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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 , Criança , Humanos , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Método Duplo-Cego , Eosinófilos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Severe asthma exacerbations increase the risk of accelerated lung function decline. This analysis examined the effect of dupilumab on forced expiratory volume in 1 s (FEV1 ) in patients with moderate-to-severe asthma and elevated type 2 biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854). METHODS: Changes from baseline in pre- and post-bronchodilator (BD) FEV1 and 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients with elevated type 2 biomarkers at baseline (type 2-150/25: eosinophils ≥150 cells/µl and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2-300/25: eosinophils ≥300 cells/µl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation during the study) or non-exacerbators. RESULTS: In exacerbators and non-exacerbators, dupilumab increased pre-BD FEV1 by Week 2 vs placebo; differences were maintained to Week 52 (type 2-150/25: LS mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10-0.24) and 0.17 L (0.12-0.23); type 2-300/25: 0.22 L (0.13-0.30) and 0.21 L (0.15-0.28)), in exacerbators and non-exacerbators, respectively (p < .0001). Similar trends were seen for post-BD FEV1 . Dupilumab vs placebo also showed significantly greater improvements in post-BD FEV1 0-42 days after first severe exacerbation in type 2-150/25 (LSMD vs placebo: 0.13 L [0.06-0.20]; p = .006) and type 2-300/25 (0.14 L [0.06-0.22]; p = .001) patients. ACQ-5 improvements were greater with dupilumab vs placebo in both groups. CONCLUSION: Dupilumab treatment led to improvements in lung function independent of exacerbations and appeared to reduce the impact of exacerbations on lung function in patients who experienced a severe exacerbation during the study.
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Asma , Humanos , Asma/diagnóstico , Asma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Pulmão , BiomarcadoresRESUMO
BACKGROUND: Previous research has shown greater efficacy of dupilumab in patients with uncontrolled asthma and type 2 inflammation. We analyzed dupilumab's efficacy in patients from the TRAVERSE study with or without evidence of allergic asthma and type 2 inflammation per current GINA guidelines (≥150 eosinophils/µL or FeNO ≥20 ppb). METHODS: All patients aged ≥12 years who rolled over from the placebo-controlled QUEST study (NCT02414854) to TRAVERSE (NCT02134028) received add-on dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed annualized severe asthma exacerbation rates (AERs) and changes from parent-study baseline (PSBL) in pre-bronchodilator FEV1 and 5-item asthma control questionnaire (ACQ-5) score in patients with moderate-to-severe type 2 asthma with and without evidence of allergic asthma at PSBL. RESULTS: In TRAVERSE, dupilumab consistently reduced AER across all subgroups. By Week 96, dupilumab increased pre-bronchodilator FEV1 from PSBL by 0.35-0.41 L in patients receiving placebo during QUEST (placebo/dupilumab) and 0.34-0.44 L in those receiving dupilumab during QUEST (dupilumab/dupilumab) with an allergic phenotype at baseline. In patients without evidence of allergic asthma, pre-bronchodilator FEV1 improved by 0.38-0.41 L and 0.33-0.37 L, respectively. By Week 48, ACQ-5 scores decreased from PSBL by 1.63-1.69 (placebo/dupilumab) and 1.74-1.81 (dupilumab/dupilumab) points across subgroups with allergic asthma, and 1.75-1.83 (placebo/dupilumab) and 1.78-1.86 (dupilumab/dupilumab) in those without. CONCLUSIONS: Long-term treatment with dupilumab reduced exacerbation rates and improved lung function and asthma control in patients with asthma with type 2 inflammation as per current GINA guidance and irrespective of evidence of allergic asthma.
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Antiasmáticos , Asma , Humanos , Broncodilatadores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Inflamação/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.
