Respiratory Medicine 185 (2021) 106509

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Benefits of budesonide/glycopyrrolate/formoterol fumarate (BGF) on

symptoms and quality of life in patients with COPD in the ETHOS trial
Fernando J. Martinez a, *, Klaus F. Rabe b, Gary T. Ferguson c, Jadwiga A. Wedzicha d,
Roopa Trivedi e, Martin Jenkins f, Patrick Darken g, Magnus Aurivillius h, Paul Dorinsky e
a
Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA
b
LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL),
Grosshansdorf, Germany
c
Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA
d
National Heart and Lung Institute, Imperial College London, London, UK
e
AstraZeneca, Durham, NC, USA
f
AstraZeneca, Cambridge, UK
g
AstraZeneca, Gaithersburg, MD, USA
h
AstraZeneca, Gothenburg, Sweden

A R T I C L E I N F O A B S T R A C T

Keywords: Background: We report the long-term effects of triple therapy with budesonide/glycopyrrolate/formoterol
BGF MDI fumarate (BGF) vs glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF) on
Chronic obstructive pulmonary disease symptoms and health-related quality of life (HRQoL) over 52 weeks in the Phase III ETHOS study of patients with
ICS/LAMA/LABA
moderate-to-very severe COPD.
Triple therapy
Methods: ETHOS was a randomized, double-blind, multi-center, parallel-group study in symptomatic patients
with COPD who experienced ≥1 moderate/severe exacerbation in the previous year. Patients received twice-
daily BGF 320/18/9.6 μg, BGF 160/18/9.6 μg, GFF 18/9.6 μg, or BFF 320/9.6 μg, administered via a single
Aerosphere inhaler, for 52 weeks.
Results: The modified intent-to-treat population included 8509 patients (mean age 64.7 years; 59.7% male; mean
COPD Assessment Test score, 19.6). BGF significantly reduced rescue medication use vs GFF and BFF (− 0.53
puffs/day [p < 0.0001] and − 0.35 puffs/day [p = 0.0002], respectively, with BGF 320 over 52 weeks). BGF 320
also significantly improved St George’s Respiratory Questionnaire (SGRQ) total score over 24 and 52 weeks vs
dual therapies, resulting in the greatest proportion of SGRQ responders vs dual therapies over 24 weeks (52.5%
vs 42.5% [GFF] and 45.2% [BFF]) and 52 weeks (47.0% vs 37.8% [GFF] and 41.0% [BFF]). Similar results were
observed with BGF 160.
Benefits were also observed vs dual therapies in symptomatic endpoints including Transition Dyspnea Index focal
score, EXAcerbations of Chronic pulmonary disease Tool total scores and Evaluating Respiratory Symptoms in
COPD total scores over 24 and 52 weeks.
Conclusions: BGF triple therapy improved symptoms and HRQoL vs dual therapies over 24 and 52 weeks in
patients with moderate-to-very severe COPD.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BID, twice daily; CAT, COPD Assessment Test; CI,
confidence interval; COPD, chronic obstructive pulmonary disease; E-RS™:COPD, Evaluating Respiratory Symptoms in COPD; EXACT, Exacerbations of Chronic
Pulmonary Disease Tool; FEV1, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; GOLD, Global Initiative for Chronic Obstructive Lung
Disease; HRQoL, health-related quality of life; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LSM, least squares
mean; MCID, minimum clinically important difference; MDI, metered dose inhaler; mITT, modified-intent-to-treat; OR, odds ratio; PRO, patient-reported outcome;
SD, standard deviation; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.
* Corresponding author.
E-mail address: fjm2003@med.cornell.edu (F.J. Martinez).

https://doi.org/10.1016/j.rmed.2021.106509
Received 24 March 2021; Received in revised form 7 June 2021; Accepted 8 June 2021
Available online 18 June 2021
0954-6111/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
F.J. Martinez et al. Respiratory Medicine 185 (2021) 106509

