SummaryBackgroundThe omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excellent safety profile. Therefore, we aimed to test the efficacy of EPA and aspirin, alone and in combination and compared with a placebo, in individuals with sporadic colorectal neoplasia detected at colonoscopy.MethodsIn a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial, patients aged 55–73 years who were identified during colonoscopy as being at high risk in the English Bowel Cancer Screening Programme (BCSP; ≥3 adenomas if at least one was ≥10 mm in diameter or ≥5 adenomas if these were <10 mm in diameter) were recruited from 53 BCSP endoscopy units in England, UK. Patients were randomly allocated (1:1:1:1) using a secure web-based server to receive 2 g EPA-free fatty acid (FFA) per day (either as the FFA or triglyceride), 300 mg aspirin per day, both treatments in combination, or placebo for 12 months using random permuted blocks of randomly varying size, and stratified by BCSP site. Research staff and participants were masked to group assignment. The primary endpoint was the adenoma detection rate (ADR; the proportion of participants with any adenoma) at 1 year surveillance colonoscopy analysed in all participants with observable follow-up data using a so-called at-the-margins approach, adjusted for BCSP site and repeat endoscopy at baseline. The safety population included all participants who received at least one dose of study drug. The trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN05926847.FindingsBetween Nov 11, 2011, and June 10, 2016, 709 participants were randomly assigned to four treatment groups (176 to placebo, 179 to EPA, 177 to aspirin, and 177 to EPA plus aspirin). Adenoma outcome data were available for 163 (93%) patients in the placebo group, 153 (85%) in the EPA group, 163 (92%) in the aspirin group, and 161 (91%) in the EPA plus aspirin group. The ADR was 61% (100 of 163) in the placebo group, 63% (97 of 153) in the EPA group, 61% (100 of 163) in the aspirin group, and 61% (98 of 161) in the EPA plus aspirin group, with no evidence of any effect for EPA (risk ratio [RR] 0·98, 95% CI 0·87 to 1·12; risk difference −0·9%, −8·8 to 6·9; p=0·81) or aspirin (RR 0·99 (0·87 to 1·12; risk difference −0·6%, −8·5 to 7·2; p=0·88). EPA and aspirin were well tolerated (78 [44%] of 176 had ≥1 adverse event in the placebo group compared with 82 [46%] in the EPA group, 68 [39%] in the aspirin group, and 76 [45%] in the EPA plus aspirin group), although the number of gastrointestinal adverse events was increased in the EPA alone group at 146 events (compared with 85 in the placebo group, 86 in the aspirin group, and 68 in the aspirin plus placebo group). Six upper-gastrointestinal bleeding events were reported across the treatment groups (two in the EPA group, three in the aspirin group, and one in the placebo group).InterpretationNeithe...

Objectivesto test whether an occupation-based lifestyle intervention can sustain and improve the mental well-being of adults aged 65 years or over compared to usual care, using an individually randomised controlled trial.Participants288 independently living adults aged 65 years or over, with normal cognition, were recruited from two UK sites between December 2011 and November 2015.Interventionslifestyle Matters is a National Institute for Health and Care Excellence recommended multi-component preventive intervention designed to improve the mental well-being of community living older people at risk of decline. It involves weekly group sessions over 4 months and one to one sessions.Main outcome measuresthe primary outcome was mental well-being at 6 months (mental health (MH) dimension of the SF-36). Secondary outcomes included physical health dimensions of the SF-36, extent of depression (PHQ-9), quality of life (EQ-5D) and loneliness (de Jong Gierveld Loneliness Scale), assessed at 6 and 24 months.Resultsdata on 262 (intervention = 136; usual care = 126) participants were analysed using intention to treat analysis. Mean SF-36 MH scores at 6 months differed by 2.3 points (95 CI: −1.3 to 5.9; P = 0.209) after adjustments.Conclusionsanalysis shows little evidence of clinical or cost-effectiveness in the recruited population with analysis of the primary outcome revealing that the study participants were mentally well at baseline. The results pose questions regarding how preventive interventions to promote well-being in older adults can be effectively targeted in the absence of proactive mechanisms to identify those who at risk of decline.Trial RegistrationISRCTN67209155.

