Telerehabilitation consultations with a physiotherapist for chronic knee pain versus in-person consultations in Australia: the PEAK non-inferiority randomised controlled trial.

BACKGROUND: Telerehabilitation whether perceived as less effective than in-person care for musculoskeletal problems. We aimed to determine if physiotherapy video conferencing consultations were non-inferior to in-person consultations for chronic knee pain. METHODS: In this non-inferiority randomised controlled trial, we recruited primary care physiotherapists from 27 Australian clinics. Using computer-generated blocks, participants with chronic knee pain consistent with osteoarthritis were randomly assigned (1:1, stratified by physiotherapist and clinic) in-person or telerehabilitation (ie, video conferencing) physiotherapist consultations. Participants and physiotherapists were unmasked to group assignment. Both groups had five consultations over 3 months for strengthening, physical activity, and education. Primary outcomes were knee pain (on a numerical rating scale of 0-10) and physical function (using the Western Ontario and McMaster Universities osteoarthritis index of 0-68) at 3 months after randomisation. Primary analysis was by modified intention-to-treat using all available data. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12619001240134. FINDINGS: Between Dec 10, 2019, and June 17, 2022, 394 adults were enrolled, with 204 allocated to in-person care and 190 to telerehabilitation. 15 primary care physiotherapists were recruited. At 3 months, 383 (97%) participants provided information for primary outcomes and both groups reported improved pain (mean change 2·98, SD 2·23 for in-person care and 3·14, 1·87 for telerehabilitation) and function (10·20, 11·63 and 10·75, 9·62, respectively). Telerehabilitation was non-inferior for pain (mean difference 0·16, 95% CI -0·26 to 0·57) and function (1·65, -0·23 to 3·53). The number of participants reporting adverse events was similar between groups (40 [21%] for in-person care and 35 [19%] for telerehabilitation) and none were serious. INTERPRETATION: Telerehabilitation with a physiotherapist is non-inferior to in-person care for chronic knee pain. FUNDING: National Health and Medical Research Council.

A simple and effective method for simulating nested exchangeable correlated binary data for longitudinal cluster randomised trials.

BACKGROUND: Simulation is an important tool for assessing the performance of statistical methods for the analysis of data and for the planning of studies. While methods are available for the simulation of correlated binary random variables, all have significant practical limitations for simulating outcomes from longitudinal cluster randomised trial designs, such as the cluster randomised crossover and the stepped wedge trial designs. For these trial designs as the number of observations in each cluster increases these methods either become computationally infeasible or their range of allowable correlations rapidly shrinks to zero. METHODS: In this paper we present a simple method for simulating binary random variables with a specified vector of prevalences and correlation matrix. This method allows for the outcome prevalence to change due to treatment or over time, and for a 'nested exchangeable' correlation structure, in which observations in the same cluster are more highly correlated if they are measured in the same time period than in different time periods, and where different individuals are measured in each time period. This means that our method is also applicable to more general hierarchical clustered data contexts, such as students within classrooms within schools. The method is demonstrated by simulating 1000 datasets with parameters matching those derived from data from a cluster randomised crossover trial assessing two variants of stress ulcer prophylaxis. RESULTS: Our method is orders of magnitude faster than the most well known general simulation method while also allowing a much wider range of correlations than alternative methods. An implementation of our method is available in an R package NestBin. CONCLUSIONS: This simulation method is the first to allow for practical and efficient simulation of large datasets of binary outcomes with the commonly used nested exchangeable correlation structure. This will allow for much more effective testing of designs and inference methods for longitudinal cluster randomised trials with binary outcomes.

Unravelling the effect of anaesthesia provider sex on patient outcomes: statistical analyses for sound conclusions.

Unravelling the impact of the sex of the anaesthesia provider on the outcomes of patients requires careful statistical analysis and the validity of many assumptions. A recent study in the British Journal of Anaesthesia investigates the effect of anaesthesia provider sex on patient outcomes, using data from two academic healthcare networks in the USA. The authors show that female provider sex was associated with a lower risk of intraoperative complications. They also show that there was no meaningful difference between male and female providers with respect to postoperative outcomes. There have been several recent studies considering the effect of healthcare provider sex on outcomes. We will discuss the interpretation of these results and the validity of the underlying assumptions.

Efficient designs for three-sequence stepped wedge trials with continuous recruitment.

