Impact of dupilumab on SNOT-22 sleep and function scores in CRSwNP
2022; Elsevier BV; Volume: 10; Issue: 9 Linguagem: Inglês
10.1016/j.jaip.2022.05.013
ISSN2213-2201
AutoresWilliam W. Busse, Andrew Wellman, Zuzana Diamant, Noah Cohen, Adam Chaker, Claus Bachert, Shahid Siddiqui, Haixin Zhang, Scott D. Nash, Asif Khan, Juby A. Jacob‐Nara, Paul J. Rowe, Yamo Deniz,
Tópico(s)Asthma and respiratory diseases
ResumoClinical ImplicationsChronic rhinosinusitis with nasal polyps (CRSwNP) frequently affects patients' sleep and functioning. Patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52.Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the upper airways.1Bachert C. Han J.K. Wagenmann M. Hosemann W. Lee S.E. Backer V. et al.EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management.J Allergy Clin Immunol. 2021; 147: 29-36Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Symptoms of CRSwNP are burdensome and impact patients' health-related quality of life (HRQoL), often impairing sleep quality,1Bachert C. Han J.K. Wagenmann M. Hosemann W. Lee S.E. Backer V. et al.EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management.J Allergy Clin Immunol. 2021; 147: 29-36Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 2Khan A. Vandeplas G. Huynh T.M.T. Joish V.N. Mannent L. Tomassen P. et al.The Global Allergy and Asthma European Network (GALEN) rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps.Rhinology. 2019; 57: 32-42Crossref PubMed Scopus (72) Google Scholar, 3Serrano E. Neukirch F. Pribil C. Jankowski R. Klossek J.M. Chanal I. et al.Nasal polyposis in France: impact on sleep and quality of life.J Laryngol Otol. 2005; 119: 543-549Crossref PubMed Scopus (40) Google Scholar resulting in daytime sleepiness and compromising ability to function and work.2Khan A. Vandeplas G. Huynh T.M.T. Joish V.N. Mannent L. Tomassen P. et al.The Global Allergy and Asthma European Network (GALEN) rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps.Rhinology. 2019; 57: 32-42Crossref PubMed Scopus (72) Google Scholar,4Stull D.E. Roberts L. Frank L. Heithoff K. Relationship of nasal congestion with sleep, mood, and productivity.Curr Med Res Opin. 2007; 23: 811-819Crossref PubMed Scopus (61) Google Scholar The condition is often nonresponsive to standard treatments including systemic corticosteroids (SCS), which may drive patients to seek more intense disease management (eg, surgery).5DeConde A.S. Mace J.C. Bodner T. Hwang P.H. Rudmik L. Soler Z.M. et al.SNOT-22 quality of life domains differentially predict treatment modality selection in chronic rhinosinusitis.Int Forum Allergy Rhinol. 2014; 4: 972-979Crossref PubMed Scopus (143) Google Scholar Despite the frequency of sleep disturbance, awareness may be lacking among patients and caregivers of the impact of CRSwNP on sleep quality and the consequences of disturbed sleep. As a result, sleep is often overlooked in diagnosis and as a target for treatment.Dupilumab is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, which are key drivers of type 2 inflammation in multiple diseases including CRSwNP.6Le Floc'h A. Allinne J. Nagashima K. Scott G. Birchard D. Asrat S. et al.Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation.Allergy. 2020; 75: 1188-1204Crossref PubMed Scopus (101) Google Scholar In 2 randomized, placebo-controlled, phase 3 studies, SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454), in patients with CRSwNP, dupilumab treatment was associated with a significant reduction in nasal polyp score and nasal congestion compared with placebo, improved smell, and was generally well tolerated.7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google ScholarAs CRSwNP symptoms frequently impact patients' sleep and functioning, we assessed the effect of dupilumab on the 22-Item Sinonasal Outcome Test (SNOT-22) sleep and function (fatigue, productivity, and concentration) domain scores in SINUS-24 and SINUS-52.Full details of SINUS-24 and SINUS-52 have been published previously.7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar This post hoc analysis included data for patients who received subcutaneous dupilumab (300 mg) or placebo to week 24 in SINUS-24 and to week 52 in SINUS-52.Outcome measures included the sleep and fatigue domains based on SNOT-22, validated in the CRSwNP population,8Khan A. Reaney M. Guillemin I. Nelson L. Qin S. Kamat S. et al.Development of Sinonasal Outcome Test (SNOT-22) domains in chronic rhinosinusitis with nasal polyps.Laryngoscope. 