Reporting of Factorial Randomized Trials: Extension of the CONSORT 2010 Statement.

Importance: Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal. Objective: To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials. Design: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist. Findings: This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported. Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.

Consensus Statement for Protocols of Factorial Randomized Trials: Extension of the SPIRIT 2013 Statement.

Importance: Trial protocols outline a trial's objectives as well as the methods (design, conduct, and analysis) that will be used to meet those objectives, and transparent reporting of trial protocols ensures objectives are clear and facilitates appraisal regarding the suitability of study methods. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, no extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement, which provides guidance on reporting of trial protocols, for factorial trials is available. Objective: To develop a consensus-based extension to the SPIRIT 2013 Statement for factorial trials. Evidence Review: The SPIRIT extension for factorial trials was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework. First, a list of reporting recommendations was generated using a scoping review of methodological articles identified using a MEDLINE search (inception to May 2019), which was supplemented with relevant articles from the personal collections of the authors. Second, a 3-round Delphi survey (January to June 2022, completed by 104 panelists from 14 countries) was conducted to assess the importance of items and identify additional recommendations. Third, a hybrid consensus meeting was held, attended by 15 panelists to finalize selection and wording of the checklist. Findings: This SPIRIT extension for factorial trials modified 9 of the 33 items in the SPIRIT 2013 checklist. Key reporting recommendations were that the rationale for using a factorial design should be provided, including whether an interaction is hypothesized; the treatment groups that will form the main comparisons should be identified; and statistical methods for each main comparison should be provided, including how interactions will be assessed. Conclusions and Relevance: In this consensus statement, 9 factorial-specific items were provided that should be addressed in all protocols of factorial trials to increase the trial's utility and transparency.

Deferred cord clamping, cord milking, and immediate cord clamping at preterm birth: a systematic review and individual participant data meta-analysis.

BACKGROUND: Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth. METHODS: We conducted a systematic review and individual participant data meta-analysis. We searched medical databases and trial registries (from database inception until Feb 24, 2022; updated June 6, 2023) for randomised controlled trials comparing deferred (also known as delayed) cord clamping, cord milking, and immediate cord clamping for preterm births (<37 weeks' gestation). Quasi-randomised or cluster-randomised trials were excluded. Authors of eligible studies were invited to join the iCOMP collaboration and share individual participant data. All data were checked, harmonised, re-coded, and assessed for risk of bias following prespecified criteria. The primary outcome was death before hospital discharge. We performed intention-to-treat one-stage individual participant data meta-analyses accounting for heterogeneity to examine treatment effects overall and in prespecified subgroup analyses. Certainty of evidence was assessed with Grading of Recommendations Assessment, Development, and Evaluation. This study is registered with PROSPERO, CRD42019136640. FINDINGS: We identified 2369 records, of which 48 randomised trials provided individual participant data and were eligible for our primary analysis. We included individual participant data on 6367 infants (3303 [55%] male, 2667 [45%] female, two intersex, and 395 missing data). Deferred cord clamping, compared with immediate cord clamping, reduced death before discharge (odds ratio [OR] 0·68 [95% CI 0·51-0·91], high-certainty evidence, 20 studies, n=3260, 232 deaths). For umbilical cord milking compared with immediate cord clamping, no clear evidence was found of a difference in death before discharge (OR 0·73 [0·44-1·20], low certainty, 18 studies, n=1561, 74 deaths). Similarly, for umbilical cord milking compared with deferred cord clamping, no clear evidence was found of a difference in death before discharge (0·95 [0·59-1·53], low certainty, 12 studies, n=1303, 93 deaths). We found no evidence of subgroup differences for the primary outcome, including by gestational age, type of delivery, multiple birth, study year, and perinatal mortality. INTERPRETATION: This study provides high-certainty evidence that deferred cord clamping, compared with immediate cord clamping, reduces death before discharge in preterm infants. This effect appears to be consistent across several participant-level and trial-level subgroups. These results will inform international treatment recommendations. FUNDING: Australian National Health and Medical Research Council.

Short, medium, and long deferral of umbilical cord clamping compared with umbilical cord milking and immediate clamping at preterm birth: a systematic review and network meta-analysis with individual participant data.

