Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study of electronic primary care data.

OBJECTIVES: Antiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na+) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in patients with breast, bowel and prostate cancer. DESIGN: Retrospective cohort study. SETTING: Individual electronic primary healthcare records extracted from the Clinical Practice Research Datalink. PARTICIPANTS: Records for 132 996 patients with a diagnosis of breast, bowel or prostate cancer. OUTCOME MEASURES: Adjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias. RESULTS: During 1 002 225 person-years of follow-up, there were 42 037 cancer-specific deaths. 53 724 (40.4%) patients with cancer had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (HR 1.59, 95% CI 1.56 to 1.63, p<0.001). This applied to VGSC-inhibiting tricyclic antidepressants (HR 1.61, 95% CI 1.50 to 1.65, p<0.001), local anaesthetics (HR 1.49, 95% CI 1.43 to 1.55, p<0.001) and anticonvulsants (HR 1.40, 95% CI 1.34 to 1.48, p<0.001) and persisted in sensitivity analyses. In contrast, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival (HR 0.75, 95% CI 0.64 to 0.88, p<0.001 and HR 0.54, 95% CI 0.33 to 0.88, p=0.01, respectively). CONCLUSIONS: Association between VGSC inhibitor use and mortality in patients with cancer varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).

Adapting and validating the Autism Diagnostic Observation Schedule Version 2 for use with deaf children and young people.

We report a Delphi Consensus modification and first validation study of the Autism Diagnostic Observation Schedule - 2 with deaf children and young people (ADOS-2 Deaf adaptation). Validation included 122 deaf participants (aged 2-18 years), 63 with an Autism Spectrum Disorder (ASD). This was compared to a National Institute for Health and Clinical Excellence (NICE) guideline standard clinical assessment by blinded independent specialist clinicians. Results showed overall sensitivity 73% (95%CI 60%, 83%); specificity 71% (95%CI 58%, 82%), and for the more common modules 1-3 (combined as in previous studies) sensitivity 79% (95% CI 65-89%); specificity 79% (95% CI 66-89%) suggesting this instrument will be a helpful addition for use with deaf children and young people.

Adapting and validating the Autism Diagnostic Interview - Revised for use with deaf children and young people.

LAY ABSTRACT: Autism assessment processes need to improve for deaf children as they are currently being diagnosed later than their hearing counterparts and misdiagnosis can occur. We took one of the most commonly used parent developmental interviews for autism spectrum disorder the Autism Diagnostic Interview-Revised and adapted it using international expert advice. Modifications were proposed and agreed by the expert panel for 45% of items; the remaining 55% of items were unchanged. We then tested the revised version, adapted for deaf children (Autism Diagnostic Interview-Revised Deaf Adaptation), in a UK sample of 78 parents/carers of deaf children with autism spectrum disorder and 126 parents/carers with deaf children without autism spectrum disorder. When compared to National Institute for Health and Care Excellence guideline standard clinical assessments, the Autism Diagnostic Interview-Revised Deaf Adaptation diagnostic algorithm threshold scores could identify those deaf children with a definite diagnosis (true autism spectrum disorder positives) well (sensitivity of 89% (79%-96%)) and those deaf children who did not have autism spectrum disorder (true autism spectrum disorder negatives) well (specificity of 81% (70%-89%)). Our findings indicate that the Autism Diagnostic Interview-Revised Deaf Adaptation is likely to prove a useful measure for the assessment of deaf children with suspected autism spectrum disorder and that further research would be helpful.

Performance status and trial site-level factors are associated with missing data in palliative care trials: An individual participant-level data analysis of 10 phase 3 trials.

