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Additional file 1. Data extraction form.

Additional file 8. BOTS Risk Assessment Tool (BRAT).

Additional file 2. Online survey.

Additional file 4. Additional analyses.

Additional file 7. BOTS guidance.

Additional file 6. BOTS stakeholder group membership.

Additional file 5. BOTS stakeholder survey responses.

Background There is an urgent clinical need for evidence based psychosocial interventions for people with mild dementia. We aimed to determine clinical and cost-effectiveness of Journeying through Dementia (JtD), an intervention designed to promote wellbeing and independence in people with mild dementia. Methods We conducted a phase 3, two-arm parallel group, superiority, individually randomised controlled trial. Thirteen NHS sites across England recruited community-dwelling people with mild dementia and Mini-Mental State Examination score of ≥18. Centralised randomisation (1:1) was conducted for participants to receive JtD plus usual care or usual care (control), stratified by site. The JtD Intervention comprised 12 group and four one-to-one sessions, delivered in the community at each site. The primary endpoint was Dementia Related Quality of Life (DEMQOL), eight-months postrandomisation. Only outcome assessors were blinded. Analysis was by intention-to-treat. Costeffectiveness analysis reported cost per quality adjusted life year (QALY) from a UK NHS and social care perspective. Findings In total 480 people were randomised to intervention (241) or control (239) arms. Intervention adherence was very good. Mean DEMQOL scores at eight months were intervention arm 93·3 (SD 13·0, n=191) and control 91·9 (SD 14·6, n=197). Difference in means was 0·9 (95% CI -1·2 to 3·0) after adjustment for covariates, lower than that identified as clinically meaningful. Incremental cost per QALY ranged from £88K to -£205K, indicating that JtD was not cost-effective. Unrelated serious adverse events were experienced by 17% (40/241) of intervention and 15% (35/239) of control participants. Interpretation In common with other recently reported studies the JtD intervention was not provenly effective. However, this complex trial successfully recruited and retained people with dementia without necessarily involving carers, and people with dementia they were actively involved as participants and study advisors throughout. Further research into methods of measuring small, meaningful changes in this population is needed. Questions remain regarding how services can match the complex, diverse and individual needs of people with mild dementia, and how interventions to meet such needs can be delivered at scale.

Additional file 1. Participant information sheet.

Additional file 4. The consolidated criteria for reporting qualitative research (COREQ).

Additional file 2. Informed consent form.

Additional file 3. Topic guide.

Additional file 1.

Background: Recruitment to randomised controlled trials (RCTs) can be challenging, with most trials not reaching recruitment targets. Randomised feasibility studies can be set up prior to a main trial to identify and overcome recruitment obstacles. This paper reports on an intervention – the QuinteT Recruitment Intervention (QRI) - to optimise recruitment within a randomised feasibility study of surgical treatments for patients with Dupuytren’s contracture (the HAND-1 study).Methods: The QRI was introduced in 2-phases: phase 1 sought to understand the recruitment challenges by interviewing trial staff, scrutinising screening logs and analysing audio recorded patient consultations; in phase 2 a tailored plan of action consisting of recruiter feedback and training was delivered to address the identified challenges.Results: Two key recruitment obstacles emerged: 1) issues with the recruitment pathway, in particular methods to identify potentially eligible patients and; 2) equipoise of recruiters and patients. These were addressed by liaising with centres to share good practice and refine their pathway, and by providing bespoke feedback and training on consent discussions to individual recruiters and centres whilst recruitment was ongoing. The HAND-1 study subsequently achieved its recruitment target.Conclusions: Transferable lessons learnt from the QRI in the feasibility study will be implemented in the definitive RCT, enabling a ‘head start’ in the tackling of wider issues around screening methods and consent discussions in the set up/early recruitment study phases, with ongoing QRI addressing specific issues with new centres and recruiters. Findings from this study are likely to be relevant to other surgical and similar trials that are anticipated to encounter issues around patient and recruiter equipoise of treatments and variation in recruitment pathways across centres. The study also highlights the value of feasibility studies in fine-tuning design and conduct issues for definitive RCTs. Embedding a QRI in an RCT, at feasibility or main stage, offers an opportunity for a detailed and nuanced understanding of key recruitment challenges and the chance to address them in ‘real-time’ as recruitment proceeds.

