Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study

Figures & data

Table 1 Patient baseline demographics and disease characteristics

Parameter	Study Part 1 (n=27)	Study Part 2 (n=38)
Male gender, n (%)	7 (26)	15 (39)
Race, caucasian, n (%)	27 (100)	37 (97)
Age, years, mean (range)	57.5 (42–72)	56.8 (42–73)
Smoking status, n (%)
Ex-smoker	16 (59)	17 (45)
Smoker	11 (41)	21 (55)
Pack-years, mean (range)	36.6 (20.0–52.3)	36.3 (15.0–93.0)
Duration of smoking, years, mean (range)	38.3 (13.6–54.6)	39.4 (24.0–54.0)
FEV1, L, mean ± SDa	1.67±0.54	1.70±0.46
FEV1, % predicted, mean ± SDa	65.3±11.0	63.1±10.6
FEV1 reversibility, %, mean ± SD	21.7±12.7	20.9±13.0
FEV1/FVC, mean ± SDa	0.54±0.09	0.52±0.11

Note:

a Post-bronchodilator.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

Figure 1A Patient flow through Part 1 of the study.

Notes: ^aIncluding four replacement patients. ^bPatients were replaced, with replacements starting from the next treatment planned to be administered to the withdrawn patients, such that there were 12 evaluable patients in each treatment period.

Abbreviation: ECG, electrocardiogram.

Figure 1B Patient flow through Part 2 of the study.

Note: ^aReasons included spirometry results, poor venous access and recruitment having been stopped.

Figure 2 Study Part 1: Change from baseline in FEV₁ AUC_0–12h after a single dose.

Note: Data are mean and 95% CI.

Abbreviations: AUC, area under the curve; CI, confidence interval; GB, glycopyrronium bromide; FEV₁, forced expiratory volume in 1 second; n, number of randomized patients.

Figure 3 Study Part 1: Change from baseline in peak FEV₁ after a single dose.

Note: Data are mean and 95% CI.
Abbreviations: CI, confidence interval; GB, glycopyrronium bromide; FEV₁, forced expiratory volume in 1 second; n, number of randomized patients.

Figure 4 Study Part 2: Adjusted mean 12 h trough FEV₁ on Day 7.

Notes: *P<0.001 versus placebo. Data plotted are adjusted mean and 95% CI.
Abbreviations: BID, twice daily; CI, confidence interval; GB, glycopyrronium bromide; FEV₁, forced expiratory volume in 1 second; n, number of randomized patients.

Figure 5 Study Part 2: Adjusted mean FEV₁ AUC_0–12h on Day 7.

Notes: *P<0.001 versus placebo. Data plotted are adjusted mean and 95% CI.
Abbreviations: AUC, area under the curve; BID, twice daily; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; GB, glycopyrronium bromide; n, number of randomized patients.

Figure 6 Study Part 2: Adjusted mean pre-dose morning FEV₁ on Day 8.

Notes: *P<0.001 versus placebo; ^‡P<0.05 versus GB 12.5 μg BID; ^§P<0.05 versus tiotropium. Data plotted are adjusted mean and 95% CI.
Abbreviations: BID, twice daily; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; GB, glycopyrronium bromide; n, number of randomized patients; OD, once daily.

Figure 7 Study Part 2: Difference in peak FEV₁ between Day 7 and Day 8, following administration of formoterol.

Notes: *P<0.001 versus Day 7. Data plotted are mean and 95% CI. Abbreviations: BID, twice daily; CI, confidence interval; GB, glycopyrronium bromide; FEV₁, forced expiratory volume in 1 second; n, number of randomized patients.

Figure 8 Study Part 2: Difference in FEV₁ AUC_0–12h between Day 7 and Day 8, following administration of formoterol.

Notes: *P<0.001 versus Day 7. Data plotted are mean and 95% CI.
Abbreviations: AUC, area under the curve; BID, twice daily; CI, confidence interval; GB, glycopyrronium bromide; FEV₁, forced expiratory volume in 1 second; n, number of randomized patients.

Table 2 Study Part 1: Overall experience of AEs and SAEs

	Placebo (n=10)	GB
		12.5 µg (n=10)	25 µg (n=9)	50 µg (n=10)	100 µg (n=9)	200 µg (n=10)
Any treatment-emergent AE, n (%)	8 (80.0)	5 (50.0)	3 (33.3)	5 (50.0)	4 (44.4)	4 (40.0)
Most frequently reported treatment-emergent AE (≥2 patients with any treatment)a
Headache, n (%)	3 (30.0)	3 (30.0)	1 (11.1)	3 (30.0)	0	3 (30.0)
Oropharyngeal pain, n (%)	1 (10.0)	0	0	0	2 (22.2)	0
Constipation, n (%)	2 (20.0)	0	0	0	0	0
AEs considered treatment related by the investigator, n (%)	1 (10.0)	0	0	1 (10.0)	0	1 (10.0)
AE leading to study withdrawal, n (%)	1 (10.0)	0	0	1 (10.0)	0	0
SAEs, n (%)	1 (10.0)	0	0	0	0	0

Note:

a Sorted by frequency in GB treatments.