BACKGROUND: Missing data compromise the internal and external validity of trial findings, however there is limited evidence on how best to reduce missing data in palliative care trials. AIM: To assess the association between participant and site level factors and missing data in palliative care trials. DESIGN AND SETTING: Individual participant-level data analysis of 10 phase 3 palliative care trials using multi-level cross-classified models. RESULTS: Participants with missing data at the previous time-point and poorer performance status were more likely to have missing data for the primary outcome and quality of life outcomes, at the primary follow-up point and end of follow-up. At the end of follow-up, the number of site randomisations and number of study site personnel were significantly associated with missing data. Trial duration and the number of research personnel explained most of the variance at the trial and site-level respectively, except for the primary outcome where the amount of data requested was most important at the trial-level. Variance at the trial level was more substantial than at the site level across models and considerable variance remained unexplained for all models except quality of life at the end of follow-up. CONCLUSION: Participants with a poorer performance status are at higher risk of missing data in palliative care trials and require additional support to provide complete data. Performance status is a potential auxiliary variable for missing data imputation models. Reducing trial variability should be prioritised and further factors need to be identified and explored to explain the residual variance.

Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.

Bland-Altman methods for comparing methods of measurement and response to criticisms.

Introduced in 1983, Bland-Altman methods is now considered the standard approach for assessment of agreement between two methods of measurement. The method is widely used by researchers in various disciplines so that the Bland-Altman 1986 Lancet paper has been named as the 29th mostly highly cited paper ever, over all fields. However, two papers by Hopkins (2004) and Krouwer (2007) questioned the validity of the Bland-Altman analysis. We review the points of critical papers and provide responses to them. The discussions in the critical papers of the Bland-Altman method are scientifically delusive. Hopkins misused the Bland-Altman methodology for research question of model validation and also incorrectly used least-square regression when there is measurement error in the predictor. The problem with Krouwers' paper is making sweeping generalisation of a very narrow and somewhat unrealistic situation. The method proposed by Bland and Altman should be used when the research question is method comparison.

Doug Altman: Driving critical appraisal and improvements in the quality of methodological and medical research.

Doug Altman was a visionary leader and one of the most influential medical statisticians of the last 40 years. Based on a presentation in the "Invited session in memory of Doug Altman" at the 40th Annual Conference of the International Society for Clinical Biostatistics (ISCB) in Leuven, Belgium and our long-standing collaborations with Doug, we discuss his contributions to regression modeling, reporting, prognosis research, as well as some more general issues while acknowledging that we cannot cover the whole spectrum of Doug's considerable methodological output. His statement "To maximize the benefit to society, you need to not just do research but do it well" should be a driver for all researchers. To improve current and future research, we aim to summarize Doug's messages for these three topics.

Modifying and validating the social responsiveness scale edition 2 for use with deaf children and young people.

A Delphi consensus methodology was used to adapt a screening tool, the Social Responsiveness Scale- 2 (SRS-2), for use with deaf children including those whose preferred communication method is sign language. Using this approach; 27 international experts (The Delphi International Expert Panel), on the topic of autism spectrum disorder (ASD) in deaf people, contributed to the review of item content. A criterion for agreement was set at 80% of experts on each item (with 75% acceptable in the final fourth round). The agreed modifications are discussed. The modified SRS-2 research adaptation for deaf people (referred to here as the "SRS-2 Deaf adaptation") was then translated into British Sign Language using a robust translation methodology and validated in England in a sample of 198 deaf children, 76 with Autism Spectrum Disorders (ASD) and 122 without ASD. The SRS-2 Deaf adaptation was compared blind to a NICE (National Institute for Health and Care Excellence) guideline standard clinical assessment. The area under the Receiver Operating (ROC) curve was 0.811 (95% CI: 0.753, 0.869), with an optimal cut-off value of 73, which gave a sensitivity of 82% and a specificity of 67%. The Cronbach Alpha coefficient was 0.968 suggesting high internal consistency. The Intraclass Correlation Coefficient was 0.897, supporting test-retest reliability. This performance is equivalent to similar instruments used for screening ASD in the hearing population.

Diabetes and Composition of Weight Lifting and Cardio in Exercise.