BACKGROUND/AIMS: The standard approach to designing stepped wedge trials that recruit participants in a continuous stream is to divide time into periods of equal length. But the choice of design in such cases is infinitely more flexible: each cluster could cross from the control to the intervention at any point on the continuous time-scale. We consider the case of a stepped wedge design with clusters randomised to just three sequences (designs with small numbers of sequences may be preferred for their simplicity and practicality) and investigate the choice of design that minimises the variance of the treatment effect estimator under different assumptions about the intra-cluster correlation. METHODS: We make some simplifying assumptions in order to calculate the variance: in particular that we recruit the same number of participants, m, from each cluster over the course of the trial, and that participants present at regularly spaced intervals. We consider an intra-cluster correlation that decays exponentially with separation in time between the presentation of two individuals from the same cluster, from a value of ρ for two individuals who present at the same time, to a value of ρτ for individuals presenting at the start and end of the trial recruitment interval. We restrict attention to three-sequence designs with centrosymmetry - the property that if we reverse time and swap the intervention and control conditions then the design looks the same. We obtain an expression for the variance of the treatment effect estimator adjusted for effects of time, using methods for generalised least squares estimation, and we evaluate this expression numerically for different designs, and for different parameter values. RESULTS: There is a two-dimensional space of possible three-sequence, centrosymmetric stepped wedge designs with continuous recruitment. The variance of the treatment effect estimator for given ρ and τ can be plotted as a contour map over this space. The shape of this variance surface depends on τ and on the parameter mρ/(1-ρ), but typically indicates a broad, flat region of close-to-optimal designs. The 'standard' design with equally spaced periods and 1:1:1 allocation rarely performs well, however. CONCLUSIONS: In many different settings, a relatively simple design can be found (e.g. one based on simple fractions) that offers close-to-optimal efficiency in that setting. There may also be designs that are robustly efficient over a wide range of settings. Contour maps of the kind we illustrate can help guide this choice. If efficiency is offered as one of the justifications for using a stepped wedge design, then it is worth designing with optimal efficiency in mind.

Practical and methodological challenges when conducting a cluster randomized trial: Examples and recommendations.

The use of cluster randomized trial design to answer research questions is increasing. This design and associated variants such as the cluster randomized crossover and stepped wedge are useful to assess complex interventions in a pragmatic way but when adopting such designs, one may face specific implementation challenges. This article summarizes common challenges faced when conducting cluster randomized trials, cluster randomized crossover trials, and stepped wedge trials, and provides recommendations.

What type of cluster randomized trial for which setting?

The cluster randomized trial allows a randomized evaluation when it is either not possible to randomize the individual or randomizing individuals would put the trial at high risk of contamination across treatment arms. There are many variations of the cluster randomized design, including the parallel design with or without baseline measures, the cluster randomized cross-over design, the stepped-wedge cluster randomized design, and more recently-developed variants such as the batched stepped-wedge design and the staircase design. Once it has been clearly established that there is a need for cluster randomization, one ever important question is which form the cluster design should take. If a design in which time is split into multiple trial periods is to be adopted (e.g. as in a stepped-wedge), researchers must decide whether the same participants should be measured in multiple trial periods (cohort sampling); or if different participants should be measured in each period (continual recruitment or cross-sectional sampling). Here we outline the different possible options and weigh up the pros and cons of the different design choices, which revolve around statistical efficiency, study logistics and the assumptions required.

SCANPatient: study protocol for a multi-centre, batched, stepped wedge, comparative effectiveness, randomised clinical trial of synoptic reporting of computerised tomography (CT) scans assessing cancers of the pancreas.

BACKGROUND: Complete surgical removal of pancreatic ductal adenocarcinoma (PDAC) is central to all curative treatment approaches for this aggressive disease, yet this is only possible in patients technically amenable to resection. Hence, an accurate assessment of whether patients are suitable for surgery is of paramount importance. The SCANPatient trial aims to test whether implementing a structured synoptic radiological report results in increased institutional accuracy in defining surgical resectability of non-metastatic PDAC. METHODS: SCANPatient is a batched, stepped wedge, comparative effectiveness, cluster randomised clinical trial. The trial will be conducted at 33 Australian hospitals all of which hold regular multi-disciplinary team meetings (MDMs) to discuss newly diagnosed patients with PDAC. Each site is required to manage a minimum of 20 patients per year (across all stages). Hospitals will be randomised to begin synoptic reporting within a batched, stepped wedge design. Initially all hospitals will continue to use their current reporting method; within each batch, after each 6-month period, a randomly selected group of hospitals will commence using the synoptic reports, until all hospitals are using synoptic reporting. Each hospital will provide data from patients who (i) are aged 18 or older; (ii) have suspected PDAC and have an abdominal CT scan, and (iii) are presented at a participating MDM. Non-metastatic patients will be documented as one of the following categories: (1) locally advanced and surgically unresectable; (2) borderline resectable; or (3) anatomically clearly resectable (Note: Metastatic disease is treated as a separate category). Data collection will last for 36 months in each batch, and a total of 2400 patients will be included. DISCUSSION: Better classifying patients with non-metastatic PDAC as having tumours that are either clearly resectable, borderline or locally advanced and unresectable may improve patient outcomes by optimising care and treatment planning. The borderline resectable group are a small but important cohort in whom surgery with curative intent may be considered; however, inconsistencies with definitions and an understanding of resectability status means these patients are often incorrectly classified and hence overlooked for curative options. TRIAL REGISTRATION: The SCANPatient trial was registered on 17th May 2023 in the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12623000508673).

