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1.
Artigo em Inglês | MEDLINE | ID: mdl-31351189

RESUMO

BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13 signaling, key drivers of type 2 inflammation. In the phase 3 study (NCT02414854), add-on dupilumab 200mg/300mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in those with a high baseline type 2 phenotype. OBJECTIVE: To assess the efficacy and safety of dupilumab in uncontrolled, moderate-to-severe asthma patients with or without self-reported comorbid chronic rhinosinusitis (CRS or non-CRS). METHODS: Comorbid CRS was self-reported by patients using an e-diary. Annualized severe exacerbation rates, changes from baseline in pre- and post-bronchodilator FEV1, patient-reported outcomes, type 2 biomarkers, and safety were assessed. RESULTS: CRS was self-reported by 382/1902 (20.1%) patients. Dupilumab 200mg/300mg reduced annualized severe exacerbation rates by 63%/61%, respectively, in patients with CRS, and by 42%/40% in patients without CRS (all P<.001 vs placebo). Dupilumab also improved lung function and patient-reported asthma control and quality of life, and suppressed type 2 biomarkers versus placebo in both subgroups. Clinical responses were rapid, with near-maximal responses observed at the earliest measured timepoints and sustained at week 52. Improvements observed in the CRS subgroup were similar to or numerically greater than those in the non-CRS subgroup. CONCLUSION: Dupilumab showed efficacy and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma with or without CRS.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30138668

RESUMO

BACKGROUND: In a pivotal, phase 2b study (NCT01854047) in patients with uncontrolled persistent asthma, despite using medium-to-high-dose inhaled corticosteroids plus long-acting ß2 agonists, dupilumab improved lung function, reduced severe exacerbations, and showed an acceptable safety profile. OBJECTIVE: To assess the impact of dupilumab on asthma control, symptoms, quality of life (QoL), and productivity. METHODS: Data are shown for the intention-to-treat population receiving dupilumab 200/300 mg every 2 weeks (doses being assessed in phase 3; NCT02414854), or placebo. Predefined analyses of total scores were conducted at week 24 for the 5-item Asthma Control Questionnaire (ACQ-5), patient-reported morning/evening (AM/PM) asthma symptoms, Asthma Quality of Life Questionnaire (AQLQ), and asthma-related productivity loss. Responder rate analyses for these measures, subgroup analyses by baseline characteristics, and asthma-related productivity loss analyses were conducted post hoc. RESULTS: Data from 465 patients were analyzed (158 placebo; 307 dupilumab). Both dupilumab doses significantly improved scores through week 24 (all outcomes, overall population). The proportion of patients meeting or exceeding the minimal clinically important difference for the overall population were significantly greater vs placebo (P < .05) for ACQ-5 (range, 72.6%-76.7% vs 61.4%), for AM/PM asthma symptoms score (48.7%-54.1% vs 34.2% and 52.7%-53.5% vs 34.2%, respectively) and for AQLQ (64.0%-65.0% vs 51.3%). The effect of dupilumab was consistent across most subgroups. Productivity loss was significantly higher in placebo- vs dupilumab-treated patients (P < .0001). CONCLUSION: Dupilumab produced significant, clinically meaningful improvements in asthma control, symptoms, QoL, and productivity. REGISTRATION: ClinicalTrials.gov Identifier: NCT01854047.

4.
Adv Ther ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725983

RESUMO

INTRODUCTION: Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. METHODS: Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. CONCLUSION: Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc. CLINICAL TRIALS. GOV IDENTIFIER: NCT02414854.

