Efficacy of tiotropium–olodaterol fixed-dose combination in COPD

Figures & data

Table 1 Completed Phase III studies comparing clinical effects of tiotropium–olodaterol fixed-dose combinations with monocomponents and/or placebo in patients with COPD

Title	Study	Daily treatments (patients randomized)	Primary end point	Key secondary end points
ANHELTO 1+2	ZuWallack et al^Citation30	OLO 5 μg + TIO 18 μg (567/566)a	FEV1 AUC0–3 at week 12	SGRQ total score at week 12
		TIO 18 μg (565/566)	Trough FEV1 at week 12
TONADO 1+2	Buhl et al^Citation27	TIO/OLO 5/5 μg (522/507)	FEV1 AUC0–3 at week 24	TDI at week 24
		TIO/OLO 2.5/5 μg (522/508)	Trough FEV1 at week 24
		OLO 5 μg (528/510)	SGRQ at week 24
		TIO 5 μg (527/506)
		TIO 2.5 (525/507)
VIVACITO	Beeh et al^Citation26	TIO/OLO 5/5 μg (139)	FEV1 AUC0–24 at week 6	FEV1 AUC0–12 at week 6
		TIO/OLO 2.5/5 μg (136)		FEV1 AUC12–24 at week 6
		OLO 5 μg (138)		Peak FEV1 AUC0–3 at week 6
		TIO 5 μg (138)		Trough FEV1 at week 6
		TIO 2.5 (137)		ΔRV and ΔFRC at week 6
		PLA (138)
OTEMTO 1+2	Singh et al^Citation28	TIO/OLO 5/5 μg (204/202)	SGRQ at week 12	TDI at week 12
		TIO/OLO 2.5/5 μg (202/202)	FEV1 AUC0–3 at week 12
		TIO 5 μg (204/203)	Trough FEV1 at week 12
		PLA (204/202)
ENERGITO	Beeh et al^Citation29	TIO/OLO 5/5 μg (221)	FEV1 AUC0–12 at week 6	FEV1 AUC0–24
		TIO/OLO 2.5/5 μg (215)		FEV1 AUC12–24 at week 6
		SALM/FLU 50/500 μg BID (215)		Peak FEV1 AUC0–3 at week 6
		SALM/FLU 50/250 μg BID (212)		Trough FEV1 at week 6
TORRACTO	Maltais et al^Citation32,b	TIO/OLO 5/5 μg (139)	Endurance time during constant work rate cycle ergometry at week 12	Endurance time during shuttle walking test at week 12
		TIO/OLO 2.5/5 μg (133)
		PLA (132)		Pre-exercise IC at week 12
MORACTO 1+2	O’Donnell et al^Citation31	TIO/OLO 5/5 μg (226/224)	Pre-exercise IC at week 6
		TIO/OLO 2.5/5 μg (223/219)	Endurance time during constant work-rate cycle ergometry at week 6
		TIO 5 μg (227/218)
		OLO 5 μg (217/219)
		PLA (222/216)

Notes:

a Treatments were inhaled separately via OLO Respimat and TIO HandiHaler;

b available only as abstract. 1+2, replicate studies.

Abbreviations: AUC, area under the curve; BID, bis in die (twice daily); FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; PLA, placebo; SALM/FLU, salmeterol/fluticasone; SGRQ, St George’s Respiratory Questionnaire (score); TDI, Transition Dyspnea Index; TIO/OLO, tiotropium–olodaterol fixed-dose combination; ΔRV, change in RV after treatment versus placebo; ΔFRC, change in FRC after treatment versus placebo.

Table 2 Differences in TIO/OLO 5/5 μg, TIO monotherapy, OLO monotherapy, and PLA for different spirometric end points derived from key clinical studies

Study	AUC0–24 FEV1 (mL)	Peak0–3 FEV1 (mL)	AUC0–3 FEV1 (mL)	Trough FEV1 (mL)
TIO/OLO 5/5 μg vs PLA
Beeh et al^Citation26	Δ=280	411 vs 72		201 vs −6
Singh et al^Citation28			Δ=331 and Δ=299	Δ=162 and Δ=166
TIO/OLO 5/5 μg vs TIO 5 μg
Beeh et al^Citation26	Δ=110	411 vs 300		201 vs 122
Singh et al^Citation28			Δ=111 and Δ=105	Δ=28 and Δ=39
Buhl et al^Citation27			Δ=117 and Δ=103	Δ=71 and Δ=50
TIO 18 μg + OLO 5 μga vs TIO 18 μg
ZuWallack et al^Citation30			Δ=117 and Δ=106	Δ=60 and Δ=40
TIO/OLO 5/5 μg vs OLO 5 μg
Beeh et al^Citation26	Δ=115			201 vs 109
Buhl et al^Citation27			Δ=123 and Δ=132	Δ=82 and Δ=88

Note:

a Treatments inhaled separately via OLO Respimat and TIO HandiHaler.

