Kerry Hood

Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants’ views on the processes in the life of a randomised trial that should be covered by Trial Forge.General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a ‘go to’ website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.

One-year investigator-blind randomized multicenter trial comparing Asacol 2.4 g once daily with 800 mg three times daily for maintenance of remission in ulcerative colitis.

Background: Mesalazine (Asacol) is still widely prescribed in divided doses for ulcerative colitis (UC), despite evidence that adherence is improved by once‐daily (OD) prescribing. We aimed to investigate whether OD Asacol was as effective as three times (TDS) daily dosing, and to evaluate the role of treatment adherence. Methods: An investigator‐blind randomized trial was undertaken comparing OD Asacol (three 800 mg tablets) versus one 800 mg TDS in maintenance of remission of UC over 1 year. The primary endpoint was relapse rate, and noninferiority would be concluded if the lower limit of the two‐sided 95% confidence interval (CI) of the difference in proportions relapsing (TDS‐OD) exceeded −10%. Adherence was measured by tablet counts and self‐reported adherence. A subgroup of patients used a bottle cap that recorded all bottle opening events. Results: In all, 213 patients were randomized. In the intention‐to‐treat (ITT) population, relapse rates were 31% (95% CI 22%–40%) in the OD and 45% (95% CI 35%–54%) in the TDS group. Primary analysis confirmed the noninferiority of OD dosing. Two of the study populations, ITT and per‐protocol (PP), showed potential superiority of OD dosing. All measures of adherence showed that it was significantly better in the OD group. Multivariate analysis, however, showed OD dosing was associated with lower relapse risk independently of adherence. Conclusions: OD dosing with Asacol 2.4 g is as safe and effective as TDS dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit, however, was clinically borderline and may relate in part to ease of adherence. (Inflamm Bowel Dis 2012)

Fissure Seal or Fluoride Varnish? A Randomized Trial of Relative Effectiveness

Fissure sealant (FS) and fluoride varnish (FV) are effective in preventing dental caries when compared with a no-treatment control. However, the relative clinical effectiveness of these interventions is uncertain. The objective of the study was to compare the clinical effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- to 7-y-olds. The study design was a randomized clinical trial, with 2 parallel arms. The setting was a targeted-population program that used mobile dental clinics in schools located within areas of high social and economic deprivation in South Wales. A total of 1,016 children were randomized 1:1 to receive either FS or FV. Resin-based FS was applied to caries-free FPMs and maintained at 6-mo intervals. FV was applied at baseline and at 6-mo intervals for 3 y. The main outcome measures were the proportion of children developing caries into dentine (D4-6MFT) on any 1 of up to 4 treated FPMs after 36 mo. At 36 mo, 835 (82%) children remained: 417 in the FS arm and 418 in the FV arm. A smaller proportion of children who received FV (n = 73, 17.5%) versus FS (n = 82, 19.6%) developed caries into dentine on at least 1 FPM (odds ratio [OR] = 0.84; 95% CI, 0.59 to 1.21; P = 0.35), a nonstatistically significant difference between FS and FV treatments. The results were similar when the number of newly decayed teeth (OR = 0.86; 95% CI, 0.60 to 1.22) and tooth surfaces (OR = 0.85; 95% CI, 0.59 to 1.21) were examined. In a community oral health program, semiannual application of FV resulted in caries prevention that was not significantly different from that obtained by applying and maintaining FS after 36 mo (EudraCT: 2010-023476-23; ISRCTN: ISRCTN17029222).

Measurement tools for mental health problems and mental well-being in people with severe or profound intellectual disabilities : a systematic review

Mental health problems affect people with intellectual disabilities (ID) at rates similar to or in excess of the non-ID population. People with severe ID are likely to have persistent mental health problems. In this systematic review (PROSPERO 2015:CRD42015024469), we identify and evaluate the methodological quality of available measures of mental health problems or well-being in individuals with severe or profound ID. Electronic searches of ten databases identified relevant publications. Two reviewers independently reviewed titles and abstracts of retrieved records (n=41,232) and full-text articles (n=573). Data were extracted and the quality of included papers was appraised. Thirty-two papers reporting on 12 measures were included. Nine measures addressed a broad spectrum of mental health problems, and were largely observational. One physiological measure of well-being was included. The Aberrant Behavior Checklist, Diagnostic Assessment for the Severely Handicapped Scale-II and Mood, Interest and Pleasure Questionnaire are reliable measures in this population. However, the psychometric properties of six other measures were only considered within a single study - indicating a lack of research replication. Few mental health measures are available for people with severe or profound ID, particularly lacking are tools measuring well-being. Assessment methods that do not rely on proxy reports should be explored further.