BACKGROUND: Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants. METHODS: We searched medical databases and trial registries from inception until Feb 24, 2022 (updated June 6, 2023) for randomised controlled trials comparing cord clamping strategies for preterm infants. Individual participant data were harmonised and assessed for risk of bias and quality. Interventions were grouped into immediate clamping, short deferral (≥15 s to <45 s), medium deferral (≥45 s to <120 s), long deferral (≥120 s), and intact cord milking. The primary outcome was death before hospital discharge. We calculated one-stage, intention-to-treat Bayesian random-effects individual participant data network meta-analysis. This study was registered with PROSPERO, CRD42019136640. FINDINGS: We included individual participant data from 47 trials with 6094 participants. Of all interventions, long deferral reduced death before discharge the most (compared with immediate clamping; odds ratio 0·31 [95% credibility interval] 0·11-0·80; moderate certainty). The risk of bias was low for 10 (33%) of 30 trials, 14 (47%) had some concerns, and 6 (20%) were rated as having a high risk of bias. Heterogeneity was low, with no indication of inconsistency. INTERPRETATION: This study found that long deferral of clamping leads to reduced odds of death before discharge in preterm infants. In infants assessed as requiring immediate resuscitation, this finding might only be generalisable if there are provisions for such care with the cord intact. These results are based on thoroughly cleaned and checked individual participant data and can inform future guidelines and practice. FUNDING: Australian National Health and Medical Research Council.

Optimising the analysis of vascular prevention trials: Re-Assessment of the TARDIS trial, the first prevention trial to adopt an ordinal primary outcome measure.

Background: Ordinalised vascular outcomes incorporating event severity are more informative than binary outcomes that just include event numbers. The TARDIS trial was the first vascular prevention study to use an ordinalised vascular outcome as its primary efficacy and safety measures and collected severity information for other vascular events. Methods: TARDIS was an international prospective randomised open-label blinded-endpoint trial assessing one month of intensive versus guideline antiplatelet therapy in patients with acute non-cardioembolic stroke or TIA. Vascular events and their severity were recorded up to final follow-up at 90 days post randomisation. For each outcome, statistical techniques compared ordinal/continuous (10 models) and dichotomous (5 models) analyses; results were then ranked with the smallest p-value being given the smallest rank. Outcomes were also assessed within the pre-defined subgroup of participants with mild stroke (NIHSS≤3), or TIA recruited within 24 h. Results: Ordinal versions of vascular event outcomes were created in 3096 participants for stroke, myocardial infarction, major cardiac events, bleeding events, serious adverse events and venous thromboembolism (VTE), with 32 outcomes being created overall (29 in the subgroup population due to the absence of VTE events). Overall, the tests run on ordinal outcomes tended to rank higher than tests performed on binary outcomes. 764 (24.7%) participants were recruited within 24 h of a mild stroke/TIA; again, tests run on ordinal outcomes ranked higher. Conclusions: In TARDIS, tests performed on ordinal vascular outcomes tended to attain a higher rank than those performed on binary outcomes. Trial registration: ISRCTN47823388.

Emollients for preventing atopic eczema: Cost-effectiveness analysis of the BEEP trial.

BACKGROUND: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy. OBJECTIVE: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis. METHODS: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years. RESULTS: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group. CONCLUSIONS: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective.

Bleeding with intensive versus guideline antiplatelet therapy in acute cerebral ischaemia.

Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24-3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8-35 day period but not in the 0-7 or 36-90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains.Trial registration ISRCTN47823388 .

Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease: baseline data and statistical analysis plan for the Lacunar Intervention Trial-2 (LACI-2) (ISRCTN14911850).

BACKGROUND: Cerebral small vessel disease (SVD) causes lacunar strokes (25% of all ischaemic strokes), physical frailty and cognitive impairment and vascular and mixed dementia. There is no specific treatment to prevent progression of SVD. METHODS: The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression. We aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol, isosorbide mononitrate, both or neither, in addition to guideline secondary ischaemic stroke prevention, in a partial factorial design. The primary outcome is feasibility of recruitment and adherence to medication; key secondary outcomes include: drug tolerability; recurrent vascular events, cognition and function at 1 year after randomisation; and safety (bleeding, falls, death). Data are number (%) and median (IQR). RESULTS: The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised, with the following baseline characteristics: average age 64 (56.0, 72.0) years, female 112 (30.9%), stroke onset to randomisation 79.0 (27.0, 244.0) days, hypertension 267 (73.6%), median blood pressures 143.0 (130.0, 157.0)/83.0 (75.0, 90.0) mm Hg, current smokers 67 (18.5%), educationally achieved end of school examinations (A-level) or higher 118 (32.5%), modified Rankin scale 1.0 (0.0, 1.0), National Institutes Health stroke scale 1.0 (1.4), Montreal Cognitive Assessment 26.0 (23.0, 28.0) and total SVD score on brain imaging 1.0 (0.0, 2.0). This publication summarises the baseline data and presents the statistical analysis plan. SUMMARY: The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022. TRIAL REGISTRATION NUMBER: ISRCTN14911850.

