Helen Nankervis

Towards global consensus on outcome measures for atopic eczema research: results of the HOME II meeting

The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence‐based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence‐based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long‐term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research.

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME)

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6–7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient‐reported symptoms, long‐term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long‐term control is needed before progress can be made towards recommending a core outcome measure.

A systematic review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many options, no standards

BACKGROUND Investigators often use global assessments to provide a snapshot of overall disease severity in dermatologic clinical trials. Although easy to perform, the frequency of use and standardization of global assessments in studies of atopic dermatitis (AD) is unclear. OBJECTIVES We sought to assess the frequency, definitions, and methods of analysis of Investigator Global Assessment in randomized controlled trials of AD. METHODS We conducted a systematic review using all published randomized controlled trials of AD treatments in the Global Resource of Eczema Trials database (2000-2014). We determined the frequency of global scales application and defining features. RESULTS Among 317 trials identified, 101 trials (32%) used an investigator-performed global assessment as an outcome measure. There was large variability in global assessments between studies in nomenclature, scale size, definitions, outcome description, and analysis. Both static and dynamic scales were identified that ranged from 4- to 7-point scales. North American studies used global assessments more commonly than studies from other countries. LIMITATIONS The search was restricted to the Global Resource of Eczema Trials database. CONCLUSION Global assessments are used frequently in studies of AD, but their complete lack of standardized definitions and implementation preclude any meaningful comparisons between studies, which in turn impedes data synthesis to inform clinical decision-making. Standardization is urgently required.

Prospective Registration and Outcome-Reporting Bias in Randomized Controlled Trials of Eczema Treatments: A Systematic Review

We assessed completeness of trial registration and the extent of outcome-reporting bias in published randomized controlled trials (RCTs) of eczema (atopic dermatitis) treatments by surveying all relevant RCTs published from January 2007 to July 2011 located in a database called the Global Resource of Eczema Trials (GREAT). The GREAT database is compiled by searching six bibliographic databases, including EMBASE and MEDLINE. Out of 109 identified RCTs, only 37 (34%) had been registered on an approved trial register. Only 18 out of 109 trials (17%) had been registered “properly” in terms of submitting the registration before the trial end date and nominating a primary outcome. The proportion of “any registered” and “properly registered” RCTs increased from 19% and 10% in 2007 to 57% and 36% in 2011, respectively. Assessment of selective outcome-reporting bias was difficult even among the properly registered trials owing to unclear primary outcome description especially with regard to timing. Only 5 out of the 109 trials (5%) provided enough information for us to be confident that the outcomes reported in the published trial were consistent with the original registration. Adequate trial registration and description of primary outcomes for eczema RCTs is currently poor.

Evaluation of the measurement properties of symptom measurement instruments for atopic eczema: A systematic review

Symptoms have been identified as a core outcome domain for atopic eczema (AE) trials. Various instruments exist to measure symptoms in AE, but they vary in quality and there is a lack of standardization between clinical trials. Our objective was to systematically evaluate the quality of the evidence on the measurement properties of AE symptom instruments, thereby informing consensus discussions within the Harmonising Outcome Measures for Eczema (HOME) initiative regarding the most appropriate instruments for the core outcome domain symptoms.

What is the evidence-base for atopic eczema treatments? A summary of published randomised controlled trials

Atopic eczema (AE) is a common chronic inflammatory skin condition. While many AE treatment options are available, the evidence to support their efficacy varies in depth and quality. In 2000, a National Institute for Health Research (NIHR) Health Technology Assessment systematic review identified and evaluated existing randomized controlled trials (RCTs) of AE treatments. To ensure continuing utility, the NIHR commissioned an update to the review. Here, we present an overview of the updated report and its key findings. Systematic reviews and RCTs of AE treatments that included participants with AE (criteria based or diagnosed) were identified using Medline, Embase, CENTRAL, Latin American and Caribbean Health Sciences, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Cochrane Skin Group Specialised Register [searched to 31 August 2013 (RCTs) and 31 December 2015 (systematic reviews)]. Outcome measures included symptoms, AE severity, quality of life and adverse effects. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Of the 287 new RCTs identified, only 22 (8%) were judged to have a low risk of bias. When combined with RCTs from the previous review (n = 254), we found ‘reasonable evidence of benefit’ for corticosteroids, calcineurin inhibitors, Atopiclair®, ciclosporin, azathioprine, ultraviolet radiation and education programmes. Interventions with reasonable evidence of ‘no benefit’ included some dietary interventions, ion exchange water softeners, multiple daily applications of topical corticosteroids and antibiotic‐containing corticosteroids for noninfected AE. Many common treatments lack evidence of efficacy and warrant further evaluation. The evidence base for AE is still hampered by poor trial design and reporting. The trials included in this review were used to establish the Global Resource of EczemA Trials (GREAT) database.

