Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.

Bathing Adaptations in the Homes of Older Adults (BATH-OUT-2): study protocol for a randomised controlled trial, economic evaluation and process evaluation.

BACKGROUND: The onset of disability in bathing is particularly important for older adults as it can be rapidly followed by disability in other daily activities; this may represent a judicious time point for intervention in order to improve health, well-being and associated quality of life. An important environmental and preventative intervention is housing adaptation, but there are often lengthy waiting times for statutory provision. In this randomised controlled trial (RCT), we aim to evaluate the effectiveness and cost-effectiveness of bathing adaptations compared to no adaptations and to explore the factors associated with routine and expedited implementation of bathing adaptations. METHODS: BATH-OUT-2 is a multicentre, two-arm, parallel-group RCT. Adults aged 60 and over who are referred to their local authority for an accessible level access shower will be randomised, using pairwise randomisation, 1:1, to receive either an expedited provision of an accessible shower via the local authority or a usual care control waiting list. Participants will be followed up for a maximum of 12 months and will receive up to four follow-ups in this duration. The primary outcome will be the participant's physical well-being, assessed by the Physical Component Summary score of the Short Form-36 (SF-36), 4 weeks after the intervention group receives the accessible shower. The secondary outcomes include the Mental Component Summary score of the SF-36, self-reported falls, health and social care resource use, health-related quality of life (EQ-5D-5L), social care-related quality of life (Adult Social Care Outcomes Toolkit (ASCOT)), fear of falling (Short Falls Efficacy Scale), independence in bathing (Barthel Index bathing question), independence in daily activities (Barthel Index) and perceived difficulty in bathing (0-100 scale). A mixed-methods process evaluation will comprise interviews with stakeholders and a survey of local authorities with social care responsibilities in England. DISCUSSION: The BATH-OUT-2 trial is designed so that the findings will inform future decisions regarding the provision of bathing adaptations for older adults. This trial has the potential to highlight, and then reduce, health inequalities associated with waiting times for bathing adaptations and to influence policies for older adults. TRIAL REGISTRATION: ISRCTN Registry ISRCTN48563324. Prospectively registered on 09/04/2021.

Can we achieve better trial recruitment by presenting patient information through multimedia? Meta-analysis of 'studies within a trial' (SWATs).

BACKGROUND: People need high-quality information to make decisions about research participation. Providing information in written format alone is conventional but may not be the most effective and acceptable approach. We developed a structure for the presentation of information using multimedia which included generic and trial-specific content. Our aim was to embed 'Studies Within A Trial' (SWATs) across multiple ongoing trials to test whether multimedia presentation of patient information led to better rates of recruitment. METHODS: Five trials included a SWAT and randomised their participants to receive a multimedia presentation alongside standard information, or standard written information alone. We collected data on trial recruitment, acceptance and retention and analysed the pooled results using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised following an invitation to take part. RESULTS: Five SWATs provided data on the primary outcome of proportion of participants randomised. Multimedia alongside written information results in little or no difference in recruitment rates (pooled odds ratio = 0.96, 95% CI: 0.79 to 1.17, p-value = 0.671, I2 = 0%). There was no effect on any other outcomes. CONCLUSIONS: Multimedia alongside written information did not improve trial recruitment rates. TRIAL REGISTRATION: ISRCTN71952900, ISRCTN 06710391, ISRCTN 17160087, ISRCTN05926847, ISRCTN62869767.

Trial Forge Guidance 3: randomised trials and how to recruit and retain individuals from ethnic minority groups-practical guidance to support better practice.

Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities.This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, examples of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations.We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.

Bah humbug! Association between sending Christmas cards to trial participants and trial retention: randomised study within a trial conducted simultaneously across eight host trials.

