NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma

Abstract

Background: Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study.

Methods: NAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids (N = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/μL) and low (< 300 cells/μL) blood eosinophil counts. The study comprises a 5-6-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients will receive their prescribed controller medications without change throughout the study. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints include the effect of tezepelumab on lung function, asthma control and health-related quality of life.

Discussion: NAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR (N = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life.

Trial registration: NCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.

Keywords: Clinical trial; Severe asthma; Tezepelumab; Thymic stromal lymphopoietin.

Fig. 1

Mechanism of action by which tezepelumab improves clinical outcomes in patients with severe asthma. TSLP is released from the airway epithelium in response to insults such as viruses, allergens and pollutants, triggering an inflammatory cascade. Overexpression of TSLP can result in pathologic inflammation that can lead to asthma exacerbations, symptoms, and physiological effects such as bronchoconstriction and airway hyperresponsiveness and remodelling. Tezepelumab specifically blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various inflammatory cytokines and cell types. Treatment with tezepelumab has thus far been shown to reduce eosinophils, IgE, IL-5, IL-13 and FeNO. FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cell; Th, T-helper; TSLP, thymic stromal lymphopoietin

Fig. 2

Overview of ongoing phase 2 and phase 3 clinical studies of tezepelumab. ACQ, Asthma Control Questionnaire; BD, bronchodilator; EOS, blood eosinophils; FEV₁, forced expiratory volume in 1 s; HRQoL, health-related quality of life; ICS, inhaled corticosteroids; LTE, long-term extension; N, number of patients; OCS, oral corticosteroids; Q4W, every 4 weeks; RBM, reticular basement membrane; SC, subcutaneously; T2, type 2

Fig. 3

Study design. ^aPatients who enrol in the extension study on the same day as the end-of-treatment visit in NAVIGATOR will not attend follow-up visits at week 58 and week 64. Q4W, every 4 weeks; SC, subcutaneously

Fig. 4

Hierarchical testing strategy for primary and key secondary endpoints. Testing will be performed at a two-sided 5% significance level unless otherwise stated. ^aA truncated Hochberg adjustment will be used for level 4. As such, the higher of the two level 4 p values will be evaluated at a 3.75% significance level (two-sided). If it is significant at the 3.75% level, both level 4 null hypotheses will be rejected, and testing will proceed to level 5. If it is not significant at the 3.75% level, the lower of the two level 4 p values will be evaluated at a 2.5% significance level (two-sided). If significant, the relevant null hypothesis will be rejected, and testing will proceed to level 5. ^bIf both null hypotheses are rejected at level 4, level 5 will be tested at a two-sided 5% significance level. If only one null hypothesis is rejected at level 4, level 5 will be tested at a two-sided 1.25% significance level. AAER, annualized asthma exacerbation rate; ACQ-6, Asthma Control Questionnaire-6; AQLQ(S) + 12, Asthma Quality of Life Questionnaire standardized for patients 12 years and older; FEV₁, forced expiratory volume in 1 s