Dupilumab Reduces Asthma Disease Burden and Recurrent SCS Use in Patients with CRSwNP and Coexisting Asthma.

Purpose: Dupilumab significantly reduced the requirement for systemic corticosteroids (SCS) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with CRSwNP and coexisting asthma typically have a higher disease burden and have more difficulty in managing disease. Here, we report an analysis of asthma outcomes and SCS use in patients with CRSwNP and coexisting asthma. Patients and Methods: This was a post hoc analysis of the randomized, placebo-controlled SINUS-24 and SINUS-52 studies (NCT02912468/NCT02898454) in patients with severe CRSwNP and coexisting asthma (patient self-reported) from the pooled intention-to-treat population randomized to dupilumab 300 mg every 2 weeks or placebo. On-treatment SCS use was estimated using Kaplan-Meier analysis. Forced expiratory volume in 1 s (FEV1), percent predicted FEV1, and the 6-item Asthma Control Questionnaire (ACQ-6) were assessed at baseline and Week 24 (pooled SINUS-24/52) in patients with/without history of asthma exacerbation or prior SCS use. Results: Of 337 patients with coexisting asthma, 88 (26%) required on-treatment SCS use. The requirement for on-treatment SCS use for any reason was significantly lower with dupilumab (20/167 patients; 12%) vs placebo (68/170; 40%); hazard ratio (95% confidence interval) 0.248 (0.150-0.409); p < 0.0001. The most frequent reasons for SCS use were nasal polyps (dupilumab 3% and placebo 27%) and asthma (2% and 9%, respectively). FEV1, percent predicted FEV1, and ACQ-6 were all significantly improved at Week 24 with dupilumab vs placebo irrespective of history of asthma exacerbation or prior SCS use (all p < 0.01). Conclusion: Dupilumab significantly reduced the requirement for SCS and improved asthma outcomes irrespective of history of asthma exacerbation or prior SCS use vs placebo in patients with CRSwNP and coexisting asthma, demonstrating concomitant reduction of SCS use and asthma disease burden in these patients.

Prevalence of type 2 inflammatory signatures and efficacy of dupilumab in patients with chronic rhinosinusitis with nasal polyps from two phase 3 clinical trials: SINUS-24 and SINUS-52.

BACKGROUND: This post hoc analysis of the international SINUS-24/-52 trials (NCT02912468/NCT02898454) aimed to assess dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) according to different definitions of type 2 inflammatory signature. METHODS: Six definitions of type 2 inflammation were used: ≥150 eosinophils/µL or total immunoglobulin E (IgE) ≥100 IU/mL with a coexisting type 2 condition; ≥150 eosinophils/µL or total IgE ≥100 IU/mL; ≥150 eosinophils/µL; ≥250 eosinophils/µL or total IgE ≥100 IU/mL; coexisting asthma or ≥300 eosinophils/µL; presence of a coexisting type 2 condition. Odds ratios (ORs; dupilumab vs. placebo) for achieving clinically meaningful improvement (≥1 point) from baseline to week 24 (pooled SINUS-24/-52) and week 52 (SINUS-52) were calculated for nasal polyp score (NPS; range 0-8), nasal congestion/obstruction score (NC; 0-3), and loss of smell score (LoS; 0-3). RESULTS: At baseline (n = 724), most patients displayed a type 2 inflammatory signature across definitions (64.2%-95.3%). At week 24, ORs for clinically meaningful improvement ranged from 11.9 to 14.9 for NPS across type 2 definitions, 6.5-9.6 for NC, and 12.2-17.8 for LoS (all p < 0.0001). OR ranges were similar or greater at week 52: 19.0-36.6, 7.6-12.1, and 9.2-33.5, respectively (all p < 0.0001). CONCLUSION: Most patients with CRSwNP in the SINUS study had type 2 inflammation. Dupilumab demonstrated robust efficacy across definitions of type 2 inflammation, consistent with its profile as an inhibitor of Interleukin-4 and Interleukin-13 signaling, key and central drivers of type 2 inflammation in CRSwNP. KEY POINTS: This study assessed type 2 inflammation prevalence and dupilumab efficacy in chronic rhinosinusitis with nasal polyps according to algorithm-defined type 2 inflammation Dupilumab efficacy was similar across all type 2 definitions.

