Available online 11 April 2024

Author links open overlay panelRemy S. Petersen M.D. 1, Lauré M. Fijen M.D., Ph.D 1, Christian Apfelbacher Ph.D. 2, Markus Magerl M.D. 3 4, Karsten Weller M.D. 3 4, Werner Aberer M.D. 5, Adil Adatia M.D. 6, Paul Audhya M.D., MBA 7, Noémi-Anna Bara M.D., Ph.D. 8, Stephen Betschel M.D. 9, Isabelle Boccon-Gibod M.D. 10, Laurence Bouillet M.D., Ph.D. 10 11, Nicholas Brodszki M.D., Ph.D. 12, Paula J. Busse M.D. 13, Thomas Buttgereit M.D. 3 4, Anette Bygum M.D., DMSci 14, Mauro Cancian M.D., Ph.D. 15, Timothy Craig D.O, Ph.D. 16, Dorottya Csuka Ph.D. 17, Henriette Farkas M.D., PhD., DSc 17…Danny M. Cohn M.D., Ph.D. 1Show moreAbstractBackground

Clinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits 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 comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks.

Methods

A Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, 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

Fifty-eight 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% 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, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction.

Conclusion

This international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

Key words

Acute treatment

consensus

core outcome set

Delphi

hereditary angioedema

randomized controlled trial

outcome

Recommended articles

Conflict of interest

Remy S. Petersen has received speaking fees from Pharvaris and Astria.

Lauré M. Fijen has received a conference travel grant from Ionis Pharmaceuticals, Inc. and has acted as a consultant for Pharvaris in the past.

Christian Apfelbacher has received institutional funding from the Dr Wolff Group and Bionorica , and consultancy fees from the Dr Wolff Group, Sanofi, Bionorica, Rheacell and LEO Pharma.

Markus Magerl has received personal fees from CSL Behring, Takeda-Shire, Pharming, BioCryst, Novartis, Octapharma, and KalVista.

Karsten Weller has received research grant support and/or honoraria for educational lectures or consulting from BioCryst, CSL Behring, Moxie, Novartis, Pharvaris, and Takeda.

Werner Aberer has received speaking fees from BioCryst, CSL Behring and Takeda.

Adil Adatia has received speaker/advisor fees, travel support, and/or research funding from Astria, Biocryst, Covis Pharma, CSL Behring, Ionis Pharmaceuticals, and Takeda.

Paul Audhya is an employee of KalVista and a shareholder of KalVista Pharmaceuticals Inc.

Noémi-Anna Bara has received grants, consulting fees, payments, honoraria for lecturers and presentations from CSL Behring, Shire/Takeda, Pharming, BioCryst, and Kalvista.

Stephen Betschel has received speaker/advisor fees and/or research funding from Astria, Canadian Blood Services, CSL Behring, Grifols, Ionis Pharmaceuticals, Kalvista Novartis, Octapharma, Pharvaris, Sanofi, Takeda.

Isabelle Boccon-Gibod has consulted/ served as speaker for, engaged in research and educational projects with or accepted travel grants from Biocryst, Takeda, CSL Behring, Biomarin, Kalvista, Pharvaris.

Laurence Bouillet has consulted/ served as speaker for, engaged in research and educational projects with or accepted travel grants from BioCryst, CSL Behring, Takeda, Novartis, GSK, and Blueprint.

Nicholas Brodszki has received speaker/consultancy fees from BioCryst, CSL Behring, and Shire-Takeda.

Paula J. Busse has received grant research support from Takeda, CSL Behring, Kalvista and consulting support from Takeda, CSL Behring, Kalvista, Biomarin, Pharvaris, Novartis, Astria, CVS/Caremark, and ADARx.

Thomas Buttgereit is or recently was a speaker and/or advisor for Astra- Zeneca, BioCryst, CSL-Behring, GlaxoSmithKline (GSK), Hexal, KalVista, Medac, Novartis, Pharming, Roche, Sanofi, and Takeda, outside the submitted work.

Anette Bygum has received consulting fees from Biocryst, CSL Behring, and Takeda.

Mauro Cancian has received grand research support and/or speaker/consultancy fees from BioCryst, CSL Behring, Kalvista, Pharming, Shire-Takeda, and SOBI; Clinical trial/registry investigator for BioCryst, CSL Behring, Ionis, Kalvista, Novartis, Pharming, Pharvaris, Shire-Takeda, and UCB.

Timothy Craig is a speaker for, CSL Behring, Takeda, and Grifols; has received research and or consultancy fees from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, , Kalvista, Pharvaris, Astria, and Intellia; and is on the Medical Advisory Board for the US Hereditary Angioedema Association, and Director of ACARE Angioedema Center at Penn State University, Hershey.

Dorottya Csuka has no conflicts of interest.

Henriette Farkas has received research grants from CSL Behring, Takeda, and Pharming and served as an advisor for these companies and Kalvista, ONO Pharmaceutical, Pharvaris, Astria and Biocryst.

Daria Fomina has consulted/ served as speaker for, engaged in research and educational projects with or accepted travel grants from CSL Behring, Takeda, Novartis, Astra Zeneca, Sanofi/Regeneron and Sobi.

Johana Gil-Serrano has no conflicts of interest.

Mark Gompels has received support from pharmaceutical industry to attend conferences. Previous advisory boards none related in last 2 years. Principal Investigator local for Pharvaris and Ionis trials.

Guillermo Guidos Fogelbach has no conflicts of interest.