Emollients for prevention of atopic dermatitis: 5-year findings from the BEEP randomized trial.

BACKGROUND: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. METHODS: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. RESULTS: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. CONCLUSIONS: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.

Should we adjudicate outcomes in stroke trials? A systematic review.

BACKGROUND: Central adjudication of outcomes is common in randomized clinical trials in stroke. The rationale for adjudication is clear; centrally adjudicated outcomes should have less random and systematic errors than outcomes assessed locally by site investigators. However, adjudication brings added complexities to a clinical trial and can be costly. AIM: To assess the evidence for outcome adjudication in stroke trials. SUMMARY OF REVIEW: We identified 12 studies evaluating central adjudication in stroke trials. The majority of these were secondary analyses of trials, and the results of all of these would have remained unchanged had central adjudication not taken place, even for trials without sufficient blinding. The largest differences between site-assessed and adjudicator-assessed outcomes were between the most subjective outcomes, such as causality of serious adverse events. We found that the cost of adjudication could be upward of £100,000 for medium to large prevention trials. These findings suggest that the cost of central adjudication may outweigh the advantages it brings in many cases. However, through simulation, we found that only a small amount of bias is required in site investigators' outcome assessments before adjudication becomes important. CONCLUSION: Central adjudication may not be necessary in stroke trials with blinded outcome assessment. However, for open-label studies, central adjudication may be more important.

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial.

PURPOSE: Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro. We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents. METHODS: We performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary nitrate, and ordinal infection/clinical events. RESULTS: Of 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7-12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18-175] v 18 [10-50] mg/L, difference 25 [0-90]. Data paucity precluded clinical between-group comparisons; the outcome distribution was as follows: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common. CONCLUSIONS: Recruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary nitrate. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. TRIAL REGISTRATION: ISRCTN51124684. Application date 7/12/2020; assignment date 13/1/2021.

Using the Vitiligo Noticeability Scale in clinical trials: construct validity, interpretability, reliability and acceptability.

BACKGROUND: Validated outcome measures are needed for vitiligo trials. OBJECTIVES: To assess construct validity, interpretability, reliability and acceptability of the Vitiligo Noticeability Scale (VNS). METHODS: We used images of vitiligo before and after treatment, plus outcome data, from the HI-Light Vitiligo trial. We compared outcome assessments made by trial participants with assessments of images by clinicians and people with vitiligo who were not trial participants [Patient and Public Involvement (PPI) panel]. Hypothesis testing assessed psychometric properties of the VNS, with κ statistics to assess agreement between outcomes. Three focus groups and two online discussion groups provided insight into the use of VNS by people with vitiligo. RESULTS: Our hypothesis of a positive association between VNS and participant-reported global treatment success was supported for trial participants (κ = 0·41 if VNS success was defined as ≥ 4; κ = 0·71 if VNS success was defined as ≥ 3), but not for the blinded PPI panel (κ = 0·28). As hypothesized, the association with participant-reported global success was higher for VNS (κ = 0·41) than for clinician-reported percentage repigmentation (κ = 0·17). Seventy-five per cent of trial participants valued a VNS of 3 (partial response) as a treatment success. Test-retest reliability was good: κ = 0·69 (95% confidence interval 0·63-0·74). Age and skin phototype did not influence interpretation of the VNS scores. To people with vitiligo, the VNS is an acceptable and meaningful patient-reported outcome measure. CONCLUSIONS: Trial participants may assess their vitiligo differently compared with blinded assessors. A VNS score of 3 may be more highly valued by people undergoing vitiligo treatment than was previously thought. What is already known about this topic? Vitiligo is a common condition, and can have a considerable psychological impact. A Vitiligo Core Outcome Set is being developed, to enable the results of vitiligo trials to be compared and combined more easily. The Vitiligo Noticeability Scale (VNS) is a patient-reported outcome measure (PROM) developed in partnership with people with vitiligo; initial validation studies have been promising. What does this study add? The VNS shows good construct validity, reliability and acceptability; it can be used in all ages and skin phototypes. All five levels of the VNS scale should be reported for transparency, to aid interpretation of trial findings, and to facilitate meta-analysis in systematic reviews. VNS assessments made by trial participants and independent observers are likely to be qualitatively different, making blinded assessment of VNS by independent observers difficult to interpret. Blinding of participants to trial interventions is recommended whenever possible. What are the clinical implications of the work? The VNS can be used as a PROM to assess the cosmetic acceptability of repigmentation at individual patches of vitiligo. A VNS score of 3 or more is likely to be valued by patients as a treatment success.