1. Introduction
Chronic obstructive pulmonary disease (COPD) is an increasing
contributor to disability, morbidity, and mortality worldwide, ranking
as the third global leading cause of death [1,2]. The assessment of a
patient’s symptoms is used to guide the pharmacologic management of
COPD [1]. The Global Initiative for Chronic Obstructive Lung Disease
(GOLD) proposes the use of airflow limitation severity, modified Medi­
cal Research Council dyspnea scale, COPD Assessment Test (CAT) and
exacerbation history to categorize symptomatic impact and estimate
future risk of exacerbations.
Currently available treatments are directed toward improving
symptoms and health-related quality of life (HRQoL) while improving
lung function/preventing disease progression and reducing exacerba­
tion risk [1]. While HRQoL instruments are not measured routinely in
clinical practice, they are recognized as being useful in determining the
effects of therapy, which is important to patients. Patient-reported
outcome measures such as rescue medication use, the St George’s Res­
piratory Questionnaire (SGRQ) [3], Transition Dyspnea Index (TDI) [4],
EXAcerbations of Chronic pulmonary disease Tool (EXACT) and Evalu­
ating Respiratory Symptoms in COPD (E-RS™:COPD) [5,6] can be
assessed in patients with COPD to determine how the disease is
impacting HRQoL.
The use of inhaled corticosteroid/long-acting muscarinic antagonist/
long-acting β2-agonist (ICS/LAMA/LABA) triple therapy is suggested for
patients who experience persistent exacerbations or symptoms despite
the use of dual LAMA/LABA, or ICS/LABA inhaled therapies [1]. Inhaled
triple therapy has been shown to improve lung function and symptoms,
and reduce the frequency of COPD exacerbations in patients with high
symptom burden and at high risk of COPD exacerbations [1].
The ETHOS study (NCT02465567) assessed the efficacy and safety of
the ICS/LAMA/LABA triple fixed-dose combination therapy budeso­
nide/glycopyrrolate/formoterol fumarate (BGF), at two ICS dose levels,
delivered via a single metered dose Aerosphere inhaler, over a 52-week
treatment period in symptomatic patients with moderate-to-very severe
COPD, who had experienced moderate or severe exacerbations in the
previous 12 months [7].
We previously reported improvements in symptoms and all-cause
mortality in the ETHOS study with BGF vs glycopyrrolate/formoterol
fumarate (GFF) and budesonide/formoterol fumarate (BFF) [7,8].
Additionally, both ICS dose levels of BGF reduced exacerbations vs GFF
and BFF over 52 weeks [7]. Here we extend those observations to further
characterize the effects of triple therapy with BGF relative to GFF and
BFF dual therapies on symptoms and HRQoL over the entire 52-week
duration of the study.
2. Methods
2.1. Study design
Details of the ETHOS study design have been published [7,9]. Briefly,
ETHOS was a 52-week, randomized, double-blind, parallel-group trial
conducted across 26 countries. Patients received twice-daily dosing with
BGF 320/18/9.6 μg, BGF 160/18/9.6 μg, GFF 18/9.6 μg, or BFF 320/9.6
μg. All treatments were delivered from a single metered dose Aerosphere
inhaler, each dose representing the sum of two actuations (Fig. S1).
Patients were 40–80 years of age, with symptomatic COPD (CAT score
≥10 at screening despite receiving ≥2 inhaled maintenance therapies),
smoking history ≥10 pack-years, and had a post-bronchodilator forced
expiratory volume in 1 s (FEV1) 25–65% of predicted normal. Patients
were required to have a documented history of COPD exacerbations in the
previous year; if post-bronchodilator FEV1 was <50% of predicted normal,
a history of ≥1 moderate or severe COPD exacerbation was required, and
if post-bronchodilator FEV1 was ≥50% of predicted normal, a history of
≥2 moderate or ≥1 severe COPD exacerbations was required. Patients
with a current diagnosis of asthma, a significant respiratory disease other
than COPD, or other clinically significant uncontrolled disease (eg, cardiac
disease) were excluded [7,9].
2.2. Endpoints and assessments
2.2.1. HRQoL and symptom assessments
Secondary and other symptom endpoints in ETHOS were previously
published in part [7]. The following HRQoL and COPD symptom end­
points were assessed over 24 and 52 weeks: change from baseline in
average daily rescue medication use within the rescue albuterol user
population and percentage of days with no rescue medication use,
change from baseline in SGRQ total score, the percentage of patients
achieving a minimum clinically important difference (MCID) of ≥4 units
reduction in SGRQ total score (responders) [10], TDI focal score, the
percentage of patients achieving an MCID of ≥1 unit increase in TDI
focal score [11], change from baseline in EXACT total score, and change

