Patient Feedback Helps Define Success Threshold for Grass Allergy Trials

A study using patient feedback and RESONATE data suggests that a phase 3 allergen immunotherapy trial should show at least a -0.22-point reduction on the Combined Symptom and Medication Score (CSMS or the CSM0-6) scale and a 16% improvement on the composite primary endpoint to be considered successful.1

“An interesting additional finding is that this is the first time that a relative MCID for CSMS0–6 ranging from approximately −17% to −15% has been verified based on two independent methods (i.e., a patient survey and a data analysis approach,” wrote investigators, led by Oliver Pfaar, MD, from the department of otorhinolaryngology, head and neck surgery at the University Hospital Marburg, Philipps-Universität Marburg, in Germany.1

Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as the primary endpoint for phase 3 allergen immunotherapy trials targeting allergic rhinoconjunctivitis. Like many European regulatory authorities, the European Academy of Allergy and Clinical Immunology (EAACI) proposed the CSM0-6 as the primary endpoint of these trials.

Although many composite primary endpoint scales exist, none are validated. They also do not have a justified minimal clinically important difference (MCID). Trials have proposed an MCID to be either a 2-point improvement in a single allergy symptom (i.e., “moderate” to “none” or “severe” to “mild”) or a 1-point improvement (“moderate” to “mild” or “severe” to “moderate”

To investigators’ surprise, no patient surveys were published to validate these MCID definitions against actual patient populations. The team conducted a survey on 1071 patients with moderate to severe grass allergies to validate and determine MCID thresholds for phase 3 allergen immunotherapy trials. They also analyzed data from RESONATE, a phase 3 trial of Pollinex Quattro Grass (27600 SU cumulative dose), which measured a combined score and medication score as its primary endpoints.2

More than half of patients with a grass allergy (69%) were satisfied with a 1-point improvement in their most severe symptom. The analysis showed that an MCID for the CSM0-6 scale between -0.23 to -0.21 points, or -17% to -16%, can be justified as a threshold.1

Few participants (14.8%) considered a ≥ 2-point improvement in the single most severe symptom or ≥ 1 point improvement in each of the 2 most severe symptoms clinically important for a grass allergy product.

Phase 3 trials on registered SLIT grass tablets established that a -0.34-point improvement in the Rhinitis Quality of Life Questionnaire compared to placebo is clinically meaningful. Using this as a benchmark, the RESONATE study determined that a -0.21-point (16%) reduction in CSM0-6 score represents a meaningful improvement.1

The study found participants had significantly improved combined symptom and medication scores at peak grass pollen season and across the whole season. Eye symptoms improved the most (P < .0001), followed by nasal symptoms and daily activity limitations.

Investigators highlighted several limitations, including the fact that the MCID for CSM0-6 score may depend on the type of respiratory allergen causing the allergic rhinitis or conjunctivitis. Additionally, the study only uses the symptom component of the composite CSM0-6 score, which assumes no change in medication use.

“In conclusion, a patient-centric approach was applied to establish the MCID for the EAACI recommended CSMS0-6, which is generally accepted as the primary endpoint for pivotal Phase III AIT clinical trials,” investigators concluded.1 “These results revealed that an approximately 1-point improvement on the single most severe symptom score after a grass allergy product was considered clinically relevant by most grass-allergic patients.”

References

1. Pfaar O, Mösges R, Blaiss MS, et al. The Minimal Clinically Important Difference in Allergen Immunotherapy: An Evidence-Based Approach. Allergy. Published online July 18, 2025. doi:10.1111/all.16654

2. De-Kam P, Bernstein J, Armfield, O, et al. Compelling phase III efficacy after only 6 pre-seasonal injections of Pollinex Quattro Grass. Annals of Allergy, Asthma & Immunology, Volume 133, Issue 6, S2