RESUMEN
BACKGROUND: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases. METHODS: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline. RESULTS: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups. CONCLUSIONS: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.).
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Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Antiasmáticos/administración & dosificación , Antiasmáticos/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Asma/fisiopatología , Biomarcadores/análisis , Pruebas Respiratorias , Niño , Método Doble Ciego , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado , Humanos , Inyecciones Subcutáneas , Pulmón/fisiopatología , Masculino , Óxido Nítrico/administración & dosificación , Gravedad del Paciente , Brote de los SíntomasRESUMEN
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 6-11â years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150â cells·µL-1 or fractional exhaled nitric oxide ≥20â ppb; n=350) were treated with dupilumab or placebo for 52â 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 ≥0.5â points); proportion of patients achieving well-controlled asthma or better (ACQ-7-IA ≤0.75â 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 ≤0.75â 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 6-11â 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.
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Antiasmáticos , Asma , Niño , Humanos , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Método Doble Ciego , Eosinófilos , Calidad de Vida , Resultado del TratamientoRESUMEN
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.
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Asma , Humanos , Adulto , Femenino , Asma/tratamiento farmacológico , Asma/epidemiología , Estudios Prospectivos , Volumen Espiratorio Forzado , Hospitalización , Corticoesteroides/uso terapéutico , Pulmón , Progresión de la EnfermedadRESUMEN
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.
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Asma , Dermatitis Atópica , Pólipos Nasales , Rinitis , Sinusitis , Humanos , Dermatitis Atópica/complicaciones , Dermatitis Atópica/epidemiología , Pólipos Nasales/complicaciones , Pólipos Nasales/epidemiología , Prevalencia , Rinitis/complicaciones , Rinitis/epidemiología , Inflamación , Asma/complicaciones , Comorbilidad , Sinusitis/complicaciones , Sinusitis/epidemiología , Enfermedad CrónicaRESUMEN
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),
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Pólipos Nasales , Rinitis Alérgica , Rinitis , Sinusitis , Humanos , Pólipos Nasales/complicaciones , Pólipos Nasales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Crónica , Sinusitis/complicaciones , Sinusitis/tratamiento farmacológico , Rinitis Alérgica/tratamiento farmacológico , Biomarcadores , Rinitis/complicaciones , Rinitis/tratamiento farmacológico , Resultado del Tratamiento , Calidad de VidaRESUMEN
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high symptom burden and reduced health-related quality of life (HRQoL). This report aimed to comprehensively understand the effects of dupilumab on domains of HRQoL, their individual elements, and health status in patients with severe CRSwNP from phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials. METHODS: Patients were randomized to dupilumab (n = 438) or placebo (n = 286) for 24 weeks (SINUS-24), or 52 weeks (SINUS-52). Disease-specific HRQoL using 22-item sino-nasal outcome test (SNOT-22), and health status using EuroQoL-visual analog scale (EQ-VAS) was evaluated in the pooled intention-to-treat (ITT) population (Week 24), SINUS-52 ITT (Week 52) and in the subgroups with/without asthma; non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD); and prior sinus surgery. RESULTS: At baseline, patients had poor disease-specific HRQoL and general health status and identified "Decreased sense of smell/taste" and "Nasal blockage" as the most important symptoms. Dupilumab significantly improved SNOT-22 total, domain (Nasal, Sleep, Function, Emotion, and Ear/facial), and 22-item scores, and EQ-VAS, at Week 24 vs placebo (all p < .0001), with continued improvements to Week 52 in SINUS-52. Improvements occurred irrespective of comorbid asthma, NSAID-ERD, or prior surgery. A significantly greater proportion of dupilumab-treated patients exceeded clinically meaningful thresholds for SNOT-22 total score and EQ-VAS vs placebo (all subgroups p < .05 except patients without surgery at Week 24). CONCLUSIONS: Dupilumab treatment led to significant clinically meaningful improvements across all aspects of disease-specific HRQoL, and general health status in patients with severe CRSwNP.