Table 1
Baseline characteristics of patients in ETHOS (mITT population).
BGF BGF GFF BFF
320/18/9.6 μg 160/18/9.6 μg 18/9.6 μg 320/9.6 μg
(N = 2137) (N = 2121) (N = 2120) (N = 2131)

Age, years, mean (SD) 64.6 (7.6) 64.6 (7.6) 64.8 (7.6) 64.6 (7.6)
Male, n (%) 1260 (59.0) 1298 (61.2) 1244 (58.7) 1279 (60.0)
White, n (%) 1819 (85.1) 1783 (84.1) 1808 (85.3) 1816 (85.2)
Current smoker, n (%) 910 (42.6) 865 (40.8) 856 (40.4) 864 (40.5)
Median no. pack-years smoked (range) 42 (10–214) 43 (3–188) 43 (10–212) 42 (7–250)
COPD exacerbations in the past 12 months, n (%)
0 2 (0.1) 2 (0.1) 2 (0.1) 2 (0.1)
1 940 (44.0) 932 (43.9) 907 (42.8) 912 (42.8)
≥2 1195 (55.9) 1187 (56.0) 1211 (57.1) 1217 (57.1)
CAT score, mean (SD) 19.7 (6.5) 19.6 (6.6) 19.5 (6.6) 19.5 (6.5)
Mean post-bronchodilator FEV1, % predicted (SD) 43.6 (10.3) 43.1 (10.4) 43.5 (10.2) 43.4 (10.4)
Baseline number of daily rescue puffs, mean (SD) 4.6 (3.1) 4.6 (2.9) 4.6 (3.0) 4.7 (3.1)
Baseline SGRQ total score, mean (SD) 50.6 (16.6) 50.6 (17.2) 49.8 (16.6) 50.0 (17.0)
Baseline Dyspnea Index focal score, mean (SD) 5.9 (1.9) 5.8 (2.0) 5.9 (1.9) 5.9 (2.0)
Baseline EXACT total score, mean (SD) 36.8 (10.9) 36.7 (10.9) 36.4 (10.8) 36.4 (11.2)
Baseline E-RS™:COPD total score, mean (SD) 12.7 (6.1) 12.7 (6.0) 12.6 (5.9) 12.6 (6.1)

BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary
disease; E-RS™:COPD, Evaluating Respiratory Symptoms in COPD; EXACT, EXAcerbations of Chronic pulmonary disease Tool; FEV1, forced expiratory volume in 1 s;
GFF, glycopyrrolate/formoterol fumarate; mITT, modified intent-to-treat; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.

2
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(caption on next page)

