Background
Tobacco smoking is well established as a major risk factor for the development of chronic obstructive pulmonary disease (COPD) [
1‐
4]. A Swedish cohort study reported that approximately 50% of smokers eventually develop COPD [
5], and according to World Health Organization data in 2012, 42% of all COPD-related deaths were attributable to tobacco smoking [
6]. Unfortunately, approximately 40% of patients continue to smoke following diagnosis of COPD [
7]. Smoking has been shown to reduce the efficacy of inhaled corticosteroids (ICS) in patients with asthma [
8,
9] and leads to faster decline of lung function among patients with COPD treated with bronchodilator/ICS combinations [
10,
11]. Smoking affects the exposure and efficacy of ICS by disrupting the histone deacetylase 2 enzyme system, increasing production of inflammatory cytokines, and activating the p38 MAPK pathway [
12].
Glycopyrrolate inhalation powder (GLY; SEEBRI® NEOHALER®, Sunovion Pharmaceuticals Inc.) is a long-acting muscarinic antagonist (LAMA) approved by the US Food and Drug Administration at a dose of 15.6 μg twice daily (BID) for the long-term maintenance treatment of airflow obstruction in patients with COPD [
13]. Two replicate, 12-week Phase III studies,
Glycopyrrolate
Effect on sy
Mptoms and lung function 1 and 2 (GEM1 and GEM2), demonstrated the efficacy and safety of GLY vs placebo in patients with moderate-to-severe COPD and a smoking history of ≥10 pack-years [
14,
15]. The proportions of current smokers were 61% in GEM1 and 53% in GEM2. Treatment with GLY resulted in significantly improved lung function, as assessed by forced expiratory volume in 1 s (FEV
1) area under the curve from 0 to 12 h (AUC
0–12h) and trough FEV
1, as well as patient-reported outcomes (PROs) [
14,
15] compared with placebo. GLY was well-tolerated in both studies, with safety outcomes similar to placebo. In the primary analysis of the GEM1 and GEM2 studies, it was shown that the primary endpoint, FEV
1 AUC
0–12h was improved to a similar extent in both current and ex-smokers [
14,
15].
Given the significant proportion of COPD patients who smoke, and the potential for treatment efficacy to be impaired among current smokers, evaluation of the impact of smoking status on bronchodilator efficacy and safety may help to inform clinical decision-making [
8]. While the primary analyses of the 2 studies briefly assessed the impact of smoking status on the primary endpoint, in this post-hoc analysis of pooled data from GEM1 and GEM2, we evaluated the impact of patients’ baseline smoking status on all efficacy and safety responses to GLY compared to placebo over 12 weeks.
Methods
Study design
The study designs of GEM1 (NCT01709864) and GEM2 (NCT01715298) have been published previously [
14,
15]. Briefly, GEM1 and GEM2 were replicate, multicenter, double-blind, placebo-controlled studies that evaluated the efficacy and safety of GLY in patients with moderate-to-severe COPD (Additional file
1: Figure S1). Patients were randomized 1:1 to receive either GLY 15.6 μg BID or placebo delivered via the NEOHALER® device for 12 weeks; randomization was stratified according to baseline smoking status (current or ex-smoker). Ex-smokers were defined as patients who had not smoked for ≥6 months at screening. Patients’ smoking history and status, including pack-years (calculated as number of packs/day multiplied by the number of years of smoking) and date of quitting for ex-smokers, were reported using a questionnaire; smoking history was assessed at screening (pre-dose) only, while current smoking status was assessed at randomization and week 12 or at treatment discontinuation. Background ICS at stable doses and albuterol (as rescue medication) were permitted throughout the studies.
Patients
Eligibility criteria have been published previously [
14,
15]. Briefly, enrolled patients included males or females ≥40 years of age with stable, symptomatic COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2011, stages 2 and 3) [
16]. Patients were current or ex-smokers with ≥10 pack-year smoking history and had qualifying post-bronchodilator FEV
1 (1 h after inhalation of ipratropium bromide 84 μg) ≥30% and < 80% of predicted normal, a FEV
1/forced vital capacity (FVC) ratio < 0.70, and modified Medical Research Council grade ≥ 2 at the run-in visit. Patients were asked to refrain from smoking one hour before scheduled clinic visits and spirometry testing.