OBJECTIVES: To determine the effectiveness of sending Christmas cards to participants in randomised controlled trials to increase retention rate at follow-ups, and to explore the feasibility of doing a study within a trial (SWAT) across multiple host trials simultaneously. DESIGN: Randomised SWAT conducted simultaneously across eight host trials. SETTING: Eight randomised controlled trials researching various areas including surgery and smoking cessation. PARTICIPANTS: 3223 trial participants who were still due at least one follow-up from their host randomised controlled trial. INTERVENTION: Participants were randomised (1:1, separately by each host trial) to either received a Christmas card in mid-December 2019 or to not receive a card. MAIN OUTCOME MEASURE: Proportion of participants completing their next follow-up (retention rate) within their host randomised controlled trial. RESULTS: 1469 participants (age 16-94 years; 70% (n=1033) female; 96% (813/847) white ethnicity) across the eight host randomised controlled trials were involved in the analysis (cut short owing to covid-19). No evidence was found of a difference in retention rate between the two arms for any of the host trials when analysed separately or when the results were combined (85.3% (639/749) for cards versus 85.4% (615/720) for no card; odds ratio 0.96, 95% confidence interval 0.71 to 1.29; P=0.77). No difference was observed when comparing just participants who were due a follow-up in the 30 days after receiving the card (odds ratio 0.96, 0.42 to 2.21). No evidence of a difference in time to complete the questionnaire was found (hazard ratio 1.01, 95% confidence interval 0.91 to 1.13; P=0.80). These results were robust to post hoc sensitivity analyses. The cost of this intervention was £0.76 (€0.91; $1.02) per participant, and it will have a carbon footprint of approximately 140 g CO2 equivalent per card. One benefit of this approach was the need to only submit one ethics application. CONCLUSIONS: Sending Christmas cards to participants in randomised controlled trials does not increase retention. Undertaking a SWAT within multiple randomised controlled trials at the same time is, however, possible. This approach should be used more often to build an evidence base to support selection of recruitment and retention strategies. Although no evidence of a boost to retention was found, embedding a SWAT in multiple host trials simultaneously has been shown to be possible. STUDY REGISTRATION: SWAT repository https://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,846275,en.pdf#search=SWAT%2082.

Can we achieve better recruitment by providing better information? Meta-analysis of 'studies within a trial' (SWATs) of optimised participant information sheets.

BACKGROUND: The information given to people considering taking part in a trial needs to be easy to understand if those people are to become, and then remain, trial participants. However, there is a tension between providing comprehensive information and providing information that is comprehensible. User-testing is one method of developing better participant information, and there is evidence that user-tested information is better at informing participants about key issues relating to trials. However, it is not clear if user-testing also leads to changes in the rates of recruitment in trials, compared to standard trial information. As part of a programme of research, we embedded 'studies within a trial' (SWATs) across multiple ongoing trials to see if user-tested materials led to better rates of recruitment. METHODS: Seven 'host' trials included a SWAT evaluation and randomised their participants to receive routine information sheets generated by the research teams, or information sheets optimised through user-testing. We collected data on trial recruitment and analysed the results across these trials using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised in a host trial following an invitation to take part. RESULTS: Six SWATs (n=27,805) provided data on recruitment. Optimised participant information sheets likely result in little or no difference in recruitment rates (7.2% versus 6.8%, pooled odds ratio = 1.03, 95% CI 0.90 to 1.19, p-value = 0.63, I2 = 0%). CONCLUSIONS: Participant information sheets developed through user testing did not improve recruitment rates. The programme of work showed that co-ordinated testing of recruitment strategies using SWATs is feasible and can provide both definitive and timely evidence on the effectiveness of recruitment strategies. TRIAL REGISTRATION: Healthlines Depression (ISRCTN14172341) Healthlines CVD (ISRCTN27508731) CASPER (ISRCTN02202951) ISDR (ISRCTN87561257) ECLS (NCT01925625) REFORM (ISRCTN68240461) HeLP Diabetes (ISRCTN02123133).

Randomised study within a trial (SWAT) to evaluate personalised versus standard text message prompts for increasing trial participant response to postal questionnaires (PROMPTS).

BACKGROUND: Use of a person's name in a text message has been shown to be effective in instigating behaviour change. We evaluated the effectiveness of a personalised text message (including the recipient's name) versus a standardised text message for prompting a response from trial participants to complete and return postal follow-up questionnaires. METHODS: Using a randomised study within a trial (SWAT) embedded within the host GRASP (Getting it Right: Addressing Shoulder Pain) trial, participants who provided a mobile telephone number were randomised (1:1) by a central computer system to receive either (1) a personalised text message which included their name or (2) a standard text message. Text messages were sent by the trial office on the same day as the 6-month GRASP follow-up questionnaire. The primary outcome was questionnaire response rate, defined as the proportion of 6-month GRASP follow-up questionnaires returned by participants. Secondary outcomes included time to response, the proportion of participants sent a reminder follow-up questionnaire, and cost. RESULTS: Between March 2017 and May 2019 (recruitment period for GRASP trial), 618 participants were randomised to a personalised (n = 309) or standard (n = 309) text message and all were included in the analysis. The overall questionnaire response rate was 87% (n = 537/618); 90% (n = 277/309) of participants responded in the personalised text message group compared to 84% (n = 260/309) in the standard text message group (relative risk (RR) 1.07; 95% CI 1.00 to 1.13). Participants randomised to receive the personalised text message were more likely to return their initial postal questionnaire than those who received the standard text message (n = 185/309; 60% vs. n = 160/309; 52%) (RR 1.16; 95% CI 1.00 to 1.33); this represents an absolute percentage difference between intervention groups of 8%. Post hoc subgroup analysis showed that males under 65 years were the group most likely to return their initial questionnaire if they received a personalised text message. CONCLUSION: Overall, participants who received a personalised text message were more likely to return their questionnaire than those who received the standard text message. TRIAL REGISTRATION: GRASP Trial ISRCTN16539266 ; SWAT Repository ID 35.