Impact of Dupilumab on Sinonasal Symptoms and Outcomes in Severe Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: To assess the severity of the top 5 22-item Sino-Nasal Outcome Test (SNOT-22) items ranked most important by patients with chronic rhinosinusitis with nasal polyps (CRSwNP), the effect of dupilumab on these items, and their association with objective disease measures. STUDY DESIGN: Post hoc analysis of the SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) clinical trials. SETTING: Multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. METHODS: Patients ranked the SNOT-22 items most affecting their health at baseline. Item symptom severity (0-5 scale) was assessed at baseline, Week 24 (W24), and Week 52 (W52). Changes in nasal polyps score (NPS) and Lund-Mackay (LMK) scores were assessed in patients with/without SNOT-22 items improvements of at least 1 severity group point at W24 and W52. RESULTS: The SNOT-22 items ranked most important at baseline were "decreased sense of smell/taste" (87% of patients), followed by "nasal blockage" (82%), "postnasal discharge" (40%), "thick nasal discharge" (37%), and "wake up at night" (26%); 82%, 61%, 32%, 40%, and 26% of patients reported severe symptoms (score 4 or 5) for these items, respectively. Dupilumab improved score severity for all top 5 items versus placebo at W24 and W52. Improvements in NPS and LMK scores were numerically greater in patients with improvements in the SNOT-22 top 5 items. CONCLUSION: Loss of smell/taste was ranked as the most important symptom by patients with CRSwNP. Dupilumab reduced the severity of the top 5 most important SNOT-22 items versus placebo, in parallel with improvements in objective disease measures. CLINICAL TRIAL REGISTRATION: SINUS-24 and SINUS-52 clinical trials were registered with ClinicalTrials.gov, identifiers NCT02912468 and NCT02898454, respectively.

Dupilumab leads to better-controlled asthma and quality of life in children: the VOYAGE study.

BACKGROUND: Dupilumab has shown long-term treatment benefits in children with uncontrolled asthma. We assessed in more detail the impact of dupilumab on asthma control and health-related quality of life (HRQoL) in children and their caregivers. METHODS: Children aged 6-11 years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥20 ppb; n=350) were treated with dupilumab or placebo for 52 weeks in the VOYAGE study. Primary outcomes of these analyses were asthma control (change from baseline in Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) and achieving a clinically meaningful response of ≥0.5 points); proportion of patients achieving well-controlled asthma or better (ACQ-7-IA ≤0.75 points); effect on patients' (Standardised Paediatric Asthma Quality of Life Questionnaire Interviewer-Administered (PAQLQ(S)-IA)) and caregivers' (Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ)) HRQoL; and allergic rhinitis-related QoL. RESULTS: Dupilumab versus placebo significantly improved children's ACQ-7-IA scores by week 4 with sustained improvements through week 52 (least squares mean difference at week 52: -0.44, 95% CI -0.59- -0.30; p<0.0001); a higher proportion achieved a clinically meaningful response (week 52: 86% versus 75%; p=0.0051). At weeks 24 and 52, more children who received dupilumab achieved well-controlled asthma (ACQ-7-IA ≤0.75 points: 61% versus 43%; p=0.0001 and 70% versus 46%; p<0.0001, respectively). Significant improvements in PAQLQ(S)-IA and PACQLQ scores were observed by week 52. CONCLUSIONS: In children aged 6-11 years with moderate-to-severe type 2 asthma, dupilumab treatment was associated with rapid, sustained improvements in asthma control. HRQoL was significantly improved for children and their caregivers.

Dupilumab efficacy in high sleep disturbance management among patients with type 2 asthma.

BACKGROUND: Patients with asthma often experience sleep disturbances. We assessed the 5-item Asthma Control Questionnaire (ACQ-5) score ≥2.5 as a useful threshold to identify patients with moderate-to-severe type 2 asthma and high sleep disturbance (HSD) and investigated dupilumab efficacy on clinical and sleep-related outcomes among patients with HSD. METHODS: QUEST (NCT02414854) data were used in this post hoc analysis. A composite endpoint from validated patient-reported outcomes was developed to identify patients with HSD using sleep-related items from the ACQ-5, Asthma-Related Quality-of-Life Questionnaire, Rhino-Conjunctivitis Quality-of-Life Questionnaire, and Sino-Nasal Outcome Test-22. Impairment in at least 1 item was considered an indication of HSD. Change from baseline to Week 52 in nighttime symptoms, ACQ-5 score, lung function, annualized severe exacerbation rates (AER), and short-acting ß-agonists use during treatment was used to assess dupilumab efficacy. RESULTS: In type 2 asthma patients, 64% had HSD at baseline; of those with ACQ-5 ≥2.5 at baseline, 82% had HSD. In this population, dupilumab reduced nighttime symptoms and ACQ-5 score by 0.31 and 0.56 points, respectively, by Week 52 versus placebo, and led to a 66% reduction in AER during QUEST and 0.34 L improvement in pre-bronchodilator (pre-BD) forced expiratory volume in 1 s (FEV1) at Week 52. CONCLUSION: A majority of patients with moderate-to-severe type 2 asthma with ACQ-5 ≥2.5 at baseline had HSD. Dupilumab reduced nighttime symptoms and exacerbations, and improved lung function, overall asthma control, and quality of life. Further studies are needed to confirm the association between ACQ-5 score ≥2.5 and higher sleep disturbance rates.

