Objectives

To compare an inhaled glucocorticoid with placebo and a long-acting muscarinic antagonist (LAMA) with placebo in patients with mild, persistent asthma, according to the patient’s sputum eosinophil level at baseline.

Background

At the time of this study, guidelines recommended the use of inhaled glucocorticoids, which target inflammation, in all patients with persistent asthma. However, previous studies found that approximately half of all patients with asthma have a poor response to inhaled glucocorticoids. These studies also found that not all patients have eosinophilic airway inflammation. SIENA was a prospective study to determine if patients with low sputum eosinophil levels benefit from inhaled glucocorticoids and/or an alternative treatment with a LAMA.

Participants

Patients were at least 12 years of age, had received a clinical diagnosis of asthma and met the guideline criteria of the National Asthma Education and Prevention Program for step 2 asthma treatment. The asthma diagnosis was confirmed by either an increase of 200 ml in the FEV1 (and representing an increase of ≥12%) after the administration of albuterol or a 20% reduction in FEV1 in response to a provocative concentration of inhaled methacholine (PC20) of 16 mg per milliliter or less. Patients were excluded if they had received an inhaled glucocorticoid within 3 weeks, an oral glucocorticoid within 6 weeks, or omalizumab within 3 months; had a respiratory infection within 4 weeks; had any cigarette use during the previous 12 months or a lifetime use of more than 10 pack-years; had a history of life-threatening asthma; or had an FEV1 of less than 70% of the predicted value.

295 patients underwent randomization: 221 were assigned to the low-eosinophil subgroup and 74 were assigned to the high-eosinophil subgroup. Among the 221 patients with a low eosinophil level, those who completed at least two trial periods and provided data for each comparison in the primary analysis included 176 for the comparison between the inhaled glucocorticoid and placebo and 181 for the comparison between the LAMA and placebo. Among the 74 patients with a high eosinophil level, 67 completed the analysis periods for the comparison between the inhaled glucocorticoid and placebo and 62 completed the periods for the comparison between the LAMA and placebo.

Design

SIENA was a randomized, double-blind, placebo-controlled crossover trial conducted at 24 sites in the United States that are included in the AsthmaNet consortium. All enrolled patients were randomly assigned to a three-treatment, crossover trial for a total of 36 weeks of randomized treatment. During each 12-week period, the patients received twice-daily inhaled glucocorticoid (mometasone at a dose of 220 μg or 200 μg, depending on the delivery device), once-daily LAMA (tiotropium at a dose of 5 μg), or twice-daily placebo. Trial-group assignments were masked by the use of matched masked inhalers that delivered placebo. All the patients used an electronic diary to record symptoms, medication use, nighttime awakenings, and morning and evening peak expiratory flow. The patients were seen every 6 weeks and assessed by phone at the 3-week point between visits. Standard AsthmaNet procedures were used to assess asthma characteristics. In addition, the Asthma Control Test (which ranges from 5 [uncontrolled] to 25 [well controlled]) and the Asthma Bother Profile (which ranges from 0 [minimum effect] to 75 [maximum effect]) were administered at every visit. During visits 3, 5, 7, and 9, the Asthma Symptom Utility Index (which ranges from 0 [worse symptoms] to 1 [fewer symptoms]), the Asthma-Specific Work Productivity and Activities Impairment Questionnaire (with results expressed as an impairment percentage), and the Sinonasal Questionnaire (which evaluates the frequency of nasal symptoms on a scale from 0 [never] to 3 [daily]) were administered. To account for transitioning from one trial group to another, diary data from the initial 4 weeks of each 12-week treatment period were omitted from the analysis. Treatment failure and asthma exacerbations that occurred during this 4-week transition period were counted as events assigned to the ongoing trial agent.

The patients were enrolled in a 6-week, single-blind placebo run-in period for characterization of their asthma, sputum eosinophilia, and asthma control and to establish adherence of more than 75% to the trial agent and daily completion of an electronic diary. Spirometric measurements were performed and albuterol reversibility was assessed at the first visit. If reversibility was not shown, the patients returned for methacholine bronchoprovocation before the second visit. Sputum induction was performed up to three times during the run-in period to obtain two acceptable samples for cell counts on the basis of a validated protocol. The patients were classified as having a high eosinophil level if eosinophils made up at least 2% of at least one sputum sample. Patients with two sputum samples that contained less than 2% of eosinophils were designated as having a low eosinophil level. Samples of serum periostin, blood eosinophils, and exhaled nitric oxide were obtained each time sputum induction was performed. The patients entered the double-blind crossover phase at the end of the run-in period if they continued to meet the criteria for step 2 treatment, had provided two acceptable sputum samples, met the adherence criteria for medication use and diary completion, did not have two or more episodes of treatment failure or one asthma exacerbation, and the severity of asthma had not escalated to meet the criteria for step 3 treatment.

The primary outcome was the response to an inhaled glucocorticoid as compared with placebo and to a LAMA as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second.

Conclusions

Among the patients with a low eosinophil level and a differential response to one of the three trial agents, there was no significant difference between the percentage who had a better response to inhaled glucocorticoid and those who had a better response to placebo; there was also no significant difference in the percentage who had a better response to a LAMA and those who had a better response to placebo. These conclusions did not change with sensitivity analyses that included adjustment for differences in the trial period, season of enrollment, and inhaled glucocorticoid delivery device. These findings provide clinical equipoise for a larger and longer study to compare inhaled glucocorticoids with other treatments for the large number of patients with mild or moderate asthma.

Lazarus SC, Krishnan JA, King TS, et al. Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level. N Engl J Med. 2019;380(21):2009–2019. doi:10.1056/NEJMoa1814917

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