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials.

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Promoting Independence in Dementia (PRIDE): A Feasibility Randomized Controlled Trial.

BACKGROUND: There is a need for interventions to foster and maintain independence for people with dementia to support community living, improve morale, and reduce stigma. We investigated a social intervention to promote living well and enhance independence for people with mild dementia. METHODS: In this two arm parallel group, feasibility RCT at six sites in England, participants were randomized (1:1) to the PRIDE intervention (encompassing social, physical, and cognitive domains supported by a facilitator over three sessions) compared to usual care only. The main objective was to determine the feasibility of a main trial with respect to measures of recruitment, retention, and adherence to the intervention. RESULTS: During a 7-month period, 402 people were invited to the trial, 148 were screened (37%, 95% confidence interval (CI)=32-42%), 137 were eligible at pre-consent, 94 consented to the trial (69% of those eligible, 95% CI=60-76%), and 92 were randomized (46 to each group). Of those allocated to the intervention, 42 (91%) received at least one of three intervention sessions. Outcome assessment follow-up visits were completed for 73 participants at 6 months (79%, 95% CI=70-87%), and this was similar for both groups. CONCLUSION: A large multi-center trial of the PRIDE intervention in community-dwelling people with mild dementia is feasible using systematic recruitment strategies. The intervention was successfully delivered and well received by participants. Findings from this study will be used to refine the design and processes for a definitive RCT. TRIAL REGISTRATION: ISRCTN, ISRCTN11288961, registered on 23 October 2018.

TANDEM TRIAL: a factorial randomised controlled trial of dose and review schedule of bevacizumab (Avastin) for neovascular macular degeneration in the East Midlands.

OBJECTIVE: Neovascular age-related macular degeneration (nAMD) causes damage to the macula and severe vision loss. Bevacizumab is the most cost-effective nAMD treatment. The TANDEM trial was designed to determine whether, in patients with nAMD, low-dose bevacizumab is non-inferior to the standard dose in terms of visual deterioration and whether a bimonthly regimen is non-inferior to monthly, treatment as required, regimens. METHODS: This was a multicentre, 2×2 factorial, double-masked, non-inferiority randomised trial with patients considered eligible if they met the National Institute for Health and Care Excellence criteria for nAMD treatment with ranibizumab. Participants were randomly assigned to standard (1.25 mg) or low (0.625 mg) dose bevacizumab and either monthly or bimonthly review regimen. The primary outcome was time to vision deterioration, defined as reduction of ≥15 letters (three lines) during the loading phase (visual acuity scores at visits B and C compared with the initial visit A), or ≥6 letters (one line) during the maintenance phase (visual acuity scores at subsequent visits compared with mean vision at visits A-C). RESULTS: In total 812 participants (918 eyes) were randomised into the trial. The low dose showed some evidence of being non-inferior to standard dose (HR 1.07; 95% CI 0.80 to 1.42), however, there was no strong evidence of bimonthly review being non-inferior to monthly review (HR 1.45; 95% CI 1.09 to 1.94). There was no difference in visual acuity when assessed at 9 months and no major differences in the frequency of serious adverse events or reactions between the groups. CONCLUSION: The standard dose of bevacizumab can be halved without compromising efficacy. Bimonthly review cannot be considered to be no worse than monthly review.

Optimising recruitment to the HAND-1 RCT feasibility study: integration of the QuinteT Recruitment Intervention (QRI).

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.

Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT.