The prevalence of type-2 diabetes(T2D) has increased globally. This has led to greater mortality, morbidity and disability in the general population. It is thus crucial to identify methods to prevent its onset among the healthy, and to also discover solutions to adequately manage the complications among those affected. Most research in this area has focused on the role of diet and exercise. More recently, different exercise types and their relationship with T2D has received considerable attention. In our work, we investigate the association between T2D (primary outcome) and two types of exercises: cardio (CR) and weight lifting (WL). Specifically, the relationship between duration of time spent in the two exercises and the odds of T2D is explored. Data are obtained from the Behavioural Risk Factor Surveillance System (BRFSS) survey, USA. Three ethnic populations are considered: White American, Black American and Hispanic American. Both WL and CR are found to be associated with negative log-odds of diabetes across all three ethnicities (WL: p <; 0.0001 and CR: p=0.00431). The association between WL and T2D is found to be modified for females (interaction-term coefficient: -0.096 (p=0.0115)).

Practical help for specifying the target difference in sample size calculations for RCTs: the DELTA2 five-stage study, including a workshop.

BACKGROUND: The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in the primary outcome between the intervention effects for the population of interest. This difference is called the 'target difference' and should be appropriate for the principal estimand of interest and determined by the primary aim of the study. The target difference between treatments should be considered realistic and/or important by one or more key stakeholder groups. OBJECTIVE: The objective of the report is to provide practical help on the choice of target difference used in the sample size calculation for a randomised controlled trial for researchers and funder representatives. METHODS: The Difference ELicitation in TriAls2 (DELTA2) recommendations and advice were developed through a five-stage process, which included two literature reviews of existing funder guidance and recent methodological literature; a Delphi process to engage with a wider group of stakeholders; a 2-day workshop; and finalising the core document. RESULTS: Advice is provided for definitive trials (Phase III/IV studies). Methods for choosing the target difference are reviewed. To aid those new to the topic, and to encourage better practice, 10 recommendations are made regarding choosing the target difference and undertaking a sample size calculation. Recommended reporting items for trial proposal, protocols and results papers under the conventional approach are also provided. Case studies reflecting different trial designs and covering different conditions are provided. Alternative trial designs and methods for choosing the sample size are also briefly considered. CONCLUSIONS: Choosing an appropriate sample size is crucial if a study is to inform clinical practice. The number of patients recruited into the trial needs to be sufficient to answer the objectives; however, the number should not be higher than necessary to avoid unnecessary burden on patients and wasting precious resources. The choice of the target difference is a key part of this process under the conventional approach to sample size calculations. This document provides advice and recommendations to improve practice and reporting regarding this aspect of trial design. Future work could extend the work to address other less common approaches to the sample size calculations, particularly in terms of appropriate reporting items. FUNDING: Funded by the Medical Research Council (MRC) UK and the National Institute for Health Research as part of the MRC-National Institute for Health Research Methodology Research programme.

This Difference ELicitation in TriAls² (DELTA²) advice and recommendations document aims to help researchers choose the 'target difference' in a type of research study called a randomised controlled trial. The number of people needed to be involved in a study ­ the sample size ­ is usually based on a calculation aimed to ensure that the difference in benefit between treatments is likely to be detected. The calculation also accounts for the risk of a false-positive finding. No more patients than necessary should be involved. Choosing a 'target difference' is an important step in calculating the sample size. The target difference is defined as the amount of difference in the participants' response to the treatments that we wish to detect. It is probably the most important piece of information used in the sample size calculation. How we decide what the target difference should be depends on various factors. One key decision to make is how we should measure the benefits that treatments offer. For example, if we are evaluating a treatment for high blood pressure, the obvious thing to focus on would be blood pressure. We could then proceed to consider what an important difference in blood pressure between treatments would be, based on experts' views or evidence from previous research studies. This document seeks to provide assistance to researchers on how to choose the target difference when designing a trial. It also provides advice to help them clearly present what was done and why, when writing up the study proposal or reporting the study's findings. The document is also intended to be read by those who decide whether or not a proposed study should be funded. Clarifying a study's aim and getting a sensible sample size is important. It can affect not only those involved in the study, but also future patients who will receive treatment.