Dupilumab efficacy in patients with chronic rhinosinusitis with nasal polyps with and without allergic rhinitis.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease, which often coexists with allergic rhinitis (AR). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. Objective: This post hoc analysis investigated the efficacy and safety of dupilumab in patients with severe CRSwNP with or without coexisting AR in the pooled phase III SINUS-24/SINUS-52 studies. Methods: Patients randomized to subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) were analyzed. Pooled data from the first 24 weeks of treatment are presented. Changes from baseline in disease outcome measures and biomarker levels were analyzed by the patient-reported history of AR status. Results: Overall, 338 of 724 patients (46.7%) had AR. Baseline characteristics were generally similar between patients with and those without AR. Dupilumab significantly improved objective and patient-reported measures of CRSwNP, including loss of smell, and reduced systemic and nasal biomarker levels versus placebo at week 24, with no significant treatment difference between patients with and those without AR. Use of systemic corticosteroids and/or sinonasal surgery during treatment was significantly reduced with dupilumab versus placebo, irrespective of AR status (p ≤ 0.0029). The safety profile of dupilumab was similar in patients with and in patients without AR. Conclusion: Dupilumab demonstrated significant improvements in both clinical end points and symptom scores versus placebo in patients with severe CRSwNP, irrespective of comorbid AR status, a common subgroup of patients often associated with poorer CRSwNP outcomes. Clinical trials NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52), www.clinicaltrials.gov.

Health-Related Quality of Life Impairment Among Patients with Severe Chronic Rhinosinusitis with Nasal Polyps in the SINUS-24 Trial.

Purpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases. Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4-83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma. Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity. Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.

Content Validation of Patient-Reported Sleep Measures and Development of a Conceptual Model of Sleep Disturbance in Patients with Moderate-to-Severe, Uncontrolled Asthma.

Purpose: Sleep disturbance is common in patients with asthma and can lead to subsequent impacts on health-related quality of life (HRQOL). Fit-for-purpose patient-reported outcome measures (PROMs) assessing asthma-related sleep disturbance and next-day HRQOL impact (next-day impact) are needed to evaluate disease burden and treatment effects. Patients and Methods: Adults (18-65 years) from three US clinics were recruited for semistructured interviews. Concept elicitation (CE) identified how asthma affects participants' sleep and how asthma-related sleep disturbances impact their daily lives, which informed conceptual model development. Cognitive debriefing (CD) of the Asthma Sleep Disturbance Questionnaire (ASDQ), Sleep Diary, and Patient-Reported Outcomes Measurement Information System Sleep-Related Impairment Short Form 8a (PROMIS SRI SF8a) was completed to assess each measure's content validity. Results: Twelve individuals participated in two interview rounds (6 individuals per round). Participants most frequently reported asthma-related nighttime awakening and decreased sleep quality and duration. Negative impacts of a poor night's sleep due to asthma symptoms included feeling tired/fatigue/lack of energy and subsequent negative impacts on physical functioning, emotions and mood, mental functioning, work or volunteerism, and social functioning. Across both rounds of CD interviews, participants generally found the Sleep Diary and PROMIS SRI SF8a items relevant and easy to complete with no modifications. The ASDQ was modified for clarity and consistency. Conclusion: As described in the conceptual model, asthma affects multiple aspects of sleep that can cause next-day fatigue and other subsequent negative HRQOL impacts. This study demonstrates that the ASDQ, Sleep Diary, and PROMIS SRI SF8a items are comprehensive, relevant, and appropriate for patients with moderate-to-severe, uncontrolled asthma. Evaluation of psychometric properties for the ASDQ, Sleep Diary, and PROMIS SRI SF8a based on clinical trial data in patients with moderate-to-severe, uncontrolled asthma will further support their use.

Prevalence and Severity Distribution of Type 2 Inflammation-Related Comorbidities Among Patients with Asthma, Chronic Rhinosinusitis with Nasal Polyps, and Atopic Dermatitis.

This observational study assessed the prevalence of co-existing type 2 inflammatory conditions [T2Cs; asthma, atopic dermatitis (AD), allergic rhinitis, and chronic rhinosinusitis with nasal polyps (CRSwNP)] in patients with moderate-to-severe (M/S) type 2 asthma, M/S CRSwNP, or M/S AD, in the real-world setting. Data from 761 physicians in the US and EUR5 were sourced from Adelphi Disease-Specific Programmes covering patients with M/S asthma (n = 899), M/S CRSwNP (n = 683), and M/S AD (n = 1497). At least one T2C was identified in 66%, 69%, and 46% of M/S asthma, M/S CRSwNP, and M/S AD cohorts, respectively, and 24%, 36% and 16% had at least two T2Cs; trends were similar in the US and EUR5. In patients with M/S asthma or M/S CRSwNP, T2Cs commonly presented as mild or moderate. The comorbidity burden suggests that an integrated treatment approach is warranted to address underlying type 2 inflammation in patients with M/S type 2 diseases.

Dupilumab provides early and durable improvement of symptoms in patients with chronic rhinosinusitis with nasal polyps.

Objectives: To evaluate within-patient symptom improvement in the dupilumab SINUS-24/-52 studies in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT02912468/NCT02898454). Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) on background intranasal corticosteroids. Patients daily reported symptoms of nasal congestion (NC), loss of smell (LoS) and rhinorrhoea on a scale of 0-3 (0 - no symptoms, 1 - mild, 2 - moderate, 3 - severe symptoms). The proportions of patients with moderate-to-severe symptoms (score ≥ 2) at baseline who improved to no-to-mild symptoms (score ≤ 1) were determined at Weeks 2, 24 (pooled studies) and 52 (SINUS-52). Subgroups with prior sinonasal surgery and coexisting asthma were analysed. Results: At baseline in the pooled intention-to-treat population (n = 724), the proportions of patients with scores ≥ 2 for NC, LoS and rhinorrhoea were 87, 94 and 64%, respectively. Significantly, more patients achieved scores ≤ 1 (no/mild symptoms) with dupilumab vs placebo for each symptom at each time point {Week 2 NC 12% vs 2% [odds ratio 8.9 (95% CI 3.0-26.3)], LoS 5% vs 1% [4.6 (1.3-16.8)], rhinorrhoea 9% vs 2% [4.8 (1.5-15.4)], all P < 0.05; Week 24 NC 54% vs 14% [8.7 (5.6-13.5)], LoS 43% vs 6% [14.4 (7.9-26.0)], rhinorrhoea 53% vs 16% [6.6 (4.1-10.9)], all P < 0.0001}. Results were similar in subgroups with prior surgery and coexisting asthma. Conclusion: Significantly, more patients achieved improvement from moderate-to-severe symptoms to no-to-mild symptoms with dupilumab than placebo, regardless of prior surgery or coexisting asthma. Improvement was observed as early as Week 2 and continued through to Week 52.

Impact of exacerbations on lung function, resource utilization, and productivity: results from an observational, prospective study in adults with uncontrolled asthma.

Background: Exacerbations have a major impact on the well-being of patients with uncontrolled asthma. This study evaluated lung function, healthcare resource utilization (HCRU), and productivity loss following asthma exacerbations.Methods: This single-center, observational, prospective cohort study recruited US patients presenting clinically with an acute asthma exacerbation; a reference group without exacerbations was included for comparison. Lung function (forced expiratory volume in 1 second [FEV1]) was collected at baseline, daily during Month 1, and monthly for Months 2-5, and reported as FEV1 percent predicted (FEV1pp). HCRU (outpatient visits to a healthcare practitioner, emergency room [ER] visits, and hospitalizations for asthma), oral corticosteroid (OCS) use, and asthma-related work/school absence were collected monthly for 6 months.Results: Overall, 150 patients were recruited (exacerbation: n=102; reference: n=48; mean [SD] age: 42.7 [15.2] and 49.6 [12.4] years; female: 73% and 71%). In both groups, similar trends were observed in FEV1, with significant improvement from baseline to Week 1 (p<0.05), followed by a continuous decline. FEV1p was 7.7% lower at baseline and 8.6% lower at Month 5 in the exacerbation group versus the reference group. The exacerbation group had significantly higher rates of OCS prescription during follow-up versus reference group (p=0.04). Over half (52.9%) of patients in the exacerbation group had a recurrent exacerbation during follow-up, increased HCRU (outpatient visits, ER visits, and hospitalizations), and impaired productivity.Conclusion: Although patients with exacerbations had rapid recovery of lung function, this was not maintained and declined faster than in patients without exacerbations. Additionally, patients experienced increased HCRU after exacerbations.

