The Minimal Clinically Important Difference in Allergen Immunotherapy: An Evidence-Based Approach

Oliver Pfaar, Section of Rhinology and Allergy, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany.
Ralph Mösges, IMSB, Medical Faculty University at Cologne, Cologne, Germany.
Michael S. Blaiss, Division of Allergy and Immunology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Sven Becker, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of Eberhard-Karls University Tuebingen, Tuebingen, Germany.
Lawrence DuBuske, George Washington University Hospital, Washington, District of Columbia, USA.
Jonathan A. Bernstein, Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Uwe E. Berger, Department of Botany, University of Innsbruck, Innsbruck, Austria.
Markus Berger, Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Klinik Landstraße, Wiener Gesundheitsverbund, Vienna, Austria.
Stephanie Dramburg, Department of Pediatric Respiratory Care, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Mohamed H. Shamji, National Heart and Lung Institute, Imperial College London, London, UK.
Anke Graessel, Bencard Allergie GmbH, Munich, Germany.
Sviatlana Starchenka, Allergy Therapeutics, Worthing, UK.
Katrin Birkholz, Bencard Allergie GmbH, Munich, Germany.
Oliver Armfield, Allergy Therapeutics, Worthing, UK.
Fiona Sellwood, Allergy Therapeutics, Worthing, UK.
Matthias F. Kramer, Bencard Allergie GmbH, Munich, Germany.
Murray A. Skinner, Allergy Therapeutics, Worthing, UK.
Pieter-Jan de Kam, Allergy Therapeutics, Worthing, UK.

Document Type

Journal Article

Publication Date

7-18-2025

Journal

Allergy

DOI

10.1111/all.16654

Keywords

EAACI CSMS0–6; allergic rhinoconjunctivitis; grass pollen allergy; pivotal phase III clinical trial; subcutaneous immunotherapy

Abstract

BACKGROUND: Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well-justified minimal clinically important difference (MCID). METHODS: Direct patient feedback from 1071 grass-allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS. Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). RESULTS: 69% of grass-allergic patients were satisfied with a 1-point-improvement (e.g., from "severe" to "moderate") in their most severe symptom. This translated into an MCID range for CSMS of -0.23 to -0.21 points or -17% to -16%. Furthermore, a -0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS of -0.21 points (-16%) was derived using RESONATE. CONCLUSIONS: Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS scale and -16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

Department

Medicine

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