Correction to: Choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial - the development of the DELTA2 guidance.

Following publication of the original article [1], we have been notified of a few mistakes.

Prevalence and Incidence of Anxiety and Depression Among Children, Adolescents, and Young Adults With Life-Limiting Conditions: A Systematic Review and Meta-analysis.

IMPORTANCE: Children, adolescents, and young adults with life-limiting conditions experience various challenges that may make them more vulnerable to mental health problems, such as anxiety and depression. However, the prevalence and incidence of anxiety and depression among this population appears to be unknown. OBJECTIVE: To conduct a systematic review and meta-analysis to estimate the prevalence and/or incidence of anxiety and depression in children, adolescents, and young adults with life-limiting conditions. DATA SOURCES: Searches of MEDLINE (PubMed), PsycInfo, and Embase were conducted to identify studies published between January 2000 and January 2018. STUDY SELECTION: Studies were eligible for this review if they provided primary data of anxiety or depression prevalence and/or incidence, included participants aged 5 to 25 years with a life-limiting condition, were conducted in an Organisation for Economic Co-operation and Development country, and were available in English. DATA EXTRACTION AND SYNTHESIS: Random-effects meta-analyses were generated to provide anxiety and depression prevalence estimates. Meta-regression was conducted to analyze associations between study characteristics and each prevalence estimate. MAIN OUTCOMES AND MEASURES: Prevalence of anxiety and depression. RESULTS: A total of 14 866 nonduplicate articles were screened, of which 37 were included in the review. Of these, 19 studies reported anxiety prevalence, and 36 studies reported depression prevalence. The mean (range) age of participants was 15.4 (6-25) years. The meta-analysis of anxiety prevalence (n = 4547 participants) generated a pooled prevalence estimate of 19.1% (95% CI, 14.1%-24.6%). Meta-regression analysis found statistically significant differences in anxiety prevalence by assessment tool; diagnostic interviews were associated with higher anxiety prevalence (28.5% [95% CI, 13.2%-46.8%]) than self-reported or parent-reported measures (14.9% [95% CI, 10.9%-19.4%]). The depression meta-analysis (n = 5934 participants) found a pooled prevalence estimate of 14.3% (95% CI, 10.5%-18.6%). Meta-regression analysis revealed statistically significant differences in depression prevalence by the mean age of the sample (ß = 0.02 [95% CI, 0.01-0.03]; P = .001). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, the prevalence of anxiety and depression among children, adolescents, and young adults with life-limiting conditions was high, highlighting the need for increased psychological assessment and monitoring. Further research is required to determine the prevalence and incidence of anxiety and depression in a larger sample of children, adolescents, and young adults with a broader range of life-limiting conditions.

Airflow relieves chronic breathlessness in people with advanced disease: An exploratory systematic review and meta-analyses.

BACKGROUND: Chronic breathlessness is a neglected symptom of advanced diseases. AIM: To examine the effect of airflow for chronic breathlessness relief. DESIGN: Exploratory systematic review and meta-analysis. DATA SOURCES: Medline, CINAHL, AMED and Cochrane databases were searched (1985-2018) for observational studies or randomised controlled trials of airflow as intervention or comparator. Selection against predefined inclusion criteria, quality appraisal and data extraction was conducted by two independent reviewers with access to a third for unresolved differences. 'Before and after' breathlessness measures from airflow arms were analysed. Meta-analysis was carried out where possible. RESULTS: In all, 16 of 78 studies (n = 929) were included: 11 randomised controlled trials of oxygen versus medical air, 4 randomised controlled trials and 1 fan cohort study. Three meta-analyses were possible: (1) Fan at rest in three studies (n = 111) offered significant benefit for breathlessness intensity (0-100 mm visual analogue scale and 0-10 numerical rating scale), mean difference -11.17 (95% confidence intervals (CI) -16.60 to -5.74), p = 0.06 I2 64%. (2) Medical air via nasal cannulae at rest in two studies (n = 89) improved breathlessness intensity (visual analogue scale), mean difference -12.0 mm, 95% CI -7.4 to -16.6, p < 0.0001 I2 = 0%. (3) Medical airflow during a constant load exercise test before and after rehabilitation (n = 29) in two studies improved breathlessness intensity (modified Borg scale, 0-10), mean difference -2.9, 95% CI -3.2 to -2.7, p < 0.0001 I2 = 0%. CONCLUSION: Airflow appears to offer meaningful relief of chronic breathlessness and should be considered as an adjunct treatment in the management of breathlessness.

