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

NAVIGATOR is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group study that aims to evaluate the effect of tezepelumab 210 mg Q4W administered subcutaneously in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma. Patient recruitment for NAVIGATOR has been completed. A total of 1061 patients were randomized from 294 study sites in 18 countries; 82 of these patients were adolescents. Patients were stratified by region (Asia-Pacific, Central or Eastern Europe, Western Europe, Australia, North America, South America and the rest of the world) and age (adults or adolescents). To be eligible for the study, patients must have been receiving medium- to high-dose ICS (fluticasone propionate ≥500 μg dry powder formulation equivalent total daily dose) for at least 3 months before screening, and must have been taking at least one additional controller medication with or without OCS in the 3 months before the date of informed consent. Patients who had received marketed or non-investigational biologic treatments were permitted to enter the study if the last dose was taken more than 4 months or more than 5 half-lives before visit 1. Patients must also have had an Asthma Control Questionnaire (ACQ)-6 score of greater than or equal to 1.5 at both screening and randomization. Key additional inclusion and exclusion criteria are shown in Table 1.

The total study population was monitored to ensure a broad patient distribution across the following three key clinical factors. Approximately 20% of the study population comprises patients who were receiving daily medium-dose ICS (fluticasone propionate 440–500 μg dry powder formulation equivalent total daily dose) plus at least one additional controller medication, with or without OCS in the 3 months before the date of informed consent. Approximately 40% of the study population comprises patients who had at least three exacerbations in the 12 months before the date of informed consent, with the remaining 60% of patients having had two exacerbations during that time period. The study population includes similar proportions of patients with an eosinophil count of less than 300 cells/μL and patients with at least 300 cells/μL, and approximately 25% of patients have an eosinophil count of less than 150 cells/μL or of greater than 450 cells/μL. These study population targets were applied to adults only.

The study comprises a 5- to 6-week screening and run-in period, followed by a treatment period of 52 weeks and a post-treatment follow-up period of 12 weeks (Fig. 3). Patients were randomized in a 1:1 ratio to receive tezepelumab 210 mg Q4W subcutaneously (administered using a single-use vial and syringe) or placebo Q4W for 48 weeks. Neither treatment will be administered at week 52. For the duration of the study, all patients will receive their prescribed ICS plus additional controller medications without change. Patients will be permitted to use short-acting β₂ agonists as relief medication for symptoms of asthma as required. Patients who complete the treatment period as defined in the study protocol may be eligible to enrol in a separate extension study (DESTINATION); these patients will not attend follow-up visits at weeks 58 and 64. Patients who discontinue treatment early will be encouraged to undergo applicable study-related visits and/or procedures for the 52-week study period.

Owing to the COVID-19 virus pandemic, the NAVIGATOR protocol was amended. This amendment was necessary to address the issue of social distancing and the possibility that site visits would be limited. If site visits by patients were not possible, efficacy (e.g., exacerbations, spirometry and patient-reported outcomes) and safety data may not have been collected. In addition, patients would not have been able to receive study drug. The amendment specifically allowed for virtual visits (instead of site visits) to collect appropriate efficacy and safety information (except for spirometry), and for at-home dosing of study drug when possible. Notification of the planned changes to the study protocol as a result of the pandemic was provided to each study site, and virtual visits and at-home dosing commenced, if permitted by the local regulatory authorities, ethics committees and Institutional Review Boards, and if required. Instructions for at-home dosing of study drug by a healthcare professional (e.g. transportation, preparation, handling and administration) were provided to each site. To date (July 2020), only 17 of over 17,000 completed visits have taken place virtually, and only 25 of approximately 13,000 doses were missed by patients who have completed the study or who are still participating in the study, owing to travel restrictions or to patient choice. In addition, no at-home dosing has taken place.

Written informed consent was obtained from all patients or their guardians before enrolment into the study. The study is being conducted in accordance with the principles established in the Declaration of Helsinki and the International Council for Harmonisation guidelines for good clinical practice.

A summary of the primary and secondary objectives and endpoints for this study is given in Table 2. The primary objective of this study is to assess the effect of tezepelumab compared with placebo on asthma exacerbations over the 52-week treatment period. This will be assessed by the annualized asthma exacerbation rate (AAER). In addition to the overall population, the primary objective will be assessed in a subgroup of patients with blood eosinophil counts less than 300 cells/μL.

Key secondary objectives include assessing the effect of tezepelumab compared with placebo on pulmonary function (pre-bronchodilator forced expiratory volume in 1 s [FEV₁]) and on patient-reported outcomes, including HRQoL (using the Asthma Quality of Life Questionnaire standardized for patients 12 years and older [AQLQ(S) + 12]), asthma control (using the ACQ-6) and asthma symptoms (using the Asthma Symptom Diary, which is underdoing validation in line with FDA requirements for patient-reported outcome measures [33‐35]). Additional secondary objectives include assessing the effect of tezepelumab on type 2 inflammatory biomarkers (including FeNO, blood eosinophils and total serum IgE), as well as on other endpoints related to exacerbations (including time to first exacerbation, the proportion of patients without an exacerbation, and the annualized rate of exacerbations associated with hospital, emergency room or urgent care visits), asthma control measures (including rescue medication use, night-time awakenings and peak expiratory flow) and healthcare resource use.