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F.J. Martinez et al.
Fig. 1. A) Change from baseline in the mean daily number of puffs of rescue medicationa, B) change from baseline in SGRQ total score, C) TDI focal score, D) change
from baseline in EXACT total score, and E) change from baseline in E-RS™:COPD total score for the efficacy estimand over 24 and 52 weeks (mITT population).
a
Rescue albuterol user population. Data for rescue medication use, SGRQ total score, and TDI focal score over 24 weeks and EXACT total score over 52 weeks have
been previously reported [7].
BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; E-RS™:COPD; Evaluating Respiratory Symptoms in COPD; EXACT,
Exacerbations of Chronic Pulmonary Disease Tool; GFF, glycopyrrolate/formoterol fumarate; LSM, least square mean; mITT, modified-intent-to-treat; SE, standard
error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.
from baseline in the E-RS™:COPD total score.
Additionally, the percentage of patients achieving an MCID of ≥4 units
reduction in SGRQ total score (responders) was assessed at Week 24 and
Week 52.
The SGRQ is a questionnaire to assess HRQoL, composed of 50
weighted items, with a total score range from 0 to 100 [3]. The ques­
tionnaire measures three domains: symptoms, activity, and impacts,
each with an associated score ranging from 0 to 100; higher scores
indicate greater impairment, and a negative change indicates improve­
ment. TDI is an evaluative instrument to measure changes in dyspnea
from the baseline state. TDI consists of three components that contribute
to breathing difficulty based on activities of daily living – functional
impairment, magnitude of task, and magnitude of effort. Each of the
three components is graded from − 3 (major deterioration) to +3 (major
improvement), where a lower score indicates greater disease impair­
ment [4]. The EXACT is a daily diary consisting of 14 items. The purpose
is to standardize the assessment of the patient’s condition and charac­
terize the change in respiratory symptoms during, and following, an
exacerbation. The EXACT total score ranges from 0 to 100, where a
higher score indicates a more severe condition, and a negative change
indicates an improvement. The E-RS™:COPD is a derivative instrument
comprising a subset of 11 respiratory symptom items from EXACT, with
total scores ranging from 0 to 40, consisting of breathlessness (range:
0 to 17), cough, and sputum (range: 0 to 11), and chest symptoms
(range: 0 to 11) domains, to test the effect of treatment on the severity of
respiratory symptoms in stable COPD [5,6].
2.3. Statistical analysis
Secondary symptom-related endpoints were based on data from the
modified intent-to-treat (mITT) population of ETHOS, containing all
post-randomization data obtained prior to discontinuation from treat­
ment. Regional differences in rescue albuterol usage were expected with
patients in some regions using virtually no rescue medication at study
entry. Therefore, the rescue albuterol user population was defined as all
patients in the intent-to-treat population with average baseline rescue
albuterol use of ≥1.0 puff/day.
Treatment comparisons were made as follows: BGF 320 vs GFF, BGF
320 vs BFF, BGF 160 vs GFF, and BGF 160 vs BFF [9].
Endpoints differed according to regulatory requirements. For the US
regulatory approach, change from baseline in average daily rescue
medication use over 24 weeks and the percentage of patients achieving
an MCID of ≥4 units reduction in SGRQ total score at Week 24 were
assessed. For the ex-US regulatory approach, change from baseline in
average daily rescue medication use over 24 weeks, change from base­
line in SGRQ total score over 24 weeks, TDI focal score over 24 weeks,
and change from baseline in EXACT total score over 52 weeks were
assessed. Type I error for the secondary endpoints was controlled using
Hochberg multiplicity correction procedure at a 2-sided familywise
