The Effect of Baseline Rescue Medication Use on Efficacy and Safety of Nebulized Glycopyrrolate Treatment in Patients with COPD from the GOLDEN 3 and 4 Studies

Figures & data

Figure 1 GOLDEN 3 and GOLDEN 4 study designs: 12-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter studies.⁷

Notes: ^aSAEs were monitored for 30 days after the last dose of study treatment; ^bData for the GLY 50 µg BID treatment arm are not presented in this post-hoc analysis but were used in the modeling and in defining the rescue medication subgroups studied in this analysis; inclusion of the 50 µg BID data in the modeling does not confound the interpretation of the GLY 25 µg BID dose.
Abbreviations: BID, twice daily; CS, closed system; GLY, nebulized glycopyrrolate; GOLDEN, Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer; ICS, inhaled corticosteroids; LABA, long-acting beta₂-agonist; min, minimum; SAE, serious adverse event; tx, treatment.

Table 1 Patient Grouping Based on Baseline Rescue Medication Use Quartiles

Rescue Medication Use	Q1		Q2		Q3		Q4
	Placebo n=97	GLY 25 µg BID n=91	Placebo n=113	GLY 25 µg BID n=93	Placebo n=86	GLY 25 µg BID n=112	Placebo n=93	GLY 25 µg BID n=96
Average number of puffs/day, median (range)	0.1 (0–0.9)	0.1 (0–0.9)	1.8 (1.0–2.7)	1.8 (1.0–2.7)	4.1 (2.7–5.2)	3.9 (2.8–5.2)	6.6 (5.3–14.1)	6.8 (5.2–10.4)

Abbreviations: BID, twice daily; GLY, nebulized glycopyrrolate; Q, quarter.

Table 2 Patient Demographics and Baseline Characteristics by Baseline Rescue Medication Subgroups

