Efficacy and safety of the long-acting β₂-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease

Figures & data

Figure 1 Study design: 4-week, randomized, double-blind, placebo-controlled, parallel-group study.

Abbreviation: QD, once daily.

Table 1 Patient demographics and baseline characteristics

	Placebo (n=79)	Olodaterol
		2 µg QD (n=84)	5 µg QD (n=79)	10 µg QD (n=86)	Total (n=328)
Sex, n (%)
Male	75 (94.9)	79 (94.0)	76 (96.2)	80 (93.0)	310 (94.5)
Female	4 (5.1)	5 (6.0)	3 (3.8)	6 (7.0)	18 (5.5)
Mean (SD) age, years	68.9 (6.5)	68.9 (7.6)	70.1 (6.7)	69.3 (7.4)	69.3 (7.1)
Smoking status, n (%)
Current smokers	20 (25.3)	22 (26.2)	23 (29.1)	21 (24.4)	86 (26.2)
Ex-smokers	59 (74.7)	62 (73.8)	56 (70.9)	65 (75.6)	242 (73.8)
Mean (SD) smoking, pack-years	65.47 (31.5)	59.15 (27.9)	64.80 (35.0)	60.19 (43.8)	62.31 (35.1)
Pre-bronchodilator screeninga
Mean FEV1, L (SD)	1.23 (0.37)	1.27 (0.51)	1.25 (0.41)	1.24 (0.44)	1.25 (0.43)
Post-bronchodilator screeninga
Mean FEV1, L (SD)	1.40 (0.37)	1.43 (0.50)	1.41 (0.40)	1.39 (0.41)	1.41 (0.42)
Mean FVC, L (SD)	3.06 (0.59)	3.11 (0.66)	3.03 (0.56)	3.08 (0.59)	3.07 (0.60)
Mean FEV1/FVC, % (SD)	46.13 (10.95)	45.64 (11.50)	46.74 (11.17)	45.58 (11.14)	46.01 (11.15)
COPD severity according to GOLD, n (%)
Moderate/severe/very severeb	43/35/1 (54.4/44.3/1.3)	43/40/1 (51.2/47.6/1.2)	41/38/0 (51.9/48.1/0.0)	45/41/0 (52.3/47.7/0.0)	172/154/2 (52.4/47.0/0.6)
Pre-study respiratory medication use, n (%)
Long-acting inhaled anticholinergics	32 (40.5)	29 (34.5)	28 (35.4)	39 (45.4)	128 (39.0)
Short-acting inhaled anticholinergics	9 (11.4)	12 (14.3)	10 (12.7)	12 (14.0)	43 (13.1)
Long-acting β2-adrenergics	20 (25.3)	15 (17.9)	18 (22.8)	24 (27.9)	77 (23.5)
Short-acting inhaled β2-adrenergics	5 (6.3)	2 (2.4)	3 (3.8)	4 (4.7)	14 (4.3)
Inhaled steroids	16 (20.3)	11 (13.1)	9 (11.4)	21 (24.4)	57 (17.4)
Oral steroids	1 (1.3)	0 (0.0)	1 (1.3)	1 (1.2)	3 (0.9)

Notes:

a 10–15 minutes after 400 µg of salbutamol.

b Although the inclusion criteria only included moderate and severe COPD, two patients with very severe COPD were included.

Abbreviations: QD, once daily; SD, standard deviation; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; GOLD, Global initiative for chronic Obstructive Lung Disease.

Figure 2 CONSORT diagram illustrating participant flow.

Abbreviations: QD, once daily; AE, adverse event; CONSORT, Consolidated Standards of Reporting Trials.

Table 2 Adjusted mean trough FEV₁ after 4 weeks of treatment

	Trough FEV1	Difference from placebo
	Treatment mean, L (SE)	Mean, L (SE)	95% CI
Placebo	−0.032 (0.015)
Olodaterol 2 µg QD	0.059 (0.015)	0.091 (0.020)*	0.051, 0.131
Olodaterol 5 µg QD	0.100 (0.015)	0.132 (0.021)*	0.091, 0.172
Olodaterol 10 µg QD	0.100 (0.015)	0.132 (0.020)*	0.092, 0.172

Note:

* P<0.0001.