Economic evaluation of nebulized magnesium sulphate in acute severe asthma in children

OBJECTIVES The aim of this study was to estimate the cost-effectiveness of nebulized magnesium sulphate (MgSO4) in acute asthma in children from the perspective of the UK National Health Service and personal social services. METHODS An economic evaluation was conducted based on evidence from a randomized placebo controlled multi-center trial of nebulized MgSO4 in severe acute asthma in children. Participants comprised 508 children aged 2-16 years presenting to an emergency department or a childrens assessment unit with severe acute asthma across thirty hospitals in the United Kingdom. Children were randomly allocated to receive nebulized salbutamol and ipratropium bromide mixed with either 2.5 ml of isotonic MgSO4 or 2.5 ml of isotonic saline on three occasions at 20-min intervals. Cost-effectiveness outcomes were constructed around the Yung Asthma Severity Score (ASS) after 60 min of treatment; whilst cost-utility outcomes were constructed around the quality-adjusted life-year (QALY) metric. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves at alternative cost-effectiveness thresholds for either: (i) a unit reduction in ASS; or (ii) an additional QALY. RESULTS MgSO4 had a 75.1 percent probability of being cost-effective at a GBP 1,000 (EUR 1,148) per unit decrement in ASS threshold, an 88.0 percent probability of being more effective (in terms of reducing the ASS) and a 36.6 percent probability of being less costly. MgSO4 also had a 67.6 percent probability of being cost-effective at a GBP 20,000 (EUR 22,957) per QALY gained threshold, an 8.5 percent probability of being more effective (in terms of generating increased QALYs) and a 69.1 percent probability of being less costly. Sensitivity analyses showed that the results of the economic evaluation were particularly sensitive to the methods used for QALY estimation. CONCLUSIONS The probability of cost-effectiveness of nebulized isotonic MgSO4, given as an adjuvant to standard treatment of severe acute asthma in children, is less than 70 percent across accepted cost-effectiveness thresholds for an additional QALY.

Once daily Asacol

Introduction Mesalazine has traditionally been administered in divided doses, but there is emerging evidence that once daily dosing is no less effective and may improve treatment adherence. Methods The Colitis Once Daily Asacol® (CODA) study was designed to assess the efficacy and safety of once daily dosing with Asacol® 2.4 g given as 3 × 800 mg tablets (OD) in comparison with three times daily dosing (one 800 mg tablet three times daily) (TDS). Adult UC patients taking mesalazine or sulphasalazine in remission for >4 weeks and <2 years were randomised (investigator-blind) to OD or TDS dosing. The primary end-point was the difference between groups in relapse rates over one year. Relapse was defined as typical symptoms of relapse with a Baron sigmoidoscopy score of 2 or 3. With estimated relapse rate of 20–30%, and a meaningful difference of 10% between groups, 250 patients were required to demonstrate non-inferiority with one-sided α of 5% and 1-β of 80%. Non-inferiority would be concluded if the upper limit of the 95% confidence interval (CI) for the difference between treatments was <10% for both per protocol (PP) and intention to treat (ITT) population. (For ITT analysis, missing data was imputed as relapse.) Results 213 patients were recruited in 32 UK centres. Groups were well matched. There was no difference in adverse events between OD and TDS groups. Primary analysis confirmed non-inferiority of once-daily dosing. In a secondary analysis, (table 1) both ITT and per protocol (PP) populations demonstrated superiority of OD versus TDS dosing which was statistically significant. A multivariable analysis of baseline factors predicting relapse will be presented. Self-reported adherence at 12 months or relapse was >90% in 97% of patients (OD group) and 85% (TDS group). When asked how easy it was to remember to take tablets, it was reported to be very or fairly easy in 98% (OD group) versus 73% (TDS group). Table 1 OC-074 Relapse rate at 1 year OD (n = 103) TDS (n = 110) Difference No. of relapses 23 33 Relapse rate (95% CI) ITT population 31% (22–40%)] 45% (35–54%) −13% (−26 to −1%) Relapse rate [95% CI] PP population 20% (11–28%) 35% (24–45%) −15% (−29 to −2%) Conclusion Once daily dosing with Asacol™ 2.4 g is as safe and effective as three times daily dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit was, however, clinically borderline and may relate to ease of adherence.

A reaction-time study of social, health, and personal attributions in relation to fluorosed teeth

Abstract This reaction time study assessed the valence and strength of evaluations of people with differing levels of fluorosed teeth. Eighty participants rated photographs of smiling faces with four levels of digitally manipulated fluorosed teeth. Faces were presented on a computer screen for a period of 2000 ms followed by a single word descriptor. Participants quickly indicated whether the descriptor applied to the preceding face using a response key. Descriptors included health, aesthetic, and personal judgments. Logistic and linear regressions revealed that participants were significantly more likely to make negative judgments involving health, aesthetic, and person attributions about faces with high levels of fluorosis, and to make negative judgments more quickly and positive judgments more slowly than those with lower levels of fluorosis. These data are consistent with the view that people use negative, easily accessible, stereotypes of individuals presenting with health problems.