2022; 132: 933-941Crossref PubMed Scopus (5) Google Scholar which were assessed to week 24 (SINUS-24) and week 52 (SINUS-52). The sleep domain of SNOT-22 comprises 4 items: "difficulty falling asleep," "wake up at night," "lack of a good night's sleep," and "wake up tired." The function domain of SNOT-22 comprises 3 items: "fatigue," "reduced productivity," and "reduced concentration." Item level scores for both the sleep and the function domains range from 0 to 5 (0 = no problem; 5 = problem as bad as can be), with higher scores indicating greater disease severity. Individual item scores were summed, and an average domain score was derived.Analyses were conducted in the intent-to-treat population and in subgroups: patients with/without comorbid asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD), SCS use in the previous 2 years, allergic rhinitis, and prior sinonasal surgery for nasal polyps, and patients reporting 1 SNOT-22 sleep or function domain item as most important at baseline.Mean changes in average SNOT-22 sleep and function domain scores from baseline up to week 24 (SINUS-24) and week 52 (SINUS-52) were determined, and least-squares (LS) mean differences (95% confidence interval [CI]) for dupilumab versus placebo were calculated. Data were analyzed using the worst observation carried forward and multiple imputation methods followed by an analysis of covariance model. The analysis is post hoc and P values are nominal.Baseline characteristics, including average SNOT-22 sleep and function domain scores, were balanced across treatment arms (Table I). The baseline average SNOT-22 sleep and function domain scores ranged from 2.25 to 2.50 for placebo and from 2.00 to 2.25 for dupilumab.Table IDemographics and baseline characteristics of patients with CRSwNP (ITT population)Demographic/CharacteristicSINUS-24SINUS-52Placebo (n = 133)Dupilumab (n = 143)Placebo (n = 153)Dupilumab (n = 150)Age (y), median (IQR)50 (41-60)52 (39-61)53 (44-61)51 (42-61)Men, n (%)70 (53)88 (62)95 (62)97 (65)Women, n (%)63 (47)55 (39)58 (38)53 (35)Nasal polyp duration (y)10.8 (8.6)11.4 (9.7)10.9 (9.4)11.3 (10.4)Nasal polyp score∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis. (scale 0-8)5.86 (1.31)5.64 (1.23)5.96 (1.21)6.07 (1.22)Asthma, n (%)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.77 (58)78 (55)91 (59)83 (55)NSAID-ERD, n (%)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.37 (28)43 (30)44 (29)34 (23)Any prior nasal polyp surgery, n (%)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis. ≥1 previous surgery ≥3 previous surgeries98 (74)99 (74)29 (22)96 (67)99 (69)33 (23)88 (58)88 (58)18 (12)85 (57)88 (59)22 (15)Allergic rhinitis history, n (%)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.65 (49)75 (52)88 (58)89 (59)SCS use in the preceding 2 y, n (%)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.85 (64)90 (63)122 (80)119 (79)Nasal congestion or obstruction score (scale 0-3)2.45 (0.55)2.26 (0.57)2.38 (0.54)2.48 (0.62)SNOT-22 Total score (scale 0-110)50.9 (20.2)48.0 (20.2)53.5 (21.9)50.2 (19.7) Average sleep domain score (scale 0-5)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.2.25 (1.35)2.25 (1.41)2.50 (1.45)2.25 (1.33) Average function domain score (scale 0-5)∗Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis.2.10 (1.32)2.12 (1.38)2.33 (1.44)2.00 (1.36)Data are mean (SD), unless specified.CRSwNP, Chronic rhinosinusitis with nasal polyps; IQR, interquartile range; ITT, intent-to-treat; NSAID-ERD, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; SCS, systemic corticosteroid; SD, standard deviation; SNOT-22, 22-Item Sinonasal Outcome Test.∗ Descriptive statistics include patients after worst observation carried forward at each visit; patients whose values at each visit were imputed by multiple imputation methods were excluded from the analysis. Open table in a new tab Improvements in average SNOT-22 sleep domain scores were greater with dupilumab versus placebo at week 24 in the SINUS-24 study (−1.38 vs −0.41; LS mean difference vs placebo: −0.97; 95% CI: −1.24, −0.71; P < .0001) and at week 52 in the SINUS-52 study (−1.27 vs −0.34; LS mean difference vs placebo: −0.93; 95% CI: −1.18, −0.68; P < .0001). Differences were observable as early as week 8 (P < .0001; Figure 1 and Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). The corresponding LS mean percent change in sleep domain score from baseline with dupilumab and placebo was −53.03% and −3.76%, respectively, at week 24 (SINUS-24; P < .0001), and −27.23% and 13.82%, respectively, at week 52 (SINUS-52; P = .0023).Improvements in average SNOT-22 function domain scores were greater with dupilumab versus placebo at week 24 in the SINUS-24 study (−1.31 vs −0.44; LS mean difference vs placebo: −0.86; 95% CI: −1.11, −0.61; P < .0001) and at week 52 in the SINUS-52 study (−1.08 vs −0.32; LS mean difference vs placebo: −0.76; 95% CI: −1.01, −0.51; P < .0001). Differences were observable as early as week 8 (P < .0001; Figure 1 and Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). The corresponding LS mean percent change in function domain score from baseline with dupilumab and placebo was −50.92% and −6.47%, respectively, at week 24 (SINUS-24; P < .0001), and −41.19% and −5.27%, respectively, at week 52 (SINUS-52; P < .0001).Changes in sleep and function item scores were also assessed by change in nasal polyp score (groups assessed: improvement <1 point, ≥1 but <2 points, and ≥3 points). Improvements versus placebo were observed in dupilumab-treated patients for all sleep and function item scores at week 24 (SINUS-24) and week 52 (SINUS-52), regardless of change in nasal polyp score (data not shown).The beneficial effect of dupilumab versus placebo on SNOT-22 sleep and function domain scores was also observed in all predefined patient subgroups at week 24 (SINUS-24) and at week 52 (SINUS-52) (Table E1, available in this article's Online Repository at www.jaci-inpractice.org). Although the reduced sleep and function domain scores with dupilumab were statistically significant versus placebo in all subgroups, some numerical differences were apparent at week 52. For example, numerically greater improvements in function were seen in patients with asthma versus those without asthma and in patients with prior nasal polyp surgery versus those without surgery. Although the reduced sleep and function domain scores with dupilumab were statistically significant versus placebo in all subgroups, some differences were apparent at week 52 (Table E1, available in this article's Online Repository at www.jaci-inpractice.org).In this analysis, patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning as measured by SNOT-22 sleep and function domain scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52. The positive effect of dupilumab occurred irrespective of comorbid asthma, NSAID-ERD, allergic rhinitis, prior surgery, and/or SCS use.Patients showed improved outcomes in fatigue, productivity, and concentration as measured by SNOT-22 function domain scores. As impaired sleep is known to have a detrimental impact on HRQoL and functioning,9Mahdavinia M. Schleimer R.P. Keshavarzian A. Sleep disruption in chronic rhinosinusitis.Expert Rev Anti Infect Ther. 2017; 15: 457-465Crossref PubMed Scopus (18) Google Scholar our results suggest a broader impact for dupilumab on HRQoL beyond symptomatic relief from CRSwNP. However, data were not collected using standard sleep scales (eg, Pennsylvania Sleep Inventory) during