5.
N Engl J Med ; 378(26): 2486-2496, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29782217

RESUMO

BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. METHODS: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. RESULTS: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. CONCLUSIONS: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Adolescente , Adulto , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Asma/classificação , Broncodilatadores/uso terapêutico , Criança , Método Duplo-Cego , Quimioterapia Combinada , Eosinofilia/induzido quimicamente , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Injeções Subcutâneas/efeitos adversos , Análise de Intenção de Tratamento , Interleucina-13 , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-4/antagonistas & inibidores , Adulto Jovem
6.
N Engl J Med ; 378(26): 2475-2485, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29782224

RESUMO

BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. METHODS: We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. RESULTS: The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). CONCLUSIONS: In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Glucocorticoides/administração & dosagem , Administração Oral , Adolescente , Adulto , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Asma/classificação , Criança , Método Duplo-Cego , Quimioterapia Combinada , Eosinofilia/induzido quimicamente , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Injeções Subcutâneas/efeitos adversos , Análise de Intenção de Tratamento , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-4/antagonistas & inibidores , Adulto Jovem
7.
J Allergy Clin Immunol ; 142(1): 171-177.e1, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29355679

RESUMO

BACKGROUND: Dupilumab, an anti-IL-4 receptor α mAb, inhibits IL-4/IL-13 signaling, key drivers of type 2/TH2 immune diseases (eg, atopic/allergic disease). In a pivotal, phase 2b study (NCT01854047), dupilumab reduced severe exacerbations, improved lung function and quality of life, and was generally well tolerated in patients with uncontrolled persistent asthma despite using medium-to-high-dose inhaled corticosteroids plus long-acting ß2-agonists. OBJECTIVE: To examine dupilumab's effect on the 22-item Sino-Nasal Outcome Test (SNOT-22) total score and its allergic rhinitis (AR)-associated items in asthma patients with comorbid perennial allergic rhinitis (PAR). METHODS: A post hoc analysis reporting data from the phase 2b study for the 200 and 300 mg every 2 week (q2w) doses under investigation in phase 3 (NCT02414854) was carried out. PAR was defined at study entry as a specific response to typical perennial antigens (IgE ≥0.35 Ku/L). RESULTS: Overall, 241 (61%) patients had PAR. In asthma patients with PAR, dupilumab 300 mg q2w versus placebo significantly improved SNOT-22 total score (least squares mean difference, -5.98; 95% CI, -10.45 to -1.51; P = .009) and all 4 AR-associated symptoms evaluated (nasal blockage, -0.60; 95% CI, -0.96 to -0.25; runny nose, -0.67; 95% CI, -1.04 to -0.31; sneezing, -0.55; 95% CI, -0.89 to -0.21; postnasal discharge, -0.49; 95% CI, -0.83 to -0.16; all P < .01). Dupilumab 200 mg q2w demonstrated numerical, but not statistically significant, decreases in SNOT-22 total score (-1.82; 95% CI, -6.46 to 2.83; P = .443 vs placebo) and in each AR-associated symptom. In patients without PAR, no differences were observed for these measures versus placebo. CONCLUSIONS: Dupilumab 300 mg q2w significantly improved AR-associated nasal symptoms in patients with uncontrolled persistent asthma and comorbid PAR.

9.
Lancet ; 388(10039): 31-44, 2016 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-27130691

RESUMO

BACKGROUND: Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist, irrespective of baseline eosinophil count. METHODS: We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per µL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. FINDINGS: 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per µL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per µL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per µL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per µL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per µL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%). INTERPRETATION: Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting ß2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. FUNDING: Sanofi-Genzyme and Regeneron Pharmaceuticals.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Asma/tratamento farmacológico , Administração por Inalação , Adulto , Antiasmáticos/uso terapêutico , Asma/fisiopatologia , Testes Respiratórios , Combinação Budesonida e Fumarato de Formoterol/uso terapêutico , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Combinação Fluticasona-Salmeterol/uso terapêutico , Volume Expiratório Forçado , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Combinação Furoato de Mometasona e Fumarato de Formoterol/uso terapêutico , Óxido Nítrico/análise , Resultado do Tratamento
10.
Lancet ; 387(10013): 40-52, 2016 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-26454361

RESUMO

BACKGROUND: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS: Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING: Sanofi and Regeneron Pharmaceuticals.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Adolescente , Adulto , Idoso , Canadá , República Tcheca , Método Duplo-Cego , Feminino , Alemanha , Humanos , Hungria , Injeções Subcutâneas , Japão , Masculino , Pessoa de Meia-Idade , Polônia , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos , Adulto Jovem
11.
Pediatr Pulmonol ; 49(5): 441-50, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24019197

RESUMO

BACKGROUND: The bronchodilatory effect of mometasone furoate/formoterol fumarate (MF/F) administered by metered-dose inhaler (MDI) with or without a spacer has not been evaluated previously in children aged 5-11 years. METHODS: This was a randomized, multicenter, placebo-controlled, single-dose, four-period crossover study. Children with persistent asthma aged 5-11 years participated in this study. Subjects used inhaled corticosteroids with/without long-acting beta-2 agonists for 12 weeks before enrollment and at screening had forced expiratory volume in 1 sec (FEV1 ) ≥70% predicted. Subjects received MF/F MDI 100/10 µg with/without spacer (AeroChamber Plus® with Flow-Vu® Anti-Static Valved Holding Chamber), F-Dry Powder Inhaler (F-DPI) 10 µg, and placebo MDI with/without spacer in separate treatment periods. The primary endpoint was FEV1 area under the curve from 0 to 12 hr (AUC0-12hr ) for the comparison of MF/F with spacer versus placebo. Secondary measurements included MF/F without spacer versus placebo, as well as MF/F with spacer versus MF/F without spacer, and F-DPI versus placebo. Analysis was performed with an analysis of covariance model for a crossover study. RESULTS: Data from 87 subjects were analyzed. MF/F with spacer demonstrated a larger change in mean FEV1 AUC0-12hr versus placebo (115 vs. -9 mL), with a treatment difference of 124 mL (95% CI 94-154, P < 0.001). Similarly, MF/F without spacer versus placebo resulted in a 102 mL difference in mean-adjusted FEV1 AUC0-12hr (95% CI 73-131, P < 0.001), whereas the difference between MF/F with spacer versus MF/F without spacer was 22 mL (95% CI -8 to 52, P = 0.144). The difference between F-DPI versus placebo was 106 mL (95% CI 77-135, P < 0.001). No unexpected adverse events were observed. CONCLUSIONS: In this trial, MF/F MDI 100/10 µg demonstrated significant bronchodilation in children aged 5-11 years regardless of the use of a spacer. No difference in bronchodilation was observed between MF/F MDI and F-DPI.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Etanolaminas/uso terapêutico , Espaçadores de Inalação , Inaladores Dosimetrados , Pregnadienodiois/uso terapêutico , Área Sob a Curva , Criança , Pré-Escolar , Estudos Cross-Over , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol , Humanos , Masculino , Furoato de Mometasona , Resultado do Tratamento
12.
World Allergy Organ J ; 6(1): 5, 2013 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-23663488

RESUMO

BACKGROUND: In surveys of children with allergic rhinitis (AR), nasal congestion has been identified as the most frequently experienced and bothersome symptom. This analysis was conducted to investigate the effect of mometasone furoate nasal spray (MFNS) on congestion in children with AR. METHODS: Two multicenter, double-blind, placebo-controlled studies randomly assigned children to MFNS 100 µg or placebo, 1 spray/nostril QD for 4 weeks (Study 1: ages 6-11 years with seasonal AR [SAR] ≥1 year; Study 2: ages 3-11 years with perennial AR [PAR] ≥1 year). Least square (LS) means were obtained from an ANCOVA model with treatment and study center effects, with baseline score as a covariate. We conducted post hoc evaluation of changes from baseline in AM/PM PRIOR (average of reflective AM and PM scores) nasal congestion (0=none to 3=severe). RESULTS: Study 1: MFNS (n=134) reduced congestion significantly more than placebo (n=135) on day 2 (P=.004) and on 23/29 days (P≤.037). Change from baseline was -0.53 and -0.28 for MFNS and placebo (P<.001) over days 1-15 and -0.64 and -0.38 for MFNS and placebo (P<.001) over days 1-29. Study 2: MFNS (n=185) reduced congestion significantly more than placebo (n=189) on day 3 (P=.015) and on 22/29 days (P≤.047). Change from baseline was -0.56 and -0.36 for MFNS and placebo (P<.001) over days 1-15 and -0.64 and -0.45 for MFNS and placebo (P<.001) over days 1-29. MFNS was well tolerated, with no unusual or unexpected adverse events. CONCLUSION: MFNS effectively relieved nasal congestion and was well tolerated in children with SAR or PAR.