error rate of 4.6% within each comparison and statistical significance is
reported for these endpoints according to the procedure to which they
belonged (US vs ex-US) [12]. Other endpoints reported here used a
nominal significance level of 5%, 2-sided, without multiplicity
adjustment.
Change from baseline in average daily albuterol use, change from
baseline in SGRQ total score, TDI focal score, change from baseline in
EXACT total score, and change from baseline in E-RS™:COPD total score
were analyzed using similar repeated measures models, using either visit
4
Respiratory Medicine 185 (2021) 106509
(for in-clinic assessments) or time interval (for diary-based assessments),
treatment, treatment by visit/time interval interaction, and ICS use at
screening as categorical covariates. The appropriate baseline covariate
for each tool, log transformed blood eosinophil count, percent predicted
post-bronchodilator FEV1 and percentage reversibility were continuous
covariates. Responder analyses were conducted using logistic regression
with similar covariates to the change from baseline analysis; patients
who discontinued study medication prematurely in the respective
timeframe were considered to be non-responders. These were reported
using odds ratios and absolute differences in responders, with 95% CIs.
3. Results
3.1. Study population
A total of 8588 patients were randomized, and the mITT population
included 8509 patients. Full baseline demographics have been previously
published [7]. Clinical and demographic characteristics were similar
across treatment groups (Table 1). Overall, the mITT population had a
mean age of 64.7 years (standard deviation [SD] 7.6), 59.7% male and
comprised patients with symptomatic disease (mean total CAT score at
baseline, 19.6 [SD 6.5]) many of whom had experienced ≥2 exacerbations
in the prior year (56.5%). Symptom scores at baseline were similar across
treatment groups. Overall, 41.1% of the mITT population were current
smokers and baseline FEV1% predicted post-bronchodilator was 43.4%.
3.2. Daily rescue albuterol use
There were 5639 patients within the rescue albuterol user population
(BGF 320 N = 1430, BGF 160 N = 1391, GFF N = 1389, and BFF N =
1429; Fig. S2). Patients treated with BGF 320 reported the largest mean
reduction in rescue medication use (albuterol) of − 1.2 puffs/day over 24
weeks and − 1.1 puffs/day over 52 weeks (Fig. 1A). Rescue medication use
was statistically significantly reduced for patients receiving BGF 320 and
BGF 160 vs GFF or BFF over 24 weeks (all p ≤ 0.0127; Table 2). These
significant reductions were maintained over 52 weeks, except for BGF 160
vs BFF (Table 2). Additionally, patients treated with both doses of BGF
reported a greater proportion of days over 52 weeks, where no rescue
medication use was necessary compared with GFF and BFF (all unadjusted
p ≤ 0.0443; Table 2).
3.3. SGRQ
Improvements from baseline in SGRQ total score exceeded the MCID of
a 4-unit decrease over 24 and 52 weeks for all treatment groups (Fig. 1B).
Change from baseline in SGRQ total score was significantly improved with
both BGF 320 and BGF 160 vs GFF and BFF over 24 weeks (p ≤ 0.0017 for
all) with reductions also seen over 52 weeks (unadjusted p ≤ 0.0020 for all;
Table 2). The greatest reduction in SGRQ total score over 24 weeks was
reported with BGF 320 (− 6.5), which was maintained over 52 weeks
(− 6.4; Fig. 1B). The improvements in SGRQ were consistent at each post-
randomization visit throughout the 52-week treatment period (Fig. 2A).
Results for individual SGRQ domain scores indicated that no individual
domain dominated the improvements observed for the overall score
(Table S1).
Significantly greater proportions of SGRQ responders were observed
for both doses of BGF vs GFF and BFF at Week 24 (p ≤ 0.0103 for all;
Table 2; Fig. 3A). In addition, greater proportions of SGRQ responders
 Table 2