Summary Background Gonorrhoea is a common sexually transmitted infection for which ceftriaxone is the current first-line treatment, but antimicrobial resistance is emerging. The objective of this study was to assess the effectiveness of gentamicin as an alternative to ceftriaxone (both combined with azithromycin) for treatment of gonorrhoea. Methods G-ToG was a multicentre, parallel-group, pragmatic, randomised, non-inferiority trial comparing treatment with gentamicin to treatment with ceftriaxone for patients with gonorrhoea. The patients, treating physician, and assessing physician were masked to treatment but the treating nurse was not. The trial took place at 14 sexual health clinics in England. Adults aged 16–70 years were eligible for participation if they had a diagnosis of uncomplicated genital, pharyngeal, or rectal gonorrhoea. Participants were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (gentamicin group) or ceftriaxone 500 mg (ceftriaxone group). All participants also received a single 1 g dose of oral azithromycin. Randomisation (1:1) was stratified by clinic and performed using a secure web-based system. The primary outcome was clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post treatment. Primary outcome analyses included only participants who had follow-up data, irrespective of the baseline visit N gonorrhoeae test result. The margin used to establish non-inferiority was a lower confidence limit of 5% for the risk difference. This trial is registered with ISRCTN, number ISRCTN51783227. Findings Of 1762 patients assessed, we enrolled 720 participants between Oct 7, 2014, and Nov 14, 2016, and randomly assigned 358 to gentamicin and 362 to ceftriaxone. Primary outcome data were available for 306 (85%) of 362 participants allocated to ceftriaxone and 292 (82%) of 358 participants allocated to gentamicin. At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6·4%, 95% CI −10·4% to −2·4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference −4·4%, −8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15·3%, −24·0 to −6·5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7·8%, −13·6 to −2·0). Thus, we did n...

Background The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile. Objectives The objectives were to determine whether or not EPA prevents colorectal adenomas, either alone or in combination with aspirin, and to assess the safety/tolerability of EPA, in the free fatty acid (FFA) form or as the triglyceride (TG), and aspirin. Design This was a randomised, blinded, placebo-controlled, 2 × 2 factorial trial. Setting The NHS Bowel Cancer Screening Programme (BCSP). Participants Patients (aged 55–73 years) identified as ‘high risk’ (i.e. those who have five or more colorectal adenomas of < 10 mm in size or three or more colorectal adenomas if one is ≥ 10 mm in size) at screening colonoscopy. Interventions The interventions were capsules containing 2000 mg of 99% EPA–FFA or 2780 mg of 90% EPA–TG (equivalent to 2000 mg of FFA) taken daily, or identical placebo capsules; and 300 mg of aspirin taken daily, or an identical placebo, enteric-coated tablet. Both were taken for ≈1 year until surveillance colonoscopy. All participants and staff were unaware of treatment allocation. Main outcome measures The primary outcome was the number of participants with one or more colorectal adenomas [adenoma detection rate (ADRa)] at surveillance colonoscopy. Outcomes were analysed for all participants with observable follow-up data by an ‘at-the-margins’ approach, adjusted for BCSP site and by the need for repeat baseline endoscopy. Secondary outcome measures – these included the number of colorectal adenomas per patient [mean adenomas per patient (MAP)], ‘advanced’ ADRa and colorectal adenoma location (right/left) and type (conventional/serrated). Results Between November 2011 and June 2016, 709 participants were randomised, with 707 providing data (80% male, mean age 65 years). The four treatment groups (EPA + aspirin, n = 177; EPA, n = 179; aspirin, n = 177; placebo, n = 176) were well matched for baseline characteristics. Tissue EPA levels and tolerability were similar for FFA and TG users. There was no evidence of any difference in ADRa between EPA users (62%) and non-users (61%) [risk difference –0.9%, 95% confidence interval (CI) –8.8% to 6.9%] or for aspirin users (61%) versus non-users (62%) (risk difference –0.6%, 95% CI –8.5% to 7.2%). There was no evidence of an interaction between EPA and aspirin for ADRa. There was no evidence of any effect on advanced ADRa of either EPA (risk difference –0.6%, 95% CI –4.4% to 3.1%) or aspirin (risk difference –0.3%, 95% CI –4.1% to 3.5%). Aspirin use was associated with a reduction in MAP [incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.90), with preventative efficacy against conventional (IRR 0.82, 95% CI 0.71 to 0.94), serrated (IRR 0.46, 95% CI 0.25 to 0.87) and right-sided (IRR 0.73, 95% CI 0.61 to 0.88) lesions, but not left-sided (IRR 0.85, 95% CI 0.69 to 1.06) adenomas. There was evidence of chemopreventive efficacy of EPA on conventional (IRR 0.86, 95% CI 0.74 to 0.99) and left-sided (IRR 0.75, 95% CI 0.60 to 0.94) adenomas, but not on total MAP (IRR 0.91, 95% CI 0.79 to 1.05) or serrated (IRR 1.44, 95% CI 0.79 to 2.60) or right-sided (IRR 1.02, 95% CI 0.85 to 1.22) adenomas. EPA and aspirin treatment were well tolerated, with excess mild/moderate gastrointestinal (GI) adverse events (AEs) in the EPA alone group. There were six GI bleeding AEs. Conclusion EPA and aspirin treatment were not associated with a reduction in ADRa. However, both agents displayed evidence of chemopreventive efficacy, based on adenoma number reduction, which was specific to adenoma type and location, and is compatible with known anti-CRC activity of aspirin. Limitations Limitations of the trial included the failure to recruit to the target sample size of 853, and an unexpected switch of EPA formulation mid-trial. Future work A future objective should be to understand the mechanism(s) of action of EPA and aspirin using the trial biobank. Established trial infrastructure will enable future trials in the BCSP. Trial registration Current Controlled Trials ISRCTN05926847. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

