Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study

Craig LaForce, Gregory Feldman, Selwyn Spangenthal, Joerg H Eckert, Michelle Henley, Francesco Patalano, Peter D'Andrea, Craig LaForce, Gregory Feldman, Selwyn Spangenthal, Joerg H Eckert, Michelle Henley, Francesco Patalano, Peter D'Andrea

Abstract

Background: The purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation.

Methods: The GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler(®) device. The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12. Other outcomes included additional spirometric end points, transition dyspnea index, St George's Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary. Safety was also assessed during the study.

Results: Of the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase. Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo. Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George's Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12. Safety was comparable between the treatment groups.

Conclusion: Significant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.

Keywords: bronchodilator; chronic obstructive pulmonary disease; glycopyrrolate; glycopyrronium; long-acting muscarinic antagonist; lung function; twice daily.

Figures

Figure 1
Figure 1
Study design. Note:aFlexible between 1 and 7 days.
Figure 2
Figure 2
Improvement in FEV1 AUC0–12 h on day 1 and at week 12 (FAS). Notes: Data are LSM (SE); *P<0.001. Abbreviations: CI, confidence interval; FAS, full analysis set; LSM, least squares mean; FEV1, forced expiratory volume in 1 second; AUC, area under the curve; SE, standard error.
Figure 3
Figure 3
Forest plot of the treatment differences between glycopyrrolate and placebo in FEV1 AUC0–12 h by subgroups at week 12. Notes: All P-values are ≤0.001 except GOLD 3 subgroup; N1= number of patients analyzed in the glycopyrrolate group; N2= number of patients analyzed in the placebo group. Abbreviations: CI, confidence interval; LSM, least squares mean; ICS, inhaled corticosteroids; FEV1, forced expiratory volume in 1 second; AUC, area under the curve; GOLD, Global Initiative for Chronic Obstruc tive Lung Disease.
Figure 4
Figure 4
Improvement in trough FEV1 (FAS). Notes: Data are LSM (SE); differences between glycopyrrolate and placebo were significant (P<0.001) at each visit during the treatment period; glycopyrrolate (n=217–218) and placebo (n=208–214). Abbreviations: FEV1, forced expiratory volume in 1 second; FAS, full analysis set; LSM, least squares mean; SE, standard error.
Figure 5
Figure 5
Serial measurements of FEV1 by timepoint on (A) day 1 and (B) week 12 (FAS). Notes: Data are LSM (SE); treatment differences: P<0.001 for glycopyrrolate versus placebo at each assessed timepoint. Abbreviations: FEV1, forced expiratory volume in 1 second; FAS, full analysis set; LSM, least squares mean; SE, standard error.
Figure 6
Figure 6
SGRQ total score at week 12 in FAS (A) change from baseline in each treatment group and (B) percentages of patients achieving the MCID (≥4 units reduction) in SGRQ total score. Notes: *P<0.05. Data are LSM (SE) in (A). Abbreviations: FAS, full analysis set; LSM, least squares mean; MCID, minimal clinically important difference; OR, odds ratio; SE, standard error; SGRQ, St George’s Respiratory Questionnaire.
Figure 7
Figure 7
Improvement in TDI focal score in FAS (A) TDI focal score after 12 weeks and (B) percentages of patients achieving the MCID (≥1 unit). Notes: *P<0.01, **P<0.001. Data are LSM (SE) in (A). Abbreviations: FAS, full analysis set; LSM, least squares mean; MCID, minimal clinically important difference; OR, odds ratio; SE, standard error; TDI, transition dyspnea index.

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