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.</p

The Foot Orthoses versus Hip eXercises (FOHX) trial for patellofemoral pain:a protocol for a randomized clinical trial to determine if foot mobility is associated with better outcomes from foot orthoses

Background: Patellofemoral pain (PFP) is a prevalent, often recalcitrant and multifactorial knee pain condition. One method to optimize treatment outcome is to tailor treatments to the patient's presenting characteristics. Foot orthoses and hip exercises are two such treatments for PFP with proven efficacy yet target different ends of the lower limb with different proposed mechanisms of effect. These treatments have not been compared head-to-head, so there is a dearth of evidence for which to use clinically. Only foot orthoses have been explored for identifying patient characteristics that might predict a beneficial effect with either of these two treatments. Preliminary evidence suggests patients will do well with foot orthoses if they have a midfoot width in weight bearing that is≥11mm more than in non-weight bearing, but this has yet to be verified in a study that includes a comparator treatment and an adequate sample size. This trial will determine if: (i) hip exercises are more efficacious than foot orthoses, and (ii) greater midfoot width mobility will be associated with success with foot orthoses, when compared to hip exercises. Methods: Two hundred and twenty participants, aged 18-40 years, with a clinical diagnosis of PFP will be randomly allocated with a 1:1 ratio to receive foot orthoses or progressive resisted hip exercises, and stratified into two subgroups based on their presenting midfoot width mobility (high mobility defined as ≥11mm). The primary outcome will be a 7-point Likert scale for global rating of change. All analyses will be conducted on an intention-to-treat basis using regression models. Discussion: This trial is designed to compare the efficacy of foot orthoses versus hip exercise, as well as to determine if high midfoot width mobility is associated with better outcomes with foot orthoses when compared to hip exercises. Results of this trial will assist clinicians in optimising the management of those with PFP by testing whether a simple measure of midfoot width mobility can help to determine which patients are most likely to benefit from foot orthoses. Trial registration: This trial is registered on the Australian New Zealand Clinical Trials Register (ACTRN12614000260628

Are objective measures of sleep and sedentary behaviours related to low back pain flares?

Final peer-reviewed manuscript[Abstract] Risk factors for low back pain (LBP) flares have been considered about self-reported measures. This case–crossover study aimed to investigate whether (1) objective measures of physical activity and sleep were associated with the risk of experiencing LBP flares and (2) these associations differed for flares defined as pain 2 or more points greater than average pain over the period using an 11-point Numerical rating scale (0-no pain and 10-worst pain imaginable) (pain-defined flare: PDF) and flares identified by participants according to a broader definition that considered emotions or coping (self-reported flare [SRF]). We included 126 participants who had experienced LBP for >3 months. Physical activity and sleep were monitored for 28 days using wearable sensors. Occurrence of flares (PDF or SRF) was assessed daily using a smartphone application. Data on exposure to risk factors 1, 2, and 3 days preceding PDF or SRF were compared with nonflare control periods. Conditional logistic regression determined association between each factor and flares. Data show that day-to-day variation in physical activity and in-bed time are associated with the risk of LBP flares, but associations differ depending on how flare is defined. Longer in-bed time increased the risk of PDF but not SRF. Although physical activity was not associated with the risk of PDF, greater sedentary behaviour increased the risk of SRF and being more physically active decreased the risk for SRF. These results highlight the potential role of targeting sleep and physical activity in interventions to prevent LBP flares and indicate that risk factors differ depending on how LBP flares are defined.Centre of Research Excellence (Australia); APP1091302Centre of Research Excellence (Australia); APP1079078National Health and Medical Research Council (NHMRC) of Australia; PH—APP1102905National Health and Medical Research Council (NHMRC) of Australia; MF—APP114359

Effectiveness of Switching Smoking-Cessation Medications Following Relapse

Introduction—Nicotine dependence is a chronic disorder often characterized by multiple failed quit attempts (QAs). Yet, little is known about the sequence of methods used across multiple QAs or how this may impact future ability to abstain from smoking. This prospective cohort study examines the effectiveness of switching smoking-cessation medications (SCMs) across multiple QAs. Methods—Adult smokers (aged ≥ 18 years) participating in International Tobacco Control surveys in the United Kingdom, U.S., Canada, and Australia (N=795) who: (1) completed two consecutive surveys between 2006 and 2011; (2) initiated a QA at least 1 month before each survey; and (3) provided data for the primary predictor (SCM use during most recent QA), outcome (1-month point prevalence abstinence), and relevant covariates. Analyses were conducted in 2016. Results—Five SCM user classifications were identified: (1) non-users (43.5%); (2) early users (SCM used for initial, but not subsequent QA; 11.4%); (3) later users (SCM used for subsequent, but not initial QA; 18.4%); (4) repeaters (same SCM used for both QAs; 10.7%); and (5) switchers (different SCM used for each QA; 14.2%). Abstinence rates were lower for non-users (15.9%, OR=0.48, p=0.002), early users (16.6%, OR=0.27, p=0.03), and repeaters (12.4%, OR=0.36, p=0.004) relative to switchers (28.5%). Conclusions—Findings suggest smokers will be more successful if they use a SCM in QAs and vary the SCM they use across time. That smokers can increase their odds of quitting by switching SCMs is an important message that could be communicated to smokers

Effect of a consumer-focused website for low back pain on health literacy, treatment choices, and clinical outcomes: randomized controlled trial