Pharmacoepidemiologic Evaluation of Birth Defects from Health-Related Postings in Social Media During Pregnancy.

INTRODUCTION: Adverse effects of medications taken during pregnancy are traditionally studied through post-marketing pregnancy registries, which have limitations. Social media data may be an alternative data source for pregnancy surveillance studies. OBJECTIVE: The objective of this study was to assess the feasibility of using social media data as an alternative source for pregnancy surveillance for regulatory decision making. METHODS: We created an automated method to identify Twitter accounts of pregnant women. We identified 196 pregnant women with a mention of a birth defect in relation to their baby and 196 without a mention of a birth defect in relation to their baby. We extracted information on pregnancy and maternal demographics, medication intake and timing, and birth defects. RESULTS: Although often incomplete, we extracted data for the majority of the pregnancies. Among women that reported birth defects, 35% reported taking one or more medications during pregnancy compared with 17% of controls. After accounting for age, race, and place of residence, a higher medication intake was observed in women who reported birth defects. The rate of birth defects in the pregnancy cohort was lower (0.44%) compared with the rate in the general population (3%). CONCLUSIONS: Twitter data capture information on medication intake and birth defects; however, the information obtained cannot replace pregnancy registries at this time. Development of improved methods to automatically extract and annotate social media data may increase their value to support regulatory decision making regarding pregnancy outcomes in women using medications during their pregnancies.

DELTA2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial.

BACKGROUND: A key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adequate statistical power) of detecting a target difference between the treatments should one exist. The sample size has many implications for the conduct and interpretation of the study. Despite the critical role that the target difference has in the design of a RCT, the way in which it is determined has received little attention. In this article, we summarise the key considerations and messages from new guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation. This article on choosing the target difference for a randomised controlled trial (RCT) and undertaking and reporting the sample size calculation has been dual published in the BMJ and BMC Trials journals METHODS: The DELTA2 (Difference ELicitation in TriAls) project comprised five major components: systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2); a Delphi study (stage 3); a two-day consensus meeting bringing together researchers, funders and patient representatives (stage 4); and the preparation and dissemination of a guidance document (stage 5). RESULTS AND DISCUSSION: The key messages from the DELTA2 guidance on determining the target difference and sample size calculation for a randomised caontrolled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.

AVURT: aspirin versus placebo for the treatment of venous leg ulcers - a Phase II pilot randomised controlled trial.