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Antiasmáticos , Asma , Humanos , Criança , Broncodilatadores/uso terapêutico , Antiasmáticos/farmacologia , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/induzido quimicamente , Interleucina-13 , Método Duplo-Cego , Imunoglobulina E/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma. OBJECTIVE: To assess the pharmacokinetics of dupilumab and type 2 biomarker changes in children with type 2 asthma in VOYAGE. METHODS: Patients were randomized to dupilumab 100 mg (≤30 kg) or 200 mg (>30 kg) or placebo every 2 weeks for 52 weeks. Dupilumab concentrations and changes in type 2 biomarkers were assessed at each visit. RESULTS: Dupilumab concentrations in serum reached a steady state by week 12, with mean concentrations of 51.2 mg/L and 79.4 mg/L in children receiving dupilumab 100 mg every 2 weeks and 200 mg every 2 weeks, respectively (therapeutic range in adults and adolescents: 29-80 mg/L). Reductions in type 2 biomarkers were comparable between regimens, and greater in patients treated with dupilumab vs placebo. In children treated with dupilumab 100 mg and 200 mg every 2 weeks, the median percent changes (Q1-Q3) from baseline at week 52 were, respectively, -78.6% (-86.3 to -69.80) and -78.6% (-84.9 to -70.1) for serum total immunoglobulin E, -53.6% (-66.4 to -34.6) and -43.7% (-58.6 to -28.5) for thymus and activation-regulated chemokine; -25.7% (-60.0 to 27.6) and -33.3% (-60.6 to 16.6) for blood eosinophils, and -47.7% (-73.8 to 18.9) and -55.6% (-73.6 to -20.0) for fractional exhaled nitric oxide. CONCLUSION: Weight-tiered dose regimens achieved mean concentrations within the dupilumab therapeutic range. The median decreases in type 2 biomarker levels were similar between dose regimens. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948959.
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Anticorpos Monoclonais , Asma , Adulto , Adolescente , Humanos , Criança , Anticorpos Monoclonais/uso terapêutico , Método Duplo-Cego , Asma/tratamento farmacológico , Asma/induzido quimicamente , Inflamação/tratamento farmacológico , Biomarcadores , Resultado do TratamentoRESUMO
Background: Asthma creates a substantial burden on the pediatric healthcare system, particularly by those with moderate-to-severe disease. As few studies have been published specific to clinician evaluation and management of this population, this analysis serves to begin to identify educational needs and potential clinical impact.Methods: We conducted a case-based survey of US general pediatric (n = 227), allergy (n = 158), and pediatric pulmonology (n = 70) clinicians to understand the current approach to management of pediatric patients with moderate-to-severe asthma.Results: Results show inconsistencies in guideline adherence, identification of disease severity and control, referral practices, and knowledge of phenotypes, which may impact clinical decision making. While most clinicians refer to guidelines when managing pediatric patients with moderate-to-severe asthma, there is no preferred set, and they find the guidelines to be moderately useful. General pediatricians are more likely than specialists to have difficulty distinguishing control and severity and may not be familiar with the concept of asthma phenotype. Most surveyed pediatricians indicated they refer patients to a specialist, but did not always do so in the cases. Clinicians have little consensus on the best approach to manage patients with uncontrolled symptoms after optimized therapy. Many clinicians may have uncertainty about how elevated eosinophils or FeNO could affect patient management. Further, there may be gaps in incorporating parents and pediatric patients into shared decision-making in their care.Conclusions: Understanding the needs of those managing patients with moderate-to-severe asthma is critical to developing effective continuing education activities to improve patient outcomes.
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Asma , Hipersensibilidade , Humanos , Asma/diagnóstico , Asma/terapia , Consenso , Gravidade do PacienteRESUMO
OBJECTIVE: While advances in asthma care have been made in Latin America, there is still a large unmet need in patients with uncontrolled asthma. This post hoc analysis of the QUEST study assessed safety and efficacy of dupilumab in the subgroup of patients enrolled in Latin American countries with a type 2 inflammatory asthma phenotype (blood eosinophils ≥ 150cells/µL or FeNO ≥25ppb). METHODS: LIBERTY ASTHMA QUEST (NCT02414854) was a phase 3, multinational, randomized, double-blind, placebo-controlled study in patients with uncontrolled, moderate-to-severe asthma. Eligible patients ≥ 12 years of age were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on subcutaneous dupilumab 200 or 300 mg every 2 weeks or matched-volume placebos. Pre-specified co-primary efficacy endpoints were the annualized rate of severe exacerbations during the treatment period and the change from baseline in pre-bronchodilator FEV1 at treatment week 12. Asthma control, changes in asthma biomarker levels, and dupilumab safety were also evaluated. RESULTS: 530 (27.9% of the overall QUEST population; dupilumab: 353, placebo: 177) Latin-American patients were recruited; 420 (79.2%) had a type 2 inflammatory asthma phenotype. Dupilumab vs placebo reduced the annualized rate of severe exacerbations by 52.7% (P < 0.001) and increased pre-bronchodilator FEV1 at week 12 by 0.15 L (P < 0.001), in the type 2 population. Safety was consistent with the known dupilumab safety profile. CONCLUSIONS: Consistent with the results in the overall population, dupilumab reduced the risk of severe asthma exacerbations and improved lung function in Latin American patients with uncontrolled, moderate-to-severe asthma and a type 2 phenotype.