AROMA: real-world global registry of dupilumab for chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease of the nasal and paranasal sinuses. Dupilumab is a monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, which are key and central drivers of type 2 inflammation. In clinical trials, dupilumab significantly improved objective and patient-reported measures of CRSwNP versus placebo and was well tolerated. Dupilumab is approved in the European Union, USA and Japan as add-on maintenance treatment for adults with inadequately controlled CRSwNP. There exists an important evidence gap between efficacy and effectiveness data for dupilumab in severe CRSwNP. In order to bridge this gap, the AROMA prospective global registry (ClinicalTrials.gov: NCT04959448) was established. AROMA will collect long-term data on the utilisation, effectiveness and safety of dupilumab for CRSwNP treatment in real-world clinical practice. AROMA will enrol approximately 1000 adults starting dupilumab for severe CRSwNP across 120 global sites. Baseline data will include patient demographics, medical/surgical history and presence of type 2 comorbidities. Effectiveness outcome assessments will include objective measures of CRSwNP assessed as part of routine clinical care and various patient-reported questionnaires. Treatment patterns, concomitant medications and long-term safety will also be recorded. Results from AROMA, the first prospective, real-world, global registry to characterise patients with severe CRSwNP starting dupilumab, will provide evidence on the real impact of dupilumab in patients with CRSwNP and complement the data from randomised clinical trials. The registry will also provide evidence on disease progression in patients with CRSwNP, including those with coexisting diseases.

Immunolab: Combining targeted real-world data with advanced analytics to generate evidence at scale in immunology.

Real-world evidence (RWE) has traditionally been used by regulatory or payer authorities to inform disease burden, background risk, or conduct post-launch pharmacovigilance, but in recent years RWE has been increasingly used to inform regulatory decision-making. However, RWE data sources remain fragmented, and datasets are disparate and often collected inconsistently. To this end, we have constructed an RWE-generation platform, Immunolab, to facilitate data-driven insights, hypothesis generation and research in immunological diseases driven by type 2 inflammation. Immunolab leverages a large, anonymized patient cohort from the Optum electronic health record and claims dataset containing over 17 million patient lives. Immunolab is an interactive platform that hosts three analytical modules: the Patient Journey Mapper, to describe the drug treatment patterns over time in patient cohorts; the Switch Modeler, to model treatment switching patterns and identify its drivers; and the Head-to-Head Simulator, to model the comparative effectiveness of treatments based on relevant clinical outcomes. The Immunolab modules utilize various analytic methodologies including machine learning algorithms for result generation which can then be presented in various formats for further analysis and interpretation.

Improvement in Health-Related Quality of Life with Dupilumab in Patients with Moderate-to-Severe Asthma with Comorbid Chronic Rhinosinusitis with/without Nasal Polyps: An Analysis of the QUEST Study.

Patients with asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, increasing disease burden and complicating treatment. These post hoc analyses investigated disease-specific health-related quality of life (HRQoL) and general health status in the randomized, placebo-controlled QUEST study (NCT02414854) in patients treated with dupilumab for moderate-to-severe asthma with comorbid CRS. Patients received 300 mg of dupilumab or placebo every 2 weeks for 52 weeks. CRS HRQoL was assessed by the 22-item Sino-Nasal Outcome Test (SNOT-22; items scored 0-5). The 22 items are categorized into 5 domains (nasal, ear/facial, sleep, function, and emotion), and patients report the top 5 most important items affecting their health. General health status was assessed by Euro-QoL visual analog scale (EQ-VAS). Of 1902 patients, 382 (20.1%) self-reported comorbid CRS; 193 patients receiving dupilumab 300 mg q2w or matched placebo were included in this analysis. At baseline, the most impacted SNOT-22 domain was nasal, and general health status was below population norms. Patients rated "decreased sense of taste/smell," "nasal blockage," "cough," "reduced productivity," and "wake up tired" as the 5 most important SNOT-22 items affecting their health. Percentage change from baseline in SNOT-22 total score was significantly greater for dupilumab vs placebo at Weeks 24, 36, and 52 (all p < 0.05). Improvements from baseline were significantly greater for dupilumab vs placebo at Week 52 for all SNOT-22 domains (p < 0.05), except emotion. At Week 52, significant changes from baseline with dupilumab vs placebo were observed for all 5 most important SNOT-22 items affecting their health (all p < 0.05). EQ-VAS was significantly improved with dupilumab vs placebo by Week 12, with improvements sustained to Week 52 (all p < 0.01). In patients with moderate-to-severe asthma who self-reported comorbid CRS, dupilumab treatment vs placebo improved CRS-specific HRQoL and general health status.