Developing the INCLUDE Ethnicity Framework-a tool to help trialists design trials that better reflect the communities they serve.

BACKGROUND: Ensuring that a trial is designed so that its participants reflect those who might benefit from the results, or be spared harms, is key to the potential benefits of the trial reaching all they should. This paper describes the process, facilitated by Trial Forge, that was used between July 2019 and October 2020 to develop the INCLUDE Ethnicity Framework, part of the wider INCLUDE initiative from the National Institute for Health Research to improve inclusion of under-served groups in clinical research studies. METHODS: Development of the Framework was done in seven phases: (1) outline, (2) initial draft, (3) stakeholder meeting, (4) modify draft, (5) Stakeholder feedback, (6) applying the Framework and (7) packaging. Phases 2 and 3 were face-to-face meetings. Consultation with stakeholders was iterative, especially phases 4 to 6. Movement to the next phase was done once all or most stakeholders were comfortable with the results of the current phase. When there was a version of the Framework that could be considered final, the Framework was applied to six trials to create a set of examples (phase 6). Finally, the Framework, guidance and examples were packaged ready for dissemination (phase 7). RESULTS: A total of 40 people from stakeholder groups including patient and public partners, clinicians, funders, academics working with various ethnic groups, trial managers and methodologists contributed to the seven phases of development. The Framework comprises two parts. The first part is a list of four key questions: 1. Who should my trial apply to? 2. Are the groups identified likely to respond in different ways? 3. Will my study intervention make it harder for some groups to engage? 4. Will the way I have designed the study make it harder for some groups to engage? The second part is a set of worksheets to help trial teams address these questions. The Framework can be used for any stage of trial, for a healthcare intervention in any disease area. The Framework was launched on 1st October 2020 and is available open access at the Trial Forge website: https://www.trialforge.org/trial-forge-centre/include/ . CONCLUSION: Thinking about the number of people in our trials is not enough: we need to start thinking more carefully about who our participants are.

A multicentre, randomized, parallel group, superiority study to compare the clinical effectiveness and cost-effectiveness of external frame versus internal locking plate for complete articular pilon fracture fixation in adults.

AIMS: A pilon fracture is a severe ankle joint injury caused by high-energy trauma, typically affecting men of working age. Although relatively uncommon (5% to 7% of all tibial fractures), this injury causes among the worst functional and health outcomes of any skeletal injury, with a high risk of serious complications and long-term disability, and with devastating consequences on patients' quality of life and financial prospects. Robust evidence to guide treatment is currently lacking. This study aims to evaluate the clinical and cost-effectiveness of two surgical interventions that are most commonly used to treat pilon fractures. METHODS: A randomized controlled trial (RCT) of 334 adult patients diagnosed with a closed type C pilon fracture will be conducted. Internal locking plate fixation will be compared with external frame fixation. The primary outcome and endpoint will be the Disability Rating Index (a patient self-reported assessment of physical disability) at 12 months. This will also be measured at baseline, three, six, and 24 months after randomization. Secondary outcomes include the Olerud and Molander Ankle Score (OMAS), the five-level EuroQol five-dimenison score (EQ-5D-5L), complications (including bone healing), resource use, work impact, and patient treatment preference. The acceptability of the treatments and study design to patients and health care professionals will be explored through qualitative methods. DISCUSSION: The two treatments being compared are the most commonly used for this injury, however there is uncertainty over which is most clinically and cost-effective. The Articular Pilon Fracture (ACTIVE) Trial is a sufficiently powered and rigorously designed study to inform clinical decisions for the treatment of adults with this injury. Cite this article: Bone Jt Open 2021;2(3):150-163.