13.
Am J Rhinol Allergy ; 27(2): 102-8, 2013 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23562197

RESUMO

BACKGROUND: Allergic rhinitis (AR) and associated congestion adversely affect patients' lives. The intranasal corticosteroid mometasone furoate nasal spray (MFNS) is effective for AR symptoms including nasal congestion, and the intranasal decongestant oxymetazoline (OXY) is effective against nasal congestion, but the combination has not been fully studied. This study was designed to assess the efficacy of the combination of MFNS and OXY for the relief of seasonal allergic rhinitis (SAR) symptoms. METHODS: This phase 2 controlled clinical trial randomized adolescent and adult subjects (≥12 years; 2-year SAR) to MFNS q.d. (200 µg) + 3 sprays/nostril of OXY 0.05% (MFNS + OXY3); MFNS q.d. + 1 spray/nostril of OXY (MFNS + OXY1); MFNS q.d.; OXY b.i.d.; or placebo for 15 days, with 1-week follow-up. Coprimary end points were change from baseline in morning/evening (A.M./P.M.) instantaneous (NOW) total nasal symptom score (TNSS) over days 1-15 and AUC (AUC[0-4 hr]) change from baseline in day 1 congestion. RESULTS: In 705 subjects, both combinations reduced A.M./P.M. NOW TNSS over days 1-15 significantly more than OXY b.i.d. or placebo (p ≤ 0.002). Mean standardized AUC(0-4 hr) day 1 congestion change from baseline was significantly greater in combination and OXY b.i.d. groups (MFNS + OXY3, -0.92; MFNS + OXY1, -0.80; OXY b.i.d., -1.06) versus placebo (-0.57) and MFNS q.d. (-0.63). Combinations and MFNS q.d. were significantly effective for A.M./P.M. NOW TNSS over each weekly period; OXY b.i.d. was superior to placebo in week 1. Adverse events (AEs) were few and similar across treatments; one MFNS q.d. and one placebo subject experienced a serious AE, with neither considered treatment related. CONCLUSION: Combining MFNS with OXY relieves SAR symptoms, including congestion, with faster onset of action than MFNS q.d. and better sustained efficacy than OXY b.i.d.


Assuntos
Antialérgicos/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Obstrução Nasal/tratamento farmacológico , Sprays Nasais , Oximetazolina/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Antialérgicos/efeitos adversos , Criança , Quimioterapia Combinada , Seguimentos , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Pessoa de Meia-Idade , Oximetazolina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
14.
Pediatr Allergy Immunol ; 24(1): 33-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23331528

RESUMO

BACKGROUND: Mometasone furoate nasal spray (MFNS) improves nasal symptoms and reduces polyp size in adults with nasal polyposis. This 4-month, multinational, randomized, double-blind study was conducted to assess the safety of MFNS in pediatric subjects aged 6-17 yr. METHODS: Subjects aged 6-11 yr with bilateral nasal polyps received MFNS 100 µg once or twice daily or placebo; those aged 12-17 yr received MFNS 200 µg once or twice daily or placebo. End-points included change in 24-h urinary free cortisol (primary), change in 24-h urinary free cortisol corrected for creatinine (key secondary), and adverse events. Efficacy parameters included polyp size, nasal symptoms, and investigator-evaluated therapeutic response, although the study was not powered for statistical analysis of efficacy. RESULTS: Least squares baseline mean urinary free cortisol level (nmol/24 h) for both age groups combined (N = 127) was 49.5 in the MFNS once-daily group, 39.6 in the MFNS twice-daily group, and 49.8 in the placebo group. Change in 24-h urinary free cortisol did not significantly differ among MFNS- and placebo-treated subjects. Least squares mean 24-h urinary free cortisol levels corrected for creatinine also showed no significant differences among MFNS- and placebo-treated subjects. No safety issues emerged. CONCLUSIONS: Results of this study confirm the safety profile of MFNS in pediatric patients with bilateral nasal polyps over 4 months, even at double the recommended pediatric dosage for allergic rhinitis.


Assuntos
Anti-Inflamatórios/efeitos adversos , Pólipos Nasais/tratamento farmacológico , Pregnadienodiois/efeitos adversos , Administração Intranasal , Adolescente , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Furoato de Mometasona , Sprays Nasais , Pregnadienodiois/administração & dosagem , Pregnadienodiois/uso terapêutico , Resultado do Tratamento
15.
J Allergy Clin Immunol Pract ; 1(6): 649-55.e1, 2013 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24565713

RESUMO

BACKGROUND: Associations of inhaled corticosteroids (ICS) with bone mineral density (BMD) loss have not been characterized consistently. OBJECTIVE: This randomized, double-blind study assessed effects of mometasone furoate (MF) administered via dry powder inhaler on BMD of patients with persistent asthma. METHODS: Adults with mild-moderate persistent asthma who did not receive ICS for ≥3 months were randomized to MF 400 µg once daily (QD) in the evening (pm), MF 200 µg QD pm, montelukast sodium (ML) 10 mg QD pm, or fluticasone propionate (FP) 250 µg twice daily. Included patients had 25-hydroxy vitamin D levels ≥15 ng/mL at baseline. All the patients received calcium and vitamin D supplements for daily use during the trial. Duplicate BMD scans were done at baseline, 6 months, and 1 year. The mean percentage change in lumbar spine (LS) BMD from baseline to end point for MF 400 µg versus ML 10 mg was the primary analysis. Changes from baseline in left total femur BMD and femoral neck BMD were secondary assessments. RESULTS: At the end point, mean LS BMD increased 0.9% (MF 400 µg), 1.2% (ML), 0.7% (MF 200 µg), and 1.1% (FP), with no significant differences for MF 400 µg versus ML (-0.3% [95% CI, -1.01 to 0.27]) for LS BMD. No significant differences among treatments occurred for changes in left total femur BMD; all were slight increases. Changes in femoral neck BMD were 0.4% (MF 400 µg), -0.2% (ML), -0.2% (MF 200 µg), and -0.4% (FP); only the difference between MF 400 µg and FP was statistically significant (P = .044). CONCLUSION: No detrimental effects on lumbar BMD were observed after up to 1 year of treatment with MF in comparison with ML for patients who received calcium and vitamin D supplements.


Assuntos
Acetatos/administração & dosagem , Androstadienos/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Pregnadienodiois/administração & dosagem , Quinolinas/administração & dosagem , Administração por Inalação , Administração Oral , Adulto , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Fêmur , Fluticasona , Humanos , Masculino , Furoato de Mometasona , Comprimidos
16.
Ann Allergy Asthma Immunol ; 108(5): 359-62, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22541408

RESUMO

BACKGROUND: Intranasal steroids relieve nasal symptoms and ocular itch in allergic rhinitis. Itchy ear and palate are also common and bothersome symptoms but have received little attention in clinical trials of allergic rhinitis. OBJECTIVE: To ascertain the efficacy of mometasone furoate nasal spray in alleviating itchy ear and palate in seasonal allergic rhinitis. METHODS: Data were pooled from 4 randomized, double-blind, placebo-controlled trials of mometasone furoate nasal spray, 200 µg/d. Participants rated ear and palate itching from baseline through treatment day 15 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. RESULTS: A total of 962 study participants received mometasone furoate nasal spray or placebo. Baseline least squares mean itchy ear and palate score was 1.81 for participants receiving mometasone furoate nasal spray (n = 480) and 1.85 for participants receiving placebo (n = 482). Mometasone furoate nasal spray was associated with a greater decrease in itchy and ear palate score vs placebo during the 15-day study period (least squares mean change, -0.73 vs -0.45; P < .001). The difference reached significance on day 2 and persisted through day 15 (P ≤ .01 for each day). Results were similar in a subgroup of patients (n = 305) with moderate-to-severe symptoms at baseline. Adverse events with mometasone furoate nasal spray were similar to those observed in other studies of intranasal steroid therapy. CONCLUSION: These preliminary findings suggest that mometasone furoate nasal spray effectively treats itchy ear and palate in individuals with seasonal allergic rhinitis. Itchy ear and palate is a relevant end point for future clinical trials of allergic rhinitis.