BACKGROUND: The internet is used for information related to health conditions, including low back pain (LBP), but most LBP websites provide inaccurate information. Few studies have investigated the effectiveness of internet resources in changing health literacy or treatment choices. OBJECTIVE: This study aims to evaluate the effectiveness of the MyBackPain website compared with unguided internet use on health literacy, choice of treatments, and clinical outcomes in people with LBP. METHODS: This was a pragmatic, web-based, participant- and assessor-blinded randomized trial of individuals with LBP stratified by duration. Participants were randomly allocated to have access to the evidence-based MyBackPain website, which was designed with input from consumers and expert consensus or unguided internet use. The coprimary outcomes were two dimensions of the Health Literacy Questionnaire (dimension 2: “having sufficient information to manage my health;” dimension 3: “actively managing my health;” converted to scores 1-100) at 3 months. Secondary outcomes included additional Health Literacy Questionnaire dimensions, quality of treatment choices, and clinical outcomes. RESULTS: A total of 453 participants were recruited, and 321 (70.9%) completed the primary outcomes. Access to MyBackPain was not superior to unguided internet use on primary outcomes (dimension 2: mean difference −0.87 units, 95% CI −3.56 to 1.82; dimension 3: mean difference −0.41 units, 95% CI −2.78 to 1.96). Between-group differences in other secondary outcomes had inconsistent directions and were unlikely to be clinically important, although a small improvement of unclear importance in the quality of stated treatment choices at 1 month was found (mean difference 0.93 units, 95% CI 0.03 to 1.84). CONCLUSIONS: MyBackPain was not superior to unguided internet use for health literacy, but data suggest some short-term improvement in treatment choices. Future research should investigate if greater interactivity and engagement with the website may enhance its impact. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001292369; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372926 INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-02751

Improving rural and regional access to long-acting reversible contraception and medical abortion through nurse-led models of care, task-sharing and telehealth (ORIENT): a protocol for a stepped-wedge pragmatic cluster-randomised controlled trial in Australian general practice

INTRODUCTION: Women living in rural and regional Australia often experience difficulties in accessing long-acting reversible contraception (LARC) and medical abortion services. Nurse-led models of care can improve access to these services but have not been evaluated in Australian general practice. The primary aim of the ORIENT trial (ImprOving Rural and regIonal accEss to long acting reversible contraceptioN and medical abortion through nurse-led models of care, Tasksharing and telehealth) is to assess the effectiveness of a nurse-led model of care in general practice at increasing uptake of LARC and improving access to medical abortion in rural and regional areas. METHODS AND ANALYSIS: ORIENT is a stepped-wedge pragmatic cluster-randomised controlled trial. We will enrol 32 general practices (clusters) in rural or regional Australia, that have at least two general practitioners, one practice nurse and one practice manager. The nurse-led model of care (the intervention) will be codesigned with key women's health stakeholders. Clusters will be randomised to implement the model sequentially, with the comparator being usual care. Clusters will receive implementation support through clinical upskilling, educational outreach and engagement in an online community of practice. The primary outcome is the change in the rate of LARC prescribing comparing control and intervention phases; secondary outcomes include change in the rate of medical abortion prescribing and provision of related telehealth services. A within-trial economic analysis will determine the relative costs and benefits of the model on the prescribing rates of LARC and medical abortion compared with usual care. A realist evaluation will provide contextual information regarding model implementation informing considerations for scale-up. Supporting nurses to work to their full scope of practice has the potential to increase LARC and medical abortion access in rural and regional Australia. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Monash University Human Research Ethics Committee (Project ID: 29476). Findings will be disseminated via multiple avenues including a knowledge exchange workshop, policy briefs, conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000086763)

Intra-cluster correlations from the CLustered OUtcome Dataset bank to inform the design of longitudinal cluster trials.

BACKGROUND: Sample size calculations for longitudinal cluster randomised trials, such as crossover and stepped-wedge trials, require estimates of the assumed correlation structure. This includes both within-period intra-cluster correlations, which importantly differ from conventional intra-cluster correlations by their dependence on period, and also cluster autocorrelation coefficients to model correlation decay. There are limited resources to inform these estimates. In this article, we provide a repository of correlation estimates from a bank of real-world clustered datasets. These are provided under several assumed correlation structures, namely exchangeable, block-exchangeable and discrete-time decay correlation structures. METHODS: Longitudinal studies with clustered outcomes were collected to form the CLustered OUtcome Dataset bank. Forty-four available continuous outcomes from 29 datasets were obtained and analysed using each correlation structure. Patterns of within-period intra-cluster correlation coefficient and cluster autocorrelation coefficients were explored by study characteristics. RESULTS: The median within-period intra-cluster correlation coefficient for the discrete-time decay model was 0.05 (interquartile range: 0.02-0.09) with a median cluster autocorrelation of 0.73 (interquartile range: 0.19-0.91). The within-period intra-cluster correlation coefficients were similar for the exchangeable, block-exchangeable and discrete-time decay correlation structures. Within-period intra-cluster correlation coefficients and cluster autocorrelations were found to vary with the number of participants per cluster-period, the period-length, type of cluster (primary care, secondary care, community or school) and country income status (high-income country or low- and middle-income country). The within-period intra-cluster correlation coefficients tended to decrease with increasing period-length and slightly decrease with increasing cluster-period sizes, while the cluster autocorrelations tended to move closer to 1 with increasing cluster-period size. Using the CLustered OUtcome Dataset bank, an RShiny app has been developed for determining plausible values of correlation coefficients for use in sample size calculations. DISCUSSION: This study provides a repository of intra-cluster correlations and cluster autocorrelations for longitudinal cluster trials. This can help inform sample size calculations for future longitudinal cluster randomised trials

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis)

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial. Design, setting, and participants: The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial. 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 patients discharged home. Results and conclusions: Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias