An Evaluation Of Single And Dual Long-Acting Bronchodilator Therapy As Effective Interventions In Maintenance Therapy-Naïve Patients With COPD

Figures & data

Table 1 Studies Investigating The Efficacy Of Maintenance Treatments In Treatment-Naïve Patients With COPD

Study	Type Of Analysis/Study	Number Of Maintenance-Therapy-Naïve Patients	Disease Severity	Treatments	Finding
RCTs
Troosters et al Eur Respir J. 2010^Citation24	Pre-specified subgroup analysis of a 4-year RCT (UPLIFT^®)	N=810	GOLD stage II = 60%; stage III = 34%; stage IV = 5%	Tiotropium versus placebo	Improved FEV1 and SGRQ total score versus placebo Reduced lung function decline
Vogelmeier et al Respir Med. 2013^Citation22	Pre-specified subgroup analysis of a 1-year RCT (POET-COPD^®)	N=1343	GOLD stage II = 48–54%; stage III = 41–37%	Tiotropium versus salmeterol	Reduced annual exacerbation rate versus salmeterol
Troosters et al NPJ Prim Care Resp Med. 2014^Citation21	24-week RCT	N=457	GOLD stage II = 100%	Tiotropium versus placebo	Improved FEV1, Physician’s Global Assessment, and WPAI questionnaire
Decramer et al Respir Med. 2012^Citation23	Post-hoc subgroup analysis of pooled data from two 6-month RCTs and one 12-month RCT	N=933	GOLD stage I–II = 62–71%	Indacaterol versus tiotropium and placebo	Indacaterol improved trough FEV1, TDI, rescue use, and SGRQ vs placebo Tiotropium improved trough FEV1 and TDI total score vs placebo
Singh et al Respir Res. 2016^Citation18	Post-hoc subgroup analysis of two 12-week RCTs (OTEMTO^® 1 and 2)	N=678	GOLD stage II–III = 100%	Tiotropium + olodaterol versus tiotropium monotherapy or placebo	Improved FEV1, SGRQ, and TDI vs monotherapy or placebo
Maleki-Yazdi et al Adv Ther. 2017^Citation16	Post-hoc subgroup analysis of pooled data from three 24-week RCTs	N=533	GOLD stage II = 55–56%; stage III = 37–38%	Umeclidinium + vilanterol versus tiotropium	Improved trough FEV1, rescue use, SGRQ and short-term clinically important deterioration vs tiotropium
Non-interventional studies
Setoguchi et al Expert Opin Pharmacother. 2015^Citation20	Real-world, observational multicenter survey over 48 weeks	N=49	GOLD stage I = 12.2%; stage II = 40.8%; stage III = 32.7%; stage IV = 10.2%	Guideline-based pharmacotherapy^c	Improved CAT score and symptoms
Lange et al Eur Clin Respir J. 2016^Citation17	Observational multicenter study, over 24 weeks	N=245^a	GOLD B = 56%; GOLD D = 25%	Aclidinium (no comparator)	Improved CAT score, the severity of morning and nighttime symptoms, and mMRC grade in LAMA-naïve patients
Sauer et al Int J Chron Obstruct Pulmon Dis. 2016^Citation19	Observational, open-label study, over 4–6 weeks	N=567^b	GOLD B = 55%; GOLD C = 32%; GOLD D = 9%	Tiotropium + olodaterol (no comparator)	Treatment-naïve patients had higher therapeutic success rates (10-point increase in PF-10) versus those with prior maintenance therapy

Notes: ^aLAMA-naïve patients, only. In this study, there was also an additional separate subgroup of 172 patients naïve to LAMA but receiving other maintenance therapies. ^bMaintenance therapy-naïve patients, only. In total for this study, there were 1858 patients with/without prior maintenance therapy. ^cGOLD COPD stage I patients received single LAMA; GOLD stage II and III patients received LAMA plus one other of the following additional therapies: LABA, theophylline or ICS/LABA; GOLD stage IV patients received LAMA plus two of the additional therapies. A total of 205 results were identified by the search terms stated; only relevant, original studies showing clinical outcomes in a COPD maintenance therapy-naïve patient population or with a COPD maintenance therapy-naïve sub-population, are shown. Maintenance therapy-naïve was generally defined as naïve to the following maintenance medications: LABA, LAMA, ICS, or systemic corticosteroids and xanthines. Some studies also excluded short-acting muscarinic antagonists and leukotriene antagonists in the months preceding the study. Exclusive use of SABA was generally permitted prior to study inclusion.