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Antiasmáticos , Asma , Humanos , Asma/tratamento farmacológico , América Latina , Broncodilatadores/uso terapêutico , Anticorpos Monoclonais , Método Duplo-Cego , Resultado do Tratamento , Antiasmáticos/efeitos adversosRESUMO
Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12. Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%. Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12. Trial Registration: NCT02948959.
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Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 inflammation in multiple diseases. This post hoc analysis of the Phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959) evaluated the efficacy of dupilumab in children aged 6 to 11 years with moderate-to-severe asthma with a type 2 inflammatory phenotype (blood eosinophil count ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 ppb) and a history of 1, 2, or ≥3 prior exacerbations. The impact of baseline type 2 biomarker levels on the efficacy of dupilumab in this population was also investigated. Patients and Methods: Patients were stratified by the number of exacerbations in the prior year (1, 2, or ≥3) and level of FeNO or blood eosinophil count at baseline. Endpoints included rate of severe exacerbations, percentage of non-exacerbators, and change from baseline in both lung function parameters (pre- and post-bronchodilator [BD] percent predicted forced expiratory volume in 1 s (ppFEV1) and ppFEV1/forced vital capacity [FVC] ratio) and Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) score. Results: A total of 350 patients were included in this analysis. Across patients with 1, 2, or ≥3 prior exacerbations and different levels of type 2 biomarkers, dupilumab reduced the risk of severe asthma exacerbations vs placebo by 53.0-96.0% and improved both pre-BD ppFEV1 and pre-BD FEV1/FVC ratio at Week 52. Dupilumab led to significant reductions in ACQ-7-IA scores in all groups of patients by Week 52. Conclusion: In children with uncontrolled, moderate-to-severe asthma with a type 2 phenotype, dupilumab consistently reduced the risk of asthma exacerbations, improved lung function, and reduced ACQ-7-IA scores, regardless of exacerbation history.
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BACKGROUND: TRAVERSE (NCT02134028), a phase 3 open-label extension study, assessed dupilumab safety and efficacy in patients with asthma aged ≥12 years who completed a previous dupilumab asthma study. This analysis evaluated changes in multiple lung function parameters in patients with moderate-to-severe asthma with elevated type 2 biomarkers (baseline eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥25 ppb) who completed QUEST (parent study) and 2 years of dupilumab treatment in TRAVERSE. METHODS: Endpoints analyzed included: pre-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory flow (FEF25-75 %), and pre- and post-bronchodilator FEV1/FVC at parent study baseline (PSBL) at Weeks 0, 2, 48, and 96 in TRAVERSE, as well as pre- and post-bronchodilator FEV1 slopes in QUEST and TRAVERSE. Statistical analyses were descriptive. RESULTS: Dupilumab improved pre-bronchodilator FEV1, FVC, and FEF25-75 % in QUEST; these improvements were sustained in TRAVERSE. In QUEST patients who received placebo, dupilumab initiation in TRAVERSE resulted in rapid lung function improvements. Mean (standard deviation) changes from PSBL at TRAVERSE Weeks 48 and 96 in pre-bronchodilator FEV1 were 0.52 (0.59) and 0.45 (0.49) L in the dupilumab/dupilumab group and 0.47 (0.42) and 0.44 L (0.45) in the placebo/dupilumab group, respectively. Similar trends were observed for FVC and FEF25-75 %. Dupilumab also improved FEV1 slopes in QUEST and TRAVERSE. CONCLUSION: Dupilumab demonstrated sustained improvements across multiple spirometric lung function measurements for up to 3 years; patients who received placebo in QUEST experienced rapid lung function improvement upon initiation of dupilumab in TRAVERSE.
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Asma , Broncodilatadores , Humanos , Broncodilatadores/uso terapêutico , Asma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Pulmão , Método Duplo-CegoRESUMO
Increased understanding of the underlying pathophysiology has highlighted the heterogeneity of asthma and identified that most children with asthma have type 2 inflammation with elevated biomarkers, such as blood eosinophils and/or fractional exhaled nitric oxide. Although in the past most of these children may have been categorized as having allergic asthma, identifying the type 2 inflammatory phenotype provides a mechanism to explain both allergic and non-allergic triggers in pediatric patients with asthma. Most children achieve control with low to medium doses of inhaled corticosteroids. However, in a small but significant proportion of children, asthma remains uncontrolled despite maximum conventional treatment, with an increased risk of severe exacerbations. In this review, we focus on the role of type 2 inflammation and allergic processes in children with asthma, together with evidence of the efficacy of available treatment options for those who experience severe symptoms.