BACKGROUND: Venous leg ulcers (VLUs) are the most common cause of leg ulceration, affecting 1 in 100 adults. VLUs may take many months to heal (25% fail to heal). Estimated prevalence is between 1% and 3% of the elderly population. Compression is the mainstay of treatment and few additional therapies exist to improve healing. Two previous trials have indicated that low-dose aspirin, as an adjunct to standard care, may improve healing time, but these trials were insufficiently robust. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. OBJECTIVES: Primary objective - to assess the effects of 300 mg of aspirin (daily) versus placebo on the time to healing of the reference VLU. Secondary objectives - to assess the feasibility of leading into a larger pragmatic Phase III trial and the safety of aspirin in this population. DESIGN: A multicentred, pilot, Phase II randomised double-blind, parallel-group, placebo-controlled efficacy trial. SETTING: Community leg ulcer clinics or services, hospital outpatient clinics, leg ulcer clinics, tissue viability clinics and wound clinics in England, Wales and Scotland. PARTICIPANTS: Patients aged ≥ 18 years with a chronic VLU (i.e. the VLU is > 6 weeks in duration or the patient has a history of VLU) and who are not regularly taking aspirin. INTERVENTIONS: 300 mg of daily oral aspirin versus placebo. All patients were offered care in accordance with Scottish Intercollegiate Guidelines Network (SIGN) guidance with multicomponent compression therapy aiming to deliver 40 mmHg at the ankle when possible. RANDOMISATION: Participants were allocated in a 1 : 1 (aspirin : placebo) ratio by the Research Pharmacy, St George's University Hospitals NHS Foundation Trust, using a randomisation schedule generated in advance by the investigational medicinal product manufacturer. Randomisation was stratified according to ulcer size (≤ 5cm2 or > 5cm2). MAIN OUTCOME MEASURE: The primary outcome was time to healing of the largest eligible ulcer (reference ulcer). FEASIBILITY RESULTS ­ RECRUITMENT: 27 patients were recruited from eight sites over a period of 8 months. The target of 100 patients was not achieved and two sites did not recruit. Barriers to recruitment included a short recruitment window and a large proportion of participants failing to meet the eligibility criteria. RESULTS: The average age of the 27 randomised participants (placebo, n = 13; aspirin, n = 14) was 62 years (standard deviation 13 years), and two-thirds were male (n = 18). Participants had their reference ulcer for a median of 15 months, and the median size of ulcer was 17.1 cm2. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis for log-ulcer area and duration (hazard ratio 0.58, 95% confidence interval 0.18 to 1.85; p = 0.357). One expected, related serious adverse event was recorded for a participant in the aspirin group. LIMITATIONS: The trial under-recruited because many patients did not meet the eligibility criteria. CONCLUSIONS: There was no evidence that aspirin was efficacious in hastening the healing of chronic VLUs. It can be concluded that a larger Phase III (effectiveness) trial would not be feasible. TRIAL REGISTRATION: Clinical Trials.gov NCT02333123; European Clinical Trials Database (EudraCT) 2014-003979-39. 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. 22, No. 55. See the NIHR Journals Library website for further project information.

Choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial - the development of the DELTA2 guidance.

BACKGROUND: A key step in the design of a randomised controlled trial is the estimation of the number of participants needed. The most common approach is to specify a target difference in the primary outcome between the randomised groups and then estimate the corresponding sample size. The sample size is chosen to provide reassurance that the trial will have high statistical power to detect the target difference at the planned statistical significance level. Alternative approaches are also available, though most still require specification of a target difference. The sample size has many implications for the conduct of the study, as well as incurring scientific and ethical aspects. Despite the critical role of the target difference for the primary outcome in the design of a randomised controlled trial (RCT), the manner in which it is determined has received little attention. This article reports the development of the DELTA2 guidance on the specification and reporting of the target difference for the primary outcome in a sample size calculation for a RCT. METHODS: The DELTA2 (Difference ELicitation in TriAls) project has five components comprising systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2), a Delphi study (stage 3), a 2-day consensus meeting bringing together researchers, funders and patient representatives (stage 4), and the preparation and dissemination of a guidance document (stage 5). RESULTS: The project started in April 2016. The literature search identified 28 articles of methodological developments relevant to a method for specifying a target difference. A Delphi study involving 69 participants, along with a 2-day consensus meeting were conducted. In addition, further engagement sessions were held at two international conferences. The main guidance text was finalised on April 18, 2018, after revision informed by feedback gathered from stages 2 and 3 and from funder representatives. DISCUSSION: The DELTA2 Delphi study identified a number of areas (such as practical recommendations and examples, greater coverage of different trial designs and statistical approaches) of particular interest amongst stakeholders which new guidance was desired to meet. New relevant references were identified by the review. Such findings influenced the scope, drafting and revision of the guidance. While not all suggestions could be accommodated, it is hoped that the process has led to a more useful and practical document.