Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA

Figures & data

Table 1 Regulatory status of fixed dose LAMA/LABA combinations

Drug	Trade name	Approved dose	Approval status
Umeclidinium/vilanterol	Anoro™	62.5/25 μg once daily (USA)	FDA approved 2013
	Ellipta^®	55/22 μg once daily (Europe)	EMA positive opinion 2014
QVA149	Ultibro^® Breezhaler^®	85/43 μg once daily – Europe, Canada, Japan, Latin America	EMA positive opinion 2013, FDA application complete for 27.5/12.5 μg twice daily
Aclidinium/formoterol	Brimica^®, Genuair^®	340/12 μg twice daily	EMA positive opinion 2014
Tiotropium/olodaterol	Stiolto™, Respimat^®	2.5/2.5 μg two puffs once daily	FDA approved 2015
Glycopyrronium/formoterol	–	–	–

Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration; LABAs, long-acting β₂-agonists; LAMAs, long-acting muscarinic antagonists; QVA149, indacaterol/glycopyrronium.

Table 2 Selected outcomes and definition of significant differences

Outcome	MCID	Comments
Trough FEV1	100 mL	No MCID established for AUC, FVC
Health-related quality of life	SGRQ: 4 units	Higher score indicate poorer health status
Dyspnea	TDI ≥1 unit	–
Rescue medication use	No validated MCID	–
Exacerbations	1 exacerbation/year, 22% reduction	Definition of AECOPD varies. Seasonal variation in frequency impacts studies <12 months
Daily respiratory symptoms	E-RS total >−2	Suggested responder definition

Notes: The MCID was developed for comparison between an active treatment and placebo; MCID comparing active treatments is not defined. Copyright © 2011. Future Science Ltd. Adapted from Miles MC, Donohue JF, Ohar JA. Combination therapy for COPD: emerging evidence from recent clinical trials. J Clin Invest, 2011;1(6):879–890 with permission of Future Science Ltd.²⁷ Additional data from Cazzola et al²⁸ and Leidy et al.³⁰

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; AUC, area under the curve; E-RS total, EXACT respiratory symptoms total score; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; MCID, minimal clinically important difference; SGRQ, St George Respiratory Questionnaire; TDI, transition dyspnea index.