F.J. Martinez et al.

Between-treatment differences in symptom-related endpoints in the ETHOS study (efficacy estimanda; mITT population).
BGF 320/18/9.6 μg BGF 160/18/9.6 μg BGF 320/18/9.6 μg BGF 160/18/9.6 μg
vs GFF 18/9.6 μg vs GFF 18/9.6 μg vs BFF 320/9.6 μg vs BFF 320/9.6 μg

Change from baseline in rescue medication use (puffs/day)b

Over 24 weeksc,d, e LSM (95% CI) − 0.51 (− 0.68, − 0.34) − 0.35 (− 0.53, − 0.18) − 0.37 (− 0.54, − 0.20) − 0.22 (− 0.39, − 0.05)
p-value <0.0001 <0.0001 <0.0001 0.0127
Over 52 weeks LSM (95% CI) − 0.53 (− 0.71, − 0.34) − 0.34 (− 0.53, − 0.16) − 0.35 (− 0.53, − 0.17) − 0.16 (− 0.35, 0.02)
p-value <0.0001 0.0003 0.0002 0.0791
b
Percentage of days with no rescue medication use
Over 52 weeks LSM (95% CI) 4.98 (2.84, 7.12) 2.83 (0.68, 4.98) 4.34 (2.22, 6,47) 2.19 (0.06, 4.33)
p-value <0.0001 0.0100 <0.0001 0.0443
Change from baseline in SGRQ total score
Over 24 weeksc,e LSM (95% CI) − 1.62 (− 2.27, − 0.97) − 1.28 (− 1.93, − 0.63) − 1.38 (− 2.02, − 0.73) − 1.04 (− 1.68, − 0.39)
p-value <0.0001 0.0001 <0.0001 0.0017
Over 52 weeks LSM (95% CI) − 1.59 (− 2.27, − 0.91) − 1.34 (− 2.02, − 0.66) − 1.31 (− 1.99, − 0.64) − 1.06 (− 1.74, − 0.39)
p-value <0.0001 0.0001 0.0001 0.0020
Response in SGRQ total score (MCID of ≥ 4.0 units)
Over 24 weeks OR (95% CI) 1.496 (1.318, 1.697) 1.397 (1.231, 1.585) 1.336 (1.179, 1.515) 1.248 (1.100, 1.415)
p-value <0.0001 <0.0001 <0.0001 0.0006
At Week 24d,e OR (95% CI) 1.358 (1.199, 1.539) 1.283 (1.133, 1.454) 1.246 (1.100, 1.410) 1.177 (1.039, 1.333)
p-value <0.0001 <0.0001 0.0005 0.0103
Over 52 weeks OR (95% CI) 1.456 (1.282, 1.653) 1.422 (1.252, 1.615) 1.267 (1.118, 1.437) 1.237 (1.091, 1.404)
p-value <0.0001 <0.0001 0.0002 0.0009
At Week 52e OR (95% CI) 1.368 (1.206, 1.552) 1.323 (1.166, 1.502) 1.224 (1.080, 1.386) 1.183 (1.044, 1.341)
p-value <0.0001 <0.0001 0.0015 0.0084
TDI focal score
Over 24 weeksc,e LSM (95% CI) 0.40 (0.24, 0.55) 0.37 (0.21, 0.52) 0.31 (0.15, 0.46) 0.27 (0.12, 0.43)
p-value <0.0001 <0.0001 <0.0001 0.0005
Over 52 weeks LSM (95% CI) 0.34 (0.19, 0.49) 0.34 (0.18, 0.49) 0.26 (0.11, 0.41) 0.26 (0.11, 0.41)
5

p-value <0.0001 <0.0001 0.0007 0.0008

Response in TDI focal score (MCID of ≥ 1.0 units)
Over 24 weeks OR (95% CI) 1.252 (1.106, 1.417) 1.294 (1.143, 1.464) 1.124 (0.994, 1.271) 1.161 (1.027, 1.313)
p-value 0.0004 <0.0001 0.0628 0.0173
Over 52 weeks OR (95% CI) 1.194 (1.054, 1.352) 1.202 (1.061, 1.361) 1.161 (1.025, 1.314) 1.169 (1.032, 1.323)
p-value 0.0052 0.0038 0.0184 0.0138
Change from baseline in EXACT total score
Over 24 weeks LSM (95% CI) − 1.20 (− 1.64, − 0.77) − 0.99 (− 1.43, − 0.56) − 1.06 (− 1.49, − 0.63) − 0.85 (− 1.28, − 0.42)
p-value <0.0001 <0.0001 <0.0001 0.0001
Over 52 weeksc,e LSM (95% CI) − 1.14 (− 1.64, − 0.65) − 0.93 (− 1.43, − 0.44) − 1.04 (− 1.53, − 0.55) − 0.83 (− 1.32, − 0.34)
p-value <0.0001 0.0002 <0.0001 0.0010
Change from baseline in E-RS™:COPD total score
Over 24 weeks LSM (95% CI); − 0.69 (− 0.92, − 0.46); <0.0001 − 0.60 (− 0.83, − 0.37); <0.0001 − 0.62 (− 0.85, − 0.39); <0.0001 − 0.53 (− 0.76, − 0.30); <0.0001
p-value
Over 52 weeks LSM (95% CI); − 0.65 (− 0.91, − 0.39); <0.0001 − 0.58 (− 0.84, − 0.31); <0.0001 − 0.63 (− 0.89, − 0.37); <0.0001 − 0.55 (− 0.81, − 0.30); <0.0001
p-value

BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; CI, confidence interval; E-RS™:COPD, Evaluating Respiratory Symptoms in COPD; EXACT, EXAcerbations of Chronic