BACKGROUND: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo. OBJECTIVE: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo. DESIGN: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up. SETTING: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community. PARTICIPANTS: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area. INTERVENTIONS: Topical corticosteroids [mometasone furoate 0.1% (Elocon®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based. MAIN OUTCOME MEASURES: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment). RESULTS: In total, 517 participants were randomised (adults, n = 398; and children, n = 119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%; p = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%; p = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective). LIMITATIONS: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase. CONCLUSION: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed. FUTURE WORK: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17160087. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

The Home Interventions and Light therapy for the treatment of vitiligo (HI-Light Vitiligo) trial aimed to find out whether or not treating vitiligo at home with a narrowband ultraviolet B light, either by itself or with a steroid ointment, is better than treatment using a steroid ointment only. We enrolled 517 children (aged ≥ 5 years) and adults who had small, active (i.e. recently changing) patches of vitiligo into the study. Participants received one of three possible treatment options: steroid ointment (plus dummy light), hand-held narrowband ultraviolet B light therapy (plus placebo ointment) or both treatments used together. We asked participants to judge how noticeable their target vitiligo patch was after 9 months of treatment. We considered the treatment to be successful if the participants' responses were either 'a lot less noticeable' or 'no longer noticeable'. The results showed that using both treatments together was better than using a steroid ointment on its own. Around one-quarter of participants (27%) who used both treatments together said that their vitiligo was either 'no longer noticeable' or 'a lot less noticeable' after 9 months of treatment. This was compared with 17% of those using steroid ointment on its own and 22% of those using narrowband ultraviolet B light on its own. All treatments were able to stop the vitiligo from spreading. Patches on the hands and feet were less likely to respond to treatment than patches on other parts of the body. The trial found that the vitiligo tended to return once treatments were stopped, so ongoing intermittent treatment may be needed to maintain the treatment response. The treatments were found to be relatively safe and easy to use, but light treatment required a considerable time commitment (approximately 20 minutes per session, two or three times per week). This trial showed that using steroid ointment and narrowband ultraviolet B light together is likely to be better than steroid ointment alone for people with small patches of vitiligo. Steroid ointment alone can still be effective for some people and remains a useful treatment that is able to stop vitiligo from spreading. The challenge is to make hand-held narrowband ultraviolet B light treatment available as normal care in the NHS for people with vitiligo.

Data sharing: experience of accessing individual patient data from completed randomised controlled trials in vascular and cognitive medicine.

OBJECTIVES: Meta-analysis based on individual patient data (IPD) from randomised trials is superior to using published summary data since it facilitates subgroup and multiple variable analyses. Guidelines and funders expect that researchers share IPD for bona fide analyses, but in practice, this is done variably. Here, we report the experience of obtaining IPD for two collaborative analysis studies. SETTING: Two linked studies required IPD from published randomised trials. The leading researchers for eligible trials were approached and asked to share IPD including trial characteristics, patient demographics, baseline clinical data and outcome measures. PARTICIPANTS: Participants in eligible randomised controlled trials included patients with or at risk of cognitive decline/vascular events. PRIMARY AND SECONDARY OUTCOME MEASURES: Numbers (%) of trials where the leading researcher responded favourably/negatively or did not respond. If negative, reasons behind the response were collected. If positive, methods used to share IPD were recorded. RESULTS: Across the two studies, 391 completed trials were identified. Email addresses for researchers were found for 313 (80%) of the trials. One hundred and forty-eight (47%) researchers did not respond despite being sent multiple emails. Following contact, positive initial responses were received from 92 researchers, resulting in IPD being shared for 78 trials. Eighty-seven (28%) researchers declined to share data; justifications were recorded. The median time from first request to accessing data in one study was 241 (IQR 383.3) days. IPD sources included: direct from researcher, via academic trial funders repository and a website requiring remote analysis of commercial data. Where data were shared, a variety of methods were used to transfer data. CONCLUSION: Sharing of IPD from trials is desirable and a requirement of many funding bodies. However, accessing IPD faces multiple challenges including refusals to share, delays in access to data and having to perform analyses on a remote website. TRIAL REGISTRATION: Not applicable.

Cost-benefit of outcome adjudication in nine randomised stroke trials.

BACKGROUND: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. METHODS: We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators' time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. RESULTS: The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). CONCLUSIONS: Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.

Outcome assessment by central adjudicators in randomised stroke trials: Simulation of differential and non-differential misclassification.

INTRODUCTION: Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results.Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000-10,000), overall event rate (10%-50%) and treatment effect (0.67-0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level. RESULTS: For the five trials, the range of unweighted kappa values were reduced from 0.89-0.97 to 0.65-0.85 before the treatment effect was altered. This corresponded to 2.1%-6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant. DISCUSSION: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment. CONCLUSION: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary.