Evidence-based review of data on the combination inhaler umeclidinium/vilanterol in patients with COPD

Figures & data

Table 1 Widely available fixed dose of combined muscarinic receptor antagonists (MRA) and beta2 receptor agonist (B₂RA) used in COPD

First drug/MRA	Type	Dose (µg)	Second drug/B2RA	Type	Dose (µg)	Third drug (ICS)	Dose (µg)	Inhalations	Brand name	Frequency	Type	FDA^a Indications
Ipratropium	SAMA	500	Albuterol	SABA	3000	-	-	NA	Generic + DuoNeb^®	q6h	Neb	COPD
Ipratropium	SAMA	20	Albuterol	SABA	100	-	-	1	Combivent Respimat^®	q6h	SDMI	COPD
Ipratropium	SAMA	500	Fenoterol	SABA	1.25	-	-	NA	DuoVent^®	q6h	Neb	COPD#
Tiotropium	LAMA	2.5	Olodaterol	LABA	2.5	-	-	2	Stiolto Respimat^®	Qd	SDMI	COPD
Tiotropium	LAMA	2.5	Olodaterol	LABA	2.5	-	-	2	Spiolto Respimat^®	Qd	SDMI	COPD#
Aclidinium	LAMA	400	Formoterol	LABA	12	-	-	1	Duaklir Pressair^®	Bid	DPI	COPD
Aclidinium	LAMA	340	Formoterol	LABA	12	-	-	1	Duaklir Genuair^®	Bid	DPI	COPD#*
Aclidinium	LAMA	340	Formoterol	LABA	12	-	-	1	Brimica Genuair^®	Bid	DPI	COPD#
Umeclidinium	LAMA	62.5	Vilanterol	LABA	25	-	-	1	Anora Ellipta^®	Qd	DPI	COPD
Umeclidinium	LAMA	62.5	Vilanterol	LABA	25	-	-	1	Laventair Ellipta^®	Qd	DPI	COPD#
Glycopyrronium^b	LAMA	50	Indacaterol	LABA	110	-	-	1	Ultibro Breezhaler^®	Qd	DPI	COPD#
Glycopyrronium	LAMA	43	Indacaterol	LABA	85	-	-	1	Ulunar Breezhaler^®	Qd	DPI	COPD#
Glycopyrronium	LAMA	43	Indacaterol	LABA	85	-	-	1	Xoterna Breezhaler^®	Qd	DPI	COPD#
Glycopyrrolate	LAMA	15.6	Indacaterol	LABA	27.5	-	-	1	Ultibron Neohaler^®	Bid	DPI	COPD
Glycopyrrolate	LAMA	9	Formoterol	LABA	4.8	-	-	2	Bevespi Aerosphere^®	Bid	MDI	COPD
Glycopyrronium	LAMA	9	Formoterol	LABA	5	BEC	87	2	Trimbow^®	Bid	MDI	COPD#
Glycopyrronium	LAMA	12.5	Formoterol	LABA	6	BEC	100	2	Trydonis^®	Bid	MDI	COPD#
Glycopyrronium	LAMA	9	Formoterol	LABA	5	BEC	87	2	Riarify^®	Bid	MDI	COPD#
Umeclidinium	LAMA	62.5	Vilanterol	LABA	25	FF	100	1	Trelegy Ellipta^®	Qd	DPI	COPD
Umeclidinium	LAMA	62.5	Vilanterol	LABA	25	FF	100	1	Elebrato Ellipta^®	Qd	DPI	COPD#

Notes: All are US Food and Drug Administration (FDA) approved unless otherwise noted. ^aFDA Indications unless otherwise marked as approved in another jurisdiction. *= Approved by European Medicine Agency (EMA) (aclidinium 340 µg) and by Health Canada (aclidinium 400 µg) for COPD; #= approved by EMA or in Canada; ^bGlycopyrronium is the same as glycopyrrolate which is the United States Adopted Name (USAN).

Abbreviations: B2RA, beta₂ receptor agonist; MRA, muscarinic receptor antagonist; LAMA, long-acting MRA; LABA, long-acting B2RA; SAMA, short-acting MRA; SABA, short-acting B2RA; ICS, inhaled corticosteroid; FF, fluticasone furoate; Bec, beclomethasone; NA, not applicable; q6h, every 6 h; bid, twice-a-day; qd, once-a-day, Neb, nebulized; MDI, metered dose inhaler; SDMI, spring-driven mist inhaler; DPI, dry powder inhaler.

