Tiotropium Plus Olodaterol Fixed-Dose Combination Therapy Provides Lung Function Benefits When Compared With Tiotropium Alone, Irrespective Of Prior Treatment With A Long-Acting Bronchodilator: Post Hoc Analyses Of Two 1-Year-Studies

Rationale: Tiotropium + olodaterol (T+O) is a novel once-daily, fixed-dose combination of the long-acting muscarinic antagonist (LAMA) tiotropium (T) and the long-acting β₂-agonist (LABA) olodaterol, for use as maintenance treatment in chronic obstructive pulmonary disease (COPD). These post hoc analyses of data from the two pivotal 1-year TONADO studies determined whether treatment with a long-acting bronchodilator (LABD) prior to randomization affected the lung-function benefits of T+O 5/5 µg (via Respimat^®) compared to T 5 µg (Respimat^®).

Methods: 2124 patients had not received prior LABD treatment (T+O n = 426; T n = 454) and 3038 patients had (T+O n = 603, T n = 579; 60.6% LAMA, 78.8% LABA). Baseline characteristics for all patients and a sub-group with GOLD 2 lung-function impairment are presented in the Table. Forced expiratory volume in 1 second (FEV₁) area under the curve from 0 – 3 hours (AUC_{0 – 3}) response (change from baseline) and trough FEV₁ response were primary end points in the studies.

Results: Comparable responses for both FEV₁ AUC_{0 – 3} and trough FEV₁ were observed in patients previously treated and untreated with LABD (see Table). The between-treatment differences (adjusted mean response [standard error (SE)]; mL) for no prior LABD and prior LABD treatment, respectively, were: 116 (13) and 105 (11) for FEV₁ AUC_{0 – 3}, and 76 (14) and 49 (11) for trough FEV₁. In the GOLD 2 subgroup the between-treatment differences (adjusted mean response [standard error (SE)]; mL) for no prior LABD and prior LABD treatment, respectively, were: 114 (19) and 123 (17) for FEV₁ AUC_{0 – 3}, and 79 (20) and 61 (18) for trough FEV₁.

Conclusions: Our analyses demonstrate the robust lung-function efficacy of T+O, compared with T alone, independent of the requirement for, or prior use of, LABD. These findings suggest a benefit of combination therapy over the mono-product as a first-line maintenance treatment.

	No prior LABD treatment				Prior LABD treatment
	All		GOLD 2		All		GOLD 2
	T+O	T	T+O	T	T+O	T	T+O	T
Baseline characteristics
n	426	454	228	240	603	579	274	277
Age (years), mean ± SD	62.7 ± 8.3	62.6 ± 8.8	63.0 ± 8.2	62.5 ± 8.9	64.6 ± 8.3	64.8 ± 8.2	65.3 ± 8.9	64.8 ± 8.7
Male, n (%)	291 (68.3)	338 (74.4)	148 (64.9)	160 (66.7)	442 (73.3)	417 (72.0)	202 (73.7)	180 (65.0)
Ex-smoker, n (%)	241 (56.6)	278 (61.2)	117 (51.3)	128 (53.3)	388 (64.3)	385 (66.5)	176 (64.2)	179 (64.6)
Post-bronchodilator FEV 1 (L), mean ± SD	1.38 ± 0.52	1.43 ± 0.54	1.72 ± 0.44	1.77 (0.47)	1.32 (0.50)	1.32 (0.51)	1.69 (0.44)	1.69 (0.45)
Post-bronchodilator FEV 1 (% predicted), mean ± SD	50.7 ± 16.0	50.8 ± 15.7	63.2 ± 8.8	63.1 ± 8.4	48.3 ± 14.7	48.8 ± 15.6	62.0 ± 7.4	62.7 ± 8.1
Reversibility (mL), mean ± SD	158 ± 160	166 ± 144	175 ± 156	184 ± 163	169 ± 138	174 ± 147	201 ± 151	196 ± 170
Lung function after 24 weeks of treatment
Adjusted mean FEV1 AUC0 – 3, (mL)± SE	270 ± 10	154 ± 9	289 ± 13	175 ± 13	256 ± 8	150 ± 8	302 ± 12	179 ± 12
Adjusted mean trough FEV1 (mL)± SE	148 ± 10	72 ± 10	146 ± 14	68 ± 14	134 ± 8	86 ± 8	156 ± 13	95 ± 13
SD, standard deviation

Funding: Boehringer Ingelheim