Post-hoc analysis
Data from the GEM1 and GEM2 studies were pooled to compare the effect of baseline smoking status in patients receiving GLY or placebo. Evaluated endpoints included lung function (assessed by changes from baseline in FEV1 AUC0-12h, trough FEV1, and FVC at Week 12) and PROs (measured by changes from baseline in St George’s Respiratory Questionnaire [SGRQ] total score, COPD Assessment Test [CAT™] score, and transition dyspnea index [TDI] focal score at Week 12). Changes from baseline over 12 weeks in symptom burden and rescue medication use were assessed using data from patient diaries. Safety assessments included incidence of adverse events (AEs), serious AEs (SAEs), and serious cerebro- and cardio-vascular (CCV) AEs. Trough FEV1 was further analyzed based on the presence/absence of background ICS use.
Statistical analyses
The full analysis set was used for all efficacy outcomes and included all randomized patients who received at least one dose of treatment. Changes from baseline in FEV
1 AUC
0-12h, trough FEV
1, and FVC at Week 12 were analyzed using a mixed-model for repeated measures. Changes from baseline in SGRQ total score, CAT score, symptom scores, and rescue medication use over 12 weeks, and overall changes in TDI focal score at Week 12 were analyzed using a linear mixed model. The proportions of patients achieving the thresholds for minimal clinically important differences (reduction in SGRQ total score ≥ 4 units [
17] and change in TDI focal score ≥ 1 [
18]) were analyzed using a logistic regression model with the same terms as the linear mixed model. All models included covariates for baseline smoking status (current smoker or ex-smoker) and baseline ICS use (yes/no). Reduction in CAT score ≥ 2 [
19] was also assessed by smoking status. No multiplicity adjustments were made for the post-hoc multiple comparisons.
The safety set included all patients who received at least one dose of treatment, and was used for analysis of all safety variables. Safety data were analyzed by smoking status using descriptive statistics. AEs were coded according to Medical Dictionary for Regulatory Activities version 17.0. All statistical procedures were performed using SAS® version 9.2 or higher (SAS Institute Inc., Cary, NC).
Discussion
Smoking status is known to impact the efficacy of ICS treatment in asthma [
8,
9] and leads to faster decline in patients with COPD [
10,
11]. However, studies of the LAMA tiotropium [
20,
21] showed non-significant long-term differences in bronchodilator response between current and ex-smokers. The results of this pooled analysis of data from the GEM1 and GEM2 studies showed that baseline smoking status did not have a significant impact on the efficacy or safety profile of GLY.
The magnitude of the effect of GLY (relative to placebo) on FEV
1 AUC
0-12h, trough FEV
1, and trough FVC at 12 weeks was greater in ex-smokers than current smokers, but none of the differences between current and ex-smokers were significant. The effects of GLY were not impacted by baseline ICS use, while the impact on PROs was numerically but not significantly greater in current than ex-smokers. Conversely, in patients receiving tiotropium for 12 weeks there were numerical but not statistical improvements in FEV
1 in current vs ex-smokers [
20]. However, in the same study among current smokers, baseline airflow obstruction was less severe in the tiotropium arm than the placebo arm, whereas for ex-smokers the opposite was true. This may have accounted for the apparently greater response to tiotropium in current smokers, consistent with observations that bronchodilator responsiveness appears to be related to the degree of airflow obstruction, with patients having moderate obstruction showing greater responses to bronchodilators than those with severe obstruction by FEV
1 criteria [
22]. In contrast, in the current study, baseline lung function was similar between treatment arms and between current and ex-smokers. This may account for the slight difference in outcomes with regard to current versus ex-smokers. In the 4-year UPLIFT trial, tiotropium treatment led to greater improvement in lung function in continuing current smokers than in ex-smokers. However, these results may also have been confounded by the fact that baseline airflow obstruction was greater in ex-smokers than current smokers, and concomitant treatment with long-acting β2-agonists, ICS and methylxanthines was permitted throughout the trial [
21]. Importantly, in the current analysis, improvement in lung function outcomes with placebo were greater in current smokers than ex-smokers; this may have influenced the differences in placebo-adjusted outcomes between current and ex-smokers.