SINUS-24 and SINUS-52. Hence, although demonstrating a beneficial effect of dupilumab compared with placebo on sleep and functioning, our data do not permit evaluation of how this might translate into overall improvements in general health and functioning. Any potential contribution of obstructive sleep apnea was also beyond the scope of the current analysis.Despite these limitations, this analysis suggests a reduction in daily CRSwNP symptoms (eg, congestion/rhinorrhea) with dupilumab7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar may be responsible for the improvement in sleep scores, which in turn may be responsible for the observed improvement in function scores. Clinical ImplicationsChronic rhinosinusitis with nasal polyps (CRSwNP) frequently affects patients' sleep and functioning. Patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52. Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently affects patients' sleep and functioning. Patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52. Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently affects patients' sleep and functioning. Patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52. Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the upper airways.1Bachert C. Han J.K. Wagenmann M. Hosemann W. Lee S.E. Backer V. et al.EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management.J Allergy Clin Immunol. 2021; 147: 29-36Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Symptoms of CRSwNP are burdensome and impact patients' health-related quality of life (HRQoL), often impairing sleep quality,1Bachert C. Han J.K. Wagenmann M. Hosemann W. Lee S.E. Backer V. et al.EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management.J Allergy Clin Immunol. 2021; 147: 29-36Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 2Khan A. Vandeplas G. Huynh T.M.T. Joish V.N. Mannent L. Tomassen P. et al.The Global Allergy and Asthma European Network (GALEN) rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps.Rhinology. 2019; 57: 32-42Crossref PubMed Scopus (72) Google Scholar, 3Serrano E. Neukirch F. Pribil C. Jankowski R. Klossek J.M. Chanal I. et al.Nasal polyposis in France: impact on sleep and quality of life.J Laryngol Otol. 2005; 119: 543-549Crossref PubMed Scopus (40) Google Scholar resulting in daytime sleepiness and compromising ability to function and work.2Khan A. Vandeplas G. Huynh T.M.T. Joish V.N. Mannent L. Tomassen P. et al.The Global Allergy and Asthma European Network (GALEN) rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps.Rhinology. 2019; 57: 32-42Crossref PubMed Scopus (72) Google Scholar,4Stull D.E. Roberts L. Frank L. Heithoff K. Relationship of nasal congestion with sleep, mood, and productivity.Curr Med Res Opin. 2007; 23: 811-819Crossref PubMed Scopus (61) Google Scholar The condition is often nonresponsive to standard treatments including systemic corticosteroids (SCS), which may drive patients to seek more intense disease management (eg, surgery).5DeConde A.S. Mace J.C. Bodner T. Hwang P.H. Rudmik L. Soler Z.M. et al.SNOT-22 quality of life domains differentially predict treatment modality selection in chronic rhinosinusitis.Int Forum Allergy Rhinol. 2014; 4: 972-979Crossref PubMed Scopus (143) Google Scholar Despite the frequency of sleep disturbance, awareness may be lacking among patients and caregivers of the impact of CRSwNP on sleep quality and the consequences of disturbed sleep. As a result, sleep is often overlooked in diagnosis and as a target for treatment. Dupilumab is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, which are key drivers of type 2 inflammation in multiple diseases including CRSwNP.6Le Floc'h A. Allinne J. Nagashima K. Scott G. Birchard D. Asrat S. et al.Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation.Allergy. 