Table 2 Clinical efficacy trials in patients with COPD and treatment with combined umeclidinium/vilanterol inhalers

Study (year published)	Trial number	N	Design	Daily doses (µg)	Device	Background therapies	Results
Donohue, JF Respir Med^Citation24 (2013)	NCT1313650	1532	24 wk, R, DB, MC, P-G, PC	UMEC/VI 62.5/25 UMEC 62.5 VI 25 P	DPI	prn salbutamol (albuterol) MDI	Day 169, 23–24 h post dose weighted FEV1, significantly > for all drugs over P (all P<0.001). UMEC/VI > than monotherapies (P≤0.004). Reduced need for rescue medication with UMEC/VI vs P (P=0.001).
Celli, B Chest^Citation23 (2014)	NCT1313637	1489	24 wk, R, DB, MC, P-G, PC	UMEC/VI 125/25 UMEC 125 VI 25 P	DPI	prn albuterol (salbutamol) MDI	Day 169 trough FEV1, all active treatments > FEV1 than P (P<0.001). UMEC/VI > Increase in FEV1 than VI or UMEC alone (both P≤0.001).
Donohue, JF Respir Res^Citation39 (2014)	NCT1316887	562	52 wk, R, DB, MC, P-G, PC	UMEC/VI 125/25 UMEC 125 P	DPI	prn salbutamol or ipratropium MDI	No significant difference in AEs/SAEs including labs, glucose and in special cardiac interest group. Both UMEC/VI and UMEC had greater changes from baseline through FEV1 than P. Both had fewer exacerbations and rescue medication use then P.
Decramer, M Lancet Respir Med^Citation40 (2014)	NCT1316900 NCT1316913	1141 1191	24 wk, 2 studies, R, DB, MC, DD, P-G, AC	UMEC/VI 125/25 UMEC/VI 62.5/25 TIO 18 VI 25 (study 1) UMEC 125 (study 2)	DPI	prn salbutamol (albuterol) MDI/Neb	Day 169 trough FEV1 post dose, UMEC/VI 125/25 and UMEC/VI 62.5/25 both had > FEV1 than TIO (P=0.0001 and P=0.0006, respectively). UMEC/VI 125/25 and 62.5/25 both > FEV1 than VI alone (P=0.001 and P=0.0006, respectively). No statistical improvement of UMEC/VI 125/25 and 62.5/25 compared to UMEC 125 alone.
Maleki-Yazdi^Citation71 (2014)	NCT1777334	905	24 wk, R, DB, MC, P-G, DD, AC	UMEC/VI 62.5/25 TIO 18	DPI	50% patients on ICS both groups prn albuterol (salbutamol) MDI	Weighted FEV1 over 1–6 h at day 168 and trough FEV1 Day 169 both improved with UMEC/VI compared to TIO alone (P<0.001 and P<0.001 respectively). UMEC/VI also improved health-related quality of life and reduced rescue medication use compared to TIO.
Maltais Ther Adv Respir Dis^Citation41 (2014)	NCT1323660 NCT1328444	307 348	12 wk, R, DB, MC, incomplete BXO	Each patient received 2 of 6 treatments in 12 wk of segments. P UMEC/VI 125/25 UMEC/VI 62.5/25 VI 25 UMEC 62.5 or UMEC 125	DPI	prn salbutamol MDI	ETT and FEV1 at week 12, both UMEC/VI doses resulted in week 12 increases in ETT (P<0.01 both doses) compared to P in one study with increases in both doses also seen in second study but without reaching statistical significance. Week 12, FEV1 increased compared to P in both studies (P<0.001 in both doses UMEC/VI and both studies).
Donahue, DF Resp Med^Citation47 (2015)	NCT1817764 NCT1879410	706 697	12 wk, R, DB, MC, P-G, DD, AC	UMEC/VI 62.5/25 FP/SAL 250/50 (twice daily)	DPI	prn salbutamol MDI	Weighted FEV1 0–24 h Day 84, trough FEV1 day 85, both studies showed Day 84 weighted FEV1 0–24 hr > with UMEC 62.5/25 than FP/SAC (P<0.001 both studies). In addition, both studies showed trough Day 85 FEV1> in UMEC/VI treatment than FP/SAL (P<0.001 for both).
Zheng, J Int J COPD^Citation45 (2015)	NCT1636713	580	24 wk, R, DB, PC, P-G, MC	UMEC/VI 125/25 UMEC/VI 62.5/25 P	DPI	prn albuterol MDI	Day 169, both UMEC/VI 125/25 µg and UMEC/VI 62.5/25 µg trough FEV1> P (both P<0.001). Significant (P<0.001) reduction week 0–24 by both UMEC/VI dose compared to P in rescue medication.
Singh, D BMC Pulmon Med^Citation3 (2015)	NCT1822899	717	12 wk, R, DB, MC, P-G, DD, AC	UMEC/VI 62.5/25 FP/SAL 500/50 (twice-daily)	DPI	prn salbutamol MDI	Day 84 weighted mean FEV1 0–24 h and Day 85 trough FEV1. Both the weighted mean FEV1 and trough FEV1 were increased with UMEC/VI compared to FP/SAL (both P<0.001).
Kalberg, C Drugs R D^Citation48 (2016)	NCT2257385	961	12 wk, R, DB, TD, P-G, AC	UMEC/VI 62.5/25 TIO/IND 18/150 (as two inhalers)	DPI	prn salbutamol MDI	Day 84 weighted mean FEV1 0–24 h and day 85 trough FEV1 improvements were comparable between UMEC/VI and TIO/IND demonstrating non-inferiority.
