No difference found in time to publication by statistical significance of trial results: a methodological review

Objective: Time-lag from study completion to publication is a potential source of publication bias in randomised controlled trials. This study sought to update the evidence base by identifying the effect of the statistical significance of research findings on time to publication of trial results.Design: Literature searches were carried out in four general medical journals from June 2013 to June 2014 inclusive (BMJ, JAMA, the Lancet and the New England Journal of Medicine). Setting: Methodological review of four general medical journals. Participants: Original research articles presenting the primary analyses from phase 2, 3 and 4 parallel-group randomised controlled trials were included. Main outcome measures: Time from trial completion to publication.Results: The median time from trial completion to publication was 431 days (n ¼ 208, interquartile range 278–618). A multivariable adjusted Cox model found no statistically significant difference in time to publication for trials reporting positive or negative results (hazard ratio: 0.86, 95% CI 0.64 to 1.16, p ¼ 0.32). Conclusion: In contrast to previous studies, this review did not demonstrate the presence of time-lag bias in time to publication. This may be a result of these articles being published in four high-impact general medical journals that may be more inclined to publish rapidly, whatever the findings. Further research is needed to explore the presence of time-lag bias in lower quality studies and lower impact journals

Qualitative research to inform hypothesis testing for fidelity-based sub-group analysis in clinical trials : lessons learnt from the process evaluation of a multifaceted podiatry intervention for falls prevention

Background: Ensuring fidelity to complex interventions is a challenge when conducting pragmatic randomised controlled trials. We explore fidelity through a qualitative process evaluation, which was conducted alongside a pragmatic, multicentre, two-arm cohort randomised controlled trial: the REFORM (Reducing Falls with Orthoses and a Multifaceted podiatry intervention) trial. The paper aims, through a qualitative process evaluation, to explore some of the factors that may have affected the delivery of the REFORM intervention and highlight how project-specific fidelity can be assessed using a truly mixed-methods approach when informed by qualitative insights. Design: Semi-structured qualitative interviews carried out as part of a process evaluation. Interviews were analysed thematically. Setting: Seven NHS trusts in the UK and a University podiatry school in Ireland. Interviews were undertaken face-toface or over the telephone. Participants: Twenty-one REFORM trial participants and 14 podiatrists who delivered the REFORM intervention. Results: Factors affecting fidelity included: how similar the intervention was to routine practice; the challenges of delivering a multifaceted intervention to a heterogeneous older population; and practical issues with delivery such as time and training. Trial participants’ views of the intervention, whether falls prevention is a personal priority, their experience of being part of a trial and individual factors such as medical conditions may also have affected intervention fidelity. Conclusions: Our process evaluation highlighted factors that were perceived to have affected the fidelity of the REFORM intervention and in doing so demonstrates the importance of considering fidelity when designing and evaluating pragmatic trials. We propose a number of recommendations of how important project-specific insights from qualitative work can be incorporated into the design of fidelity measurement of future trials, which build on existing conceptual fidelity frameworks. In particular, we encourage adopting a mixed-methods approach whereby qualitative insights can be used to suggest ways to enhance quantitative data collection facilitating integration through hypothesis generation, hypothesis testing and seeking explanation for trial findings. This will provide a framework of enabling measures of fidelity to be incorporated into the understanding of trial results which has been relatively neglected by existing literature. Trial registration: ISRCTN Registry: ISRCTN68240461. Registered on 01/07/2011. Keywords: Process evaluation, Randomised controlled trials, Fidelity, Mixed methods, Falls, Elderly, Ageing, Qualitativ

A Nested Randomised Controlled Trial of a Newsletter and Post-it Note Did not Increase Postal Questionnaire Response Rates in a Falls Prevention Trial

Background: Attrition (i.e. when participants do not return the questionnaires)is a problem for many randomised controlled trials. The resultant loss of dataleads to a reduction in statistical power and can lead to bias. The aim of thisstudy was to assess whether a pre-notification newsletter and/or a handwrittenor printed Post-it® note sticker, as a reminder, increased postal questionnaireresponse rates for participants of randomised controlled trials.Method: This study was a factorial trial embedded within a trial of afalls-prevention intervention among men and women aged ≥65 years underpodiatric care. Participants were randomised into one of six groups: newsletterplus handwritten Post-it®; newsletter plus printed Post-it®; newsletter only;handwritten Post-it® only; printed Post-it® only; or no newsletter or Post-it®.The results were combined with those from previous embedded randomisedcontrolled trials in a meta-analysis.Results: The 12-month response rate was 803/826 (97.2%) (newsletter 95.1%,no newsletter 99.3%, printed Post-it® 97.5%, handwritten Post-it® 97.1%, noPost-it® 97.1%). Pre-notification with a newsletter had a detrimental effect onresponse rates (adjusted odds ratio (OR), 0.14; 95% CI, 0.04 to 0.48; p<0.01)and time to return the questionnaire (adjusted hazard ratio, 0.86; 95% CI, 0.75to 0.99; p=0.04). No other statistically significant differences were observedbetween the intervention groups on response rates, time to response, and theneed for a reminder.Conclusions: Post-it® notes have been shown to be ineffective in threeembedded trials, whereas the evidence for newsletter reminders is stilluncertain.KeywordsRandomised controlled trial; randomisation; embedded trial; newsletter;Post-it® note; response rat