2020; 75: 1188-1204Crossref PubMed Scopus (101) Google Scholar In 2 randomized, placebo-controlled, phase 3 studies, SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454), in patients with CRSwNP, dupilumab treatment was associated with a significant reduction in nasal polyp score and nasal congestion compared with placebo, improved smell, and was generally well tolerated.7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar As CRSwNP symptoms frequently impact patients' sleep and functioning, we assessed the effect of dupilumab on the 22-Item Sinonasal Outcome Test (SNOT-22) sleep and function (fatigue, productivity, and concentration) domain scores in SINUS-24 and SINUS-52. Full details of SINUS-24 and SINUS-52 have been published previously.7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar This post hoc analysis included data for patients who received subcutaneous dupilumab (300 mg) or placebo to week 24 in SINUS-24 and to week 52 in SINUS-52. Outcome measures included the sleep and fatigue domains based on SNOT-22, validated in the CRSwNP population,8Khan A. Reaney M. Guillemin I. Nelson L. Qin S. Kamat S. et al.Development of Sinonasal Outcome Test (SNOT-22) domains in chronic rhinosinusitis with nasal polyps.Laryngoscope. 2022; 132: 933-941Crossref PubMed Scopus (5) Google Scholar which were assessed to week 24 (SINUS-24) and week 52 (SINUS-52). The sleep domain of SNOT-22 comprises 4 items: "difficulty falling asleep," "wake up at night," "lack of a good night's sleep," and "wake up tired." The function domain of SNOT-22 comprises 3 items: "fatigue," "reduced productivity," and "reduced concentration." Item level scores for both the sleep and the function domains range from 0 to 5 (0 = no problem; 5 = problem as bad as can be), with higher scores indicating greater disease severity. Individual item scores were summed, and an average domain score was derived. Analyses were conducted in the intent-to-treat population and in subgroups: patients with/without comorbid asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD), SCS use in the previous 2 years, allergic rhinitis, and prior sinonasal surgery for nasal polyps, and patients reporting 1 SNOT-22 sleep or function domain item as most important at baseline. Mean changes in average SNOT-22 sleep and function domain scores from baseline up to week 24 (SINUS-24) and week 52 (SINUS-52) were determined, and least-squares (LS) mean differences (95% confidence interval [CI]) for dupilumab versus placebo were calculated. Data were analyzed using the worst observation carried forward and multiple imputation methods followed by an analysis of covariance model. The analysis is post hoc and P values are nominal. Baseline characteristics, including average SNOT-22 sleep and function domain scores, were balanced across treatment arms (Table I). The baseline average SNOT-22 sleep and function domain scores ranged from 2.25 to 2.50 for placebo and from 2.00 to 2.25 for dupilumab. Data are mean (SD), unless specified. CRSwNP, Chronic rhinosinusitis with nasal polyps; IQR, interquartile range; ITT, intent-to-treat; NSAID-ERD, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; SCS, systemic corticosteroid; SD, standard deviation; SNOT-22, 22-Item Sinonasal Outcome Test. Improvements in average SNOT-22 sleep domain scores were greater with dupilumab versus placebo at week 24 in the SINUS-24 study (−1.38 vs −0.41; LS mean difference vs placebo: −0.97; 95% CI: −1.24, −0.71; P < .0001) and at week 52 in the SINUS-52 study (−1.27 vs −0.34; LS mean difference vs placebo: −0.93; 95% CI: −1.18, −0.68; P < .0001). Differences were observable as early as week 8 (P < .0001; Figure 1 and Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). The corresponding LS mean percent change in sleep domain score from baseline with dupilumab and placebo was −53.03% and −3.76%, respectively, at week 24 (SINUS-24; P < .0001), and −27.23% and 13.82%, respectively, at week 52 (SINUS-52; P = .0023). Improvements in average SNOT-22 function domain scores were greater with dupilumab versus placebo at week 24 in the SINUS-24 study (−1.31 vs −0.44; LS mean difference vs placebo: −0.86; 95% CI: −1.11, −0.61; P < .0001) and at week 52 in the SINUS-52 study (−1.08 vs −0.32; LS mean difference vs placebo: −0.76; 95% CI: −1.01, −0.51; P < .0001). Differences were observable as early as week 8 (P < .0001; Figure 1 and Figure E1, available in this article's Online Repository at www.jaci-inpractice.org). The corresponding LS mean percent change in function domain score from baseline with dupilumab and placebo was −50.92% and −6.47%, respectively, at week 24 (SINUS-24; P < .0001), and −41.19% and −5.27%, respectively, at week 52 (SINUS-52; P < .0001). Changes in sleep and function item scores were also assessed by change in nasal polyp score (groups assessed: improvement <1 point, ≥1 but <2 points, and ≥3 points). Improvements versus placebo were observed in dupilumab-treated patients for all sleep and function item scores at week 24 (SINUS-24) and week 52 (SINUS-52), regardless of change in nasal polyp score (data not shown). The beneficial effect of dupilumab versus placebo on SNOT-22 sleep and function domain scores was also observed in all predefined patient subgroups at week 24 (SINUS-24) and at week 52 (SINUS-52) (Table E1, available in this article's Online Repository at www.jaci-inpractice.org). Although the reduced sleep and function domain scores with dupilumab were statistically significant versus placebo in all subgroups, some numerical differences were apparent at week 52. For example, numerically greater improvements in function were seen in patients with asthma versus those without asthma and in patients with prior nasal polyp surgery versus those without surgery. Although the reduced sleep and function domain scores with dupilumab were statistically significant versus placebo in all subgroups, some differences were apparent at week 52 (Table E1, available in this article's Online Repository at www.jaci-inpractice.org). In this analysis, patients with CRSwNP receiving dupilumab reported less impairment in sleep and functioning as measured by SNOT-22 sleep and function domain scores versus placebo after 24 weeks of treatment, with benefits maintained at week 52. The positive effect of dupilumab occurred irrespective of comorbid asthma, NSAID-ERD, allergic rhinitis, prior surgery, and/or SCS use. Patients showed improved outcomes in fatigue, productivity, and concentration as measured by SNOT-22 function domain scores. As impaired sleep is known to have a detrimental impact on HRQoL and functioning,9Mahdavinia M. Schleimer R.P. Keshavarzian A. Sleep disruption in chronic rhinosinusitis.Expert Rev Anti Infect Ther. 2017; 15: 457-465Crossref PubMed Scopus (18) Google Scholar our results suggest a broader impact for dupilumab on HRQoL beyond symptomatic relief from CRSwNP. However, data were not collected using standard sleep scales (eg, Pennsylvania Sleep Inventory) during SINUS-24 and SINUS-52. Hence, although demonstrating a beneficial effect of dupilumab compared with placebo on sleep and functioning, our data do not permit evaluation of how this might translate into overall improvements in general health and functioning. Any potential contribution of obstructive sleep apnea was also beyond the scope of the current analysis. Despite these limitations, this analysis suggests a reduction in daily CRSwNP symptoms (eg, congestion/rhinorrhea) with dupilumab7Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar may be responsible for the improvement in sleep scores, which in turn may be responsible for the observed improvement in function scores. Medical writing/editorial assistance was provided by Stephen Whiting, PhD, of Adelphi Group. Online RepositoryTable E1Change from baseline in average SNOT-22 sleep and function domain scores for dupilumab versus placebo at week 24 (SINUS-24) and week 52 (SINUS-52) by patient subgroupSubgroupAverage SNOT-22 sleep domain score∗The sleep domain of SNOT-22 includes the items "difficulty falling asleep," "wake up at night," "lack of a good night's sleep," and "wake up tired."Average