Impact of Comorbidity Prevalence and Cardiovascular Disease Status on the Efficacy and Safety of Nebulized Glycopyrrolate in Patients with COPD

Figures & data

Table 1 Prevalence of Comorbidities in the Pooled Patient Population from GOLDEN 3 and 4

Comorbidities^a, b n (%)	Group A(≤2 Comorbidities) N=439	Group B(>2 Comorbidities) N=854
Hypertension	129 (29.4)	645 (75.5)
High cholesterol	82 (18.7)	605 (70.8)
Osteoarthritis	62 (14.1)	414 (48.5)
GERD	49 (11.2)	410 (48.0)
Depression^c	38 (8.7)	400 (46.8)
Obesity	70 (15.9)	376 (44.0)
Anxiety^c	26 (5.9)	316 (37.0)
Insomnia	34 (7.7)	284 (33.3)
Diabetes	11 (2.5)	210 (24.6)
Sleep apnea	9 (2.1)	181 (21.2)
Osteoporosis	14 (3.2)	92 (10.8)
CHD	2 (0.5)	179 (21.0)
PVD	1 (0.2)	54 (6.3)
CHF	3 (0.7)	45 (5.3)

Notes: ^aComorbidities are not mutually exclusive. ^bPreferred terms used to classify these comorbidities are provided in Supplementary Table S1. ^cBased on self-reported medical history for anxiety and depression. For other comorbidities, medical records were used when available.

Abbreviations: CHD, coronary heart disease; CHF, congestive heart failure; GERD, gastroesophageal reflux disease; PVD, peripheral vascular disease.

Table 2 Demographics and Baseline Characteristics for the Baseline Comorbidity Prevalence Groups

Characteristics	Group A(≤2 Comorbidities) N=439	Group B(>2 Comorbidities) N=854
Age, years, median (range)	62.0 (40–87)	64.0 (40–85)
Male, n (%)	273 (62.2)	451 (52.8)
Current smoker, n (%)	253 (57.6)	431 (50.5)
Pack-years, median (range)	45.0 (10–192)	47.0 (10–240)
COPD exacerbations within 12 months, n (%)	82 (18.7)	168 (19.7%)
Number of COPD exacerbations within 12 months, median (range)	0 (0–54)	0 (0–49)
Post-bronchodilator FEV1% predicted, median (range)	50.0 (20–80)	53.0 (22–80)
Post-bronchodilator FEV1/FVC, % (range)	52.9 (20–69)	56.8 (24–71)
SGRQ total score, median (range)^a	46.48 (0–98.2)	50.20 (0.75–90.50)

Notes: ^aGroup A, n=412; Group B, n=814.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SGRQ, St George’s Respiratory Questionnaire.

Table 3 Baseline FEV₁, FVC, SGRQ Total and Domain Scores in the Comorbidity Groups, by Treatment

Parameter, Median (Range)	Group A (≤2 Comorbidities)		Group B (>2 Comorbidities)
	Placebo N=138	GLY 25 μg BID N=154	Placebo N=292	GLY 25 μg BID N=277
FEV1 (L)	1.24 (0.55–3.15)^a	1.31 (0.61–3.23)^b	1.29 (0.51–2.90)^c	1.26 (0.48–3.07)^d
Post-bronchodilator FVC (L)	2.73 (1.30–5.08)	2.77 (1.56–4.95)^e	2.69 (1.48–5.62)	2.60 (1.16–5.40)
COPD exacerbations within 12 months, n (%)	33 (23.9)	27 (17.5)	60 (20.5)	57 (20.6)
Number of COPD exacerbations within 12 months	0 (0–54)	0 (0–3)	0 (0–4)	0 (0–3)
SGRQ total score	43.98 (4.0–98.21)^f	46.43 (0–95.9)^g	48.73 (1.1–90.5)^l	51.23 (0.75–90.34)^m
Activity domain	65.6 (0–100.0)^f	60.34 (0–100.0)^g	66.65 (0–100.0)^n	67.35 (0–100.0)^m
Impacts domain	29.88 (0–98.9)^h	33.56 (0–96.8)^i	33.26 (0–87.7)^l	35.63 (0–87.9)°
Symptoms domain	63.31 (7.6–100.0)^j	61.51 (0–100.0)^k	63.06 (0–100.0)^p	68.5 (0–100.0)°

Notes: ^an=133; ^bn=144; ^cn=282; ^dn=265; ^en=153; ^fn=129; ^gn=147; ^hn=130;ⁱn=146; ^jn=132; ^kn=149; ^ln=281; ^mn=260; ⁿn=280; ^on=262; ^pn=286.