Assuntos
Antialérgicos/uso terapêutico , Orelha/fisiopatologia , Palato/fisiopatologia , Pregnadienodiois/uso terapêutico , Prurido/tratamento farmacológico , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Antialérgicos/administração & dosagem , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Sprays Nasais , Pregnadienodiois/administração & dosagem , Rinite Alérgica Sazonal/fisiopatologia , Resultado do Tratamento , Adulto Jovem
17.
J Asthma ; 48(8): 848-59, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21854342

RESUMO

OBJECTIVE: To assess the effects of long-term mometasone furoate delivered via a dry powder inhaler (MF-DPI) on growth velocity and hypothalamic-pituitary-adrenal axis function in children with asthma. STUDY DESIGN: Children aged 4-9 years with asthma (n = 187) were randomized to MF-DPI 100 µg (delivered dose; actuated dose is 110 µg) once daily in the morning (QD AM), 100 µg twice daily (BID), 200 µg QD AM, or placebo for 52 weeks followed by a 3-month follow-up period. The primary outcome was growth velocity calculated from stadiometric heights recorded at each visit. Secondary outcomes included serum and 12-h urinary cortisol, serum osteocalcin, and urinary N-telopeptide. RESULTS: MF-DPI 100 µg QD AM treatment did not significantly affect growth velocity compared with placebo (-0.10 ± 0.31 cm/y, p = 0.76). When the effect of a total daily dose of 200 µg MF-DPI on growth velocity was examined, no significant effect was demonstrated for MF-DPI 100 µg BID compared with placebo (-0.64 ± 0.39 cm/y, p = 0.10), although the change in mean growth velocity with MF-DPI 200 µg QD AM reached statistical significance (-0.70 ± 0.29 cm/y, p = 0.02). The effects of all examined doses of MF-DPI on mean plasma cortisol levels were similar to cortisol changes seen in the placebo group, suggesting an absence of drug-related effects. No differences in 12-h urinary cortisol or other outcomes were observed between groups. CONCLUSIONS: One year of treatment with a total daily dose of 100 µg of MF-DPI in the morning resulted in no significant difference, whereas a total daily dose of 200 µg of MF-DPI was associated with some changes in growth velocity when compared with placebo. The differences in growth velocity, and the absence of drug-related cortisol effects, support the use of a total daily dose of 100 µg of MF-DPI in children aged 4-9 years with mild persistent asthma.


Assuntos
Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Crescimento/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Pregnadienodiois/administração & dosagem , Administração por Inalação , Asma/sangue , Asma/fisiopatologia , Asma/urina , Estatura/fisiologia , Criança , Pré-Escolar , Colágeno Tipo I/urina , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Análise dos Mínimos Quadrados , Masculino , Furoato de Mometasona , Osteocalcina/sangue , Peptídeos/urina , Testes de Função Respiratória
18.
Allergy Asthma Proc ; 32(2): 159-67, 2011 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21439168