Specific allergen immunotherapy for the treatment of atopic eczema: a Cochrane systematic review

Specific allergen immunotherapy (SIT) is an effective allergy treatment, but it is unclear whether SIT is effective for atopic eczema (AE). We undertook a systematic review to assess SIT efficacy and safety for treating AE.

Reporting of symptoms in randomized controlled trials of atopic eczema treatments: a systematic review.

‘Symptoms’ is a core outcome domain for atopic eczema (AE) trials, agreed by consensus as part of the Harmonising Outcome Measures for Eczema (HOME) initiative. To standardize and validate the core domain symptoms and symptom instruments for AE trials the HOME roadmap is followed. Its first step is to establish if and how symptoms have been measured in published AE treatment trials. Therefore the Global Resource for Eczema Trials database was used to collect all randomized controlled trials (RCTs) of treatments for AE between January 2000 and April 2014. Study selection and data extraction were performed by three reviewers independently. We identified the use of symptoms in 295 of 378 trials (78%). Symptoms as a primary end point were applied by 147 RCTs (50%). Seventeen different symptoms were measured, but mostly itch and sleep loss. Symptoms were assessed by only 37% of trials by a stand‐alone symptom measurement. Overall 63% of RCTs used a composite instrument, and 30 different instruments were identified. The Scoring Atopic Dermatitis (SCORAD) index was the most commonly applied, but only 23% of RCTs reported the SCORAD symptom score separately. This systematic review demonstrates that symptoms, most frequently itch and sleep loss, are commonly reported in AE treatment trials, but are measured using many different instruments. Often symptoms are evaluated as part of a composite instrument, and currently it is not possible to extract symptoms‐only data from most published studies. Future trials should report symptom scores to permit meta‐analysis of the core outcomes.

Validation of the global resource of eczema trials (GREAT database)

BackgroundEczema (syn. Atopic Eczema or Atopic Dermatitis) is a chronic, relapsing, itchy skin condition which probably results from a combination of genetic and environmental factors. The Global Resource of EczemA Trials (GREAT) is a collection of records of randomised controlled trials (RCTs) for eczema treatment produced from a highly sensitive search of six reference databases. We sought to assess the sensitivity of the GREAT database as a tool to save future researchers repeating extensive bibliographic searches.MethodsAll Cochrane systematic review on treatments for eczema and five non-Cochrane systematic reviews on eczema were identified as a reference set to assess the utility of the GREAT database in identifying randomised controlled trials (RCTs). RCTs included in the systematic reviews were checked for inclusion in the GREAT database by two independent authors. A third author resolved any disagreements.ResultsFive Cochrane and six non-Cochrane systematic reviews containing a total of 105 RCTs of eczema treatments were included. Of these, 95 fitted the inclusion criteria for the GREAT database and 88 were published from 2000 onwards. Of the 88 eligible studies, 92% were found in the GREAT database. Seven trials were not included in the GREAT database - two of these were reported within a review paper and one as an abstract with no trial results.ConclusionsThe sensitivity of the GREAT database for trials from 2000 onwards was high (75/88 trials, 94%). Sensitivity for the period prior to 2000 was less sensitive, due to differences in how the trials were identified prior to this time.‘Dual’ filtering for new records has recently become part of the GREAT database methodology and should further improve the sensitivity of the database in time. The GREAT database can be considered as a primary source for future systematic reviews including randomised controlled trials of eczema treatments, but searches should be supplemented by checking reference lists for eligible trials, searching trial registries and contacting pharmaceutical companies for unpublished studies.

How Clinically Relevant Are Treatment Comparisons of Topical Calcineurin Inhibitor Trials for Atopic Eczema

We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.