Parameter	Q1		Q2		Q3		Q4
	Placebo n=97	GLY 25 µg BID n=91	Placebo n=113	GLY 25 µg BID n=93	Placebo n=86	GLY 25 µg BID n=112	Placebo n=93	GLY 25 mcg BID n=96
Age, median (range)	67.0 (46–84)	67.0 (41–83)	62.0 (42–84)	63.0 (45–80)	62.0 (41–83)	63.0 (45–82)	63.0 (43–82)	60.5 (40–83)
Female, n (%)	43 (44.3)	45 (49.5)	65 (57.5)	40 (43.0)	37 (43.0)	51 (45.5)	37 (39.8)	38 (39.6)
White, n (%)	91 (93.8)	85 (93.4)	105 (92.9)	78 (83.9)	74 (86.0)	98 (87.5)	85 (91.4)	88 (91.7)
CV risk high, n (%)	68 (70.1)	58 (63.7)	66 (58.4)	64 (68.8)	56 (65.1)	68 (60.7)	61 (65.6)	56 (58.3)
LABA bg, n (%)	22 (22.7)	21 (23.1)	28 (24.8)	24 (25.8)	31 (36.0)	35 (31.3)	36 (38.7)	40 (41.7)
ICS bg, n (%)	22 (22.7)	20 (22.0)	27 (23.9)	22 (23.7)	27 (31.4)	34 (30.4)	36 (38.7)	36 (37.5)
FEV1, median (range), L	1.315 (0.520–2.665)	1.260 (0.475–2.645)	1.340 (0.540–2.895)	1.355 (0.565–2.620)	1.235 (0.510–2.585)	1.275 (0.530–2.700)	1.070 (0.545–3.145)	1.195 (0.530–3.225)
FEV1 reversibility (% improvement), median (range)	14.0 (−6–59)	15.0 (−8–55)	15.0 (−12–66)	16.0 (−16–61)	13.0 (−9–63)	18.0 (−11–74)	17.0 (−33–86)	19.0 (−9–74)
Post-bronchodilator FEV1^a n (%)
<30% predicted	1 (1.0)	3 (3.3)	5 (4.4)	4 (4.3)	7 (8.1)	7 (6.3)	11 (11.8)	13 (13.5)
≥30%–≤50% predicted	33 (34.0)	30 (33.3)	25 (22.1)	31 (33.3)	36 (41.9)	42 (37.5)	42 (45.2)	43 (44.8)
≥50% predicted	63 (64.9)	57 (63.3)	83 (73.5)	58 (62.4)	43 (50.0)	63 (56.3)	40 (43.0)	40 (41.7)
SGRQ score, median (range)^b
Total score	37.16 (1.1–76.9)	36.08 (0–89.6)	48.36 (12.5–85.3)	49.02 (14.2–89.0)	49.81 (15.6–98.2)	56.40 (0.8–95.9)	54.82 (22.4–88.2)	55.10 (11.5–90.3)
Impacts component score	59.46 (0–94.1)	53.54 (0–100)	66.19 (12.2–100)	66.94 (18.1–100)	72.82 (23.3–100)	72.82 (0–100)	72.82 (23.3–100)	73.04 (0–100)
Activity component score	22.31 0–70.3)	22.78 (0–88.7)	32.55 (3.6–79.7)	36.50 (5.3–85.2)	36.05 (5.5–98.9)	40.4 (0–96.8)	40.76 (3.9–82.4)	40.20 (1.6–87.9)
Symptoms component score	45.33 (6.3–81.7)	45.28 (0–86.3)	62.91 (8.7–97.5)	65.62 (6.3–92.8)	65.89 (7.6–100)	72.20 (5.1–100)	73.12 (15.4–100)	74.75 (24.8–100)
Total EXACT-RS, median (range)^c	8.39 (0–25.4)	6.57 (0–27.3)	11.33(0–24.1)	10.71 (0–26.2)	13.43 (0–29.7)	15.50 (0.3–30.4)	15.43 (0.1–34.7)	16.14 (3.1–32.4)
COPD exacerbations within 12 months, n (%)	22 (22.7)	9 (9.9)	24 (21.2)	20 (21.5)	17 (19.8)	21 (18.8)	19 (20.4)	24 (25.0)
Current smoker, n (%)	35 (36.1)	41 (45.1)	69 (61.1)	52 (55.9)	46 (53.5)	64 (57.1)	47 (50.5)	59 (61.5)
Number of pack-years, median (range)	52.0 (16–129)	49.0 (13–192)	45.0 (13–162)	45.0 (13–144)	45.5 (10–240)	46.0 (12–130)	45.0 (11–188)	45.0 (11–159)

Notes: ^aOne patient in the GLY 25 µg BID arm did not have post-bronchodilator FEV₁ data at baseline; ^bQ1: placebo, n=94, GLY, n=84; Q2: placebo, n=103, GLY, n=89; Q3: placebo, n=83, GLY, n=103; Q4: placebo, n=89, GLY, n=93; ^cQ1: placebo, n=94, GLY, n=91; Q2: placebo, n=113, GLY, n=92; Q3: placebo, n=85, GLY, n=111; Q4: placebo, n=92, GLY, n=94.

Abbreviations: bg, background; BID, twice daily; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; EXACT-RS, EXAcerbations of COPD Tool-Respiratory Symptoms; FEV₁, forced expiratory volume in 1 second; GLY, nebulized glycopyrrolate; ICS, inhaled corticosteroids; LABA, long-acting beta₂-agonist; Q, quarter; SGRQ, St. George’s Respiratory Questionnaire.

Figure 2 Pooled analysis of change from baseline in SGRQ (A) total score, (B) activity, (C) impacts, (D) symptoms component scores, and (E) responders at 12 weeks, by baseline rescue medication use (ITT population).

Notes: *P < 0.05; **P < 0.01 versus placebo; n-values represent the number of patients with on-treatment data at week 12.
Abbreviations: BID, twice daily; CI, confidence interval; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; OR, odds ratio; Q, quarter; SE, standard error; SGRQ, St. George’s Respiratory Questionnaire.