BackgroundA study to determine the feasibility of conducting a future population-based trial into a self-management intervention for community-living adults with early stage dementia included evaluation of intervention content and modes of delivery, staffing requirements, recruitment methods and the utility and usability of patient reported outcomes.MethodsParticipants identified through memory clinics in one city took part in an intervention called ‘Journeying through Dementia’. The 12-week programme incorporating four individual sessions with one of the facilitators encourages participants to engage in discussion and activities related to health and well-being positioning them as the expert enabling long-term behavioural change. Participants (n = 10) and their nominated carers (n = 7) were all asked to complete selected outcomes at baseline, 8 weeks (participants only) and post intervention and invited to comment on their usability. All participants and carers were qualitatively interviewed before intervention delivery about their expectations and participants; nominated carers and facilitators were all interviewed after cessation about their experiences.ResultsThe manualised intervention and modes of delivery proved acceptable to participants and carers. Reported benefits included increased confidence and self-efficacy, engagement in new or lapsed activities and re-engagement in fun and friendships. People with dementia and carers were able to self-complete all outcome measures, but time required to complete the measures is a key factor. Strategies for recruitment need to include direct contact within 24–48 h post invitation to the study. Analysis of data on the primary outcome did not reveal any trends. Facilitators found the training and support to be appropriate and helpful.ConclusionsThe tailored intervention reportedly met the needs of all participants. The study confirmed the need for careful identification and application of patient-reported outcome measures. Outcomes to measure some dimensions of reported benefit are not available.Trial registrationCurrent Controlled Trials ISRCTN67209155.

