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CONSORT 2010 Statement: Extension to Randomised Crossover Trials RESEARCH METHODS AND REPORTING CONSORT 2010 statement: extension to randomised crossover BMJ: first published as 10.1136/bmj.l4378 on 31 July 2019. Downloaded from trials Kerry Dwan,1 Tianjing Li,2 Douglas G Altman,3 Diana Elbourne4 1Review Production and Quality Evidence shows the quality of reporting good reporting and evidence based Unit, Editorial and Methods Department, Cochrane Central of randomised controlled trials is not rationale for CONSORT crossover Executive, Cochrane, St Alban’s House, London SW1Y 4QX, UK optimal. The lack of transparent checklist items are provided. 2Center for Clinical Trials and reporting impedes readers from Evidence Synthesis, Department Inadequate reporting of randomised controlled of Epidemiology, Johns Hopkins judging the reliability and validity of Bloomberg School of Public trials (RCTs) is associated with bias in the estimation 1 2 Health, Baltimore, MD, USA trial findings, prevents researchers of treatment effects ; it also impairs the critical 3Centre for Statistics in from extracting information for appraisal of the quality of randomised trials, which Medicine, Nuffield Department is important when assessing the validity of the of Orthopaedics, Rheumatology systematic reviews, and results in and Musculoskeletal Sciences, results of the individual trial and when conducting University of Oxford, Oxford, UK research waste. The Consolidated systematic reviews. To attempt to address this issue, 4London School of Hygiene and Standards of Reporting Trials the Consolidated Standards of Reporting Trials Tropical Medicine, Department (CONSORT) statement was developed and includes of Medical Statistics, London, (CONSORT) statement was developed 3 UK a set of recommendations for the reporting of RCTs. Correspondence to: K Dwan to improve the reporting of randomised The statement comprises a checklist of essential items [email protected] controlled trials. The primary focus of that should be included in reports of RCTs and a (ORCID 0000-0001-6918-1215) the statement was on parallel group diagram to document the flow of participants through Cite this as: BMJ 2019;366:l4378 the trial from before group assignment through to http://dx.doi.org/10.1136/bmj.l4378 trials with two treatment groups. the final analysis. These items are evidence based Accepted: 7 June 2019 Crossover trials are a particular type of when possible. An explanation and elaboration of the rationale for the checklist items are provided in an trial for chronic conditions in which 4 accompanying article. Many journals now require that http://www.bmj.com/ participants are randomised to a reports of RCTs conform to the recommendations in the sequence of interventions. They are a CONSORT statement.5 The primary focus of the CONSORT statement is the useful and efficient design because most common type of RCT with two treatment groups participants act as their own control. (two “arms”) using an individually randomised, However, the reporting of crossover parallel group, superiority design.3 Almost all the elements of the CONSORT statement apply equally on 30 September 2021 by guest. Protected copyright. trials has been variable and to RCTs with other designs, but some elements need incomplete, which hinders their use in adaptation, and in some cases additional issues need clinical decision making and by future to be discussed. Members of the CONSORT group have published several extension papers that augment researchers. We present the CONSORT the CONSORT statement for different types of extension to randomised crossover interventions and data. Extensions of CONSORT 2010 trials, which aims to facilitate better to different trial designs have also been published, including cluster randomised trials,6 non-inferiority reporting of crossover trials. The and equivalence trials,7 N-of-1 trials,8 pragmatic CONSORT 2010 checklist is revised for trials,9 and within person trials.10 As part of that crossover designs, and introduces a series, in this paper we extend the CONSORT 2010 recommendations to simple crossover RCTs in which modified flowchart and baseline table participants receive two treatments sequentially over to enhance transparency. Examples of two periods and the order in which treatments are received is randomised. SUMMARY POINTS Scope of this paper Firstly, we summarise the key methodological features • The Consolidated Standards of Reporting Trials (CONSORT) statement provides of crossover trials. Secondly, we consider the empirical a minimum set of 25 items to be reported with rationale and exemplars for all evidence about how common crossover trials are and randomised trials review published studies about the quality of reporting • CONSORT extension to crossover trials extends 14 items of the CONSORT of such trials. After these literature reviews, we make statement suggestions for amendments to the CONSORT checklist • The use of the CONSORT extension to crossover trials will improve reporting of adapted for crossover trials and give illustrative randomised crossover trials examples of good reporting. In this guideline we the bmj | BMJ 2019;366:l4378 | doi: 10.1136/bmj.l4378 1 RESEARCH METHODS AND REPORTING focus on the simplest and most common form of the Another issue is the “period effect,” which occurs when randomised crossover trial in which all participants the outcome of interest changes with time irrespective of BMJ: first published as 10.1136/bmj.l4378 on 31 July 2019. Downloaded from receive two interventions in one of two sequences treatment effect; for example, the condition might not be (known as the 2×2 or AB/BA design). Most of the stable or the effect of treatment is seasonal. recommendations also apply to the more complicated A further issue is the possibility of participants designs (more than two interventions, periods, or dropping out of the trial if the first intervention is sequences). In a separate section, we briefly discuss either very successful or unsuccessful; the results for specific issues that arise in trials comparing more than these participants cannot be included in the analysis. two interventions. Design Methodological features of randomised crossover trials The particular strength of the simple AB/BA crossover In contrast to a parallel group trial, each individual design is that both interventions are evaluated using in a crossover trial receives multiple interventions the same participant, which allows comparison but in a random order; that is, participants are at the individual rather than the group level. In randomised to sequences of interventions. In this way, addition, participants in a crossover trial can express each participant acts as his or her own control. Such preferences by comparing their experiences of the two prespecified designs should not be confused with trials interventions, which is not possible in a parallel group in which some individuals “cross over” through non- design because participants will only receive one compliance or use of rescue medication, or in which intervention.12 all participants in the control group are given the A crucial methodological question is whether the chance to “cross over” to the experimental treatment use of the crossover design is justified. Crossover at the end of the main trial. Zeng and colleagues found trials are most appropriate for symptomatic treatment that almost one quarter of records (n=17/72) labelled (that is, treatment for symptoms, such as pain) of as “crossover assignment” did not use a randomised conditions or diseases that are chronic or relatively crossover design to randomise participants to a stable (for example, multiple sclerosis or rheumatoid sequence; instead, these trials allowed participants to arthritis), at least over the time period under study; change intervention during the course of the trial.11 additionally, when the treatment effects are reversible Randomised crossover trials present particular and short lived. The crossover design is inappropriate challenges. One challenge is the potential for a “carry when the condition of interest can be cured or when http://www.bmj.com/ over effect”; that is, the effect of the first intervention participants will probably die during the trial period. persists into the second period so that the observed The design is commonly used, however, in less difference between the treatments depends on the order appropriate circumstances. For example, pregnancy in which they were received (see box 1 for glossary of is an intended outcome of subfertility treatment. If a terms). A carry over effect could have a range of causes. woman becomes pregnant during the first period of the In addition to the obvious problem of a drug or other trial (that is, before crossover), she will be excluded treatment remaining in the system, participants’ from subsequent phases of the trial. Nevertheless later responses can be affected by previous side the crossover design is defended in the field13 (for on 30 September 2021 by guest. Protected copyright. effects or other reactions to previous treatment. It is instance, it has been suggested that pregnancies can recommended that crossover trials should include be treated statistically as “missing at random”14), and a sufficient “washout” between the end of the first remains common despite criticism.15 intervention and the start of the second intervention, The sample size calculation for such trials is based so that any effects from the first intervention will not be on the within participant variability in responses. “carried over” to the measurement
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