Figure 3 Pooled analysis of change from baseline in EXACT-RS (A) total score and (B) responders at 12 weeks, by baseline rescue medication use (ITT population).

Notes: *P < 0.05 versus placebo; n-values represent the number of patients with on-treatment data at week 12.
Abbreviations: BID, twice daily; CI, confidence interval; EXACT-RS, EXAcerbations of COPD Tool-Respiratory Symptoms; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; OR, odds ratio; Q, quarter; SE, standard error.

Figure 4 Pooled analysis of change from baseline in trough FEV₁ at 12 weeks by baseline rescue medication use subgroup (ITT population).

Notes: *p<0.05, **p<0.01, ***p<0.001 versus placebo; n-values represent the number of patients with on-treatment data at week 12.
Abbreviations: BID, twice daily; FEV₁, forced expiratory volume in 1 second; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; Q, quarter; SE, standard error.

Figure 5 Pooled analysis of change from baseline in the number of puffs of rescue medication per day over 12 weeks by baseline rescue medication use subgroup (ITT population).

Note: n-values represent the number of patients with on-treatment data at week 12.
Abbreviations: BID, twice daily; GLY, nebulized glycopyrrolate; ITT, intent-to-treat; LS, least squares; Q, quarter; SE, standard error.

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

Preferred Term, n (%)	Q1		Q2		Q3		Q4
	Placebo n=97	GLY 25 µg BID n=91	Placebo n=113	GLY 25 µg BID n=93	Placebo n=86	GLY 25 µg BID n=112	Placebo n=93	GLY 25 µg BID n=96
Any AE	51 (52.6)	33 (36.3)	60 (53.1)	42 (45.2)	42 (48.8)	56 (50.0)	50 (53.8)	38 (39.6)
Cough	14 (14.4)	1 (1.1)	11 (9.7)	10 (10.8)	4 (4.7)	9 (8.0)	2 (2.2)	6 (6.3)
Worsening of COPD	6 (6.2)	4 (4.4)	9 (8.0)	5 (5.4)	4 (4.7)	9 (8.0)	15 (16.1)	5 (5.2)
Dyspnea	2 (2.1)	2 (2.2)	6 (5.3)	5 (5.4)	1 (1.2)	8 (7.1)	3 (3.2)	5 (5.2)
Upper respiratory tract infection	0	3 (3.3)	1 (0.9)	1 (1.1)	3 (3.5)	2 (1.8)	0	0
Nasopharyngitis	0	4 (4.4)	0	1 (1.1)	2 (2.3)	2 (1.8)	2 (2.2)	0
Urinary tract infection	0	0	3 (2.7)	3 (3.2)	1 (1.2)	2 (1.8)	2 (2.2)	4 (4.2)
Headache	2 (2.1)	3 (3.3)	1 (0.9)	1 (1.1)	4 (4.7)	0	2 (2.2)	1 (1.0)
Arthralgia	3 (3.1)	1 (1.1)	2 (1.8)	1 (1.1)	0	0	0	1 (1.0)
Gastroenteritis	1 (1.0)	0	0	0	2 (2.3)	1 (0.9)	3 (3.2)	1 (1.0)
Diarrhea	1 (1.0)	0	1 (0.9)	0	0	1 (0.9)	3 (3.2)	0
Edema peripheral	0	1 (1.1)	0	1 (1.1)	0	1 (0.9)	3 (3.2)	1 (1.0)
Any SAE	5 (5.2)	3 (3.3)	5 (4.4)	2 (2.2)	4 (4.7)	4 (3.6)	7 (7.5)	3 (3.1)

Abbreviations: AE, adverse event; BID, twice daily; COPD, chronic obstructive pulmonary disease; GLY, nebulized glycopyrrolate; Q, quarter; SAE, serious adverse event.

KerwinE, DonohueJF, GoodinT, TosielloR, WheelerA, FergusonGT. Efficacy and safety of glycopyrrolate/eFlow® CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials. Respir Med. 2017;132:238–250. doi:10.1016/j.rmed.2017.07.01128838685

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