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

Figures & data

Figure 1 Study design.

Note: ^aFlexible between 1 and 7 days.

Table 1 Baseline demographics and disease characteristics (randomized set)

Variable	Glycopyrrolate, N=222	Placebo, N=219
Age, years	62.7 (8.36)	62.1 (8.34)
Men, n (%)	124 (55.9)	132 (60.3)
Caucasian, n (%)	205 (92.3)	193 (88.1)
Smoking status at baseline, n (%)
Ex-smoker	85 (38.3)	87 (39.7)
Current smoker	137 (61.7)	132 (60.3)
Severity of COPD,a airflow limitation, n (%)
GOLD 2	138 (62.2)	144 (65.8)
GOLD 3	83 (37.4)	73 (33.3)
Severity of COPD,a combined assessment of COPD, n (%)
GOLD B	136 (61.3)	137 (62.6)
GOLD D	85 (38.3)	80 (36.5)
Duration of COPD, years	6.6 (4.85)	6.8 (5.45)
Number of COPD exacerbations in the previous year, n (%)
0	174 (78.4)	165 (75.3)
1	42 (18.9)	41 (18.7)
≥2	6 (2.7)	13 (5.9)
ICS use at baseline, n (%)	54 (24.3)	62 (28.3)
mMRC dyspnea scale, n (%)
Grade 2	121 (54.5)	113 (51.6)
Grade 3	88 (39.6)	92 (42.0)
Grade 4	12 (5.4)	13 (5.9)
BDI focal score	5.72 (2.10)	5.6 (2.06)
SGRQ total score	52.4 (17.20)	54.1 (16.84)
CAT score	20.4 (8.07)	20.7 (7.54)
Prebronchodilator FEV1, L	1.28 (0.490)	1.33 (0.502)
Postbronchodilator FEV1, L	1.52 (0.540)	1.58 (0.541)
Postbronchodilator FEV1, % predicted	54.2 (13.59)	55.7 (12.78)
Postbronchodilator FEV1 reversibility, %b	20.7 (14.90)	20.7 (14.98)

Notes:

a GOLD 2011; all data shown are presented as mean (standard deviation), unless specified;

b assessed after administration of 84 µg ipratropium bromide.

Abbreviations: BDI, baseline dyspnea index; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; mMRC, modified Medical Research Council; SGRQ, St George’s Respiratory Questionnaire; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Figure 2 Improvement in FEV₁ AUC_{0–12 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 Forest plot of the treatment differences between glycopyrrolate and placebo in FEV₁ AUC_{0–12 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 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 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 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 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.

Table 2 AEs and SAEs (≥1% of patients in either treatment group), and death (safety set)

Preferred term	Glycopyrrolate, N=222, n (%)	Placebo, N=216, n (%)
Patients with at least one AE	95 (42.8)	89 (41.2)
COPDa	23 (10.4)	29 (13.4)
Headache	8 (3.6)	6 (2.8)
Upper respiratory tract infection	8 (3.6)	6 (2.8)
Cough	7 (3.2)	5 (2.3)
Nasal congestion	4 (1.8)	4 (1.9)
Oropharyngeal pain	4 (1.8)	4 (1.9)
Pneumonia	4 (1.8)	0
Bronchitis	3 (1.4)	2 (0.9)
Lower respiratory tract infection	3 (1.4)	0
Nasopharyngitis	3 (1.4)	7 (3.2)
Sinusitis	3 (1.4)	2 (0.9)
Urinary tract infection	3 (1.4)	3 (1.4)
Vertigo	3 (1.4)	0
Upper respiratory tract infection bacterial	2 (0.9)	5 (2.3)
Upper respiratory tract infection viral	2 (0.9)	3 (1.4)
Hyperkalemia	1 (0.5)	3 (1.4)
Abdominal pain	0	3 (1.4)
Acute respiratory failure	0	3 (1.4)
Patients with at least one SAE	11 (5.0)	12 (5.6)
COPDa	2 (0.9)	3 (1.4)
Death	0	1 (0.5)

Note:

a Worsening of COPD which includes COPD exacerbation.

Abbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; SAE, serious adverse event.

Table 3 Adjudicated serious CCV AEs during the study (safety set)

Adjudicated event	Glycopyrrolate N=222, n (%)	Placebo N=216, n (%)
Patients with at least one serious CCV AE	5 (2.3)	6 (2.8)
MACE	2 (0.9)	5 (2.3)
Nonfatal myocardial infarction	2 (0.9)	1 (0.5)
Coronary revascularization (CABG or PCI)	0	3 (1.4)
Heart failure requiring hospitalization	0	1 (0.5)
Nonfatal stroke	0	1 (0.5)
Non-MACE serious CCV AE	3 (1.4)	4 (1.9)

Abbreviations: AE, adverse event; CABG, coronary artery bypass grafting; CCV, cerebro- and cardiovascular; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention.