Outcomes Research in Review

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med 2017;377:1613–29.



Study Overview

Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.

Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).

Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).

Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.

Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.

Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.

A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.

Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.

There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).

There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.

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