Mepolizumab improvements in health-related quality of life and disease symptoms in a patient population with very severe chronic rhinosinusitis with nasal polyps: psychometric and efficacy analyses from the SYNAPSE study
Authors: Fokkens Wytske , Trigg Andrew , Lee Stella E. , Chan Robert H. , Diamant Zuzana , Hopkins Claire , Howarth Peter , Lund Valerie , Mayer Bhabita , Sousa Ana R. , Yancey Steve , Tabberer Maggie ,   SYNAPSE study group, Ardusso Ledit , Bergna Miguel , De Salvo María , Elías Pedro , García Gabriel , Maspero Jorge , Rojas Ramón , Scherbovsky Pablo Saez , Tolcachier Alberto , Wehbe Luis , Yañez Anahí , Bardin Philip , Barnes Sara , Gillman Andrew , Harvey Richard , Sader Chady , Singh Narinder , Del Carpio Jaime , Corriveau Marie-Noëlle , Desrosiers Martin , Janjua Arif , Kilty Shaun , Sommer Doron , Sowerby Leigh , Spafford Peter , Betz Christian , Beule Achim , Chaker Adam , Cuevas Mandy , Groeger Moritz , Klimek Ludger , Olze Heidi , van Schaik Carolina , Wagenmann Martin , Wollenberg Barbara , Yarin Yury , Cho Hyung-Ju , Dhong Hun-Jong , Kim Chang-Hoon , Kim Seontae , Rhee Chae-Seo , Kim Soo Whan , Kim Hyo Yeol , Fokkens Wytske J. , Bronescu Valeriu , Mella Corina , Neagos Adriana , Radeanu Doinel , Stefan Catalin , Edin Anton , Karpischenko Sergey , Khanova Fatimat , Mirzabekyan Ekaterina , Ovchinnikov Andrey , Polyakov Dmitriy , Ryazantsev Sergei , Svistushkin Valeriy , Tarasova Galina , Yakusevich Vladimir , Emanuelsson Cecilia Ahlström , Hellgren Johan , Jangard Mattias , Mårtensson Anders , Toll Karin , Carrie Sean , Durham Stephen , Gane Simon , Hobson Jonathan , Hopkins Claire , Kara Naveed , Leong Samuel , Massey Neil , Scaddin Guy , Armstrong Michael , Blotter James , Brown Matthew , Courville Timothy , Damask Cecelia , DeConde Adam , Ehmer Dale , Fatakia Adil , Franzese Christine , Han Joseph , Higgins Thomas , Kerwin Edward , LaForce Craig , Lee Stella , Marple Bradley , Matz Jonathan , McDuffie Chad , Miller Steven , Moss Jonathan , Mumneh Nayla , Nathan Robert , Ow Randall , Rosenbloom Jeffrey , Schlosser Rodney , Shah-Patel Heena , Shealy Ronald , Siddiqi Ayesha , Silvers Stacey , Soong Weily , Sterling Richard , Talreja Neetu , Tarpay Martha , Webb Luke , Wedner H. James , Wright Simon , Yen David 
Published: January 2023

Abstract
Background
Although the psychometric properties of patient-reported outcome measures (e.g. the 22-item Sino-nasal Outcomes Test [SNOT-22]) in chronic rhinosinusitis with nasal polyps (CRSwNP) have been defined, these definitions have not been extensively studied in patients with very severe CRSwNP, as defined by recurrent disease despite ≥ 1 previous surgery and a current need for further surgery. Therefore, the psychometric properties of the symptoms visual analogue scales (VAS) were evaluated, and meaningful within-patient change thresholds were calculated for VAS and SNOT-22.

Methods
SYNAPSE (NCT03085797), a randomized, double-blind, placebo-controlled, 52-week trial, assessed the efficacy and safety of 4-weekly mepolizumab 100 mg subcutaneously added to standard of care in very severe CRSwNP. Enrolled patients (n = 407) completed symptom VAS (six items) daily and SNOT-22 every 4 weeks from baseline until Week 52. Blinded psychometric assessment of individual and composite VAS was performed post hoc, including anchor-based thresholds for meaningful within-patient changes for VAS and SNOT-22, supported by cumulative distribution function and probability density function plots. The effect of mepolizumab versus placebo for 52 weeks on VAS and SNOT-22 scores was then determined using these thresholds using unblinded data.

Results
Internal consistency was acceptable for VAS and SNOT-22 scores (Cronbach’s α-coefficients ≥ 0.70). Test–retest reliability was demonstrated for all symptom VAS (Intra-Class Correlation coefficients > 0.75). Construct validity was acceptable between individual and composite VAS and SNOT-22 total score (r = 0.461–0.598) and between individual symptom VAS and corresponding SNOT-22 items (r = 0.560–0.780), based upon pre-specified ranges. Known-groups validity assessment demonstrated generally acceptable validity based on factors associated with respiratory health, with all VAS responsive to change. Mepolizumab treatment was associated with significantly increased odds of meeting or exceeding meaningful within-patient change thresholds, derived for this very severe cohort using six anchor groups for individual VAS (odds ratio [OR] 2.19–2.68) at Weeks 49–52, and SNOT-22 (OR 1.61–2.96) throughout the study.

Conclusions
Symptoms VAS and SNOT-22 had acceptable psychometric properties for use in very severe CRSwNP. Mepolizumab provided meaningful within-patient improvements in symptom severity and health-related quality of life versus placebo, indicating mepolizumab provides substantial clinical benefits in very severe CRSwNP.