The GOLD 2019 report recommended the addition of ICS to long-acting bronchodilator therapies in patients with more severe disease experiencing dyspnea or exacerbations and having high eosinophil counts [
1]. Consistent with the observation that smoking can impact ICS efficacy and disease progression during treatment of patients with asthma and COPD [
8‐
11,
23‐
25], in this analysis, current smokers receiving background ICS had non-significant improvement in trough FEV
1 with GLY compared with placebo, whereas ex-smokers had a significant improvement, regardless of background ICS use; however, this was, at least in part, due to differences in lung function improvement in the placebo arm between current and ex-smokers. Provided they were not receiving background ICS, both current and ex-smokers had significant improvements in trough FEV
1.
The most notable differences between current and ex-smokers were related to changes in PROs. While SGRQ total scores and rescue medication use were significantly improved with GLY compared with placebo in both current and ex-smokers, numerically greater improvements in placebo-adjusted SGRQ total score among current smokers compared to ex-smokers receiving GLY may be attributed, in part, to the greater improvements among ex-smokers receiving placebo. In contrast, placebo-adjusted changes from baseline in CAT and symptoms scores, as well as changes in TDI focal scores at Week 12, were significantly improved only in current smokers, but not in ex-smokers. While the differences in CAT scores between current and ex-smokers may be due to greater improvements among ex-smokers compared with smokers receiving placebo, similar differences between current and ex-smokers in placebo effects were not observed in TDI focal scores. Previous studies of tiotropium showed similar significant placebo-adjusted changes from baseline in SGRQ total score irrespective of smoking status, although numerically greater improvements were observed among current smokers compared with ex-smokers [
20,
21].
The differences observed in PROs between current and ex-smokers in this analysis may have been influenced by disease severity at baseline, with patients with more severe disease having possibly ceased smoking due to worse baseline lung function. This is supported by baseline characteristics showing that more ex-smokers than current smokers had longer disease duration and were classified as GOLD 3 and GOLD group D. Another potential explanation for the greater improvements in PROs in current smokers than ex-smokers is improvements in symptoms directly driven by active smoking, such as increased mucus secretion; such improvements in symptoms directly caused by active smoking may have led to greater positive outcomes among current smokers. In addition, the central actions of nicotine in the brain, which include release of neurotransmitters such as dopamine [
26], may have a positive impact on patients’ perceptions of quality of life.
The safety profile of GLY was not substantially impacted by smoking status at baseline, although there were differences in the incidences of COPD worsening, cough, and upper respiratory tract infections between current and ex-smokers and treatment arms; these may be due to differences in baseline characteristics (e.g. disease severity) between subgroups. AEs of special interest associated with anticholinergic therapies (e.g. dry mouth and dizziness) were infrequent and were similar between treatments. Overall, the AE profile of GLY was not affected by smoking status at baseline. Although CCV AEs and MACE were most frequent in ex-smokers, the incidences were low and similar to those reported for other LAMAs [
27,
28].
The main limitation of this analysis is that post-hoc comparisons were not adjusted for multiplicity. Only a small number of patients stopped or started smoking during the GEM1 and GEM2 studies, which did not impact the observed outcomes. Additional prospective studies are needed to better understand the impact of smoking status on clinical outcomes with different bronchodilators available for the treatment of patients with COPD.
Conclusions
In this post-hoc analysis of pooled data from the GEM1 and GEM2 studies, GLY treatment led to significant improvements in lung function, SGRQ total score, and rescue medication use vs placebo in both smokers and ex-smokers. Current smokers receiving background ICS therapy on top of GLY had non-significant improvements in trough FEV1 compared with placebo; this is consistent with previous studies that demonstrated effects of smoking on ICS efficacy. GLY treatment resulted in clinically important improvements in CAT scores, TDI focal scores, and daily symptom scores in both current and ex-smokers, with significant improvements over placebo only among current smokers. These data support the use of GLY 15.6 μg BID in patients with moderate-to-severe COPD regardless of their baseline smoking status, although the magnitude of benefit may differ between current and ex-smokers.
Acknowledgements
Medical writing support was provided by Hashem Dbouk, PhD, of FireKite, an Ashfield company, part of UDG Healthcare plc, and supported by funding from Sunovion Pharmaceuticals Inc.
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