Rapid and Continuing Improvements in Nasal Symptoms with Dupilumab in Patients with Severe CRSwNP.

Purpose: In the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies in adults with severe chronic rhinosinusitis with nasal polyps (CRSwNP), dupilumab significantly improved the co-primary endpoints of change from baseline to Week 24 in nasal polyp score (NPS) and nasal congestion/obstruction (NC) vs placebo on background intranasal corticosteroids (standard of care [SOC]). This post hoc analysis of SINUS-24/-52 investigated the direction and magnitude of within-patient change in these endpoints over time. Methods: NPS (scale 0-8) was assessed at Weeks 4, 8, 16, 24, 40, and 52 in SINUS-52 and Weeks 8, 16, and 24 in SINUS-24. Daily patient-reported NC scores (0 [no symptoms]-3 [severe symptoms]) were averaged over 28 days. Within-patient changes from baseline were assessed through Week 24 in pooled SINUS-24/-52 (n = 438/286 dupilumab/SOC) and through Week 52 in SINUS-52 (n = 150/153). Results: In SINUS-52, NPS improved in 70.0% of dupilumab-treated patients at Week 4 vs 31.8% with SOC (odds ratio [OR] 5.2 [95% confidence interval 3.1-8.8]) and 78.7% vs 28.2% at Week 52 (OR 10.6 [6.0-18.7]) (all p < 0.0001). NC improved in 73.3% of dupilumab-treated patients at Week 4 vs 46.7% with SOC (OR 3.2 [2.0-5.3]) and 86.9% vs 50.7% at Week 52 (OR 6.4 [3.5-11.5]) (all p < 0.0001). Clinically meaningful (≥1 point) improvements in NPS occurred in 55.7% and 72.3% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 16.9% and 16.2% with SOC. Clinically meaningful (≥1 point) improvements in NC occurred in 16.7% and 67.6% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 3.9% and 20.8% with SOC. At Week 52, NPS worsening from baseline was observed in 5.7% of dupilumab-treated patients vs 40.1% with SOC and NC worsening in 2.1% vs 20.8%, respectively. Conclusion: Dupilumab provided rapid, continuing, and clinically relevant improvements over time in NPS and NC in most patients with severe CRSwNP in the SINUS studies.

Content validity of a newly developed observer-reported measure for pediatric asthma in children aged 2-5 years.

BACKGROUND: An observer-reported outcome (ObsRO) measure assessing both symptom control and health-related quality of life (HRQoL) in children with asthma younger than 6 years is lacking. The objective of this study was to evaluate the content validity of the Pediatric Asthma Questionnaire (PAQ), a newly developed 6-item ObsRO measure for caregivers of children aged 2-5 years diagnosed with asthma. RESULTS: In-depth, qualitative interviews were conducted with 15 parents or caregivers. The first part of the interview was an open-ended discussion whereby participants were asked to describe their observations of their child's asthma symptoms and HRQoL impacts followed by a cognitive debriefing of a draft version of the PAQ. The most frequently reported symptoms were coughing (n = 15, 100%), wheezing (n = 14, 93%), and trouble breathing (n = 10, 67%). Overall, participants found the PAQ easy to complete and relevant to their child's experience with asthma, with most reporting the instructions, response scales, and recall period for the items to be appropriate. The majority of participants (93%) believed they could accurately report on the items included in the PAQ based on their observations of their child's asthma symptoms and impacts, or reliably get the information from the child's teacher, school, or caregiver when their child was not in their presence. One item was modified based on feedback about the phrase "oral steroids" to clarify modes of administration. A few other minor changes were incorporated into the PAQ following suggestions from participants, including replacing the phrase "how often" with "how many days" in one of the items to improve clarity and overall consistency with the response options. CONCLUSION: Qualitative data support the content validity of the PAQ as a fit-for-purpose and well-understood 6-item observer-reported outcome measure to evaluate both symptoms and asthma-specific HRQoL impacts experienced by pediatric asthma patients aged 2-5 years for use in clinical and real-world studies.