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

Abstract

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). 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_0-6. 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_0-6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). 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_0-6 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_0-6 of -0.21 points (-16%) was derived using RESONATE. Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS_0-6 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.