Table 3 LAMA/LABA trials and selected outcomes

Study	Design	Treatment groups	FEV1 (vs placebo if included)	Notesa
UMEC/VI
Donohue et al^Citation43	R, DB, PC, PG 24 weeks mMRC ≥2 n=1,532	UMEC/VI 62.5/25 μgb UMEC 62.5 μg VI 25 μg Placebo	+167 mL*,c +115 mLc +72 mL**	Reduced AECOPD in UMEC/VINP All active treatments improved dyspnea,c HRQOL,c and rescue medications**
Decramer et al^Citation44 – study 1	R, blind, DD, PG 24 weeks mMRC ≥2 n=846	UMEC/VI 125/25 μg UMEC/VI 62.5/25 μgb TIO 18 μg VI 25 μg	+209 mL* +211 mL* +121 mL +121 mL	Both UMEC/VI doses reduce SABA vs TIO Dyspnea and HRQOL improved in all groups
Decramer et al^Citation44 – study 2	R, blind, DD, PG 24 weeks mMRC ≥2 n=872	UMEC/VI 125/25 μg UMEC/VI 62.5/25 μgb TIO 18 μg UMEC 125 μg	+233 mL* +208 mL* +149 mL +186 mL	Dyspnea and HRQOL improved in all groups
Donohue et al^Citation46	R, DB, PC, PG 52 weeks 30≤ FEV1 <80% n=563	UMEC/VI 125/25 μg UMEC 125 μg Placebo	+321NP +178NP	Primary outcome studied: safety More atrial arrhythmias in UMEC group, but asymptomatic Reduced AECOPD in UMEC/VI and UMEC. Informal result, study not powered for this outcome
Celli et al^Citation47	R, DB, PC, PG 24 weeks mMRC ≥2 n=1,493	UMEC/VI 125/25 μg UMEC 125 μg VI 25 μg Placebo	+238 mL vs VIc,d +160 mLc +124 mLc	Less SABA use in UMEC/VI vs other groups Time to exacerbation better with all groups vs placebo**
QVA149 (110/50 μg)
ENLIGHTEN – Dahl et al^Citation53	R, DB, PC, PG 52 weeks 30≤ FEV1 <80% n=339	QVA149 Placebo	+189 mLc	This safety study yielded similar safety results. Trend toward more pneumonia in QVA149 group, not statistically significant Less rescue medicine use and improved daily symptoms scores in QVA149 group
SHINE – Bateman et al^Citation54	R, DB, PG, PC 26 weeks 30≤ FEV1 <80% n=2,144	QVA149 Indacaterol 150 μg Glycopyrronium 50 μg TIO 18 μg Placebo	+200 mLc +130 mLc +120 mLc +130 mLc	QVA149 improved dyspnea vs placebo TIO. * Less SABA use in QVA149 vs all other groups QVA149 and indacaterol improved HRQOL more than TIO or glycopyrronium All active treatments improved dyspnea and HRQOL
SPARK – Wedzicha et al^Citation56	R, DB, PG 64 weeks, extended up to 76 weeks FEV1 <50% and 1≥ exacerbation in the last year n=2,224	QVA149 Glycopyrronium 50 μg TIO 18 μg HandiHaler (open label)	+70–80 mL vs GLY* +60–80 mL vs TIO*	QVA149 reduced moderate or severe exacerbations vs GLY but not TIO QVA149 reduced all exacerbations vs TIO, result driven by mild exacerbations HRQOL improved in QVA149 (responder analysis)*
ILLUMINATE – Vogelmeier et al^Citation57	R, DB, DD 26 weeks 40≤ FEV1 <80 n=523	QVA149 Salmeterol + fluticasone 500–50 μg BID	+138 mLd (FEV1 AUC0–12)	Dyspnea improved in QVA149 group (OR: 1.56*). Less SABA in QVA149 group
QUANTIFY – Gebner et al^Citation62	R, DB, DD 26 weeks 30≤ FEV1 <80 n=934	QVA149 TIO 18 μg QD + formoterol 12 μg BID in a free combination	+68 mL*	Trough FVC (+68 mL*) and dyspnea better in QVA149 by responder analysis Exacerbations not different, HRQOL noninferior
BLAZE – Mahler et al^Citation63	R, blind, DD, 3-period crossover with washout 6 weeks each treatment mMRC ≥2 n=247	QVA149 TIO 18 μg Placebo	+330 mL (P<0.001)c +230 mL (P<0.001)c QVA149 vs TIO 110 mL (P<0.001)d (all AUC0–4 h)	Primary outcome – dyspnea was improved in QVA149 vs placebo (OR: 2.78**) and TIO (OR: 1.78*) Less rescue SABA in QVA149
ACF
ACLIFORM – Singh et al^Citation65	R, DB, PC, PG 24 weeks 30≤ FEV1 <80 n=1,729	ACF 400/12 μg BID ACF 400/6 μg BID Aclidinium 400 μg BID Formoterol 12 μg BID Placebo BID	+143 mLc +111 mLc +117 mLc +58 mL** (trough FEV1 vs placebo)	In all groups, improvement in dyspnea and HRQOL Respiratory symptoms and dyspnea improved in ACF**,* Unreported AECOPD reduced with ACF12 vs placebo
AUGMENT – D’Urzo et al^Citation64	R, DB, PC 24 weeks Moderate-to-severe COPD n=1,729	ACF 400/12 μg BID ACF 400/6 μg BID Aclidinium 400 μg BID Formoterol 12 μg BID Placebo BID	Trough FEV1 increased with ACF 400/6 μg and 400/12 μg 111–130 mL vs placeboc Trough FEV1 +45 mL* ACF 400/12 μg vs formoterol, others not different	Greatest improvements in dyspnea in combination groupsc HRQOL improved in all active treatmentsc Rescue medication use reduced in all groups vs placebo**
T/O
TOnado 1 and 2 – Buhl et al^Citation70	R, DB, PG 52 weeks FEV1 <80 n=5,163 (combined)	T/O 2.5/5 μg T/O 5/5 μg TIO 2.5 μg TIO 5 μg Olodaterol 5 μg (all Respimat^® once-daily dose)	T/O 2.5/5 μg Trough FEV1 increased 29–67 mL* FEV1UAC increased 91–131 mL* T/O 5/5 μg Trough FEV1 increased 50–88 mL* FEV1 AUC increased 103–132 mL*	Improved trough FVC, HRQOL (responder analysis), and reduction in rescue medication favor combination agent Trend for improvements in exacerbations in combination agentNP

Notes:

* P≤0.05 vs fixed combination vs active comparator,

** P≤0.05 vs placebo.

a Comments refer to combination agent unless otherwise specified.

b The FDA approved dose of UMEC/VI is bolded for emphasis.

c Result ≥ MCID vs placebo and P≤0.05.

d Result ≥ MCID vs active comparator and P≤0.05.

NP Not powered/designed for this observation, shown for interest.

Abbreviations: ACF, aclidinium/formoterol; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; AUC, area under the curve; BID, twice daily; DB, double blind; DD, double dummy; FDA, US Food and Drug Administration; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; GLY, glycopyrronium; HRQOL, health-related quality of life; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale; MCID, minimal clinically important difference; OR, odds ratio; PC, placebo controlled; PG, parallel group; QD, once daily; QVA149, indacaterol/glycopyrronium; R, randomized; SABA, short-acting β₂-agonist; TIO, tiotropium; T/O, tiotropium/olodaterol; UAC, upper arm circumference; UMEC/VI, umeclidinium/vilanterol.

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