Abbreviations: AE, adverse event; GB, glycopyrronium bromide; n, number of randomized patients; SAE, serious adverse event.

Table 3 Study Part 2: Overall experience of AEs and SAEs

	Placebo (n=35)	GB			Tiotropium 18 µg OD (n=34)
		12.5 µg BID (n=36)	25 µg BID (n=34)	50 µg BID (n=38)
Any treatment-emergent AE, n (%)	15 (42.9)	16 (44.4)	12 (35.3)	15 (39.5)	12 (35.3)
Most frequently reported treatment-emergent AEs (>2 patients with any treatment)a
Headache, n (%)	6 (17.1)	4 (11.1)	7 (20.6)	4 (10.5)	4 (11.8)
Back pain, n (%)	2 (5.7)	1 (2.8)	1 (2.9)	1 (2.6)	3 (8.8)
Cough, n (%)	4 (11.4)	1 (2.8)	1 (2.9)	0	0
AEs considered treatment related by the investigator, n (%)	1 (2.9)	2 (5.6)	0	1 (2.6)	2 (5.9)
AE leading to study withdrawal, n (%)	0	0	0	0	0
SAEs, n (%)	0	0	0	0	0

Note:

a Sorted by frequency in GB treatments.

Abbreviations: AE, adverse event; BID, twice daily; GB, glycopyrronium bromide; n, number of randomized patients; OD, once daily; SAEs, serious adverse events.

Table 4 Study Part 2: PK parameters of GB on Day 1 and Day 7

Parameter	GB
	12.5 µg BID (n=36)	25 µg BID (n=34)	50 µg BID (n=38)
	Day 1
Plasma
Cmax (pg/mL)	24.3±13.3	45.3±26.6	86.3±68.7
tmax (h)	0.08 (0.08–0.25)	0.08 (0.08–0.53)	0.12 (0.08–1.00)
AUC0–30min (pg h/mL)	9.93±4.41	17.7±8.84	34.0±24.0
AUC0–12h (pg h/mL)	38.4±27.6	83.2±54.1	180±120
AUC0–t (pg h/mL)	32.3±27.9	76.6±55.4	177±123
Urine
Ae0–12h (μg)	0.671±0.411	1.58±0.823	2.69±1.66
CLr (mL/min)	396±217	375±171	287±153
	Day 7
Plasma
Cmax,ss (pg/mL)	39.4±17.0	86.6±46.2	160±75.6
tmax,ss (h)	0.08 (0.08–0.55)	0.12 (0.07–1.00)	0.17 (0.08–0.52)
Cmin,ss (pg/m L)	BLOQ	8.68±4.61	17.3±6.99
AUC0–30min,ss (pg h/mL)	14.6±5.59	32.5±15.5	60.7±25.1
AUC0–12h,ss (pg h/mL)	87.0±41.7	223±85.7	427±152
AUC0–t,ss (pg h/m L)	83.6±42.7	218±88.8	427±153
t½,ss (h)	4.90±3.13	11.8±12.0	10.1±7.09
Rac	2.19 (1.09–8.27)	2.52 (1.16–29.5)	2.46 (0.99–71.1)
Urine
Ae0–12h,ss (μg)	1.62±0.638	3.62±1.80	6.94±2.88
CLrss (mL/min)	356±148	291±95.5	281±79.9

Notes: Values are arithmetic mean ± SD, except median (range) for t_max and R_ac (calculated as AUC_0–12h Day 7/Day 1). PK profiles were evaluated after morning administration.

Abbreviations: Ae, cumulative urinary excretion; AUC, area under the plasma concentration curve from administration to 30 min post-dose (0–30 min), from administration to last quantifiable concentration (0–t) and over the dosing interval (0–12 h); BID, twice daily; BLOQ, below limit of quantification; CLr, renal clearance; C_max, maximum concentration; C_min, minimum concentration; GB, glycopyrronium bromide; PK, pharmacokinetics; R_ac, accumulation ratio; ss, steady state; t_½, plasma elimination half life; t_max, time of the maximum concentration.

Figure S1 Study Part 2: Difference in 12 h trough FEV₁ between Day 7 and Day 8, following administration of formoterol.

Notes: *P<0.001 versus Day 7. Data plotted are mean and 95% CI.

Abbreviations: BID, twice daily; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; GB, glycopyrronium bromide; n, number of randomized patients.