The lung function profile of once-daily tiotropium and olodaterol via Respimat^® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler^® (ENERGITO^® study)

Figures & data

Figure 1 Study design.

Notes: Treatment periods are 6 weeks and washout periods are 3 weeks. A–D refer to treatment groups.
Abbreviations: R, randomization; S, screening.

Figure 2 Patient disposition.

Notes: ^aNine patients did not complete any treatment; ^bincludes lack of efficacy; ^ccompleting ≥1 treatment arm.
Abbreviation: AE, adverse event.

Table 1 Demographic and baseline patient characteristics (treated population)

	Total (n=229)
Sex, n (%)
Male	148 (64.6)
Female	81 (35.4)
Race, n (%)
White	228 (99.6)
Asian	1 (0.4)
Region, n (%)
Western Europe	169 (73.8)
Eastern Europe	60 (26.2)
Mean (SD) age, years	63.6 (7.6)
Alcohol history, n (%)
Nondrinker	58 (25.3)
Drinker	171 (74.7)
Smoking status, n (%)
Ex-smoker	127 (55.5)
Current smoker	102 (44.5)
Mean (SD) smoking history, pack-years	39.1 (18.3)
Mean (SD) prebronchodilator screening
FEV1, L	1.425 (0.456)
% of predicted normal FEV1, L	49.490 (12.228)
Mean (SD) postbronchodilator screening
FEV1, L	1.624 (0.468)
% of predicted normal FEV1, L	56.436 (11.812)
GOLD, n (%)
1 (≥80%)	0
2 (50–<80%)	165 (72.1)
3 (30–<50%)	64 (27.9)
4 (<30%)	0
Baseline pulmonary medication, n (%)
LAMA	123 (53.7)
SABA	122 (53.3)
LABA/ICS	87 (38.0)
LABA	54 (23.6)
SAMA	24 (10.5)
ICS	22 (9.6)
Xanthines	11 (4.8)
Mucolytics	5 (2.2)
Oral β-adrenergics	2 (0.9)
Oxygen	1 (0.4)
Steroids, other	1 (0.4)

Abbreviations: FEV₁, forced expiratory volume in 1 second; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β-agonist; SAMA, short-acting muscarinic antagonist; SD, standard deviation.

Table 2 Adjusted mean FEV₁ AUC responses after 6 weeks of treatment (full analysis set)

	Tiotropium + olodaterol 5/5 µg	Tiotropium + olodaterol 2.5/5 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
Patients, n	216	214	217	211
Adjusted mean (SE) FEV1	317 (14)	295 (14)	188 (14)	192 (15)
AUC0–12 response, mL
Adjusted mean (SE) FEV1	244 (14)	228 (14)	159 (14)	162 (14)
AUC0–24 response, mL
Adjusted mean (SE) FEV1	172 (14)	160 (14)	129 (14)	132 (14)
AUC12–24 response, mL

Notes: The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: AUC, area under the curve; AUC_0–12, AUC from 0 hour to 12 hours; AUC_0–24, AUC from 0 hour to 24 hours; AUC_12–24, AUC from 12 hours to 24 hours; FEV₁, forced expiratory volume in 1 second; SE, standard error.

Table 3 Adjusted mean FEV₁ AUC_0–12, AUC_0–24, and AUC_12–24 responses after 6 weeks of treatment, showing the treatment differences (full analysis set)

	Treatment comparison
	Tiotropium + olodaterol 5/5 µg versus		Tiotropium + olodaterol 2.5/5 µg versus
	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
FEV1 AUC0–12, mL
Adjusted mean (SE)	129 (11)	125 (11)	106 (11)	103 (11)
95% CI	107, 150	103, 147	85, 128	81, 124
P-value	<0.0001	<0.0001	<0.0001	<0.0001
FEV1 AUC0–24, mL
Adjusted mean (SE)	86 (11)	82 (11)	69 (11)	65 (11)
95% CI	65, 107	61, 103	48, 90	45, 86
P-value	<0.0001	<0.0001	<0.0001	<0.0001
FEV1 AUC12–24, mL
Adjusted mean (SE)	43 (11)	39 (12)	32 (11)	28 (11)
95% CI	21, 65	17, 62	9, 54	6, 51
P-value	0.0002	0.0007	0.0055	0.0146

Notes: The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: AUC, area under the curve; AUC_0–12, AUC from 0 hour to 12 hours; AUC_0–24, AUC from 0 hour to 24 hours; AUC_12–24, AUC from 12 hours to 24 hours; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; SE, standard error.

Figure 3 Adjusted mean 24-hour FEV₁ profile after 6 weeks of treatment (full analysis set).

Abbreviations: bid, twice daily; F, fluticasone propionate; FEV₁, forced expiratory volume in 1 second; O, olodaterol; qd, once daily; S, salmeterol; T, tiotropium.