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BACKGROUND: The phase 3 VOYAGE (NCT02948959) and open-label extension EXCURSION (NCT03560466) studies evaluated dupilumab in children (6-11 years) with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed the efficacy and safety of add-on dupilumab 200 mg every 2 weeks (q2w), the largest dose cohort in both studies, in children from VOYAGE who participated in EXCURSION. METHODS: Annualized rate of severe asthma exacerbations (AERs), change in prebronchodilator percent predicted forced expiratory volume in 1 s (ppFEV1), and treatment-emergent adverse events were assessed in children with moderate-to-severe asthma who received dupilumab 200 mg q2w in VOYAGE and EXCURSION (dupilumab/dupilumab arm) and those who received placebo in VOYAGE and dupilumab 200 mg q2w in EXCURSION (placebo/dupilumab arm). These endpoints were also assessed in children with moderate-to-severe type 2 asthma (defined as blood eosinophil count ≥150 cells/µL or FeNO ≥20 ppb at the parent study baseline [PSBL]). RESULTS: In the overall population, dupilumab reduced AER and improved prebronchodilator ppFEV1 in the dupilumab/dupilumab arm (n = 158) for up to 2 years. Children receiving placebo/dupilumab (n = 85) showed similar reductions after initiation of dupilumab 200 mg q2w in EXCURSION. Similar results were observed for children with type 2 asthma at PSBL. The safety profile was consistent with the known safety profile of dupilumab. CONCLUSION: In children (6-11 years) with uncontrolled moderate-to-severe type 2 asthma, dupilumab 200 mg reduced exacerbation rates and improved lung function for up to 2 years and showed safety consistent with the known dupilumab safety profile.
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BACKGROUND: Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. OBJECTIVE: This post hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). METHODS: Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at week 52 were performed as a function of the fold change in FeNO at week 52 and the maximum fold change in Eos over weeks 0-12 (also change from baseline in pre-BD FEV1 at week 12). RESULTS: The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by week 2 and then gradually to week 52 in patients treated with dupilumab versus placebo; Eos, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with the change in biomarkers in either treatment group. The change from baseline in pre-BD FEV1 at week 52 was inversely associated with the fold change in FeNO in both groups, with a significant difference between the dupilumab and placebo curves (P = .014), and was positively associated with the fold change in Eos in both groups (P = .022). CONCLUSIONS: Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed a predictive value for lung function improvement; for FeNO, this was specific to the dupilumab treatment arm.
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Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Biomarcadores , Eosinófilos , Óxido Nítrico , Humanos , Asma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Antiasmáticos/uso terapêutico , Volume Expiratório Forçado , Índice de Gravidade de Doença , Método Duplo-Cego , Resultado do Tratamento , Progressão da Doença , Contagem de LeucócitosRESUMO
BACKGROUND: 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. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma. OBJECTIVES: The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients. METHODS: RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter. PLANNED OUTCOMES: Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded. CONCLUSION: RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04287621.
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Asma , Qualidade de Vida , Humanos , Estudos Prospectivos , Asma/tratamento farmacológico , Sistema de Registros , Resultado do TratamentoRESUMO
BACKGROUND: Type 2 cytokines IL-4/IL-5/IL-13 play an important role in pathogenesis of type 2 conditions, including asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In phase 2b (P2B) (NCT01854047) and phase 3 VENTURE (NCT02528214), dupilumab reduced annualized severe exacerbation rates (AER), improved forced expiratory volume in 1 second (FEV1), and was generally well tolerated in patients with uncontrolled, moderate-to-severe, or oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: The post hoc assessment of dupilumab efficacy versus placebo in P2B and VENTURE in patients stratified by allergic status. METHODS: Allergic asthma was defined as total serum IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline. AER, prebronchodilator (BD) FEV1, FEV1/forced vital capacity (FVC) ratio, asthma control (5-item Asthma Control Questionnaire), health-related quality of life (HRQoL; Asthma Quality of Life Questionnaire), type 2 biomarkers, specific IgE, and OCS reduction (VENTURE only) were assessed. RESULTS: In patients with allergic asthma, dupilumab (P2B: pooled 200/300 mg; VENTURE: 300 mg) every 2 weeks versus placebo reduced AER (P2B: -60%, P < .01; VENTURE: -72%, P < .001), and, in P2B, increased pre-BD FEV1 (P < .01) and FEV1/FVC (P < .05). In both studies, dupilumab significantly improved asthma control and HRQoL and reduced most type 2 biomarkers. Dupilumab significantly reduced OCS use in VENTURE. Similar benefits were observed in patients without evidence of allergic asthma. CONCLUSIONS: Dupilumab significantly reduced AER and improved lung function, asthma control, and HRQoL in patients with or without evidence of allergic asthma.