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; 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; mMRC, modified Medical Research Council; POET-COPD^®, Prevention Of Exacerbations with Tiotropium in COPD; PF-10, 10-item Physical Functioning Questionnaire; RCT, randomized controlled trial; SABA, short-acting β₂-agonist; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; WPAI, work productivity and activity impairment.

Figure 1 Treatment differences in trough FEV₁ for (A) monotherapies and (B) dual therapies among the relevant publications identified in the literature search.

Notes: Data are least square means differences unless stated otherwise. P-values and 95% CI included where available. ^aMean difference. ***P<0.001 versus placebo. Panel B is reproduced from the original publication Singh et al 2016,¹⁸ with a simplification of the figure to include only maintenance treatment-naïve subgroups. Reproduced from Singh D, Gaga M, Schmidt O, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO(R) studies. Respir Res. 2016;17(1):73. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/ and http://creativecommons.org/publicdomain/zero/1.0/.¹⁸
Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second.

Figure 2 Changes in SGRQ total score for (A) monotherapies and (B) dual therapies; (C) changes in TDI focal score for dual therapies, among the relevant publications identified in the literature search.

Notes: ^aSGRQ total units. *P<0.05; ***P <0.001 versus placebo. Panels B and C are reproduced from the original publication Singh et al 2016,¹⁸ with the simplification of the figure to include only maintenance treatment-naïve subgroups. Reproduced from Singh D, Gaga M, Schmidt O, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO(R) studies. Respir Res. 2016;17(1):73. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/ and http://creativecommons.org/publicdomain/zero/1.0/.¹⁸
Abbreviations: CI, confidence interval; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 2 Patient Demographics And Baseline Characteristics Of Patients Included In ACLIFORM And AUGMENT (Post-Hoc Analysis; ITT Population)

	Treatment-Naïve				All Treatment-Naïve^a	All Treatment-Exposed^a
	AB/FF 400/12 µg	AB 400 µg	FF 12 µg	Placebo
	N=282	N=272	N=278	N=224	N=1339	N=2055
Age, years, mean (SD)	61.9 (8.8)	62.7 (8.9)	62.3 (8.8)	61.6 (8.8)	62.0 (8.8)	64.5 (8.1)
Male, n (%)	161 (57.1)	174 (64.0)	168 (60.4)	137 (61.2)	818 (61.1)	1235 (60.1)
White, n (%)	256 (90.8)	253 (93.0)	256 (92.1)	211 (94.2)	1239 (92.5)	1954 (95.1)
Current smoker, n (%)	175 (62.1)	156 (57.4)	162 (58.3)	130 (58.0)	804 (60.0)	872 (42.4)
Pack-years, mean (SD)	46.5 (23.9)	47.0 (25.8)	47.5 (22.2)	50.0 (25.5)	47.7 (24.5)	45.5 (24.2)
Baseline GOLD
I	0 (0.0)	1 (0.4)	0 (0.0)	0 (0.0)	2 (0.1)	3 (0.1)
II	188 (66.9)	173 (63.8)	189 (68.0)	127 (56.7)	867 (64.8)	1120 (54.6)
III	92 (32.7)	96 (35.4)	86 (30.9)	95 (42.4)	460 (34.4)	922 (45.0)
IV	1 (0.4)	1 (0.4)	3 (1.1)	2 (0.9)	8 (0.6)	6 (0.3)
Number of exacerbations in previous 12 months, mean (SD)	0.4 (0.7)	0.4 (0.8)	0.3 (0.7)	0.3 (0.6)	0.3 (0.7)	0.5 (0.9)
Baseline FEV1, L, mean (SD)	1.536 (0.560)	1.478 (0.541)	1.513 (0.513)	1.471 (0.611)	1.512 (0.556)	1.312 (0.486)
	N=282	N=271	N=278	N=223	N=1337	N=2055
Baseline FEV1, % predicted, mean (SD)	52.3 (14.5)	49.8 (14.3)	51.6 (14.4)	48.0 (14.9)	50.8 (14.5)	46.8 (13.7)
	N=280	N=270	N=278	N=224	N=1335	N=2049
Reversibility, %, mean (SD)	12.9 (13.3)	15.8 (17.0)	13.7 (12.9)	16.2 (16.0)	14.6 (14.8)	15.7 (14.4)
	N=273	N=264	N=271	N=219	N=1299	N=1998
BDI focal score, mean (SD)	6.6 (2.0)	6.6 (2.1)	6.6 (2.3)	6.6 (2.2)	6.6 (2.2)	6.4 (2.1)
	N=280	N=270	N=275	N=219	N=1318	N=2018
Baseline E-RS total score, mean (SD)	11.8 (6.0)	12.0 (6.2)	11.9 (6.6)	11.5 (6.1)	11.8 (6.3)	13.1 (6.6)
	N=280	N=270	N=273	N=219	N=1316	N=2023
Baseline early-morning COPD symptom severity score, mean (SD)	1.2 (0.6)	1.2 (0.6)	1.2 (0.7)	1.1 (0.6)	1.2 (0.6)	1.3 (0.7)
Baseline overall nighttime COPD symptom severity score, mean (SD)	1.1 (0.6)	1.1 (0.7)	1.1 (0.7)	1.0 (0.7)	1.1 (0.7)	1.1 (0.7)
	N=276	N=264	N=275	N=221	N=1315	N=2009
Baseline total SGRQ, mean (SD)	47.2 (17.8)	45.7 (16.9)	45.9 (18.5)	45.4 (17.9)	46.0 (17.9)	46.2 (17.5)
	N=282	N=272	N=278	N=224	N=1339	N=2055
Any prior treatment, n (%)	138 (48.9)	143 (52.6)	137 (49.3)	110 (49.1)	671 (50.1)	2055 (100.0)
SABA	115 (40.8)	109 (40.1)	111 (39.9)	94 (42.0)	549 (41.0)	1185 (57.7)
SAMA	9 (3.2)	14 (5.1)	9 (3.2)	8 (3.6)	52 (3.9)	148 (7.2)
SABA+SAMA	24 (8.5)	29 (10.7)	24 (8.6)	19 (8.5)	125 (9.3)	188 (9.1)
LABA	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	378 (18.4)
LAMA	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	909 (44.2)
LABA+ICS	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1059 (51.5)
ICS	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	478 (23.3)
Xanthines	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	255 (12.4)
Leukotriene modifiers	0 (0.0)	2 (0.7)	1 (0.4)	1 (0.4)	4 (0.3)	41 (2.0)
Oxygen	4 (1.4)	2 (0.7)	9 (3.2)	6 (2.7)	26 (1.9)	61 (3.0)
Influenza vaccine	0 (0)	4 (1.5)	4 (1.4)	0 (0)	9 (0.7)	26 (1.3)
Systemic corticosteroid	2 (0.7)	2 (0.7)	1 (0.4)	3 (1.3)	9 (0.7)	24 (1.2)