Abbreviations: AUC, area under the curve; FEV₁, forced expiratory volume in 1 second; PLA, placebo; TIO/OLO, tiotropium–olodaterol fixed-dose combination.

Table 3 Differences in TIO/OLO 5/5 μg, TIO monotherapy, OLO monotherapy, and PLA in key clinical studies, highlighting number of responders and number needed to treat

Study	TDI	TDI responders (%)	NNT (95% CI)	SGRQ	SGRQ responders (%)	NNT (95% CI)
TIO/OLO 5/5 μg vs PLA
Singh et al^Citation28	2.1 and 1.2	53.9 vs 26.2	4 (3.1–4.2)	−4.89 and −4.59	53.1 vs 31.2 and 51.8 vs 32.6	5 (3.8–5.7) and 6 (4.2–6.6)
TIO/OLO 5/5 μg vs TIO 5 μg
Singh et al^Citation28	0.6 and 0.6	53.9 vs 41	8 (5.8–11.7)	−2.49 and −1.72	53.1 vs 41.7 and 51.8 vs 41.1	9 (6.3–14.2) and 10 (6.6–15.7)
Buhl et al^Citation27	0.4	54.9 vs 50.6 (NS)	24 (NS)	−1.23	57.5 vs 48.7	12 (7.6–22.5)
TIO 18 μg + OLO 5 μg vs TIO 18 μg
ZuWallack et al^Citation30				−1.85	49.3 vs 42.5	15 (9–40)
TIO/OLO 5/5 μg vs OLO 5 μg
Buhl et al^Citation27	0.4	54.9 vs 48.2	15 (9–42.9)	−1.69	57.5 vs 44.8	8 (5.9–12)

Abbreviations: NNT, number needed to treat; CI, confidence interval; NS, not significant; PLA, placebo; SGRQ, St George’s Respiratory Questionnaire (score); TDI, Transition Dyspnea Index; TIO/OLO, tiotropium–olodaterol fixed-dose combination.

Figure 1 Adjusted mean FRC (A) and RV (B) responses at 6 weeks ± SE, measured by body plethysmography at 2 hours 30 minutes (02:30) and 22 hours 30 minutes postdose.

Notes: *P<0.05 versus placebo; **P<0.0001 versus placebo; ^#P<0.05 versus all monotherapies; ^##P<0.01 versus all monotherapies. Reproduced from Beeh KM, Westerman J, Kirsten AM, et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32:53–59.²⁶
Abbreviations: FRC, functional residual capacity; RV, residual volume; SE, standard error; OLO, olodaterol; TIO, tiotropium; FDC, fixed-dose combination.

Table 4 Differences between several LAMA/LABA fixed-dose combinations and PLA

Study	n	Trough FEV1 (mL)	SGRQ	TDI	FRC/IC (mL)	ET (s)
GLY/IND 110/50 μg vs PLA
Bateman et al^Citation46	2,144	Δ=200	Δ=−3	Δ=1.1
Beeh et al^Citation50	84				Δ=−520/Δ=340	Δ=60
UMEC/VIL 62.5/25 μg vs PLA
Donohue et al^Citation47	1,536	Δ=167	Δ=−5.5	Δ=1.2
Maltais et al^Citation51	308				−/Δ≈250	Δ=69.4
Maltais et al^Citation51	349				−/Δ≈400	Δ=21.9
ACL/FORM 400/12 μg BID vs PLA
D’Urzo et al^Citation48	1,692	−35 vs 94	−6.57 vs −2.21	2 vs 0.6
Singh et al^Citation49	1,729	Δ=143	−8.3 vs −6.5	2.5 vs 1.2

Abbreviations: ACL/FORM, aclidinium–formoterol fixed-dose combination; BID, bis in die (twice daily); ET, endurance time (during constant work-rate cycle ergometry); FEV₁, forced expiratory volume in 1 second; FRC, functional residual capacity; GLY/IND, glycopyrronium–indacaterol fixed-dose combination; IC, inspiratory capacity; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; PLA, placebo; SGRQ, St George’s Respiratory Questionnaire (score); TDI, Transition Dyspnea Index; UMEC/VIL, umeclidinium–vilanterol fixed-dose combination.

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