Improving the safety and experience of transitions from hospital to home : a cluster randomised controlled feasibility trial of the Your Care Needs You Intervention versus usual care

Background: The ‘Your Care Needs You’ (YCNY) intervention aims to increase the safety and experience of transitions for older people through greater patient involvement during the hospital stay. Methods: A cluster-randomised controlled feasibility trial was conducted on NHS inpatient wards (clusters) where ≥40% were routinely ≥75 years. Wards were randomised to YCNY or usual care using an unequal allocation ratio (3:2). We aimed to recruit up to 20 patients per ward. Follow-up included routine data collection and questionnaires at 5, 30 and 90-days post-discharge. Eligible patients were ≥75, discharged home, stayed overnight on participating wards, and could read and understand English. The trial assessed the feasibility of delivering YCNY and the trial methodology through recruitment rates, outcome completion rates, and a qualitative evaluation. The accuracy of using routinely coded data for the primary outcome in the definitive trial was assessed by extracting discharge information for up to ten non-individual consenting patients per ward. Results: Ten wards were randomised (6 intervention, 4 control). One ward withdrew and two wards were unable to deliver the intervention. 721 patients were successfully screened, and 161 were recruited (95 intervention, 66 control). The patient post-discharge attrition rate was 17.4% (n=28). Primary outcome data were gathered for 91.9% of participants with 75.2% and 59.0% providing secondary outcome data at 5 and 30 days post discharge respectively. Item completion within questionnaires was generally high. Post-discharge follow-up was terminated early due to the COVID-19 pandemic affecting 90 day response rates (16.8%). Data from 88 non-individual consenting patients identified an error rate of 15% when using routinely coded data for the primary outcome. No unexpected serious adverse events were identified. Most patients viewed YCNY favourably. Staff agreed with it in principle, but ward pressures and organisational contexts hampered implementation. There was a need to sustain engagement, provide clarity on roles and responsibilities, and account for fluctuations in patients’ health, capacity, and preferences. Conclusions: If implementation challenges can be overcome, YCNY represents a step towards involving older people as partners in their care to improve the safety and experience of their transitions from hospital to home. Trial registration: ISRCTN: 5115494

Slip-resistant footwear reduces slips among National Health Service workers in England : a randomised controlled trial

Objectives Assess the effectiveness of 5* GRIP-rated slip-resistant footwear in preventing slips in the workplace compared to usual footwear (control group). Methods A multicentre, randomised controlled trial; 4553 National Health Service (NHS) staff were randomised 1:1 to the intervention group (provided with 5* GRIP-rated slip-resistant footwear) or the control group. The primary outcome of incidence rate of self-reported slips in the workplace over 14 weeks was analysed using a mixed-effects negative binomial model. Secondary outcome measures included incidence rate of falls from a slip, falls not from a slip, proportion of participants reporting a slip, fall or fracture and time to first slip and fall. Results 6743 slips were reported: 2633 in the intervention group (mean 1.16 per participant, range 0 to 36) and 4110 in the control group (mean 1.80 per participant, range 0 to 83). There was a statistically significant reduction in slip rate in the intervention group relative to the control group (incidence rate ratio (IRR) 0.63, 95% CI 0.57 to 0.70, p<0.001). Statistically significant differences, in favour of the intervention group, were observed in falls from a slip (IRR 0.51, 95% CI 0.28 to 0.92, p=0.03), the proportion of participants who reported a slip (OR 0.58, 95% CI 0.50 to 0.66, p<0.001) or fall (OR 0.73, 95% CI 0.54 to 0.99, p=0.04) and time to first slip (HR 0.73, 95% CI 0.67 to 0.80, p<0.001). Conclusions The offer and provision of 5* GRIP-rated footwear reduced slips in NHS staff in the workplace. Trial registration number ISRCTN33051393

A randomized, embedded trial of pre-notification of trial participation did not increase recruitment rates to a falls prevention trial