Correction to: Why do patients take part in research? An overview of systematic reviews of psychosocial barriers and facilitators.

An amendment to this paper has been published and can be accessed via the original article.

Study within a trial (SWAT) protocol. Investigating the effect of personalised versus non-personalised study invitations on recruitment: An embedded randomised controlled recruitment trial.

INTRODUCTION: Recruitment into clinical trials is a common challenge experienced by healthcare researchers. Currently, there is little evidence regarding strategies to improve recruitment into clinical trials. However, preliminary research suggests the personalisation of study invitation letters may increase recruitment rates. As such, there is a need to investigate the effectiveness of personalisation strategies on trial recruitment rates. This study within a trial (SWAT) will investigate the effect of personalised versus non-personalised study invitation letters on recruitment rates into the host trial ENGAGE, a feasibility study of an internet-administered, guided, Cognitive-Behavioural Therapy (CBT) based self-help intervention for parents of children previously treated for cancer. METHODS: An embedded randomised controlled trial (RCT) will investigate the effectiveness of a personalised study invitation letter including the potential participant's name and address compared with a standard, non-personalised letter without name or address, on participant recruitment rates into the ENGAGE study. The primary outcome is differences in the proportion of participants recruited, examined using logistic regression. Results will be reported as adjusted odds ratios with 95% confidence intervals. DISCUSSION: Even moderate effects of the personalisation of study invitation letters on recruitment rates could be of significant value by shortening study length, saving resources, and providing a faster answer to the clinical question posed by the study. This protocol can be used as a template for other researchers who wish to contribute to the evidence base for trial decision-making, by embedding a similar SWAT into their trial. TRIAL REGISTRATION: ISRCTN 57233429; ISRCTN 18404129; SWAT 112, Northern Ireland Hub for Trials Methodology Research SWAT repository (2018 OCT 1 1231).

Timing of electronic reminders did not improve trial participant questionnaire response: a randomized trial and meta-analyses.

OBJECTIVES: The objective of this study was to assess whether timing of short messaging service (SMS) reminders improved postal questionnaire return rates from participants in a randomized controlled trial (RCT). STUDY DESIGN AND SETTING: A Study Within A Trial (SWAT) embedded in a multicenter RCT evaluating three treatments for the frozen shoulder. Participants who provided a mobile telephone number were randomized to either prenotification SMS on the day of the questionnaire mail-out or postnotification SMS 4 days after questionnaire mail-out for the 3-month follow-up. The primary outcome was the proportion of participants who returned a valid questionnaire. A systematic review was undertaken to identify other embedded trials to perform a meta-analysis. RESULTS: Of the 269 participants, 122/135 (90.4%) returned a valid questionnaire in the prenotification arm and 119/134 (88.8%) in the postnotification arm (difference of -1.6%; 95% CI of difference: -8.9%, 5.7%). There was no difference in time to response (HR = 1.04; 95% CI: 0.80 to 1.34) or need for additional reminders (OR = 0.71; 95% CI: 0.43 to 1.17). Meta-analysis of two RCTs showed no difference in response rates between prenotification and postnotification reminders (OR = 0.78 95% CI: 0.42 to 1.45). CONCLUSION: Timing of SMS reminders did not improve response rates and time to response or affect the need for additional reminders.

Why do patients take part in research? An overview of systematic reviews of psychosocial barriers and facilitators.

BACKGROUND: Understanding why people take part in health research is critical to improve research efficiency and generalisability. The aim of this overview of systematic reviews was to identify psychosocial determinants of research participation and map them to psychological theory and empirical recruitment research, to identify effective strategies to increase research participation. METHODS: Qualitative and quantitative systematic reviews were systematically identified. No date or language limits were applied. Two reviewers independently selected reviews. Methodological quality was rated using AMSTAR, and poor-quality reviews (scoring 0-3) were excluded. Barriers and facilitators were coded to psychological theory (Theoretical Domains Framework) and empirical recruitment research (recruitment interventions that had been subjected to randomised controlled trial evaluation). RESULTS: We included 26 systematic reviews (429 unique primary studies), covering a wide range of patient populations and health settings. We identified five groups of facilitators, of which three were dominant (potential for personal benefit, altruism, trust) and appear to be relevant across research setting and design. We identified nine groups of barriers, which were more dependent on the particular study (context, population, design). Two determinants (participant information, social influences) were found to be both barriers and facilitators. Barriers and facilitators could be coded to the Motivation and Opportunity components of the Theoretical Domains Framework; only one was coded to a Capability component. There was some overlap between psychosocial determinants and empirical recruitment research, but some barriers and facilitators had not been tested at all. CONCLUSIONS: Identifying effective recruitment strategies could increase the efficiency and generalisability of primary research. We identified a number of barriers and facilitators that could be addressed by researchers. There is a need for more research to identify effective recruitment strategies that draw on the psychosocial facilitators and barriers identified in this overview.

Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.

Including a pen and/or cover letter, containing social incentive text, had no effect on questionnaire response rate: a factorial randomised controlled Study within a Trial.

Background: Postal questionnaires are frequently used in randomised controlled trials to collect outcome data on participants; however, poor response can introduce bias, affect generalisability and validity, and reduce statistical power. The objective of this study was to assess whether a pen and/or social incentive text cover letter sent with a postal follow-up questionnaire increased response rates in a trial. Method: A two-by-two factorial randomised controlled trial was embedded within the OTIS host trial. Participants due their 12-month (final) follow-up questionnaire were randomised to be sent: a pen; a social incentive text cover letter; both; or neither. The primary outcome measure was the proportion of participants in each group who returned the questionnaire. Secondary outcomes were: time to return, completeness of the questionnaire, necessity of a reminder letter, and the cost effectiveness. Results: The overall 12-month questionnaire response rate was 721 out of 755 (95.5%). Neither the pen nor social incentive cover letter had a statistically significant effect on response rate: pen 95.2% vs. no pen 95.8%, adjusted OR 0.90 (95% CI 0.45 to 1.80; p=0.77); social incentive cover letter 95.2% vs. no social incentive cover letter 95.8%, adjusted OR 0.84 (95% CI 0.42 to 1.69, p=0.63). No statistically significant differences were observed between either of the intervention groups on time to response, need for a reminder or completeness. Therefore, neither intervention was cost-effective. Conclusions: We found no evidence of a difference in response rates associated with the inclusion of a pen and/or social incentive cover letter with the final follow-up postal questionnaire of the host trial. However, when these results are combined with previous SWATs, the meta-analysis evidence remains that including a pen increases response rates. The social incentive cover letter warrants further investigation to determine effectiveness. Trial registration: ISRCTN22202133 (21st June 2020).

Outcome domains and outcome measures used in studies assessing the effectiveness of interventions to manage non-respiratory sleep disturbances in children with neurodisabilities: a systematic review.

OBJECTIVES: To assess whether a core outcome set is required for studies evaluating the effectiveness of interventions for non-respiratory sleep disturbances in children with neurodisabilities. DESIGN: Survey of outcome measures used in primary studies identified by a systematic review. DATA SOURCES: ASSIA, CENTRAL, Cochrane Database of Systematic Reviews, Conference Proceedings Citation Index, CINAHL, DARE, Embase, HMIC, MEDLINE, MEDLINE In-Process, PsycINFO, Science Citation Index, Social Care Online, Social Policy & Practice, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform and the UK Clinical Trials Gateway were searched up to February 2017. ELIGIBILITY CRITERIA: Studies evaluating pharmacological or non-pharmacological interventions for children (≤18 years old) with a neurodisability and experiencing non-respiratory sleep disturbance. DATA EXTRACTION AND SYNTHESIS: Outcome measures were listed from each study and categorised into domains. RESULTS: Thirty-nine studies assessed five core outcome areas: child sleep, other child outcomes, parent outcomes, adverse events and process measures. There were 54 different measures of child sleep across five domains: global measures; sleep initiation; maintenance; scheduling; and other outcomes. Fifteen non-pharmacological (58%) and four pharmacological studies (31%) reported child outcomes other than sleep using 29 different measures.One pharmacological and 14 non-pharmacological (54%) studies reported parent outcomes (17 different measures). Eleven melatonin studies (85%) recorded adverse events, with variation in how data were collected and reported. One non-pharmacological study reported an explicit method of collecting on adverse events. Several process measures were reported, related to adherence, feasibility of delivery, acceptability and experiences of receiving the intervention. CONCLUSIONS: There is a lack of consistency between studies in the outcome measures used to assess the effectiveness of interventions for non-respiratory sleep disturbances in children with neurodisabilities. A minimum core outcome set, with international consensus, should be developed in consultation with parents, children and young people, and those involved in supporting families. PROSPERO REGISTRATION NUMBER: CRD42016034067.