In addition, NAVIGATOR will investigate a number of exploratory outcomes including, but not limited to, the effect of tezepelumab on: patient health status (using St George’s Respiratory Questionnaire [SGRQ]); disease activity in a subset of adult patients (using daily domiciliary FeNO measurements); and sino-nasal specific HRQoL (using the Sino-Nasal Outcome Test [SNOT]-22) in patients with a history of nasal polyps.

During the study, the safety and tolerability of tezepelumab will be evaluated by monitoring adverse events; serious adverse events; vital signs; clinical chemistry, haematology and urinalysis parameters; and digital electrocardiograms. A data safety monitoring board (an expert advisory group that functions independently from all other study personnel) will monitor safety aspects related to the involvement of adolescent patients in the study, and will review safety data for adults to provide context for what is observed in adolescents. The data safety monitoring board will evaluate cumulative safety and other clinical trial data at regular intervals, and will make appropriate recommendations based on the available data. Serum samples will be collected throughout the study for analysis of tezepelumab pharmacokinetics (serum concentrations) and analysis of the potential immunogenicity of tezepelumab, as measured by the incidence of anti-drug antibodies and characterization of their neutralizing potential.

All statistical analyses of primary and secondary efficacy outcomes will be performed after the primary database lock, which will be conducted after the last patient completes week 52 of the study. A second database lock will be conducted when all patients have completed their follow-up visits (or entered the long-term extension study).

Statistical analyses of efficacy outcomes will be performed on all patients randomized to study treatment who receive at least one dose of tezepelumab or placebo, according to randomized treatment assignment (full analysis set). Statistical analysis of safety and anti-drug antibody incidences will be performed on the safety analysis set (all patients who receive at least one dose of tezepelumab or placebo), according to treatment received. Pharmacokinetic analyses will be performed on all patients in the full analysis set who receive tezepelumab; samples assumed to be affected by factors such as specific important protocol deviations (e.g. use of non-permitted medications or receipt of incorrect study medication) will not be included.

AAER over 52 weeks (primary efficacy endpoint) will be analysed using a negative binomial regression model, with the total number of asthma exacerbations experienced by a patient over the 52-week study period used as a response variable. Treatment, region, age (adolescents or adults) and history of exacerbations (two or more than two in the previous 12 months) will be included as covariates in the model. The logarithm of the time at risk for an exacerbation during the study (excluding the duration of an exacerbation and the 7-day period after an exacerbation, during which recurrence of symptoms will be considered part of the initial exacerbation and not a new exacerbation) will be used as an offset variable in the model. Exacerbations occurring more than once in a 7-day period will be considered the same exacerbation in the analysis. Patients lost to follow-up and those who withdraw consent will be the only sources of missing data for this analysis. Missing data from study discontinuation will be modelled based on what is observed during the study using direct likelihood approaches (which assumes data are missing at random), and sensitivity analyses using multiple imputation will be performed to explore the effect of missing data on the reliability of the results. A similar model will be used for subgroup analyses (including patients with blood eosinophil counts less than 300 cells/μL), with additional factors for the relevant subgroup variable and its interaction with treatment.

Changes from baseline for key secondary endpoints in the tezepelumab group will be compared with those seen in the placebo group using a mixed model for repeated measures, which will estimate the effect of treatment at week 52 and its 95% confidence interval for each endpoint. The response variable in the model will be the change from baseline at each scheduled post-randomization visit up to and including week 52, irrespective of whether the patient remained on treatment and/or took other treatments. Treatment, visit, region, age and treatment-by-visit interaction will be included as factors in this model. The baseline value of the corresponding endpoint will also be included in the model as a continuous linear covariate. As for the analysis of the primary endpoint, missing data will be modelled based on what is observed during the study using direct likelihood approaches. Any additional statistical analyses required due to COVID-19 will be pre-specified in the statistical analyses plan before sponsor unblinding and will be described when the results for this study are reported.

The overall type 1 error rate will be strongly controlled at the 0.05 level across the primary and key secondary endpoints. To account for multiplicity, a hierarchical testing strategy will be used to test the primary endpoint and then the key secondary endpoints (Fig. 4). To assess the primary efficacy objective across a broad population of patients, the subgroup of patients with a baseline eosinophil count less than 300 cells/μL was added to the multiple testing procedure after the primary endpoint and before the key secondary endpoints. With approximately 530 patients per treatment group it is estimated that, using the level of error control described, the power for the primary and key secondary endpoints will be at least 90%. For the primary endpoint (in all patients), assuming a placebo exacerbation rate of 0.9, a shape parameter of 2.4 (over-dispersion) and a dropout rate of 10% (uniform over the study), there will be > 99% power to detect an AAER reduction of 50% at a two-sided significance level of 1%. For AAER in patients with a blood eosinophil count less than 300 cells/μL, assuming a placebo rate of 0.6 and that half of the overall patient population will be in this group (i.e. 265 patients per treatment group), there will be 94% power to detect a rate reduction of 50% at a two-sided significance of 5% (assuming the same shape parameter and dropout assumptions as those for the overall population). For each of the key secondary endpoints (to be assessed in all patients), change from baseline in FEV₁, AQLQ(S) + 12 overall score, ACQ-6 score and Asthma Symptom Diary score, the nominal power will be 95% or higher, assuming standard deviations of 400 mL and 1.3, 1.3 and 1.3 units, respectively, and true differences of 100 mL and 0.3, 0.3 and 0.3 units, respectively. The minimum detectable differences being significant under these assumptions are 50 mL and 0.16, 0.16 and 0.16 units, respectively.