Nebulized Glycopyrrolate Reduces the Risk of Clinically Important Deterioration in Moderate-to-Severe COPD

15 Oct, 20

Introduction

The efficacy of glycopyrrolate (GLY) was evaluated in two 12-week phase 3 trials in the US – Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 3 and GOLDEN 4 in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). GLY significantly improved forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC) and the St. George Respiratory Questionnaire (SGRQ) total score. To complement the efficacy assessments, a composite endpoint for clinically important deterioration (CID) has been used in this study to achieve a more comprehensive assessment of treatment efficacy. The CID captures changes in pulmonary function, health status and exacerbations that can reflect the worsening of the disease.

Aim

This post-hoc analysis of GOLDEN 3 and 4 trials evaluated whether nebulized GLY 25 mcg and 50 mcg BID administered for 12 weeks reduced the risk of CID in patients with moderate-to-very severe COPD.

Methods

Study Design

Post-hoc analysis of pooled data from 2 randomized phase 3 trials

Patient Profile

Patients aged >40 years with moderate-to-very-severe COPD as per GOLD classification
Current or past smokers (>10 pack-year)
FEV₁ <80% of predicted normal and FEV₁/FVC ratio <0.70

Treatment Strategy

The patients were evaluated at baseline and week 12
The relative treatment efficacy of GLY versus placebo on the odds of CID (any and by component endpoints) was expressed as the odds ratio (OR) and 95% confidence interval (CI)
Subgroups categorized by age (<65/≥65 years), sex, smoking status (current/former), long-acting beta agonist (LABA) use, FEV₁ (<50%/≥50%), and peak inspiratory flow rate (PIFR) (<60 L/min/≥60 L/min) were assessed

Endpoints

CID defined as
- ≥ 100-mL decrease from baseline in post-bronchodilator trough forced expiratory volume in one second (FEV₁), or
- ≥ 4-unit increase in baseline St. George’s Respiratory Questionnaire (SGRQ) total score, or
- moderate/severe exacerbation

Results

The overall study population comprised 1293 patients randomized to GLY 25 mcg BID (n=431), GLY 50 mcg BID (n=432) and placebo (n=430)
Fewer patients in the GLY groups experienced >1 qualifying CID event as compared to placebo as seen in figure 1.

Figure 1. % Patients with >1 qualifying CID event

The risk of CID was significantly reduced by 50% (OR 0.50) and 40% (OR 0.40) in GLY 25 mcg and 50 mcg groups respectively as compared to placebo
Subjects treated with GLY 25 mcg BID and GLY 50 mcg BID were 59% and 52% less likely to experience CID in FEV₁ (OR: 0.41 and 0.48) respectively
The risk of worsening in the total SGRQ score was significantly reduced by 48% and 37% in the GLY 25 mcg and GLY 50 mcg groups respectively (OR: 0.52 and 0.67)
The incidence of moderate/severe exacerbations was low and comparable among the cohorts
The risk of CID was significantly lower for GLY 25 mcg BID than placebo (p< 0.05) irrespective of age, smoking status, LABA use, COPD severity, or PIFR.
The most pronounced reductions were seen in subjects < 65 years (OR 0.45) and those with PIFR < 60 L/min (OR 0.36)
Treatment with higher dose also demonstrated significant decreases in the risk of CID except for the subgroup aged >65 years and females

Conclusion

Nebulized glycopyrrolate (GLY) 25 mcg BID and 50 mcg BID significantly reduced the risk of clinically important deterioration in patients with moderate-to-severe COPD.
Treatment with GLY prevented clinically meaningful worsening in forced expiratory volume in 1 sec (FEV₁) and patient-reported health status.

Int J Chron Obstruct Pulm Dis. 2020 Sep; 15:2309-18.