Notes: ^aIncludes patients allocated to AB/FF 400/6 µg (not shown). Treatment-naïve patients were defined as patients who had not received prior maintenance therapy for COPD; short-acting bronchodilators were permitted.

Abbreviations: AB, aclidinium bromide; BDI, Baseline Dyspnea Index; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating-Respiratory Symptoms; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; ITT, intent-to-treat; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist; SD, standard deviation.

Figure 3 Change from baseline in (A) 1 hr morning post-dose FEV₁ and (B) trough FEV₁ for treatment-naïve patients, at Week 24 of ACLIFORM and AUGMENT (post-hoc analysis; ITT population).

Notes: **P<0.01; ***P<0.001. All data are LS mean changes from baseline. Analyses are based on the mixed model for repeated measures: treatment effects and treatment comparisons. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ).
Abbreviations: AB, aclidinium bromide; CI, confidence interval; FEV₁, forced expiratory volume in 1 sec; FF, formoterol fumarate; ITT, intent-to-treat; LS, least squares.

Figure 4 Patient-reported outcomes changes from baseline for treatment-naïve patients (A) TDI focal score at Week 24, (B) E-RS total score, (C) early morning COPD symptom severity and (D) nighttime COPD symptom severity over 24 weeks of ACLIFORM and AUGMENT (post-hoc analysis; ITT population).

Notes: *P<0.05; **P<0.01; ***P<0.001. All data are LS mean changes from baseline. Analyses are based on the mixed model for repeated measures: treatment effects and treatment comparisons. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ).
Abbreviations: AB, aclidinium bromide; CI, confidence interval; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating-Respiratory Symptoms; FF, formoterol fumarate; LS, least squares; TDI, Transition Dyspnea Index.

Figure 5 Changes from baseline for SGRQ total score for treatment-naïve patients, at Week 24 of ACLIFORM and AUGMENT (post-hoc analysis; ITT population).

Notes: *P<0.05; **P<0.01; ***P<0.001. All data are LS mean changes from baseline. LS mean differences between AB/FF 400/12 µg and treatment groups are shown (Δ). The analysis was based on a mixed model for repeated measures: treatment effects and treatment comparisons.
Abbreviations: AB, aclidinium bromide; CI, confidence interval; FF, formoterol fumarate; ITT, intent to treat; SGRQ, St George’s Respiratory Questionnaire.

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Data Availability

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.