Mar Guilarte has received honoraria for educational purposes from CSL Behring, Pharming, and Takeda; has served as advisor for Biocryst, Biomarin, CSL Behring, Kalvista, Pharvaris, and Takeda; is/has been a clinical trial/registry investigator for Biomarin, BioCryst, CSL Behring, Ionis, Kalvista, Pharming, Pharvaris, and Takeda; and is a researcher from the VHIR program for promoting research activities.

Michihiro Hide has received honoraria from CSL Behring, Takeda, and Torii Pharmaceutical; and consulting fees from BioCryst, KalVista, and Pharvaris.

Sorena Kiani-Alikhan has received honorarium for consultation and talks sponsored by Takeda, BioCryst, KalVista, Pharming.

Tamar Kinaciyan is or recently was a speaker and/or advisor for and/or has received research funding from Biocryst, CSL Behring, KalVista, Kiniksa, Novartis, Pharvaris, Sanofi/Regeneron and Takeda.

Annet Lenten is an employee of Takeda.

Ramon lleonart has received honoraria from BioCryst, CSL Behring, KalVista, Novartis, and Takeda; he has received funding to attend conferences and educational events from CSL Behring, Novartis, Pharming, and Takeda and is a clinical trial/registry investigator for BioCryst, CSL Behring, Novartis, Pharvaris, KalVista, and Takeda.

Hilary Longhurst has participated in clinical trials with/acted as advisor or speaker for BioCryst, CSL Behring, Intellia, Kalvista, Pharming, Pharvaris, and Takeda.

William R. Lumry has received consulting fees from Astria, BioCryst, Biomarin, CSL Behring, Express Scripts/CVS, Fresenius Kabi, Intellia, Kalvista, Magellan, Optum, Pharming, Pharvaris, Shire/Takeda, speaking fees from BioCryst, CSL Behring, Optinose, Pharming, Shire/Takeda, Grifols, Astra Zeneca, Sanofi/Regeneron, GSK, has received grands/research support from BioMarin, CSL Behring, Grifols, Ionis, Kalvista, Shire/Takeda, Teva and is a board member on US Hereditary Angioedema Association Medical Advisory Board.

Alejandro Malbran has no conflicts of interest.

Laura Malinauskiene has received speaking and consulting fees, participated in Clinical Research from Takeda and Pharming.

Juan J. Matta Campos has no conflicts of interest.

Joan Mendivil is a full-time employee of Pharvaris GmbH and has stock from this company.

Sandra A. Nieto-Martinez has received speaking fees from CSL Behring, Takeda and Pint Pharma.

Jonathan G. Peter has received travel support from Pharming and Takeda, and educational grants from Takeda.

Grzegorz Porebski has received speaking fees and/or consultancy fees and/or travel support from CSL Behring, Takeda, and BioCryst.

Avner Reshef has received consulting fees from BioCryst, CSL Behring, Pharming, speaking fees from BioCryst, CSL Behring, and has received grands/research support from CSL Behring, Ionis, Shire/Takeda, Pharvaris and Shulov.

Marc Riedl has received research support from Biocryst, Biomarin, CSL Behring, Ionis, Kalvista, Pharvaris, Takeda Consulting: Astria, Biocryst, Biomarin, CSL Behring, Cycle Pharma, Grifols, Intellia, Ipsen, Kalvista, Ono Pharma, Pfizer, Pharming, Pharvaris, RegenexBio, Sanofi-Regeneron, Spark, Takeda, and speaking fees from Grifols, Pharming, Takeda.

Anna Valerieva has served as a Speaker/Consultant and/or received Honoraria/Meeting sponsorship and/or participated in Clinical Research: Ionis Pharmaceuticals, Pharming Group NV, Takeda/Shire, Sobi, CSL Behring, Pharvaris, and KalVista Pharmaceuticals.

Susan Waserman has served as Speaker/Consultant and has received honoraria and consultancy fees from Takeda, and CSL Behring, KalVista, and BioCryst.

Marcus Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Astria, BioCryst, Centogene, CSL Behring, Ipsen, Kalvista, Pharvaris, and Takeda.

Danny M Cohn has received speaking fees from CSL, Ionis pharmaceuticals, Pharvaris, Takeda, consultancy fees from Astria, BioCryst, CSL Behring, Ionis Pharmaceuticals inc., KalVista, Pharming, Pharvaris, Takeda, and research support from Ionis parmaceuticals, KalVista, Pharvaris, and Takeda

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Highlights:

1. What is already known about this topic?

Clinical trials investigating acute treatment of hereditary angioedema attacks have used a large variety of outcomes to assess efficacy, limiting comparability of trial results.

2. What does this article add to our knowledge?

A panel consisting of hereditary angioedema patients, expert clinicians and researchers, pharmaceutical companies and a regulatory body agreed on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

3. How does this study impact current management guidelines?

The development, endorsement, and adoption of this Core Outcome Set by participating stakeholders will provide a standardized framework for trial outcomes, facilitating more meaningful comparisons and interpretations of future study results.

Abbreviations: COMET; Core Outcome Measures in Effectiveness Trials, COS; Core Outcome Set, COS-STAD; Core Outcome Set – STAndards for Development, COS-STAR; Core Outcome Set – STAndards for Reporting, EMA; European Medicines Agency, FDA; Food and Drug Administration, HAE; Hereditary Angioedema, HAEi; HAE international, PROM; Patient-reported outcome measure

© 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

Recommended articlesArticle Metrics