Table 4 Peak_0–3 FEV₁ response at study Day 1 and Day 43 and trough FEV₁ responses after 6 weeks of treatment (full analysis set)

	Tiotropium + olodaterol 5/5 µg	Tiotropium + olodaterol 2.5/5 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
Patients, n	218	215	218	211
Adjusted mean (SE) peak0–3
FEV1 response, mL
Day 1	345 (12)	326 (12)	265 (12)	250 (12)
Day 43	432 (16)	401 (16)	285 (15)	291 (16)
Patients, n	216	214	217	211
Adjusted mean (SE) trough	197 (14)	192 (14)	139 (14)	150 (14)
FEV1 response, mL

Notes: The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: FEV₁, forced expiratory volume in 1 second; peak_0–3 FEV₁, peak forced expiratory volume in 1 second from 0 hour to 3 hours; SE, standard error.

Table 5 Peak_0–3 FEV₁ response at study Day 1 and Day 43 and trough FEV₁ responses after 6 weeks of treatment, showing the differences between treatments (full analysis set)

	Treatment comparison
	Tiotropium + olodaterol 5/5 µg versus		Tiotropium + olodaterol 2.5/5 µg versus
	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
Peak0–3 FEV1, mL, Day 1
Adjusted mean (SE)	80 (9)	95 (9)	61 (9)	76 (9)
95% CI	62, 97	77, 112	44, 79	59, 94
P-value	<0.0001	<0.0001	<0.0001	<0.0001
Peak0–3 FEV1, mL, Day 43
Adjusted mean (SE)	147 (12)	142 (12)	116 (12)	111 (12)
95% CI	123, 171	118, 166	92, 140	87, 135
P-value	<0.0001	<0.0001	<0.0001	<0.0001
Trough FEV1, mL
Adjusted mean (SE)	58 (12)	47 (12)	54 (12)	42 (12)
95% CI	34, 82	22, 71	29, 78	18, 67
P-value	<0.0001	0.0002	<0.0001	0.0007

Notes: The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; peak_0–3 FEV₁, peak forced expiratory volume in 1 second from 0 hour to 3 hours; SE, standard error.

Figure 4 Adjusted mean 24-hour FVC profile after 6 weeks of treatment (full analysis set).

Abbreviations: bid, twice daily; F, fluticasone propionate; FVC, forced vital capacity; O, olodaterol; qd, once daily; S, salmeterol; T, tiotropium.

Table 6 Summary of AEs (treated population)

	Tiotropium + olodaterol 5/5 µg, n (%)	Tiotropium + olodaterol 2.5/5 µg, n (%)	Salmeterol + fluticasone propionate 50/500 µg, n (%)	Salmeterol + fluticasone propionate 50/250 µg, n (%)	Total, n (%)
Patients	221 (100)	215 (100)	219 (100)	212 (100)	229 (100)
Any AE	75 (33.9)	74 (34.4)	81 (37.0)	63 (29.7)	158 (69.0)
Severe AEs	6 (2.7)	7 (3.3)	11 (5.0)	5 (2.4)	24 (10.5)
Drug-related AEsa	6 (2.7)	12 (5.6)	9 (4.1)	9 (4.2)	23 (10.0)
Other significant AEsb	4 (1.8)	3 (1.4)	2 (0.9)	0 (0.0)	9 (3.9)
AEs leading to discontinuation of trial drug	6 (2.7)	4 (1.9)	3 (1.4)	2 (0.9)	15 (6.6)
Serious AEs	7 (3.2)	6 (2.8)	9 (4.1)	4 (1.9)	22 (9.6)
Fatal AEs	2 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)	2 (0.9)
Immediately life-threatening	0 (0.0)	1 (0.5)	0 (0.0)	0 (0.0)	1 (0.4)
AEs
Requiring hospitalization	5 (2.3)	6 (2.8)	9 (4.1)	4 (1.9)	20 (8.7)
Prolonged hospitalization	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.5)	1 (0.4)
AEs occurring in >2% of patients overall^c
COPD worsening	20 (9.0)	12 (5.6)	19 (8.7)	9 (4.2)	45 (19.7)
Nasopharyngitis	12 (5.4)	12 (5.6)	11 (5.0)	13 (6.1)	40 (17.5)
Cough	7 (3.2)	5 (2.3)	5 (2.3)	4 (1.9)	17 (7.4)
Dyspnea	3 (1.4)	3 (1.4)	6 (2.7)	4 (1.9)	14 (6.1)
Headache	8 (3.6)	5 (2.3)	2 (0.9)	4 (1.9)	14 (6.1)
Back pain	4 (1.8)	2 (0.9)	2 (0.9)	4 (1.9)	11 (4.8)
Dysphonia	0 (0.0)	3 (1.4)	3 (1.4)	2 (0.9)	7 (3.1)
Arthralgia	1 (0.5)	2 (0.9)	2 (0.9)	2 (0.9)	6 (2.6)
Diarrhea	1 (0.5)	2 (0.9)	1 (0.5)	2 (0.9)	5 (2.2)
Nausea	1 (0.5)	0 (0.0)	2 (0.9)	2 (0.9)	5 (2.2)
Oropharyngeal pain	1 (0.5)	2 (0.9)	2 (0.9)	0 (0.0)	5 (2.2)
Pneumonia	1 (0.5)	2 (0.9)	1 (0.5)	1 (0.5)	5 (2.2)

Notes:

a Drug-related AEs were defined by the investigator;

b according to ICH E3; ^cpercentages were calculated using the total number of patients per treatment group as the denominator.

Abbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; ICH E3, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Harmonised Tripartite Guideline E3.

Table S1 Additional exclusion criteria

Patients with any of the following conditions were to be excluded:

A diagnosis of thyrotoxicosis (due to the known class side-effect profile of β2-agonists)

A diagnosis of paroxysmal tachycardia (>100 beats/min) (due to the known class side-effect profile of β2-agonists)

A history of myocardial infarction within 1 year of the screening visit

Unstable or life-threatening cardiac arrhythmia

Hospitalization for heart failure within the past year

Known active tuberculosis

A malignancy for which the patient has undergone resection, radiation therapy, or chemotherapy within the past 5 years (except for treated basal cell carcinoma)

A history of life-threatening pulmonary obstruction

A history of cystic fibrosis

Clinically evident bronchiectasis

A history of significant alcohol or drug abuse

Patients who have undergone thoracotomy with pulmonary resection

Patients being treated with oral or patch β-adrenergics

Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1

Patients who regularly use daytime oxygen therapy for >1 hour per day and, in the investigator’s opinion, will be unable to abstain from the use of oxygen therapy during clinic visits

Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program

Patients who have taken an investigational drug within 1 month, 6 half-lives, or within the washout period (whichever is greater) prior to screening visit (Visit 1)

Patients with known hypersensitivity to β-adrenergic drugs, BAC, EDTA, or any other component of the Respimat^® inhalation solution, or lactose monohydrate

Pregnant or nursing women

Women of childbearing potential not using a highly effective method of birth control.a Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation or if in postmenopausal stage for ≥2 years

Patients who have previously been randomized in this study or are currently participating in another study

Patients who are unable to comply with pulmonary medication restrictions prior to randomization

Notes:

a Defined as those methods that result in a low failure rate (ie, <1% per year) when used consistently and correctly as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2) guidelines.

Abbreviations: BAC, benzalkonium chloride; EDTA, ethylenediaminetetraacetic acid.

Table S2 Adjusted mean FVC AUC_0–12, AUC_0–24, and AUC_12–24 responses after 6 weeks of treatment: treatment differences (full analysis set)

	Treatment comparison
	Tiotropium + olodaterol 5/5 µg versus		Tiotropium + olodaterol 2.5/5 µg versus
	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
FVC AUC0–12, mL
Adjusted mean (SE)	218 (18)*	215 (18)*	183 (18)*	180 (18)*
95% CI	184, 253	180, 250	149, 218	146, 215
FVC AUC0–24, mL
Adjusted mean (SE)	176 (17)*	177 (17)*	140 (17)*	141 (17)*
95% CI	144, 209	144, 209	108, 173	108, 173
FVC AUC12–24, mL
Adjusted mean (SE)	135 (18)*	138 (18)*	98 (18)*	101 (18)*
95% CI	100, 170	103, 174	63, 133	66, 136

Notes:

* P<0.0001. The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: AUC_0–12, area under the curve from 0 hour to 12 hours; AUC_0–24, area under the curve from 0 hour to 24 hours; AUC_12–24, area under the curve from 12 hours to 24 hours; CI, confidence interval; FVC, forced vital capacity; SE, standard error.

Table S3 Adjusted mean FVC AUC_0–3, trough FVC, and peak_0–3 FVC responses after 6 weeks of treatment: treatment differences (full analysis set)

	Treatment comparison
	Tiotropium + olodaterol 5/5 µg versus		Tiotropium + olodaterol 2.5/5 µg versus
	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg	Salmeterol + fluticasone propionate 50/500 µg	Salmeterol + fluticasone propionate 50/250 µg
FVC AUC0–3, mL
Adjusted mean (SE)	104 (13)*	110 (13)*	82 (13)*	88 (13)*
95% CI	78, 130	84, 136	56, 108	62, 114
Trough FVC, mL
Adjusted mean (SE)	145 (20)*	137 (20)*	120 (20)*	112 (20)*
95% CI	106, 183	98, 176	81, 158	74, 151
Peak0–3 FVC response, mL
Adjusted mean (SE)	215 (20)*	213 (20)*	172 (20)*	169 (20)*
95% CI	176, 255	173, 253	133, 211	130, 209

Notes:

* P<0.0001. The adjusted mean (SE) was obtained from fitting a mixed-effects repeated-measures model including the following: fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within-patient variation; and Kenward–Roger approximation of denominator degrees of freedom.

Abbreviations: AUC_0–3, area under the curve from 0 hour to 3 hours; CI, confidence interval; FVC, forced vital capacity; peak_0–3 FVC, peak forced vital capacity from 0 hour to 3 hours; SE, standard error.