RESUMO

Nasal congestion is a frequent, bothersome symptom of seasonal allergic rhinitis (SAR). Mometasone furoate nasal spray (MFNS) has established efficacy in treating nasal allergy symptoms, but no study has been conducted with the primary purpose of evaluating MFNS for relief of congestion. This study assessed MFNS for congestion and other nasal symptoms in SAR. Two double-blind, placebo-controlled studies randomized symptomatic SAR patients to 15 days of MFNS, 200 micrograms, or placebo q.d. each morning. Participants scored individual components of total nasal symptom score (TNSS; congestion, rhinorrhea, sneezing, and itching) on a 4-point scale in the morning (A.M.) and evening (P.M.). Symptoms were scored for the time of assessment (NOW) and for the previous 12 hours (PRIOR). The pooled population comprised 684 patients randomized to MFNS (n = 344) or placebo (n = 340). Change from baseline in A.M./P.M. PRIOR nasal congestion score averaged over days 1-15, the primary end point, was significantly (p < 0.001) greater with MFNS than with placebo (0.68-point [25.2%] reduction versus 0.45-point [16.0%] reduction, respectively). Reduction in A.M./P.M. PRIOR TNSS averaged over days 1-15, a key secondary end point, was also superior with MFNS (2.83 points [28.5%] versus 1.79 points [17.6%]; p < 0.001). Predose A.M. NOW congestion, other nasal symptoms, and TNSS improved significantly more with MFNS, indicating 24-hour efficacy. Adverse events were infrequent and localized; the most common (epistaxis and pharyngolaryngeal pain) occurred in 1.0% of MFNS patients. MFNS q.d. provides sustained relief for nasal congestion and other SAR symptoms.


Assuntos
Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Obstrução Nasal/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Obstrução Nasal/fisiopatologia , Sprays Nasais , Placebos , Prurido , Projetos de Pesquisa , Rinite Alérgica Sazonal/fisiopatologia , Espirro , Resultado do Tratamento
19.
J Allergy Clin Immunol ; 125(6): 1247-1253.e5, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20434199

RESUMO

BACKGROUND: Mometasone furoate nasal spray (MFNS), a potent intranasal corticosteroid with proved efficacy in relieving nasal allergic rhinitis symptoms, has demonstrated effectiveness in improving ocular symptoms associated with seasonal allergic rhinitis (SAR) in retrospective analyses. OBJECTIVE: We sought to evaluate prospectively the efficacy of MFNS in reducing total ocular symptom scores (TOSSs) and individual ocular symptoms in subjects with SAR. METHODS: Subjects 12 years or older (n = 429) with moderate-to-severe baseline symptoms were randomized to MFNS, 200 microg once daily, or placebo in this 15-day, double-blind, parallel-group study. Subjects evaluated morning instantaneous TOSSs and daily reflective TOSSs, total nasal symptom scores (TNSSs; both instantaneous TNSSs and reflective TNSSs, respectively), and individual ocular and nasal symptoms. Mean changes from baseline averaged over days 2 to 15 (instantaneous) and days 1 to 15 (reflective) were calculated. Quality of life was assessed by using the Rhinoconjunctivitis Quality of Life Questionnaire. RESULTS: MFNS treatment yielded significant reductions from baseline versus placebo in instantaneous TOSSs (-0.34, P = .026, coprimary end point), instantaneous TNSSs (-0.88, P < .001, coprimary end point), reflective TOSSs (-0.44, P = .005), and reflective TNSSs (-1.06, P < .001). Significant decreases in all individual reflective ocular symptoms and instantaneous eye itching/burning and eye watering/tearing were observed for MFNS versus placebo (P < .05). Numeric improvements in instantaneous eye redness were seen but did not reach statistical significance. Improvements in Rhinoconjunctivitis Quality of Life Questionnaire total scores and individual symptom domains were achieved with MFNS treatment versus placebo (P < .001). MFNS was well tolerated. CONCLUSION: This prospective study demonstrates that MFNS significantly reduces ocular symptoms in subjects with SAR.


Assuntos
Aerossóis/administração & dosagem , Antialérgicos/administração & dosagem , Pregnadienodiois/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adulto , Aerossóis/efeitos adversos , Antialérgicos/efeitos adversos , Método Duplo-Cego , Feminino , Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Obstrução Nasal/tratamento farmacológico , Pregnadienodiois/efeitos adversos , Prurido/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Rinite Alérgica Sazonal/fisiopatologia , Lágrimas
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