Abbreviations: FEV₁, forced expiratory volume in 1 second; SE, standard error; CI, confidence interval; QD, once daily.

Figure 3 Adjusted mean trough FEV₁ (A) and FVC (B) responses (± standard error) at Weeks 1, 2, and 4 of olodaterol and placebo treatment.

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

Table 3 Adjusted mean peak FEV₁ and FEV₁ AUC_0–3 after 4 weeks of treatment

	Treatment mean, L (SE)	Difference from placebo
		Mean, L (SE)	95% CI
Peak FEV1
Placebo	0.025 (0.017)
Olodaterol 2 µg QD	0.170 (0.017)	0.146 (0.023)*	0.101, 0.191
Olodaterol 5 µg QD	0.227 (0.017)	0.202 (0.023)*	0.157, 0.247
Olodaterol 10 µg QD	0.220 (0.017)	0.196 (0.023)*	0.151, 0.240
FEV1 AUC0–3
Placebo	−0.020 (0.017)
Olodaterol 2 µg QD	0.118 (0.016)	0.138 (0.022)*	0.095, 0.182
Olodaterol 5 µg QD	0.177 (0.017)	0.197 (0.022)*	0.154, 0.241
Olodaterol 10 µg QD	0.173 (0.016)	0.193 (0.022)*	0.150, 0.236

Note:

* P<0.0001.

Abbreviations: Peak FEV₁, peak forced expiratory volume in 1 second from 0 hour to 3 hours; FEV₁ AUC_0–3, forced expiratory volume in 1 second area under the curve from 0 hour to 3 hours; SE, standard error; CI, confidence interval; QD, once daily.

Table 4 Adjusted mean trough FVC, peak FVC, and FVC AUC_0–3 after 4 weeks of treatment

	Treatment mean, L (SE)	Difference from placebo
		Mean, L (SE)	95% CI
Trough FVC
Placebo	−0.037 (0.033)
Olodaterol 2 µg QD	0.154 (0.032)	0.191 (0.043)*	0.107, 0.275
Olodaterol 5 µg QD	0.154 (0.033)	0.191 (0.043)*	0.106, 0.276
Olodaterol 10 µg QD	0.150 (0.032)	0.187 (0.042)*	0.103, 0.270
Peak FVC
Placebo	0.109 (0.038)
Olodaterol 2 µg QD	0.362 (0.037)	0.253 (0.050)*	0.155, 0.351
Olodaterol 5 µg QD	0.351 (0.038)	0.242 (0.050)*	0.142, 0.341
Olodaterol 10 µg QD	0.335 (0.036)	0.226 (0.050)*	0.129, 0.324
FVC AUC0–3
Placebo	0.004 (0.036)
Olodaterol 2 µg QD	0.257 (0.035)	0.253 (0.047)*	0.160, 0.345
Olodaterol 5 µg QD	0.254 (0.036)	0.250 (0.047)*	0.156, 0.343
Olodaterol 10 µg QD	0.237 (0.035)	0.233 (0.047)*	0.141, 0.325

Note:

* P<0.0001.

Abbreviations: FVC, forced vital capacity; Peak FVC, peak FVC from 0 hour to 3 hours; AUC_0–3, area under the curve from 0 hour to 3 hours; SE, standard error; CI, confidence interval; QD, once daily.

Figure 4 Mean FEV₁ (A and B) and FVC (C and D) responses from −10 minutes to 3 hours on Day 1 (first administration) and Week 4.

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

Table 5 Pharmacokinetic parameters of olodaterol following first administration

Olodaterol Day 1	n	gMean (gCV%)
		Olodaterol 5 µg	Olodaterol 10 µg
Cmax, pg/mL	53/81	4.17 (46.7)	8.22 (58.3)
Cmax,norm, pg/mL/µg	53/81	0.833 (46.7)	0.822 (58.3)
tmax,a h	53/81	0.283 (0.0500–0.633)	0.300 (0.0500–0.667)
AUC0–1, pg·h/mL	30/77	3.67 (35.6)	6.08 (50.8)
AUC0–1,norm, pg·h/mL/µg	30/77	0.753 (35.6)	0.608 (50.8)

Note:

a Median (minimum–maximum).

