Andrew Menzies-Gow1, Jonathan Corren1, Arnaud Bourdin1, Geoffrey Chupp1, Elliot Israel1, Michael E Wechsler1, Christopher E Brightling1, Janet M Griffiths1, Åsa Hellqvist1, Karin Bowen1, Primal Kaur1, Gun Almqvist1, Sandhia Ponnarambil1, Gene Colice1. 1. From Royal Brompton Hospital, London (A.M.-G.), Leicester National Institute for Health Research Biomedical Research Centre, University of Leicester, Leicester (C.E.B.), and Late-stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge (S.P.) - all in the United Kingdom; the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.C.), and Global Development, Amgen, Thousand Oaks (P.K.) - both in California; Physiologie et Médecine Expérimentale du Cœur et des Muscles, Université de Montpellier, Centre National de la Recherche Scientifique, INSERM, Centre Hospitalier Universitaire de Montpellier, Montpellier, France (A.B.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT (G. Chupp); the Division of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston (E.I.); National Jewish Health, Denver (M.E.W.); Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (J.M.G.), and Biometrics (K.B.), Late-stage Development, Respiratory and Immunology (G. Colice), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD; and Biometrics (Å.H.), Late-stage Development, Respiratory and Immunology (G.A.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Abstract
BACKGROUND:Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]). RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receivetezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups. CONCLUSIONS:Patients with severe, uncontrolled asthma who receivedtezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. (Funded by AstraZeneca and Amgen; NAVIGATOR ClinicalTrials.gov number, NCT03347279.).
RCT Entities:
BACKGROUND:Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]). RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups. CONCLUSIONS:Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. (Funded by AstraZeneca and Amgen; NAVIGATOR ClinicalTrials.gov number, NCT03347279.).
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