Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level

Abstract

Background: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown.

Methods: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium 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; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level.

Results: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%).

Conclusions: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

Figure 1.. Trial Design and Randomization.

Panel A shows the trial design calling for the enrollment of patients who met the guideline criteria for step 2 asthma treatment in a 6-week single-blind placebo run-in period for characterization of asthma. Sputum induction (SI) was performed up to three times to guarantee the collection of two acceptable samples. At the end of the run-in period, patients who continued to meet the criteria for step 2 treatment and who met the adherence criteria for medication use and diary completion were stratified according to the sputum eosinophil (EOS) level (<2% or ≥2%) and were randomly assigned to receive one of three blinded regimens in random sequence for 12 weeks each. Throughout the trial, patients used an electronic diary to record asthma symptoms, nighttime awakenings, and morning and evening peak expiratory flow. Inhaler use was tracked by device dose counters. Panel B shows the number of patients who enrolled in the trial, underwent randomization, and completed the trial. A sputum sample was deemed to be unacceptable if it contained more than 80% squamous cells, if there was an inadequate sputum volume, or if the patient was unable to continue the induction procedure for at least 4 minutes. After 74 patients were categorized as being in the high-eosinophil stratum, subsequent patients with a high eosinophil level did not undergo randomization.

Figure 2.. Pairwise Comparisons of Active Treatments and Placebo in the Low-Eosinophil Stratum.

In this trial, the primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level (<2%) who had a pre-specified differential response to 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. Panel A shows the prespecified differential response to treatment with mometasone as compared with placebo and with tiotropium as compared with placebo. The patients were considered to have had a differential response if the response during at least one trial period was ranked better than the response during another trial period. In the comparison between mometasone and placebo, 34% of the patients had better asthma control while receiving mometasone, 25% had better control while receiving placebo, 21% showed no between-group difference, and 20% with missing data were imputed as having no between-group difference. In the comparison between tiotropium and placebo, 36% had better control while receiving tiotropium, 24% had better control while receiving placebo, 22% showed no between-group difference, and 18% with missing data were imputed as having no between-group difference. Panel B shows the results of a statistical comparison of the primary outcome among the patients who had a differential response to the trial agents, with a two-sided P value of less than 0.025 indicating statistical significance. There was no significant between-group difference in the percentage of patients who had a better response to mometasone than to placebo (57% vs. 43%, P=0.14) or in the percentage who had a better response to tiotropium than to placebo (60% vs. 40%, P=0.029). The I bars denote the 95% confidence interval.