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Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.
Lancet 2016; 388(10039):31-44Lct

Abstract

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 β2 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 β2 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 β2 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 β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.

FUNDING

Sanofi-Genzyme and Regeneron Pharmaceuticals.

Authors+Show Affiliations

Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wenzelse@upmc.edu.Washington University School of Medicine, Saint Louis, MO, USA.David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.Allergy and Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina.Sanofi, Bridgewater, NJ, USA.Sanofi, Bridgewater, NJ, USA.Sanofi, Bridgewater, NJ, USA.Sanofi, Bridgewater, NJ, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Sanofi, Chilly-Mazarin, France.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Regeneron Pharmaceuticals, Tarrytown, NY, USA.Sanofi, Bridgewater, NJ, USA.Sanofi, Bridgewater, NJ, USA.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27130691

Citation

Wenzel, Sally, et al. "Dupilumab Efficacy and Safety in Adults With Uncontrolled Persistent Asthma Despite Use of Medium-to-high-dose Inhaled Corticosteroids Plus a Long-acting Β2 Agonist: a Randomised Double-blind Placebo-controlled Pivotal Phase 2b Dose-ranging Trial." Lancet (London, England), vol. 388, no. 10039, 2016, pp. 31-44.
Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44.
Wenzel, S., Castro, M., Corren, J., Maspero, J., Wang, L., Zhang, B., ... Teper, A. (2016). Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet (London, England), 388(10039), pp. 31-44. doi:10.1016/S0140-6736(16)30307-5.
Wenzel S, et al. Dupilumab Efficacy and Safety in Adults With Uncontrolled Persistent Asthma Despite Use of Medium-to-high-dose Inhaled Corticosteroids Plus a Long-acting Β2 Agonist: a Randomised Double-blind Placebo-controlled Pivotal Phase 2b Dose-ranging Trial. Lancet. 2016 Jul 2;388(10039):31-44. PubMed PMID: 27130691.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. AU - Wenzel,Sally, AU - Castro,Mario, AU - Corren,Jonathan, AU - Maspero,Jorge, AU - Wang,Lin, AU - Zhang,Bingzhi, AU - Pirozzi,Gianluca, AU - Sutherland,E Rand, AU - Evans,Robert R, AU - Joish,Vijay N, AU - Eckert,Laurent, AU - Graham,Neil M H, AU - Stahl,Neil, AU - Yancopoulos,George D, AU - Louis-Tisserand,Mariana, AU - Teper,Ariel, Y1 - 2016/04/27/ PY - 2016/5/1/entrez PY - 2016/5/1/pubmed PY - 2016/8/2/medline SP - 31 EP - 44 JF - Lancet (London, England) JO - Lancet VL - 388 IS - 10039 N2 - 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 β2 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 β2 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 β2 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 β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. FUNDING: Sanofi-Genzyme and Regeneron Pharmaceuticals. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/27130691/Dupilumab_efficacy_and_safety_in_adults_with_uncontrolled_persistent_asthma_despite_use_of_medium-to-high-dose_inhaled_corticosteroids_plus_a_long-acting_β2_agonist:_a_randomised_double-blind_placebo-controlled_pivotal_phase_2b_dose-ranging_trial L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(16)30307-5 DB - PRIME DP - Unbound Medicine ER -