A core domain set for pyoderma gangrenosum trial outcomes: an international eDelphi and consensus study from the UPGRADE initiative.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 16-Week Trial to Evaluate the Efficacy and Safety of FB-401 in Children, Adolescents, and Adult Subjects (Ages 2 Years and Older) with Mild-to-Moderate Atopic Dermatitis.

BACKGROUND: Atopic dermatitis is a common chronic, relapsing, and remitting inflammatory skin disorder associated with cutaneous dysbiosis. Current treatment options often fail to adequately control the disease and have unfavorable safety profiles. There is a need for new options that address these treatment shortcomings. OBJECTIVE: The aim of the study was to evaluate the efficacy, safety, and tolerability of FB-401, a live therapeutic product of 3 strains of Roseomonas mucosa, compared to matching placebo applied topically 3 times per week to participants ages ≥2 years of age with mild-to-moderate atopic dermatitis. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. The primary outcome was the proportion of participants with 50% improvement in Eczema Area and Severity Index score from baseline at week 16. 154 subjects aged 2 or older with a clinical diagnosis of atopic dermatitis as defined by Hanifin and Rajka criteria with mild or moderate severity were randomized 1:1 via interactive web response system to FB-401 or placebo. RESULTS: The proportion of subjects who achieved the primary outcome was similar between both treatment groups, with no significant treatment group differences observed at any post-baseline visit. The number of treatment-emergent adverse events and the number of subjects with at least one were similar across treatment groups. One serious adverse event not related to treatment was reported. No treatment-emergent adverse events led to treatment discontinuation or study discontinuation. CONCLUSIONS: FB-401 showed an acceptable safety profile but failed to prove superior to placebo in treating children and adults with mild-to-moderate atopic dermatitis.

How to use the Harmonising Outcome Measures for Eczema Core Outcome Set for atopic dermatitis trials: a users' guide.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has agreed upon the Core Outcome Set (COS) for use in atopic dermatitis (AD) clinical trials, but additional guidance is needed to maximize its uptake. OBJECTIVES: To provide answers to some of the commonly asked questions about using the HOME COS; to provide data to help with the interpretation of trial results; and to support sample size calculations for future trials. METHODS AND RESULTS: We provide practical guidance on the use of the HOME COS for investigators planning clinical trials in patients with AD. It answers some of the common questions about using the HOME COS, how to access the outcome measurement instruments, what training/resources are needed to use them appropriately and clarifies when the COS is applicable. We also provide exemplar data to inform sample size calculations for eczema trials and encourage standardized data collection and reporting of the COS. CONCLUSIONS: By encouraging adoption of the COS and facilitating consistent reporting of outcome data, it is hoped that the results of eczema trials will be more comprehensive and readily combined in meta-analyses and that patient care will subsequently be improved.

Minimum data set for treatment effectiveness in pyoderma gangrenosum (MIDSTEP): an international protocol of an e-Delphi study to develop a clinical physician-driven treatment effectiveness registry on behalf of the UPGRADE initiative.

Pyoderma gangrenosum (PG) is a rare inflammatory condition with an immense disease burden that remains understudied. With limited approved treatments and low-quality clinical evidence, PG continues to have poor patient outcomes. Unfortunately, improvement in PG treatments and patient care is based on additional research endeavors that can only be developed from existing high-quality data. The following protocol outlines the development of the Minimum Data Set for Treatment Effectiveness in Pyoderma gangrenosum (MIDSTEP), a core set of domains and domain items for the Pyoderma Gangrenosum Treatment Effectiveness (PyGaTE) international registry. The outcomes and benefits are focused on providing real-world data for physicians to improve their clinical decisions on PG treatment and inform clinical trial design, promoting clinical research among the international scientific community. MIDSTEP is a multi-phase project. The first phase will produce a domain item list from a literature review to take into the second phase which would finalize the core data set by an e-Delphi exercise. There will be a single stakeholder group participating together in the e-Delphi consisting of PG experts (healthcare providers, researchers, methodologists, industry representatives, and regulators), ulcerative PG patients, and PG patient advocates. The methodology outlined in the protocol is a systematic method based on several guidelines through COMET and established dermatologic registries and outcome sets with systematic methodologies of their own. The third phase will identify the instruments for the items, the 'when to measure' the items, and the platform for the registry. The last phase is the implementation and continued maintenance of the international registry PyGaTE. By solidifying a consensus on standardized outcomes and collecting information on PG treatment effectiveness in a centralized database, existing treatments can be compared more systematically and analyzed with increased evidence. MIDSTEP and the PyGaTE international registry will have the ambitious goal to generate and disseminate real-world data that can be used by all stakeholders to improve health outcomes for PG patients. Future potential for the outcome of this project includes the development of a gold-standard PG treatment.

The Harmonising Outcome Measures for Eczema (HOME) implementation roadmap.

BACKGROUND: Core outcome sets (COS) are consensus-driven sets of minimum outcomes that should be measured and reported in all clinical trials. COS aim to reduce heterogeneity in outcome measurement and reporting, and selective outcome reporting. Implementing COS into clinical trials is challenging. Guidance to improve COS uptake in dermatology is lacking. OBJECTIVES: To develop a structured practical guide to COS implementation. METHODS: Members of the Harmonising Outcome Measurement for Eczema (HOME) executive committee developed an expert opinion-based roadmap founded on a combination of a review of the COS implementation literature, the Core Outcome Measures in Effectiveness Trials (COMET) initiative resources, input from HOME members and experience in COS development and clinical trials. RESULTS: The data review and input from HOME members was synthesized into themes, which guided roadmap development: (a) barriers and facilitators to COS uptake based on stakeholder awareness/engagement and COS features; and (b) key implementation science principles (assessment-driven, data-centred, priority-based and context-sensitive). The HOME implementation roadmap follows three stages. Firstly, the COS uptake scope and goals need to be defined. Secondly, during COS development, preparation for future implementation is supported by establishing the COS as a credible evidence-informed consensus by applying robust COS development methodology, engaging multiple stakeholders, fostering sustained and global engagement, emphasizing COS ease of use and universal applicability, and providing recommendations on COS use. Thirdly, incorporating completed COS into primary (trials) and secondary (reviews) research is an iterative process starting with mapping COS uptake and stakeholders' attitudes, followed by designing and carrying out targeted implementation projects. Main themes for implementation projects identified at HOME are stakeholder awareness/engagement; universal applicability for different populations; and improving ease-of-use by reducing administrative and study burden. Formal implementation frameworks can be used to identify implementation barriers/facilitators and to design implementation strategies. The effect of these strategies on uptake should be evaluated and implementation plans adjusted accordingly. CONCLUSIONS: COS can improve the quality and applicability of research and, so, clinical practice but can only succeed if used and reported consistently. The HOME implementation roadmap is an extension of the original HOME roadmap for COS development and provides a pragmatic framework to develop COS implementation strategies.

Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome.

Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editasewt) and either Mecp2-targeting or nontargeting gfp RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the Mecp2-targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the Mecp2-targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control gfp guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editasewt. Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.