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Antiasmáticos , Asma , Humanos , Antiasmáticos/uso terapêutico , Interleucina-4 , Interleucina-13 , Qualidade de Vida , Corticosteroides/uso terapêutico , Imunoglobulina E , Biomarcadores , Método Duplo-CegoRESUMO
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.
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Antiasmáticos , Asma , Humanos , Anticorpos Monoclonais/uso terapêutico , Qualidade de Vida , Asma/complicações , Asma/tratamento farmacológico , Asma/induzido quimicamente , Método Duplo-Cego , Resultado do TratamentoRESUMO
Background: Dupilumab has been shown to improve clinical outcomes long term while reducing oral corticosteroid (OCS) dose in patients with severe OCS-dependent asthma. This post hoc analysis assesses the impact of OCS dose at baseline (≤10 or >10â mg·day-1) on long-term outcomes of dupilumab treatment. Methods: Annualised severe asthma exacerbation rates, forced expiratory volume in 1â s (FEV1), measures of asthma control and quality of life, and OCS dose were evaluated in patients from the phase 3 VENTURE trial with severe OCS-dependent asthma, further categorised by OCS dose ≤10 or >10â mg·day-1 at parent study baseline (PSBL), who enrolled in TRAVERSE. Results: Dupilumab reduced the annualised exacerbation rate in VENTURE, and it remained low throughout TRAVERSE (0.202-0.265 (OCS ≤10â mg·day-1 at PSBL) and 0.221-0.366 (OCS >10â mg·day-1 at PSBL)). Improvements in pre-bronchodilator FEV1, asthma control and quality of life observed in VENTURE dupilumab patients were sustained throughout TRAVERSE. Patients on placebo during VENTURE showed rapid improvements in FEV1 upon initiating dupilumab in TRAVERSE, which were sustained to the end of TRAVERSE. Reductions in OCS dose observed in VENTURE were maintained throughout TRAVERSE, with more than two-thirds of patients achieving reductions in OCS doses to ≤5â mg·day-1 by TRAVERSE week 48. Conclusions: Improvements in clinical outcomes and reductions in OCS dose with dupilumab observed in VENTURE were maintained throughout TRAVERSE, regardless of baseline disease severity. Patients who switched from placebo in VENTURE to dupilumab in TRAVERSE had improved clinical outcomes and reductions in OCS dose comparable to those given dupilumab in VENTURE.
RESUMO
BACKGROUND AND OBJECTIVE: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV1), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS). METHODS: Adjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV1, and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 µg) ICS with baseline blood eosinophils ≥150 cells/µL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV1/forced vital capacity (<70%/≥70%), blood eosinophil level, exacerbation history, median baseline pre-bronchodilator FEV1, age at asthma onset (≤40/>40 years), median FEV1 reversibility, body mass index (<30/≥30 kg/m2), and sex. RESULTS: Dupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS. CONCLUSION: Dupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline. CLINICAL TRIAL REGISTRATION NUMBER: NCT02414854.
Assuntos
Antiasmáticos , Asma , Corticosteroides/uso terapêutico , Antiasmáticos/efeitos adversos , Anticorpos Monoclonais Humanizados , Broncodilatadores/uso terapêutico , Método Duplo-Cego , Humanos , Interleucina-13RESUMO
BACKGROUND: Many patients with severe asthma require chronic corticosteroid treatment to maintain asthma control. RESEARCH QUESTION: Are the reduction in oral corticosteroid (OCS) use and the clinical efficacy observed with dupilumab treatment maintained long-term in patients with severe OCS-dependent asthma? STUDY DESIGN AND METHODS: The LIBERTY ASTHMA TRAVERSE study (ClinicalTrials.gov identifier: NCT02134028) was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, we present the data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study (ClinicalTrials.gov identifier: NCT02528214), a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma, and continued in the TRAVERSE study. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control. RESULTS: Ninety patients treated with dupilumab/dupilumab and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile. INTERPRETATION: In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02134028 (TRAVERSE) and NCT02528214 (VENTURE); URL: www. CLINICALTRIALS: gov.