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Randomized Controlled Trial
. 2023 Jan 20;7(1):4.
doi: 10.1186/s41687-023-00543-5.

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

Wytske Fokkens  1 , Andrew Trigg  2 , Stella E Lee  3 , Robert H Chan  4 , Zuzana Diamant  5   6   7 , Claire Hopkins  8 , Peter Howarth  9 , Valerie Lund  10 , Bhabita Mayer  11 , Ana R Sousa  12 , Steve Yancey  13 , Maggie Tabberer  14 ; SYNAPSE study group
Collaborators, Affiliations
Randomized Controlled Trial

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

Wytske Fokkens et al. J Patient Rep Outcomes. .

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.

Keywords: Chronic rhinosinusitis with nasal polyps; Efficacy; Mepolizumab; Patient-reported outcome measures (PROMs); Psychometric; Quality of life; SNOT-22; Severity; VAS.

Plain language summary

Patients with chronic rhinosinusitis (CRS) often have blocked or runny noses, and loss of sense of smell. They can also have sac-like growths in their nose called nasal polyps, which often require surgical removement. The symptoms of CRS with nasal polyps can affect quality of life. In a clinical study named SYNAPSE, a new treatment option called mepolizumab reduced the size and severity of nasal polyps in patients suffering from very severe CRS with nasal polyps, compared with placebo. Mepolizumab also reduced the need for nasal polyp surgery. The SYNAPSE study also measured if 1 year of mepolizumab treatment improved patients’ symptoms and quality of life. This was evaluated by asking patients to complete two separate tasks. These tasks were rating symptoms on a visual analogue scale (VAS) and completing a quality of life questionnaire called SNOT-22. The objective of this analysis was to see if these questionnaires accurately assessed a patient’s quality of life. The analysis also assessed how many patients had major improvements in their symptoms with mepolizumab. Overall, data from 407 patients in the SYNAPSE study was analyzed. Results showed that both the VAS and SNOT-22 questionnaires accurately captured CRS symptoms and quality of life. In addition, patients treated with mepolizumab for 1 year had improvements in quality of life compared with placebo. In conclusion, these findings suggest that the VAS and SNOT-22 questionnaires are appropriate evaluation tools for patients with very severe CRS with nasal polyps. The findings also show that mepolizumab treatment is beneficial for these patients.

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Conflict of interest statement

WF has received clinical trial funding from Sanofi, Mylan, ALK, Allergy Therapeutics, Novartis, and Chordate, personal fees from GSK, Sanofi and Novartis, has participated on an advisory board for Lyra, and is Secretary General of the European Rhinologic Society. AT was employed by Adelphi Values during the conduct of the study and is currently an employee of Bayer Plc. SEL has participated in advisory boards and received clinical trial funding from Sanofi Genzyme, Regeneron, Genentech, AstraZeneca, and GSK. RHC, PH, BM, ARS and SY are all employees of GSK and own stocks/shares in GSK. MT was an employee of GSK at the time of the study and owns stocks/shares in GSK. ZD has acted as Research Director at QPS-NL, an institution which has received research support from HAL Allergy, Foresee Pharmaceuticals, Patara Pharma (now Respivant) and Novartis. ZD has also received honoraria or speaker fees serving on advisory boards or as a consultant for ALK, Antabio, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, QPS-NL and Sanofi-Genzyme-Regeneron. CH has received advisory board fees from Sanofi, AstraZeneca, Olympus, Dianosic, and GSK, and has received honoraria for lectures from GSK, Sanofi, Intersect, and Mylan. VL reports advisory board and lecture fees from GSK, Novartis, and Sanofi.

Figures

Fig. 1
Fig. 1
The six-domain SNOT-22 model with standardized factor loadings. The CFA model, including the standardized factor loadings (numbers on arrows) from each hypothesized domain to the SNOT-22 items and Chi-squared, CFI, RMSEA, and SRMR fit statistics. Standardized factor loadings represent the correlation coefficients between factors. CFA Confirmatory factor analysis, CFI Comparative fit index, RMSEA Root mean square error of approximation, SNOT-22 Sino-nasal outcome test-22, SRMR Standardized root mean square residual
Fig. 2
Fig. 2
Mean change in SNOT-22 score by VAS anchor in total ITT population. Overall VAS anchor groups were defined by change in overall VAS symptom score from baseline to Week 52: moderate to major improvement: ≤  − 4-point change in VAS score; minimal meaningful improvement: ≤ − 2 to > − 4-point change in VAS score; limited improvement or worsening (stable): > − 2 to < 2− point change in VAS score; CDF Cumulative distribution function, CI Confidence interval, ITT Intent-to-treat, SNOT-22 Sino-nasal outcome test-22, VAS Visual analogue scale
Fig. 3
Fig. 3
CDF plot: change from baseline in SNOT-22 total score by overall VAS anchor. Overall VAS anchor groups were defined by change in overall VAS symptom score from baseline to Week 52: moderate to major improvement: ≤ − 4-point change in VAS score; minimal meaningful improvement: ≤ − 2 to > − 4-point change in VAS score; limited improvement or worsening (stable): > − 2 to < 2-point change in VAS score. CDF Cumulative distribution function, SNOT-22 Sino-nasal outcome test-22, VAS Visual analogue scale
Fig. 4
Fig. 4
Probability of meaningful within-patient change† in VAS score (Weeks 49–52). *P < 0.001; † ≥ 2.5-point change (improvement) for overall symptoms, nasal discharge, and facial pain VAS scores, and a ≥ 3-point change (improvement) for nasal obstruction, loss of sense of smell, and mucus in throat VAS scores. CI Confidence interval, VAS Visual analogue scale
Fig. 5
Fig. 5
Change from baseline at Weeks 49–52 in individual VAS scores. *P < 0.001. CI Confidence interval, VAS Visual analogue scale
Fig. 6
Fig. 6
Change from baseline in loss of sense of smell VAS score by surgery number. CI Confidence interval, SC Subcutaneous, VAS visual analogue scale
Fig. 7
Fig. 7
Probability of patients reporting ≥ 28-point improvement from baseline in SNOT-22 total score over time. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. OR (mepolizumab vs placebo) of percentage of patients reporting ≥ 28 point improvement from baseline in SNOT-22 total score. OR > 1 indicates greater efficacy of mepolizumab. CI Confidence interval, OR Odds ratio, SC subcutaneous, SNOT-22 Sino-nasal outcome test-22
Fig. 8
Fig. 8
Change from baseline in SNOT-22 total and domain scores at Week 52. Estimates are based on weighting applied to each level of class variable determined from observed proportions. CI confidence interval, LS Least squares, SC Subcutaneous, SE Standard error, SNOT-22 Sino-nasal outcome test-22
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