Abbreviations: gMean, geometric mean; gCV, geometric coefficient of variation; C_max, maximum measured concentration of olodaterol in plasma; norm, dose normalized; t_max, time from dosing to maximum measured concentration of olodaterol in plasma; h, hours; AUC_0–1, area under the curve from 0 hour to 1 hour.

Table 6 Pharmacokinetic parameters of olodaterol following last administration

Olodaterol Week 4	n	gMean (gCV%)
		Olodaterol 5 µg	Olodaterol 10 µg
Cmax,ss, pg/mL	67/78	5.92 (57.4)	13.1 (58.6)
Cmax,ss,norm, pg/mL/µg	67/78	1.18 (57.4)	1.31 (58.6)
tmax,ss,a h	67/78	0.333 (0.0500–0.883)	0.300 (0.0830–1.00)
AUC0–1,ss, pg·h/mL	64/77	4.85 (54.6)	10.8 (54.0)
AUC0–1,ss,norm, pg·h/mL/µg	64/77	0.970 (54.6)	1.08 (54.0)
AUC0–3,ss, pg·h/mL	51/76	13.9 (45.4)	26.9 (51.7)
AUC0–3,ss,norm, pg·h/mL/µg	51/76	2.79 (45.4)	2.69 (51.7)
AUC0–24,ss, pg·h/mL	27/62	104 (36.4)	160 (40.7)
AUC0–24,ss,norm, pg·h/mL/µg	27/62	20.9 (36.4)	16.0 (40.7)
CL/Fss, mL/min	27/62	798 (36.4)	1,040 (40.7)
$R_{\mathrm{A},C_{\max }}$	47/74	1.59 (46.7)	1.60 (55.3)
$R_{\mathrm{A},{\text{AUC}}_{0-1}}$	28/71	1.69 (39.9)	1.77 (47.7)

Note:

a Median (minimum–maximum).

Abbreviations: gMean, geometric mean; gCV, geometric coefficient of variation; C_max, maximum measured concentration of olodaterol in plasma; ss, steady state; norm, dose normalized; t_max, time from dosing to maximum measured concentration of olodaterol in plasma; h, hours; AUC_0–1, area under the curve from 0 hour to 1 hour; AUC_0–3, area under the curve from 0 hour to 3 hours; AUC_0–24, area under the curve from 0 hour to 24 hours; CL/F, apparent clearance; min, minutes; $R_{\mathrm{A},C_{\max }}$, accumulation ratio based on C_max; $R_{\mathrm{A},{\text{AUC}}_{0-1}}$, accumulation ratio based on AUC_0–1.

Figure 5 Mean plasma concentration–time profiles for olodaterol.

Notes: Plasma concentrations after olodaterol 2 µg inhalation were too low to be quantified in most patients; therefore, mean plasma concentration profiles are not displayed.

Figure 6 Dose-normalized steady-state maximum concentrations (A) and AUC_0–1 (B) of olodaterol.

Note: Plasma concentrations after olodaterol 2 µg inhalation in most patients were below the limit of quantification; therefore, a gMean was not calculated.
Abbreviations: gMean, geometric mean; C_max,ss,norm, maximum measured concentration of olodaterol in plasma, steady-state, dose-normalized; AUC_{0–1,ss,norm}, area under the curve from 0 hour to 1 hour, steady-state, dose-normalized.

Table 7 Summary of AEs under treatmenta

	Placebo, n (%)	Olodaterol 2 µg, n (%)	Olodaterol 5 µg, n (%)	Olodaterol 10 µg, n (%)
Total	79 (100.0)	84 (100.0)	79 (100.0)	86 (100.0)
Patients with AEs	28 (35.4)	28 (33.3)	25 (31.6)	36 (41.9)
Frequently reported AEsb
Nasopharyngitis	3 (3.8)	9 (10.7)	3 (3.8)	5 (5.8)
COPD exacerbation	3 (3.8)	3 (3.6)	3 (3.8)	1 (1.2)
Myalgia	4 (5.1)	0 (0.0)	0 (0.0)	0 (0.0)
Patients with serious AEs	2 (2.5)	3 (3.6)	1 (1.3)	3 (3.5)

Note:

a AEs under treatment were AEs observed during, and up to 12 days following, treatment;

b AEs with an incidence >3% in any one of the treatment groups.

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