DEGREE HEART BLOCK, MOBITZ, SECOND DEGREE ATRIOVENTRICULAR HEART BLOCK, CARDIAC ARRHYTHMIA, SICK SINUS SYNDROME, ARRHYTHMIAS | Ventricular fibrillation.Ventricular tachycardia (VT) ≥120 beats per minute (bpm) for ≥30s.VT ≥120 bpm for <30 s (≥4 beats).Complete or 3rd degree heart block.Second degree atrioventricular heart block Mobitz type II.Second degree atrioventricular heart block Mobitz type I.Pause ≥6 s.Sinus pause ≥2.5 s when awake or ≥4 s at night (but <6 s).Sinus bradycardia <30 bpm.Bradycardia <40 bpm for ≥30 s.Bradycardia <40 bpm for <30 s.Sick sinus syndrome with alternating sinus bradycardia and tachycardia.Junctional/idioventricular rhythm ≥30 s in duration.Supraventricular tachycardia >100 bpm ≥30 s in duration.Atrial flutter/fibrillation with ventricular rate >100 bpm or <60 bpm ≥30 s in duration.New atrial flutter/fibrillation ≥30 s in duration.All arrhythmias will also be classed as symptomatic or asymptomatic during monitoring period.*‘Serious’ clinically significant cardiac arrhythmia. | PMC9950891 |
Trial assessments | PMC9950891 | |||
Participant identification | Potential participants will be identified from EDs/AMUs or other acute settings and approached either during their ED/AMU or hospital stay or contacted after discharge and invited to take part in the study. | PMC9950891 | ||
Participant consent | arrhythmia, syncope, PIS | EVENTS, EVENT, ARRHYTHMIA, SECONDARY | Potential participants will be given a Participant Information Sheet (PIS). Potential participants will be randomised within 72 hours of their hospital attendance. If a patient has been discharged from the hospital, then they will be contacted by the local clinical team or research team (if part of the clinical team), and a copy of the PIS will be emailed or posted out to the patient. The PIS will also be available on the trial website. A delegated member of the local study team will seek verbal consent over the telephone and will sign the consent form on behalf of the participant. The original consent form will be filed in the Investigator Site File and a copy will be sent to the participant. Alternatively, the patient can attend the hospital with travel expenses, to provide written informed consent in person. The ambulatory ECG device can be sent to the participant’s address or collected from the local study team if randomised to the intervention arm. Each participating centre will upload screening information of non-identifiable potentially eligible patients who were approached to participate in the study, onto the study database. Participants are free to withdraw from the study at any point or can be withdrawn by the investigator.Participants will have an electronic case report form completed at randomisation (Study assessmentseCRF, electronic case report form; ED, emergency department; GP, general practitioner.14-day ambulatory heart monitor (Preventice BodyGuardian Mini).Participants will be required to press the button on the heart monitor after any syncopal event. They will also record symptomatic episodes in a paper diary. The participant will wear the ambulatory ECG monitor for a maximum of 14 days after which they will remove and return it in a prepaid envelope to Preventice UK. The monitor will be reported by a cardiac physiologist, shared with the participant’s local study team, placed in the participant’s health record and shared with the participant’s treating clinician. Treatment of device findings will be at the discretion of the treating clinician at each site. The participant’s general practitioner (GP) will be informed that the participant has been enrolled in the study and will be informed of the results of any ECG investigations via routine hospital clinical correspondence. Participants will be informed of the results of any ECG investigations via routine hospital clinical correspondence. Any study participant with a serious arrhythmia (All participants will be contacted on a 4-weekly basis ±14 days for 2 years via automated text message or email (whichever they prefer) with a link to a brief web-based questionnaire asking for the number of syncope events experienced since their last response and how many of these they attended hospital for. Those who are unable to access digital forms of communication will receive phone calls. They will also be asked since their last response how many times they have visited their GP practice for any reason including all face-to-face, telephone and online consultations. This will import directly into the central ECTU study database. This patient-reported data will be used to inform the primary endpoint. The small number of participants unable to access digital forms of communication and participants not responding for 3 consecutive months will receive a phone call from the central study team (blinded to participant’s study arm allocation) to collect missing data, ensure no syncope episodes have occurred and to encourage continued future engagement. Participants with a mean of 5 or more episodes/month will also receive a phone call from the central study team to ensure that participants are recording true syncope events and are seeking appropriate medical advice.We were very thoughtful about the potential impact of COVID-19 when designing this study including ensuring ambulatory ECG monitors can be sent directly to patients and designing participant follow-up to ensure no additional research related hospital visits are required.Participants will also be contacted at one and 2 years±30 days, by the central study team (blinded to participants study arm allocation) to complete a quality-of-life questionnaire. In the event of non-response, participants will be contacted on up to three occasions. The participants’ involvement in the study will cease at 2 years. Endpoint data including NHS resource usage will be extracted by the local study team from routine hospital electronic healthcare records at 90 days, 1 and 2 years and will be entered into a bespoke database. ECTU will collect and clean primary data and perform primary and secondary analyses. | PMC9950891 |
Timelines | RECRUITMENT | The study started on 1 August 2021 and the first patient was recruited on 15 July 2022. Recruitment is planned to end on 31 December 2023, the with study completing on 31 July 2025. | PMC9950891 | |
Sample size | death, thirty-four, syncope | RECURRENCE | Two thousand two hundred and thirty-four participants (1117 standard and 1117 intervention) presenting acutely with syncope whose syncope remains unexplained after initial ED/AMU assessment will be recruited. Using an estimated mean 1-year recurrence rate in untreated patients of 42.5%The study will recruit an extra 5% in each arm (ie, 1117 participants per arm; 2234 in total) to allow for drop-out/loss to follow-up although we expect this to be low (<1% in pilot) and drop out due to death (<1% in pilot). It is expected that most people will respond to some text/email follow-ups, but few will respond to all. We will therefore call any participant who has not responded for 3 consecutive months to ensure no syncope episodes have occurred and to encourage continued future engagement. Participants will be defined as lost to follow-up only if both 1-year electronic patient health record data and 1-year self-reported data are unavailable. | PMC9950891 |
Study progression criteria | RECRUITMENT | This study will include an internal recruitment pilot phase with stop-go recruitment milestone criteria to mitigate risk to the funder. This internal pilot will be used to confirm recruitment rates and aims to recruit the first 400 participants (almost one-fifth of the sample size) from 10 sites by the end of study month 13. By the end of study month 13, the aim is to have 400 participants (18%) enrolled with an average recruitment rate/site/month of at least five participants in the best 60% of sites, with at least 10 sites open (Internal recruitment pilot study progression criteria*Sites recruitment rate will be calculated from site opening date.If by the end of study month 19, overall recruitment is less than 1300 participants (58%), OR average recruitment rate/site/month is less than 6 participants in the best 60% of sites, OR there are less than 20 sites recruiting, we will further expand the number of NHS sites recruiting. We will also consider whether study extension is required. | PMC9950891 | |
Data analysis plan | syncope | REGRESSION, EVENT, SECONDARY | The primary outcome, number of self-reported episodes of syncope in the 12 months following randomisation, will be analysed by negative binomial regression. The primary outcome event rate ratio (14-day ambulatory heart monitor vs standard care) will be reported with its 95% CI. An offset term for follow-up duration will be included to account for participants with partial follow-up.The secondary outcomes for the number of syncope episodes at 90 days and 2 years, will be analysed similarly. Binary secondary outcomes will be analysed by logistic regression, reporting the OR (14-day ambulatory heart monitor vs standard care) and its 95% CI. Full details of analysis, including the estimand(s) of interest and methods for handling missing data, will be written into a Statistical Analysis Plan, which will be finalised prior to database lock without knowledge of the unblinded treatment allocations. | PMC9950891 |
Cost-effectiveness analysis | death, syncope | EVENTS | Anonymised electronic healthcare record data will be sent to our health economist in Sheffield to apply unit costs and tariffs, to estimate within trial costs and QALYs, and then to undertake lifetime economic modelling. Both within trial and lifetime cost-effectiveness analysis will be performed. In within trial analysis, costs will be estimated by applying national unit costs to items of resource use (monitoring, hospitalisation, treatment, health and social care) to estimate the mean cost per participant in each arm of the trial. Cost-effectiveness will then be estimated as the incremental cost per syncope episode avoided and the incremental cost per QALY gained, with QALYs being estimated from EQ-5D questionnaires. Lifetime cost-effectiveness will be estimated using decision analytic modelling from published sources of life expectancy, annual costs and corresponding annual utilities. This will explore the potential impact of events, such as syncope episode resulting in death or injury, that have consequences beyond the timeframe of the trial. | PMC9950891 |
Interim analysis | RECRUITMENT | In addition to the blinded sample size review to ensure that the trial achieves the required statistical power, there will be a single interim futility analysis for the primary outcome performed after the 18th month of recruitment (end of study month 25). At this point 6 months of 1-year follow-up data will be available. We anticipate at least 400 participants will have undergone 12-month follow-up for the primary outcome at this point and will be able to be analysed in this futility analysis. | PMC9950891 | |
Patient and public involvement | ARRHYTHMIA | The ASPIRED study patient and public involvement group is made up of patient representatives, lay members and a representative from the Arrhythmia Alliance. They have been involved in informing the study research questions and study protocol in particularly the methods and timings of patient follow-up, and the development of all patient facing information. | PMC9950891 | |
Ethics and dissemination | The ASPIRED trial received a favourable ethical opinion from South East Scotland Research Ethics Committee 01 (21/SS/0073). | PMC9950891 | ||
Participant capacity and consent | temporary incapacity | Capacity will be assessed by the research team or a clinician responsible for the treatment of the participant. The trial excludes patients who have inability to give informed consent and therefore patients with temporary incapacity due to their current illness or with permanent incapacity will not be recruited. | PMC9950891 | |
Safety considerations | PMC9950891 | |||
Bias | syncope | The primary outcome is a quantitative endpoint (number of syncope episodes) collected through automated participant reporting importing directly into the ECTU central study database to reduce reporting bias. Central research staff who phone participants will be blinded to participant allocation. | PMC9950891 | |
Adverse events | SECONDARY, ADVERSE EVENT, COMPLICATIONS | A secondary endpoint for the study is serious outcomes at 90 days, 1 and 2 years. This data will therefore be routinely collected as part of the study and not recorded as an adverse event (AE). Hospital admission will also not be recorded as an AE. The only AEs recorded will be those directly related to the use of initial ambulatory ECG recording both in the intervention and standard care groups. Participants will be asked through the automated monthly email/text questionnaire at month 2, whether they suffered any complications related to wearing any monitoring devices in the first 2 months of the trial.A Trial Steering Committee (TSC) will be established to oversee the conduct and progress of the trial. The details of the TSC will be captured in a separate charter. An independent Data Monitoring Committee (DMC) will be established to oversee the safety of participants in the trial. The details of the DMC will be captured in a separate charter. | PMC9950891 | |
Data management | Identifiable data collected by the study will not be transferred to any external individuals or organisations outside of the sponsoring organisations. | PMC9950891 | ||
Study dissemination | ARRHYTHMIA | We will disseminate the results of this study widely through high impact peer-reviewed publications, presentations at international conferences, local and national websites, charity newsletters and websites and media outlets such as television and radio. We will also share our results through specific interest groups such as Arrhythmia Alliance and disseminate findings among guideline development groups such as ESC, SIGN, NICE and American College of Cardiology. | PMC9950891 | |
Supplementary Material | PMC9950891 | |||
Reviewer comments | PMC9950891 | |||
Ethics statements | PMC9950891 | |||
Patient consent for publication | Not applicable. | PMC9950891 | ||
References | PMC9950891 | |||
Objective | The objective of this clinical trial was to compare facial expressions (magnitude, shape change, time, and symmetry) before (T0) and after (T1) orthognathic surgery by implementing a novel method of four-dimensional (4D) motion capture analysis, known as videostereophotogrammetry, in orthodontics. | PMC10560183 | ||
Methods | This prospective, single-centre, single-arm trial included a total of 26 adult patients (mean age 28.4 years; skeletal class II: | PMC10560183 | ||
Results | 4D motion capture analysis was feasible in all cases. The magnitude of the expression maximum smile increased from 15.24 to 17.27 mm ( | PMC10560183 | ||
Conclusions | Orthodontic-surgical treatment not only affects static soft tissue but also soft tissue dynamics while smiling or lip pursing. | PMC10560183 | ||
Clinical relevance | To achieve comprehensive orthodontic treatment plans, the integration of facial dynamics via videostereophotogrammetry provides a promising approach in diagnostics. | PMC10560183 | ||
Trial registration number | DRKS00017206. | PMC10560183 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00784-023-05195-9. | PMC10560183 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10560183 | ||
Introduction | Facial expressions as a type of nonverbal communication play an essential role in daily conversations. When assessing emotions, facial expressions carry more weight than the spoken message [Since orthodontic treatment, and in particular orthodontic-surgical treatment, always affects the appearance of the facial soft tissue, three-dimensional (3D) imaging using stereophotogrammetry has become increasingly important in recent years. In orthodontic-surgical treatment, this helps to predict postsurgical soft tissue changes and to improve the surgical plan [Non-invasive, four-dimensional (4D) video stereophotogrammetry offers a modern and promising approach for the objective recording and evaluation of facial movements [The aim of the present study was to compare facial expressions before (T0) and after (T1) orthognathic surgery by implementing the novel method of 4D videostereophotogrammetry in orthodontics. We hypothesised that the magnitude, shape change, symmetry, and time of facial expressions change from T0 until T1. | PMC10560183 | ||
Subjects and methods | PMC10560183 |
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