General practitioner use of a C-reactive protein point-of-care test to help target antibiotic prescribing in patients with acute exacerbations of chronic obstructive pulmonary disease (the PACE study): study protocol for a randomised controlled trial

BackgroundMost patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in primary care are prescribed an antibiotic, which may not always be appropriate and may cause harm. C-reactive protein (CRP) is an acute-phase biomarker that can be rapidly measured at the point of care and may predict benefit from antibiotic treatment in AECOPD. It is not clear whether the addition of a CRP point-of-care test (POCT) to clinical assessment leads to a reduction in antibiotic consumption without having a negative impact on COPD health status.Methods/designThis is a multicentre, individually randomised controlled trial (RCT) aiming to include 650 participants with a diagnosis of AECOPD in primary care. Participants will be randomised to be managed according to usual care (control) or with the addition of a CRP POCT to guide antibiotic prescribing. Antibiotic consumption for AECOPD within 4 weeks post randomisation and COPD health status (total score) measured by the Clinical COPD Questionnaire (CCQ) at 2 weeks post randomisation will be co-primary outcomes. Primary analysis (by intention-to-treat) will determine differences in antibiotic consumption for superiority and COPD health status for non-inferiority. Secondary outcomes include: COPD health status, CCQ domain scores, use of other COPD treatments (weeks 1, 2 and 4), EQ-5D utility scores (weeks 1, 2 and 4 and month 6), disease-specific, health-related quality of life (HRQoL) at 6 months, all-cause antibiotic consumption (antibiotic use for any condition) during first 4 weeks post randomisation, total antibiotic consumption (number of days during first 4 weeks of antibiotic consumed for AECOPD/any reason), antibiotic prescribing at the index consultation and during following 4 weeks, adverse effects over the first 4 weeks, incidence of pneumonia (weeks 4 and 6 months), health care resource use and cost comparison over the 6 months following randomisation. Prevalence and resistance profiles of bacteria will be assessed using throat and sputum samples collected at baseline and 4-week follow-up. A health economic evaluation and qualitative process evaluation will be carried out.DiscussionIf shown to be effective (i.e. leads to a reduction in antibiotic use with no worse COPD health status), the use of the CRP POCT could lead to better outcomes for patients with AECOPD and help reduce selective pressures driving the development of antimicrobial resistance. PACE will be one of the first studies to evaluate the cost-effectiveness of a POCT biomarker to guide clinical decision-making in primary care on patient-reported outcomes, antibiotic prescribing and antibiotic resistance for AECOPD.Trial registrationISRCTN registry, ID: ISRCTN24346473. Registered on 20 August 2014.

Illness perception and related behaviour in lower respiratory tract infections-a European study

Background. Lower respiratory tract infection (LRTI) is a common presentation in primary care, but little is known about associated patients’ illness perception and related behaviour. Objective. To describe illness perceptions and related behaviour in patients with LRTI visiting their general practitioner (GP) and identify differences between European regions and types of health care system. Methods. Adult patients presenting with acute cough were included. GPs recorded co morbidities and clinical findings. Patients filled out a diary for up to 4 weeks on their symptoms, illness perception and related behaviour. The chi-square test was used to compare proportions between groups and the Mann-Whitney U or Kruskal Wallis tests were used to compare means. Results. Three thousand one hundred six patients from 12 European countries were included. Eighty-one per cent (n = 2530) of the patients completed the diary. Patients were feeling unwell for a mean of 9 (SD 8) days prior to consulting. More than half experienced impairment of normal or social activities for at least 1 week and were absent from work/school for a mean of 4 (SD 5) days. On average patients felt recovered 2 weeks after visiting their GP, but 21% (n = 539) of the patients did not feel recovered after 4 weeks. Twenty-seven per cent (n = 691) reported feeling anxious or depressed, and 28% (n = 702) re-consulted their GP at some point during the illness episode. Reported illness duration and days absent from work/school differed between countries and regions (North-West versus South-East), but there was little difference in reported illness course and related behaviour between health care systems (direct access versus gate-keeping). Conclusion. Illness course, perception and related behaviour in LRTI differ considerably between countries. These finding should be taken into account when developing International guidelines for LRTI and interventions for setting realistic expectations about illness course.

Measurement of side effects of anti-epileptic drugs (AEDs) in adults with intellectual disability: A systematic review

The prevalence of epilepsy in adults with an intellectual disability (ID) is up to 20 times greater than in the general population [1]. A recent survey of carers and professionals showed considerable concern over presence and impact of side effects from anti-epileptic drug (AED) treatment in people with ID (in particular drowsiness, memory problems, depression) [2]. The term side effect typically relates to any secondary undesirable effect of a treatment or drug. Physical, cognitive, behavioural or emotional side effects can cause significant impact on the quality of life of an individual. Monitoring side effects in adults with ID and epilepsy is challenging due to the commonly co-existing occurrence of behaviour and communication disorders [3]. The incidence of side effects is estimated to be as high as 58% in the wider population receiving treatment (i.e. adults with epilepsy without ID) [4]. Javed noted that patients with ID were less likely to report side effects than patients without ID, especially in regard to cognitive adverse events [5]. A recent Cochrane review concluded that side effects in the ID population are similar to the general