Respiratory Medicine 185 (2021) 106509

pulmonary disease Tool; GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MCID, minimum clinically important difference; mITT, modified intent-to-treat; OR, odds ratio; SGRQ, St George’s Respiratory
Questionnaire; TDI, Transition Dyspnea Index.
a
The efficacy estimand was defined as: the effect of the randomized treatments in all patients assuming the continuation of randomized treatments for the duration of the study, regardless of actual compliance. bRescue
albuterol user population: BGF 320/18/9.6 μg, N = 1430; BGF 160/18/9.6 μg, N = 1391; GFF 18/9.6 μg, N = 1389; BFF 320/9.6 μg, N = 1429. cSecondary efficacy endpoint in ex-US approach. dSecondary efficacy
endpoint in US approach. eLSM/OR and 95% CI previously reported [7].
F.J. Martinez et al. Respiratory Medicine 185 (2021) 106509

Fig. 2. Adjusted mean (±SE) for A) change from baseline in SGRQ, B) TDI focal score, C) change from baseline in EXACT total score, and D) change from baseline in
E-RS™:COPD total score over time for the efficacy estimand (mITT population).
Panel A from the New England Journal of Medicine, Rabe KF et al, Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD, 383:35-48
[7]. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; E-RS™:COPD; Evaluating Respiratory Symptoms in COPD; EXACT,
Exacerbations of Chronic Pulmonary Disease Tool; GFF, glycopyrrolate/formoterol fumarate; mITT, modified-intent-to-treat; SE, standard error; SGRQ, St George’s
Respiratory Questionnaire; TDI, Transition Dyspnea Index.

were also seen for both doses of BGF vs GFF and BFF at Week 52 (unad­
justed p ≤ 0.0084; Table 2; Fig. 3A) and over 24 and 52 weeks (unadjusted
p ≤ 0.0009 for all; Table 2; Fig. 3B).
3.4. TDI focal score
Improvements in the TDI met or exceeded the MCID of a 1-unit increase
for all treatment groups over both time points, except for GFF over 24
weeks (TDI value 0.9; Fig. 1C). Both doses of BGF significantly improved
TDI focal score vs GFF and BFF over 24 weeks (p ≤ 0.0005 for all; Table 2).
These improvements were generally consistent at each post-randomization
visit throughout the 52-week treatment period (Fig. 2B) and at 52 weeks
(unadjusted p ≤ 0.0008 for all; Table 2). Results for individual TDI domain
scores indicated that no individual domain dominated the improvements
observed for the overall score (Table S1).
Greater proportions of TDI responders were observed with both
doses of BGF vs GFF and BFF over 24 weeks (unadjusted p ≤ 0.0628
for all; Table 2; Fig. 3C) and over 52 weeks (unadjusted p ≤ 0.0184 for
all; Table 2; Fig. 3C).
0.0001 for all) and 52 weeks (p ≤ 0.0010 for all); Table 2; Fig. 1D). The
greatest reduction in EXACT total score over 24 weeks was reported with
BGF 320 (− 2.2) and improvements were maintained over 52 weeks
(− 1.8), with similar improvements over the treatment period (Fig. 1D).
Improvements were observed over 52 weeks and at each 4-week interval
throughout the treatment period (Fig. 2C).
3.6. E-RS™:COPD total score
Improvements were observed for the E-RS™:COPD total score (Fig. 1E)
for both doses of BGF vs GFF and BFF over 24 weeks (unadjusted p <
0.0001 for all; Table 2). The greatest reduction in E-RS™:COPD total score
over 24 weeks was reported with BGF 320 (− 1.2) and improvements were
maintained over 52 weeks (− 0.9), with similar improvements for BGF 160
over the treatment period (Fig. 1E). Improvements were observed over 52
weeks and at each 4-week interval throughout the treatment period
(Fig. 2D). Improvements for both doses of BGF versus dual therapies were
observed across the individual domains of the E-RS™:COPD score, with
improvements being greatest for the daily breathlessness score (Table S1).