SNOT-22 function domain score†The function domain of SNOT-22 includes the items "fatigue," "reduced productivity," and "reduced concentration."Change from baseline LS mean (standard error)LS mean difference (95% CI) vs placeboP valueChange from baseline LS mean (standard error)LS mean difference (95% CI) vs placeboP valuen/n‡Placebo/dupilumab.PlaceboDupilumabn/n‡Placebo/dupilumab.PlaceboDupilumabWeek 24 (SINUS-24) History of asthmaYes74/77−0.50 (0.14)−1.62 (0.14)−1.12 (−1.48, −0.77)<.000174/77−0.49 (0.13)−1.48 (0.13)−0.99 (−1.33, −0.65)<.0001No54/58−0.32 (0.17)−1.09 (0.15)−0.77 (−1.17, −0.37).000254/58−0.39 (0.15)−1.05 (0.14)−0.66 (−1.02, −0.29).0005 NSAID-ERD historyYes37/42−0.52 (0.22)−1.56 (0.21)−1.03 (−1.55, −0.52)<.000137/42−0.48 (0.20)−1.47 (0.19)−0.99 (−1.47, −0.51)<.0001No91/93−0.35 (0.12)−1.34 (0.11)−0.99 (−1.30, −0.68)<.000191/93−0.42 (0.11)−1.26 (0.11)−0.84 (−1.13, −0.55)<.0001 History of surgeryYes95/94−0.35 (0.12)−1.37 (0.12)−1.03 (−1.34, −0.71)<.000195/94−0.47 (0.11)−1.35 (0.11)−0.88 (−1.18, −0.59)<.0001No33/41−0.51 (0.19)−1.35 (0.17)−0.84 (−1.36, −0.33).001733/41−0.45 (0.17)−1.25 (0.16)−0.80 (−1.26, −0.33).0011 History of allergic rhinitisYes62/73−0.43 (0.16)−1.36 (0.14)−0.93 (−1.31, −0.54)<.000162/73−0.40 (0.16)−1.31 (0.14)−0.91 (−1.29, −0.53)<.0001No66/62−0.44 (0.15)−1.43 (0.15)−0.99 (−1.37, −0.62)<.000166/62−0.53 (0.13)−1.30 (0.13)−0.78 (−1.11, −0.44)<.0001 SCS use during past 2 yYes84/88−0.44 (0.13)−1.53 (0.12)−1.09 (−1.43, −0.75)<.000184/88−0.51 (0.12)−1.45 (0.11)−0.94 (−1.26, −0.62)<.0001No44/47−0.41 (0.28)−1.22 (0.30)−0.81 (−1.23, −0.40).000144/47−0.59 (0.26)−1.33 (0.27)−0.74 (−1.13, −0.36).0002 Patients reporting 1 SNOT-22 sleep or function domain item as most important at baseline80/87−0.56 (0.13)−1.49 (0.12)−0.94 (−1.27, −0.60)<.000153/48−0.62 (0.16)−1.59 (0.16)−0.97 (−1.39, −0.55)<.0001Week 52 (SINUS-52) History of asthmaYes84/81−0.23 (0.13)−1.18 (0.14)−0.95 (−1.29, −0.61)<.000184/81−0.08 (0.13)−1.07 (0.13)−0.99 (−1.33, −0.65)<.0001No59/62−0.39 (0.15)−1.28 (0.15)−0.89 (−1.26, −0.52)<.000159/62−0.56 (0.15)−1.01 (0.15)−0.44 (−0.82, −0.07).0201 NSAID-ERD historyYes42/34−0.22 (0.20)−1.35 (0.21)−1.12 (−1.65, −0.60)<.000142/340.08 (0.19)−1.16 (0.20)−1.24 (−1.74, −0.74)<.0001No101/109−0.34 (0.12)−1.22 (0.12)−0.88 (−1.16, −0.59)<.0001101/109−0.44 (0.12)−1.03 (0.12)−0.59 (−0.88, −0.30)<.0001 History of surgeryYes82/83−0.30 (0.13)−1.37 (0.13)−1.07 (−1.40, −0.74)<.000182/83−0.22 (0.13)−1.20 (0.13)−0.97 (−1.29, −0.66)<.0001No61/60−0.37 (0.15)−1.13 (0.15)−0.76 (−1.13, −0.38)<.000161/60−0.46 (0.16)−0.92 (0.16)−0.46 (−0.86, −0.06).0238 History of allergic rhinitisYes83/88−0.45 (0.14)−1.55 (0.14)−1.10 (−1.43, −0.78)<.000183/88−0.39 (0.14)−1.30 (0.14)−0.90 (−1.24, −0.57)<.0001No60/55−0.27 (0.15)−0.96 (0.16)−0.70 (−1.09, −0.30).000560/55−0.25 (0.14)−0.82 (0.15)−0.57 (−0.95, −0.19).0034 SCS use during past 2 yYes117/117−0.32 (0.12)−1.24 (0.12)−0.92 (−1.20, −0.64)<.0001117/117−0.42 (0.12)−1.10 (0.12)−0.68 (−0.96, −0.39)<.0001No26/26−0.52 (0.23)−1.44 (0.24)−0.92 (−1.46, −0.38).000926/26−0.02 (0.23)−1.12 (0.24)−1.11 (−1.65, −0.57)<.0001 Patients reporting 1 SNOT-22 sleep or function domain item as most important at baseline105/98−0.44 (0.13)−1.42 (0.13)−0.98 (−1.29, −0.67)<.000157/55−0.66 (0.17)−1.57 (0.17)−0.91 (−1.35, −0.47)<.0001CI, Confidence interval; LS, least squares; NSAID-ERD, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; SCS, systemic corticosteroid; SNOT-22, 22-Item Sinonasal Outcome Test.∗ The sleep domain of SNOT-22 includes the items "difficulty falling asleep," "wake up at night," "lack of a good night's sleep," and "wake up tired."† The function domain of SNOT-22 includes the items "fatigue," "reduced productivity," and "reduced concentration."‡ Placebo/dupilumab. Open table in a new tab CI, Confidence interval; LS, least squares; NSAID-ERD, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; SCS, systemic corticosteroid; SNOT-22, 22-Item Sinonasal Outcome Test.
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