Limited evidence exists on the effectiveness of education and training interventions on trial recruitment; a systematic review.

OBJECTIVE: The objective of this study was to examine the effectiveness of education and training interventions on recruitment to randomized and non-randomized trials. STUDY DESIGN AND SETTING: A systematic review of the effectiveness of education and training interventions for recruiters to trials. The review included randomized and non-randomized controlled trials of any type of education and training intervention for recruiters to trials, within any health care field. The primary outcome was recruitment rates, and secondary outcomes were quality of informed consent, recruiter self-confidence, understanding/knowledge of trial information, numbers of potential trial participants approached, satisfaction with training, and retention rates. RESULTS: Of the 19 records reviewed at full-text level, six met the inclusion criteria for our review. Owing to heterogeneity of outcomes and methods between the included studies, meta-analysis was not possible for the primary outcome. Of the three studies that reported recruitment rates, one favored the education and training intervention for increased recruitment; the remaining two found no differences between the groups. Of the reported secondary outcomes, quality of informed consent was improved, but no differences between groups in understanding/knowledge of trial information were found. CONCLUSION: There is limited evidence of effectiveness on the impact of education and training interventions on trial recruitment. Further work on developing a substantial evidence base around the effectiveness of education and training interventions for recruiters to trials is required.

SWATted away: the challenging experience of setting up a programme of SWATs in paediatric trials.

BACKGROUND: Randomised controlled trials are considered the best method for determining the effectiveness and safety of health interventions. Trials involving children are essential to ensure that treatments are safe and effective. However, many trials, in both adult and paediatric populations, do not achieve recruitment targets and/or maintain retention of participants, which can lead to a reduction in the internal and external validity of the results. Identifying ways of improving trial efficiency are important in order to increase the successful completion of trials. MAIN BODY: A 'Study Within A Trial' (SWAT) is a self-contained study embedded within an ongoing trial, which aims to establish evidence to improve the management and delivery of trials in healthcare. Increasing numbers of SWATs have been undertaken in recent years yet very few within paediatric trials. Herein, we describe some of the challenges with undertaking a programme of SWATs within paediatric clinical trials in the UK. The TRECA (TRials Engagement in Children and Adolescents) study involves developing multimedia websites for use within paediatric trials to provide recruitment information to children, young people and their families about the clinical trial. Challenges encountered included governance issues such as host trial approval processes and sharing of anonymised data, funding issues for host trials, internet quality and accessibility within the healthcare setting, and ethical concerns associated with SWAT methodology. We believe the ethical concerns are more pronounced in the paediatric setting, perhaps because of the fewer SWATs undertaken in these settings or that a more cautious, risk-averse approach to undertaking research with children is taken. CONCLUSION: SWATs are becoming increasingly common to provide an evidence base for methods to improve trial efficiency. However, we encountered a number of unanticipated challenges to embedding TRECA that have not been previously reported within the scientific literature. We believe that, if these issues were addressed through wider promotion and explanation of undertaking SWATs involving all key stakeholders, as well as by exploration of alternative funding models for SWATs, this would enable more streamlined, appropriate and timely processes for SWATs and a stronger evidence base for what works to increase trial efficiency. TRIAL REGISTRATION: The TRECA study is registered on ISRCTN, ID 73136092 . Registered on 24 August 2016.

Oral melatonin for non-respiratory sleep disturbance in children with neurodisabilities: systematic review and meta-analyses.

AIM: To evaluate the effectiveness of pharmacological interventions for managing non-respiratory sleep disturbances in children with neurodisabilities. METHOD: We performed a systematic review and meta-analyses of randomized controlled trials (RCTs). We searched 16 databases, grey literature, and reference lists of included papers up to February 2017. Data were extracted and assessed for quality by two researchers (B.B., C.M., G.S., A.S., A.P.). RESULTS: Thirteen trials were included, all evaluating oral melatonin. All except one were at high or unclear risk of bias. There was a statistically significant increase in diary-reported total sleep time for melatonin compared with placebo (pooled mean difference 29.6min, 95% confidence interval [CI] 6.9-52.4, p=0.01). Statistical heterogeneity was high (97%). For the single RCT with low risk of bias, the unadjusted mean difference in total sleep time was 13.2 minutes (95% CI -13.3 to 39.7) favouring melatonin, while the mean difference adjusted for baseline total sleep time was statistically significant (22.4min, 95% CI 0.5-44.3, p=0.04). Adverse event profile suggested that melatonin was well-tolerated. INTERPRETATION: There is a paucity of evidence on managing sleep disturbances in children with neurodisabilities, and it is mostly of limited scope and poor quality. There is evidence of the benefit and safety of melatonin compared with placebo, although the extent of this benefit is unclear. WHAT THIS PAPER ADDS: Melatonin for the management of non-respiratory sleep disturbances in children with neurodisabilities was well tolerated with minimal adverse effects. The extent of benefit and which children might benefit most from melatonin use is uncertain. Benefit may be greatest in those with autism spectrum disorder; however, this finding should be interpreted with caution.