Abbreviations: BID, twice daily; GLY, glycopyrrolate; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SGRQ, St George’s Respiratory Questionnaire.

Table 4 Participant Distribution by Baseline CVD Status

Patients, n (%)	Total N = 861	Placebo N = 430	GLY 25 μg BID N = 431
Non-CVD	691 (80.3)	337 (78.4)	354 (82.1)
CVD	170 (19.7)	93 (21.6)	77 (17.9)

Abbreviations: BID, twice daily; CVD, cardiovascular disease; GLY, nebulized glycopyrrolate.

Table 5 Baseline Demographics and Disease Characteristics by CVD Status

Parameter	Non-CVD		CVD
	Placebo N=337	GLY 25 μg BID N=354	Placebo N=93	GLY 25 μg BID N=77
Age, years	64.0 (41–84)	63.0 (40–83)	66.0 (42–81)	67.0 (47–80)
Male, n (%)	179 (53.1)	193 (54.5)	56 (60.2)	49 (63.6)
BMI, kg/m^2	27.95 (16.8–71.6)	26.83 (14.7–53.4)	29.12 (16.3–42.3)	28.69 (16.3–50.3)
Current smoker, n (%)	178 (52.8)	201 (56.8)	40 (43)	39 (50.6)
Pack years	46.0 (10–188)	45.0 (10–192)	46.0 (12–240)	54.0 (16–159)
COPD exacerbations within 12 months, n (%)	69 (20.5)	68 (19.2)	24 (25.8)	16 (20.8)
Number of COPD exacerbations within 12 months	0 (0–54)	0 (0–3)	0 (0–4)	0 (0–2)
Post-bronchodilator FEV1% predicted	52.0 (22–79)	53.0 (20–79)	56.0 (24–79)	54.0 (23–76)
Post-bronchodilator FVC (L)	2.69 (1.30–5.62)	2.70 (1.16–5.40)^a	2.70 (1.48–5.32)	2.56 (1.23–4.42)
SGRQ total score	47.96 (4.0–98.2)^b	49.25 (0.0–95.9)^c	46.41 (1.1–84.3)^g	52.76 (9.1–89.0)^h
Activity domain	66.19 (0–100.0)^b	66.2 (0–100.0)^c	66.19 (0–100.0)^i	72.82 (0–100.0)^h
Impacts domain	31.8 (0–98.9)^d	34.3 (0–96.8)^c	33.36 (0–87.7)^g	36.45 (5.5–85.2)^j
Symptoms domain	64.5 (7.6–100.0)^e	66.9 (0–100.0)^f	56.4 (0–97.5)^k	67.0 (15.2–95.6)^j

Notes: ^an=353; ^bn=321; ^cn=332; ^dn=322; ^en=328; ^fn=335; ^gn=89; ^hn=75; ⁱn=88; ^jn=76; ^kn=90. Values are median (range) unless otherwise noted.

Abbreviations: BID, twice daily; BMI, body mass index; CVD, cardiovascular disease; GLY, glycopyrrolate; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire.

Figure 1 Pooled analysis of trough FEV₁ at 12 weeks, by (A) baseline comorbidity prevalence group (Group A, ≤2 comorbidities and Group B, >2 comorbidities) and (B) baseline cardiovascular disease subgroup (ITT population). ****p<0.0001 vs placebo. The n values represent the number of patients with on-treatment data at Week 12.

Abbreviations: BID, twice daily; CVD, cardiovascular disease; FEV₁, forced expiratory volume in 1 second; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; SE, standard error.

Figure 2 Pooled analysis of SGRQ total scores and component scores at 12 weeks, by (A) baseline comorbidity prevalence (Group A, ≤2 comorbidities and Group B, >2 comorbidities) and (B) baseline cardiovascular disease subgroup (ITT population). *p<0.05; **p<0.01; ***p<0.001 for GLY vs placebo.

Abbreviations: BID, twice daily; CI, confidence interval; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire.

Figure 3 Pooled analysis of SGRQ responder rates at 12 weeks, by (A) baseline comorbidity prevalence group (Group A, ≤2 comorbidities and Group B, >2 comorbidities) and (B) cardiovascular disease subgroup (ITT population). *p<0.05, **p<0.01 vs placebo. The n values represent the number of patients with on-treatment data at Week 12.

Abbreviations: BID, twice daily; CI, confidence interval; CVD, cardiovascular disease; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; OR, odds ratio; SGRQ, St George’s Respiratory Questionnaire.

Table 6 Summary of AEs and SAEs, Including Individual AEs with Incidence ≥3% in Any Treatment Group, by Baseline Comorbidity Prevalence Group (Safety Population)

Preferred Term, n (%)	Group A (≤2 Comorbidities)		Group B (>2 Comorbidities)
	Placebo N=138	GLY 25 μg BID N=154	Placebo N=292	GLY 25 μg BID N=277
Any AE	64 (46.4)	66 (42.9)	161 (55.1)	121 (43.7)
Cough	13 (9.4)	7 (4.5)	23 (7.9)	23 (8.3)
Worsening of COPD	10 (7.2)	11 (7.1)	27 (9.2)	17 (6.1)
Dyspnea	7 (5.1)	9 (5.8)	6 (2.1)	12 (4.3)
Chest discomfort	6 (4.3)	4 (2.6)	3 (1.0)	1 (0.4)
Any SAE	6 (4.3)	4 (2.6)	18 (6.2)	9 (3.2)
AE leading to early termination from treatment	14 (10.1)	8 (5.2)	25 (8.6)	15 (5.4)

Abbreviations: AE, adverse event; BID, twice daily; GLY, nebulized glycopyrrolate; SAE, serious adverse event.

Table 7 Summary of AEs and SAEs, Including Individual AEs with Incidence ≥3% in Any Treatment Group, by Baseline CVD (Safety Population)

Preferred Term, n (%)	CVD		Non-CVD
	Placebo N=93	GLY 25 μg BID N=77	Placebo N=337	GLY 25 μg BID N=354
Any AE	49 (52.7)	29 (37.7)	176 (52.2)	158 (44.6)
Cough	4 (4.3)	5 (6.5)	32 (9.5)	25 (7.1)
Worsening of COPD	8 (8.6)	3 (3.9)	29 (8.6)	25 (7.1)
Dyspnea	1 (1.1)	4 (5.2)	12 (3.6)	17 (4.8)
Urinary tract infection	0 (0)	3 (3.9)	6 (1.8)	6 (1.7)
Upper respiratory tract infection	3 (3.2)	2 (2.6)	1 (0.3)	4 (1.1)
Pneumonia	3 (3.2)	0 (0)	2 (0.6)	0 (0)
Back pain	3 (3.2)	0 (0)	4 (1.2)	3 (0.8)
Headache	0 (0)	3 (3.9)	10 (3.0)	4 (1.1)
Any SAE	9 (9.7)	2 (2.6)	15 (4.5)	11 (3.1)
AEs leading to early termination from treatment	5 (5.4)	3 (3.9)	35 (10.4)	19 (5.4)

Abbreviations: AE, adverse event; BID, twice daily; CVD, cardiovascular disease; GLY, glycopyrrolate; SAE, serious adverse event.

Table 8 Summary of Cardiovascular AESIs and MACE in Any Treatment Group, by Baseline CVD (Safety Population)

Preferred Term, n (%)	CVD		Non-CVD
	Placebo n=93	GLY 25 μg BID n=77	Placebo n=337	GLY 25 μg BID n=354
Any cardiovascular AESI	4 (4.3)	3 (3.9)	7 (2.1)	4 (1.1)
MACE score	0	0	2 (0.6)	0

Abbreviations: AESI, adverse event of special interest; BID, twice daily; CVD, cardiovascular disease; GLY, glycopyrrolate; MACE, major adverse cardiac event.