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Anticuerpos Monoclonales Humanizados , Pólipos Nasales , Calidad de Vida , Rinitis , Sinusitis , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/epidemiología , Enfermedad Crónica , Humanos , Pólipos Nasales/tratamiento farmacológico , Rinitis/tratamiento farmacológico , Sinusitis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) and type 2 asthma share the same inflammatory pathophysiology and are frequent comorbidities. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin 4 and interleukin 13, which are key and central drivers of type 2 inflammation. OBJECTIVE: We report the effect of dupilumab vs placebo on outcome measures of the upper and lower airways and health-related quality of life (HRQoL) in the pooled population of patients with CRSwNP and comorbid asthma from the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies. METHODS: In these randomized, double-blind, placebo-controlled trials, patients received subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks on a background of mometasone furoate nasal spray. Changes from baseline at week 24 in the upper and lower airway outcome measures are reported. RESULTS: Of the 724 patients randomized, 428 (59.1%) had comorbid asthma. In patients with asthma at week 24, dupilumab vs placebo improved the nasal polyp score (-2.04), patient-reported nasal congestion score (-1.04), Lund-Mackay computed tomography scan score (-6.43), peak nasal inspiratory flow (46.15 L/min), and 22-item sinonasal outcome test score (-21.42; all P < .001). The forced expiratory volume in 1 second and 6-item asthma control questionnaire scores were also markedly improved with dupilumab vs placebo. The most common adverse events (nasopharyngitis, headache, injection-site erythema, worsening of nasal polyposis, and asthma) were more frequent with placebo than dupilumab. CONCLUSION: Dupilumab improved upper and lower airway outcome measures and HRQoL in patients with severe CRSwNP and comorbid asthma and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Pólipos Nasales/complicaciones , Rinitis/tratamiento farmacológico , Sinusitis/tratamiento farmacológico , Adulto , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Subunidad alfa del Receptor de Interleucina-4/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Furoato de Mometasona/uso terapéutico , Rociadores Nasales , Placebos/uso terapéutico , Calidad de Vida/psicología , Receptores de Interleucina-13/antagonistas & inhibidores , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). OBJECTIVE: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. METHODS: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. RESULTS: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and ≥1 perennial aeroallergen specific immunoglobulin E (IgE) level ≥0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P < .05 for both) and improved FEV1 at week 12 by 0.14 L and 0.18 L (P < .01 for both); greater efficacy was observed in patients with elevated baseline blood eosinophil counts (≥300 cells/µL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. CONCLUSION: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitis-specific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR.
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Antialérgicos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Rinitis Alérgica Perenne/tratamiento farmacológico , Adulto , Biomarcadores , Método Doble Ciego , Eosinófilos/citología , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Calidad de Vida , Receptores Tipo II de Interleucina-4/antagonistas & inhibidoresAsunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Anticuerpos Monoclonales Humanizados , Enfermedad Crónica , Humanos , Pólipos Nasales/complicaciones , Pólipos Nasales/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Calidad de Vida , Rinitis/complicaciones , Rinitis/tratamiento farmacológico , Sinusitis/complicaciones , Sinusitis/tratamiento farmacológico , OlfatoRESUMEN
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.
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Anticuerpos Monoclonales Humanizados , Pólipos Nasales , Rinitis , Rinosinusitis , Sinusitis , Humanos , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/complicaciones , Prevalencia , Rinitis/tratamiento farmacológico , Rinitis/epidemiología , Rinitis/complicaciones , Sinusitis/tratamiento farmacológico , Sinusitis/epidemiología , Sinusitis/complicaciones , Inflamación , Enfermedad Crónica , Inmunoglobulina ERESUMEN
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.
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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.
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Anticuerpos Monoclonales Humanizados , Pólipos Nasales , Rinitis , Rinosinusitis , Sinusitis , Humanos , Enfermedad Crónica , Pólipos Nasales/complicaciones , Pólipos Nasales/tratamiento farmacológico , Calidad de Vida , Rinitis/complicaciones , Rinitis/tratamiento farmacológico , Sinusitis/complicaciones , Sinusitis/tratamiento farmacológico , Método Doble CiegoRESUMEN
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.
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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.
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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.
Asunto(s)
Antiasmáticos , Asma , Humanos , Anticuerpos Monoclonales/uso terapéutico , Calidad de Vida , Asma/complicaciones , Asma/tratamiento farmacológico , Asma/inducido químicamente , Método Doble Ciego , Resultado del TratamientoRESUMEN
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.
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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.
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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.