Objectives: To design and evaluate the effectiveness of a pre-notification leaflet about research to increase recruitment to a randomised controlled trial (RCT). Methods: A methodological, two arm, randomised controlled trial was conducted, embedded within an existing cohort RCT (REFORM). Participants were randomised for the embedded trial, using a 1:2 (intervention:control) allocation ratio, prior to being randomised for the REFORM RCT. Controls received a trial recruitment pack. The intervention group received an additional pre-notification leaflet 2 to 3 weeks before the recruitment pack. Primary and secondary analyses were conducted using relative risk, the Cox Proportional Hazards Model and Incremental Cost Effectiveness Ratios. Results: Of the 1,436 intervention group participants, 73 (5.1%) were randomised into the REFORM trial compared to 126 (4.4%) of the 2,878 control group participants. The associated relative risk (1.16) was not statistically significant (95% CI 0.88 - 1.56). The leaflet did not significantly increase return rate (RR 1.10, 95% CI 0.92 -1.28) or decrease time to return (Hazard Ratio: 1.11, 95% CI 0.93 -1.33). Incremental Cost Effectiveness Ratios indicated that the intervention may be cost-effective if the true estimate of effect were close to the upper bound of the associated 95% CI. Conclusion: A pre-notification leaflet to potential trial participants demonstrated a small difference in favour of the intervention with regards randomisation (0.7% difference) and return rates (1.1% difference).Results should however be interpreted with caution as confidence intervals for these estimates cross the point of no effect. Nevertheless, this research enhances existing evidence for pre-notification to increase recruitment rates, with further development and assessment of this potentially cost-effective intervention being recommended

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Effect of Vitamin K on Bone Mineral Density and Fractures in Adults : An updated systematic review and meta-analysis of randomised controlled trials

Purpose: Vitamin K may affect bone mineral density and fracture incidence. Since publication of a previous systematic review the integrity of some of the previous evidence has been questioned and further trials have been published. Our objective was to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density and reducing fractures in adults. Methods: MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, WHO-ICTRP were searched for eligible trials. Randomised controlled trials assessing oral vitamin K supplementation that assessed bone mineral density or fractures in adult populations were included. A total of 36 studies were identified. Two independent reviewers extracted data using a piloted extraction form. Results: For post-menopausal or osteoporotic patients meta-analysis showed that the odds of any clinical fracture were lower for vitamin K compared to controls (OR:0.72, 95%CI: 0.55 to 0.95). Restricting the analysis to low risk of bias trials reduced the OR to 0.76 (95%CI: 0.58 to 1.01). There was no difference in vertebral fractures between the groups (OR:0.96, 95%CI: 0.83 to 1.11). In the bone mineral density meta-analysis, percentage change from baseline at the lumbar spine was higher at 1 year (MD:0.93, 95% CI: -0.02 to 1.89) and 2 years (MD:1.63%, 95%CI: 0.10 to 3.16) for vitamin K compared to controls; however, removing trials at high risk of bias tended to result in smaller differences that were not statistically significant. At 6 months it was higher in the hip (MD:0.42%, 95%CI: 0.01 to 0.83) and femur (MD:0.29%, 95%CI: 0.17 to 0.42). There was no significant difference at other anatomical sites. Conclusions: For post-menopausal or osteoporotic patients there is no evidence that vitamin K affects bone mineral density or vertebral fractures, it may reduce clinical fractures however the evidence is insufficient to confirm this. There are too few trials to draw conclusions for other patient groups

SSHeW study protocol : Does Slip Resistant Footwear Reduce Slips Among Healthcare Workers? A Randomised Controlled Trial

Introduction Slips, trips and falls are common causes of injuries in the workplace. It is estimated that in Great Britain, nearly 1 million days are taken off work due to these injuries. There is some evidence to suggest this accident burden could be reduced by the use of slip resistant footwear. This protocol describes a multicentre trial investigating the effectiveness and cost-effectiveness of slip resistant footwear to prevent slips in National Health Service (NHS) staff working in clinical, general or catering environments. Methods and analysis A two-arm, randomised controlled trial conducted within England, with 4400 NHS staff, aged 18 years and above, who adhere to a dress code policy and work in a clinical, catering or general hospital environment. Participants will be randomised 1:1 to the intervention or waiting list control group. The intervention group will be offered a pair of 5-star GRIP rated slip resistant footwear. The control group will be offered the footwear at the end of the trial. The primary outcome is the incidence rate of self-reported slips in the workplace over a 14-week period, as reported via weekly text messages. Secondary outcomes include: time to first slip/fall, proportion of participants who slip and fall over 14 weeks and incidence rate of falls resulting from and not resulting from a slip in the workplace over 14 weeks. An economic evaluation will assess cost-effectiveness, in terms of cost per quality-adjusted life year gained. A nested qualitative study will explore the acceptability of the footwear and compliance. Ethics and dissemination This protocol received a favourable ethical opinion from the University of York, Department of Health Sciences Research Governance Committee. The trial results will be published in peer-reviewed journals and at conferences. A summary of the findings will be made available to participants. Trial registration number ISRCTN33051393; Pre results