Objective To identify the barriers and facilitators to the implementation of a complex psychosocial intervention though a study exploring the experiences of participants, carers and interventionists during a trial. Methods Individual semi-structured interviews were conducted with participants, their carers, and interventionists from a sample of recruiting sites that took part in the Journeying through Dementia randomized controlled trial (RCT). Interview data were transcribed and analysed using framework analysis. Co-researcher data analysis workshops were also conducted to explore researcher interpretations of the data through the lens of those with lived experience of dementia. Triangulation enabled comparison of findings from the interviews with findings from the co-researcher workshops. Results Three main themes emerged from the interview data: being prepared; intervention engagement; and participation and outcomes from engagement. From these themes, a number of factors that can moderate delivery and receipt of the intervention as intended were identified. These were context and environment; readiness, training, skills and competencies of the workforce; identifying meaningful participation and relationships. Conclusion This study highlighted that the observed benefit of the intervention was nuanced for each individual. Mechanisms of change were influenced by a range of individual, social and contextual factors. Future research should therefore consider how best to identify and measure the multifaceted interplay of mechanisms of change in complex interventions. Trial Registration ISRCTN17993825.

Background: Group interventions are interventions delivered to groups of people rather than to individuals and are used in healthcare for mental health recovery, behaviour change, peer support, self-management and/or health education. Evaluating group interventions in randomised controlled trials (RCTs) presents trialists with a set of practical problems, which are not present in RCTs of one-to-one interventions and which may not be immediately obvious. Methods: Case-based approach summarising Sheffield trials unit's experience in the design and implementation of five group interventions. We reviewed participant recruitment and attrition, facilitator training and attrition, attendance at the group sessions, group size and fidelity aspects across five RCTs. Results: Median recruitment across the five trials was 3.2 (range 1.7-21.0) participants per site per month. Group intervention trials involve a delay in starting the intervention for some participants, until sufficient numbers are available to start a group. There was no evidence that the timing of consent, relative to randomisation, affected post-randomisation attrition which was a matter of concern for all trial teams. Group facilitator attrition was common in studies where facilitators were employed by the health system rather than the by the grant holder and led to the early closure of one trial; research sites responded by training 'back-up' and new facilitators. Trials specified that participants had to attend a median of 62.5% (range 16.7%-80%) of sessions, in order to receive a 'therapeutic dose'; a median of 76.7% (range 42.9%-97.8%) received a therapeutic dose. Across the five trials, 75.3% of all sessions went ahead without the pre-specified ideal group size. A variety of methods were used to assess the fidelity of group interventions at a group and individual level across the five trials. Conclusion: This is the first paper to provide an empirical basis for planning group intervention trials. Investigators should expect delays/difficulties in recruiting groups of the optimal size, plan for both facilitator and participant attrition, and consider how group attendance and group size affects treatment fidelity.

IntroductionServices are being encouraged to provide postdiagnostic treatment to those with dementia but the availability of evidence-based interventions following diagnosis has not kept pace with increase in demand. To address this need, the Journeying through Dementia (JtD) intervention was created. A randomised controlled trial (RCT), based on a pilot study, is in progress.Methods and analysisThe RCT is a pragmatic, two-arm, parallel group trial designed to test the clinical and cost-effectiveness of JtD compared with usual care. Recruitment will be through NHS services, third sector organisations and Join Dementia Research. The sample size is 486 randomised (243 to usual care and 243 to the intervention usual care). Participants can choose to ask a friend or relative (supporter) to become involved in the study. The primary outcome measure for participants is Dementia-Related Quality of Life (DEMQOL), collected at baseline and at 8 months’ postrandomisation. Secondary outcome measures will be collected from participants and supporters at those visits. Participants will also be followed up at 12 months’ postrandomisation with a reduced set of measures. A process evaluation will be conducted through qualitative and fidelity substudies. Analyses will compare the two arms of the trial on an intention to treat as allocated basis. The primary analyses will compare the mean DEMQOL scores of the participants at 8 months between the two study arms. A cost-effectiveness analysis will consider the incremental cost per Quality Adjusted Life Years of the intervention compared with usual care. Qualitative and fidelity substudies will be analysed through framework analysis and fidelity assessment tools respectively.Ethics and disseminationREC and HRA approval were obtained. A Data Monitoring and Ethics Committee has been constituted. Dissemination will be via publications, conferences and social media. Intervention materials will be made open access.Trial registration numberISRCTN17993825.