This chapter discusses the criteria for inclusion and exclusion in a clinical trial aimed at evaluating a new therapy for poorly controlled severe asthma. It covers essential participant requirements, the trial's design, recruitment strategies, and significant findings related to drug efficacy in reducing asthma exacerbations. The conversation emphasizes the importance of patient education concerning expectations and outcomes based on the trial's results.
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We’re back with another Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the NAVIGATOR trial published in NEJM in 2021 evaluating tezepelumab for adults with asthma.
Article and Reference
We are talking today about the NAVIGATOR trial evaluating the use of tezepelumab in adults with asthma.
Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, Brightling CE, Griffiths JM, Hellqvist Å, Bowen K, Kaur P, Almqvist G, Ponnarambil S, Colice G. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975. PMID: 33979488.
Asthma biologics already exist, targeting IgE and type 2 cytokines (IL-4, IL-5, IL-13), but there’s an unmet need for patients with non-allergic or non-eosinophilic phenotypes.
Tezepelumab is a monoclonal antibody targeting TSLP (thymic stromal lymphopoietin), an upstream mediator of both T2 and non-T2 inflammation, offering a potentially broader therapeutic effect.
Study Design (Navigator Trial)
Phase 3, double-blind, placebo-controlled RCT
Conducted in 18 countries from 2017-2020
N = 1,061 patients, aged 12-80 with moderate to severe asthma
All were on medium/high-dose ICS + controller med
Required ≥2 exacerbations in prior year
Outcomes
Primary Outcome: Annualized rate of asthma exacerbations (events per patient-year)
Secondary Outcomes:
Change in pre-bronchodilator FEV₁
Symptoms & quality of life (with predefined MCIDs)
Subgroup analyses by eosinophil count, FeNO, and perennial allergen sensitivity
Key Inclusion/Exclusion
Inclusion: 12-80 years, guideline-based therapy, ≥2 exacerbations
Exclusion: recent biologic use, mild/asymptomatic asthma, no reversibility on spirometry
Patient Population (Table 1 Summary)
Middle-aged, predominantly white, female
Poorly controlled severe asthma despite high-intensity therapy
~75% on high-dose ICS, ~10% on oral steroids
~40% had normal FeNO
~60% had eosinophils <300
Median IgE ~195
Results
Efficacy:
Annualized exacerbation rate:
0.93 (tezepelumab) vs. 2.1 (placebo)
Rate ratio: 0.44, p<0.001 (very positive)
In eosinophils <300 group: rate ratio 0.59, still effective
FEV₁ improved by ~+0.25 L (vs. +0.09 L placebo), significant & sustained from week 2 onward
Quality of life: statistically improved but did not meet MCID, so unclear clinical impact
Severity of exacerbations reduced: fewer hospitalizations & ED visits in the treatment arm
~40% of treated patients still had some exacerbations → not a cure, but improves severity
Safety:
Very well tolerated
77% reported adverse events (more common in placebo)
No anaphylaxis, no GBS, no cancer signal
Most common AEs: URTI, headache, nasopharyngitis
Injection site reactions: 3.6%
Serious AEs were lower in drug arm than placebo
Overall Takeaway
Tezepelumabsignificantly reduces asthma exacerbations (including in patients with low eosinophils), improves lung function, and is safe and well tolerated.
Provides a broad-acting biologic option even for patients who may not be eligible for existing T2-high biologics.
Now widely used as part of the asthma biologic armamentarium for poorly controlled asthma despite maximal inhaled therapy.
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