Additional file 1. Hand-1 Quintet Recruitment Intervention (QRI) Staff Interview Topic Guide.

Background Clostridium difficile infection (CDI) recurs after initial treatment in approximately one in four patients. A single-centre pilot study suggested that this could be reduced using ‘follow-on’ rifaximin treatment. We aimed to assess the efficacy of rifaximin treatment in preventing recurrence. Methods A multisite, parallel group, randomised, placebo controlled trial recruiting patients aged ≥18 years immediately after resolution of CDI through treatment with metronidazole or vancomycin. Participants received either rifaximin 400 mg three times a day for 2 weeks, reduced to 200 mg three times a day for a further 2 weeks or identical placebo. The primary endpoint was recurrence of CDI within 12 weeks of trial entry. Results Between December 2012 and March 2016, 151 participants were randomised to either rifaximin or placebo. Primary outcome data were available on 130. Mean age was 71.9 years (SD 15.3). Recurrence within 12 weeks was 29.5% (18/61) among participants allocated to placebo compared with 15.9% (11/69) among those allocated to rifaximin, a difference between groups of 13.7% (95% CI −28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6-month safety follow-up, nine participants died in each group (12%). Adverse event rates were similar between groups. Conclusion While ‘follow-on’ rifaximin after CDI appeared to halve recurrence rate, we failed to reach our recruitment target in this group of frail elderly patients, so the estimated effect of rifaximin lacks precision. A meta-analysis including a previous trial suggests that rifaximin may be effective; however, further, larger confirmatory studies are needed.

ObjectiveTo evaluate the impact of the Quintet Recruitment Intervention (QRI) on recruitment in challenging randomized controlled trials (RCTs) that have applied the intervention. The QRI aims to understand recruitment difficulties, and then implements ‘QRI-actions’ to address these as recruitment proceeds.Study Design and SettingA mixed-methods study, comprising: a) before-and-after comparisons of recruitment rates and numbers of patients approached, and b) qualitative case studies, including documentary analysis and interviews with RCT investigators.ResultsFive UK-based publicly-funded RCTs were included in the evaluation. All recruited to target. RCT2 and RCT5 both received up-front pre-recruitment training before the intervention was applied. RCT2 did not encounter recruitment issues and recruited above target from its outset. Recruitment difficulties, particularly communication issues, were identified and addressed through QRI-actions in RCTs 1, 3, 4 and 5. Randomization rates significantly improved post-QRI-action in RCTs 1,3, and 4. QRI-actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of, and reportedly changed their practices post QRI-action.ConclusionThere is promising evidence to suggest the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations.

Background Clostridium difficile infection (CDI) recurs after initial treatment in approximately one in four patients. A single-centre pilot study suggested that this could be reduced using ‘follow-on’ rifaximin treatment. We aimed to assess the efficacy of rifaximin treatment in preventing recurrence.Methods A multisite, parallel group, randomised, placebo controlled trial recruiting patients aged ≥18 years immediately after resolution of CDI through treatment with metronidazole or vancomycin. Participants received either rifaximin 400 mg three times a day for 2 weeks, reduced to 200 mg three times a day for a further 2 weeks or identical placebo. The primary endpoint was recurrence of CDI within 12 weeks of trial entry.Results Between December 2012 and March 2016, 151 participants were randomised to either rifaximin or placebo. Primary outcome data were available on 130. Mean age was 71.9 years (SD 15.3). Recurrence within 12 weeks was 29.5% (18/61) among participants allocated to placebo compared with 15.9% (11/69) among those allocated to rifaximin, a difference between groups of 13.7% (95% CI −28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6-month safety follow-up, nine participants died in each group (12%). Adverse event rates were similar between groups.Conclusion While ‘follow-on’ rifaximin after CDI appeared to halve recurrence rate, we failed to reach our recruitment target in this group of frail elderly patients, so the estimated effect of rifaximin lacks precision. A meta-analysis including a previous trial suggests that rifaximin may be effective; however, further, larger confirmatory studies are needed.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.