Melatonina oral para la alteración del sueño no respiratoria en niños con trastornos del neurodesarrollo: revisión sistemática y metaanálisis OBJETIVO: Evaluar la efectividad de las intervenciones farmacológicas para el tratamiento de los trastornos del sueño no respiratorios en niños con trastornos del neurodesarrollo. MÉTODO: Se realizó una revisión sistemática y un metaanálisis de ensayos controlados aleatorios (ECA). Se realizaron búsquedas en 16 bases de datos, literatura gris y listas de referencias de los artículos incluidos hasta febrero de 2.017. Dos investigadores extrajeron y evaluaron la calidad de la calidad. RESULTADOS: Se incluyeron trece ensayos, todos evaluaron la melatonina oral. Todos excepto uno tenía un riesgo alto o incierto de sesgo. Hubo un aumento estadísticamente significativo en el tiempo total de sueño informado por los registros - usando diarios de datos - para la melatonina en comparación con el placebo (diferencia de medias agrupada 29,6 min, intervalo de confianza [IC] del 95% [IC] 6,9-52,4, p = 0,01). La heterogeneidad estadística fue alta (97%). Para el ECA único con bajo riesgo de sesgo, la diferencia media no ajustada en el tiempo total de sueño fue de 13,2 minutos (IC del 95% −13,3 a 39,7) favoreciendo a la melatonina, mientras que la diferencia media ajustada para el tiempo total de sueño basal fue estadísticamente significativa (22,4 min. IC del 95%: 0,5-44,3, p = 0,04). El perfil de eventos adversos sugirió que la melatonina fue bien tolerada. INTERPRETACIÓN: Existe una escasez de evidencia sobre el manejo de los trastornos del sueño en niños con trastornos del neurodesarrollo, los datos actuales son principalmente de alcance limitado y de mala calidad. Existe evidencia del beneficio y la seguridad de la melatonina en comparación con el placebo, aunque el alcance de este beneficio no está claro.

Melatonina oral para distúrbios não-respiratórios do sono em crianças com neuro-incapacidades: revisão sistemática e metanálise OBJETIVO: Avaliar a efetividade de intervenções farmacológicas para o manejo de distúrbios não-respiratórios do sono em crianças com neuro-incapacidades. MÉTODO: Realizamos uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs). Buscamos 16 bases de dados, literatura cinzenta, e listas de referências dos artigos incluídos até fevereiro de 2017. Os dados foram extraídos e avaliados quanto a sua qualidade por dois pesquisadores. RESULTADOS: Treze estudos foram incluídos, todos avaliando a melatonina oral. Todos, com exceção de um, tinham risco de viés alto ou não esclarecido. Houve aumento estatisticamente significativo no tempo total de sono reportado em diário para melatonina comparada com placebo (diferença média agrupada 29,6min, intervalo de confiança [IC] 95% 6,9-52,4, p = 0,01). A heterogeneidade estatística foi alta (97%). Para o único ECR com baixo risco de viés, a diferença média não ajustada no tempo total de sono foi 13,2 minutos (IC 95% −13,3 a 39,7) em favor da melatonina, enquanto a diferença média ajustada para o tempo total de sono na linha de base foi estatisticamente significativa (22,4min, IC 95% 0,5-44,3, p = 0,04). O perfil de eventos adversos sugeriu que a melatonina foi bem tolerada. INTERPRETAÇÃO: Há escassez de evidência sobre o manejo de distúrbios do sono em crianças com neuroincapacidades, e a mesma tem escopo limitado e pouca qualidade. Há evidência do benefício e segurança da melatonina comparada com o placebo, embora e extensão do benefício não esteja clara.