Neuromuscular Control and Resistance Training for People With Chronic Low Back Pain: A Randomized Controlled Trial.

OBJECTIVE: To determine if adding lumbar neuromuscular control retraining exercises to a 12-week program of strengthening exercises had greater effect for improving disability than 12 weeks of strengthening exercises alone in people with chronic low back pain (LBP). DESIGN: Single-center, participant- and assessor-blinded, comparative effectiveness randomized controlled trial. METHODS: Sixty-nine participants (31 females; 29 males; mean age: 46.5 years) with nonspecific chronic LBP were recruited for a 12-week program involving lumbar extension neuromuscular retraining in addition to resistance exercises (intervention) or 12 weeks of resistance exercises alone (control). The primary outcome measure was the Oswestry Disability Index. Secondary outcome measures included the Numeric Rating Scale, Tampa Scale for Kinesiophobia, Pain Self-Efficacy Questionnaire, and the International Physical Activity Questionnaire. Outcomes were measured at baseline, 6 weeks, and 12 weeks. RESULTS: Forty-three participants (22 control, 21 intervention) completed all outcome measures at 6 and 12 weeks. Fourteen participants were lost to follow-up, and 12 participants discontinued due to COVID-19 restrictions. Both groups demonstrated clinically important changes in disability, pain intensity, and kinesiophobia. The difference between groups with respect to disability was imprecise and not clinically meaningful (mean difference, -4.4; 95% CI: -10.2, 1.4) at 12 weeks. Differences in secondary outcomes at 6 or 12 weeks were also small with wide confidence intervals. CONCLUSIONS: Adding lumbar neuromuscular control retraining to a series of resistance exercises offered no additional benefit over resistance exercises alone over a 12-week period. J Orthop Sports Phys Ther 2024;54(5):1-10. Epub 18 March 2024. doi:10.2519/jospt.2024.12349.

Same-visit hepatitis C testing and treatment to accelerate cure among people who inject drugs (the QuickStart Study): a cluster randomised cross-over trial protocol.

INTRODUCTION: Despite universal access to government-funded direct-acting antivirals (DAAs) in 2016, the rate of hepatitis C treatment uptake in Australia has declined substantially. Most hepatitis C is related to injecting drug use; reducing the hepatitis C burden among people who inject drugs (PWID) is, therefore, paramount to reach hepatitis C elimination targets. Increasing DAA uptake by PWID is important for interrupting transmission and reducing incidence, as well as reducing morbidity and mortality and improving quality of life of PWID and meeting Australia's hepatitis C elimination targets. METHODS AND ANALYSIS: A cluster randomised cross-over trial will be conducted with three intervention arms and a control arm. Arm A will receive rapid hepatitis C virus (HCV) antibody testing; arm B will receive rapid HCV antibody and rapid RNA testing; arm C will receive rapid HCV antibody testing and same-day treatment initiation for HCV antibody-positive participants; the control arm will receive standard of care. The primary outcomes will be (a) the proportion of participants with HCV commencing treatment and (b) the proportion of participants with HCV achieving cure. Analyses will be conducted on an intention-to-treat basis with mixed-effects logistic regression models. ETHICS AND DISSEMINATION: The study has been approved by the Alfred Ethics Committee (number HREC/64731/Alfred-2020-217547). Each participant will provide written informed consent. Reportable adverse events will be reported to the reviewing ethics committee. The findings will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05016609. TRIAL PROGRESSION: The study commenced recruitment on 9 March 2022 and is expected to complete recruitment in December 2024.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with hypoxic ischaemic encephalopathy (HIE) following a cardiac arrest who are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: To summarise the protocol and statistical analysis plan for the Mega-ROX HIE trial. Design setting and participants: Mega-ROX HIE is an international randomised clinical trial that will be conducted within an overarching 40,000-participant registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol approximately 4000 participants with suspected HIE following a cardiac arrest who are receiving invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX HIE will compare the effect of conservative vs. liberal oxygen therapy regimens on day-90 in-hospital mortality in adults in the ICU with suspected HIE following a cardiac arrest. The protocol and planned analyses are reported here to mitigate analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).