Siler, T Intern JCOPD^Citation43 (2016)	NCT2152605	496	12 wk, R, DB, P-G, PC, MC	UMEC/VI 62.5/25 P	DPI	prn albuterol MDI	The SGRQ total score Day 84, the rescue puffs per day for 12 wk and the trough Day 84 FEV1 were statistically (P<0.001) improved with UMEC/VI compared to P.
Donohue, DF Respir Med^Citation46 (2016)	NCT2014480 NCT1713520	207 182	14 day, R, DB, three-way CB, CO, MC, AC	UMEC/VI 62.5/25 UMEC 62.5 VI 25	DPI	prn albuterol MDI	Pooled results, found that the combination UMEC/VI provided significant greatly improvement in weighted Day 14 FEV1 and Day 15 trough FEV1 (all P<0.001). Each patient received each treatment, greater improvement to UMEC/VI in patients that responded to either VI or UMEC alone.
Kerwin, E Lung^Citation49 (2017)	NCT2487446 NCT2487498	357 355	12 wk, R, DB, DD, MC, AC, CO	UMEC/VI 62.5/25 IND/GLY 27.5/15.6 (twice-daily)	DPI	prn albuterol MDI	Both combined products showed statistically significant and clinically important week 12 FEV1 (0–24 h) comparable improvements.
Kerwin, E Intern JCOPD^Citation72 (2017)	NCT1899742	494	12 wk, R, DB, DD, P-G, MC, AC	UMEC/VI 62.5/25 TIO 18	DPI	prn albuterol MDI	Compared to TIO, UMEC/VI demonstrated greater improvement in trough Day 85 FEV1 (P<0.001). A greater reduction in rescue medication use with UMEC/VI was also seen compared to TIO (P<0.05). SGRQ scores were similar.
Feldman, GJ Adv Ther^Citation50 (2017)	NCT299784	236	8 wk, R, OL, CO, CB, AC	UMEC/VI 62.5/25 TIO/OLO 5/5	DPI SDMI	prn albuterol MDI	In per protocol group UMEC/VI non-inferior to TIO/OLO in improving week 8 trough FEV1 compared to baseline and significantly better (P<0.001) in the intent to treat group analysis. AEs were similar.
Alcázar Navarrete, B Pulm Ther^Citation51(2018)	NCT299784 (same as above study)	148	Maintenance medication – naive patients from above Feldman study (Feldman, 2017) 8 wk, R, OL, CO, CB, AC	UMEC/VI 62.5/25 TIO/OLO 5/5	DPI SDMI	prn albuterol MDI	In intent to treat analysis, maintenance medication naive patients had greater (P=0.001) improvement in week 8 trough FEV1 with UMEC/VI compared to TIO/OLO. A greater (P=0.003) reduction in use of rescue medication puffs was seen with UMEC/VI compared to TIO/OLO. AEs were similar.
Riley, JH ERJ Open Res^Citation44 (2018)	NCT2275052	198	12 wk, R, DB, PC, two period CO, MC	UMEC/VI 62.5/25 P	DPI	prn albuterol or ipratropium MDI	Primary endpoint was a 3 h post dose EET at wk 12. UMEC/VI did not result in significant increase in EET compared to baseline or P. wk 12 trough FEV1 were improved compared to baseline and P.
Lipson, DA NEJM^Citation56 (2018) Pascoe, ST Eur Respir J^Citation57 (2016)	NCT2164513	10,355	52 wk, R, DB, P-G, MC, AC	UMEC/VI/FF 62.5/25/100 VI/FF 25/100 UMEC/VI 62.5/25	DPI	prn salbutamol (albuterol) MDI	The rate of moderate to severe exacerbations with UMEC/VI/FF was<than with VI/FF or UMEC/VI (both P<0.001). Severe exacerbations requiring hospitalizations were less with UMEC/VI/FF than with UMEC/VI (P<0.001). UMEC/VI had a lower rate of pneumonia than either VI/FF or UMEC/VI/FF (P<0.001).

Abbreviations: OLO, olodaterol; SDMI, spring-driven mist inhaler; FF, fluticasone furoate; TD, triple dummy; IND, indacaterol; SGRQ, Saint George’s respiratory questionnaire; CO, crossover; GLY, glycopyrronium; OL, open-label; CB, complete block; AC, active-control; wk, week; DB, double-blind; UMEC, umeclidinium; AE/SAE, adverse event/several adverse events; FP, fluticasone propionate; SAL, salmeterol; P-G, parallel-group; MC, multicenter; PC, placebo-controlled; VI, vilanterol; P, placebo; NEB, nebulized; prn, as needed; ICS, inhaled corticosteroids; DD, double-dummy; MDI, metered-dose Inhaler; DPI, dried powder inhaler; FEV₁, forced expiratory volume 1 second; BXO, block crossover; ETT, exercise endurance test; TIO, tiotropium.

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