Background
Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants.
Objective
To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks.
Methods
We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2.
Results
A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction.
Conclusions
This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.
To develop a COS for acute treatment outcomes in hereditary angioedema
ContributorsRemy Petersen, MD
Lauré Fijen, MD
Dr. Karsten Weller
Prof. Markus Magerl
Dr. Danny Cohn
Henrik Balle Boysen
Anthony Castaldo
Prof. Marcus Maurer
Prof. Christian Apfelbacher
Disease Category: Other
Disease Name: Hereditary Angioedema
Age Range: 0
Sex: Either
Nature of Intervention: Drug
- Clinical experts
- Conference participants
- Consumers (patients)
- Epidemiologists
- Patient/ support group representatives
- Pharmaceutical industry representatives
- Regulatory agency representatives
- Researchers
- Service providers
- Service users
- COS for clinical trials or clinical research
- Delphi process
- Systematic review
(Protocol change made 3-4-2023, after round 1 of the Delphi opened on 1-2-2023)
Methods
We will undertake a consensus study in accordance with the Core Outcome Set – STAndards for Development (COS-STAD) and Core Outcome Set – STAndards for Reporting (COS-STAR) guidelines.(8, 9) The protocol will be registered in the COMET database.
A steering group will oversee the development of the core outcome set and consists of the project lead (an academic hereditary angioedema researcher with clinical hereditary angioedema experience), 5 additional researchers and clinicians, a methodologist and two HAE patients. All members will be authors on the reporting article.
The Delphi panel will consist of all stakeholder groups, which are hereditary angioedema patients (approximately 10 patients, approached via the international hereditary angioedema patient association), hereditary angioedema clinician and clinical researchers (all authors on the current guideline will be approached), and representatives of the pharmaceutical industry (one representative per pharmaceutical company with a compound for on demand treatment of hereditary angioedema). We anticipate having at least 20 individuals with representation from each of these groupings will adequately cover issues in the proposed outcome set. They will complete a web-based survey with 2 rounds. Only panellists responding to the first round will be included in the second round. Panel members will be approached with detailed information inviting them to participate in the study and to return signed consent sheets. See table 1 for the planned timeline.
For the first round of the survey, panel members will receive a link (via e-mail) to a questionnaire using Welphi. The aims of the study will be explained to the panel members in the email. They will be presented with all outcomes that have been identified in a related systematic review.(5) Where appropriate additional information in terms of use will be given, but the focus of this Delphi process is outcomes, not outcome measures. Panellists will be asked to indicate their level of agreement on whether each outcome should be included in the core set using a 9-point Likert scale (1-3 = limited importance, 4-6 = important but not critical, 7-9 = critical, and unable to score for stakeholders lacking the required expertise) and will be asked to provide comments as necessary. Using this scale, the median response and the interquartile range will be calculated. An upper quartile ranking of 3 indicates general disagreement and the outcome will be rejected, except when the median response within the stakeholder group consisting of patients is 7 or higher. In that case, the outcome will be modified based on panel feedback and will be included in the second round of the survey. A lower quartile of 7 will indicate general agreement and the outcome will be adopted. Outcomes with
interquartile ranges that include 4-6 will be modified based on panel feedback and will be included in the second round of the survey. Panellists will also be invited to contribute new outcomes during the first round of the process, which will be included in the second round if at least two of the panel members have suggested this new outcome. The first round will be open for 4 weeks. If a low response would lead to attrition rates of >20%, this period will be prolonged. All panellists who participated in both rounds will be named as authors on the reporting article, provided that they also review the reporting article and provide feedback. Non-responders will receive personalised reminder emails or telephone calls to lower the attrition rates.
The second round of the survey will use the same approach. Panellists will be informed of the previous round scores and feedback per stakeholder group. Outcomes reaching the prespecified consensus level will be advised to be included in the core outcome set. Consensus will be defined as >75% of all panellists scored 7-9 on 9-point Likert scale. Alternatively, if the first round yields a high degree of consensus regarding many outcomes, the steering committee may decide to suggest a core outcome set based on the results of the first round. In that case, panellist will be asked to indicate if they agree or disagree with the inclusion of each individual key outcomes in the core outcome set and with the core outcome set as a whole. Consensus will be defined as >75% of all panellists indicating to agree with the inclusion of the selected key outcome or the core outcome set as a whole. The steering committee will discuss the advice with key stakeholders and may decide to have an extra voting moment for the agreement on the definite COS.
All statistical analyses will be performed with RStudio.(10)
References
1. Lumry WR, Settipane RA. Hereditary angioedema: Epidemiology and burden of disease. Allergy and asthma proceedings. 2020;41(Suppl 1):S08-s13.
2. Fijen LM, Bork K, Cohn DM. Current and Prospective Targets of Pharmacologic Treatment of Hereditary Angioedema Types 1 and 2. Clin Rev Allergy Immunol. 2021.
3. Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy. 2018;73(8):1575-96.
4. Caballero T. Efficacy assessments in randomized controlled studies of acute therapy for hereditary angioedema. J Clin Immunol. 2012;32(6):1204-12.
5. Fijen LM, Petersen RS, Cohn DM. Outcome measures in randomized controlled studies of acute therapy for hereditary angioedema: A systematic review. Allergy. 2022.
6. Heneghan C, Goldacre B, Mahtani KR. Why clinical trial outcomes fail to translate into benefits for patients. Trials. 2017;18(1):122.
7. Williamson PR, Altman DG, Bagley H, Barnes KL, Blazeby JM, Brookes ST, et al. The COMET Handbook: version 1.0. Trials. 2017;18(Suppl 3):280.
8. Kirkham JJ, Davis K, Altman DG, Blazeby JM, Clarke M, Tunis S, et al. Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLoS Med. 2017;14(11):e1002447.
9. Kirkham JJ, Gorst S, Altman DG, Blazeby JM, Clarke M, Devane D, et al. Core Outcome Set-STAndards for Reporting: The COS-STAR Statement. PLoS Med. 2016;13(10):e1002148.
10. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2020.