3.5. EXACT total score 4. Discussion

Significant improvements were observed for the EXACT total score We have previously shown that triple therapy with BGF resulted in
for both doses of BGF vs GFF and BFF over 24 weeks (unadjusted p ≤ significant reductions in the rate of moderate or severe COPD

6
F.J. Martinez et al.
(caption on next column)
7
Respiratory Medicine 185 (2021) 106509
Fig. 3. Response in A) SGRQ total score (MCID ≥4.0 units) at Week 24 and 52,
B) SGRQ total score (MCID ≥4.0 units) over 24 and 52 weeks, and C) TDI focal
score (MCID ≥1.0 units) over 24 and 52 weeks for the efficacy estimand (mITT
population).
The data in panel A have been previously reported [7].
BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/­
formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; MCID; mini­
mum clinically important difference; mITT, modified-intent-to-treat; SGRQ, St
George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.
exacerbations and reduced all-cause mortality versus both dual therapies
in patients with symptomatic COPD and a prior history of exacerbations
[7,8]. While such outcomes are important, the effect of therapy on
symptoms of COPD should not be overlooked given they can dictate
day-to-day wellbeing and functional status [13,14].
HRQoL and symptoms questionnaires are widely used to assess patient
improvement over time, responsiveness to ongoing therapy, and the effect
of clinical interventions. Patient-reported outcomes (PROs) can aid the
selection of the most appropriate therapy among a broad spectrum of
therapeutic interventions [13]. In this report, we have shown that BGF, at
two ICS dose levels, improved symptoms and HRQoL compared with both
GFF and BFF dual therapies over the 52-week study duration with,
generally, no loss of effect over 52 weeks of treatment. Importantly, the
benefits were consistently seen across a range of PRO instruments
encompassing multiple domains of patients’ HRQoL. Furthermore, within
individual PROs, the benefits of BGF compared with dual therapies were
observed across all individual domains. For SGRQ and TDI, no individual
domain dominated the overall treatment differences. For E-RS™:COPD,
although improvements with BGF versus dual therapies were observed in
all domains, they were greatest for the daily breathlessness score.
The magnitude of improvements in rescue medication use was
greater in ETHOS than those observed in the KRONOS study
(NCT02497001), which compared the efficacy of BGF 320/18/9.6 μg
with corresponding dual therapies in symptomatic patients with
moderate-to-very severe COPD [15]. The improvements in ETHOS were
clinically meaningful both with respect to changes from baseline and
differences between treatments. These improvements were sustained
throughout the 52-week treatment period. The indication that rescue
medication use decreased while TDI, EXACT, E-RS™:COPD, and HRQoL
improved suggests that the treatment benefits with BGF were likely to
have been meaningful for patients and are consistent with the benefits
previously seen for BGF vs both dual therapies on exacerbation rates and
lung function [7,15]. These results also compare favorably with results
seen with other triple therapies [16–18].
In this study, all treatments resulted in reductions from baseline in
SGRQ, each with a mean improvement exceeding the MCID ≥4.0 for this
endpoint. Approximately 50% of patients reached the MCID threshold at
Week 24 with BGF compared with 42–45% with dual therapy. This
finding is not unexpected since patients entered the study having been
on multiple maintenance therapies for COPD. As such, not all patients
would be expected to demonstrate MCID for SGRQ improvement.
Importantly, the percentage of SGRQ responders, which exceeded
48.7% for both doses of BGF at Week 24, was significantly greater than
observed for GFF and BFF. Additionally, these improvements were
maintained over the 52 weeks of treatment. This is particularly impor­
tant given the severity of disease in the ETHOS patient population where
the baseline FEV1% predicted post-bronchodilator was 43.4% for the
overall population and all patients had CAT scores ≥10 at screening
despite receiving multiple inhaled maintenance therapies. The im­
provements seen in the proportion of SGRQ responders for BGF were
shown versus active comparators (GFF and BFF) where demonstration of
meaningful differences between treatments is more challenging. The
proportion of SGRQ responders in ETHOS was generally similar to those
observed in other fixed-dose triple combination studies (41–49.5%) [15,
17–20]. However, it is important to note that comparisons across trials
are difficult due to differences in patient clinical and baseline
F.J. Martinez et al.
characteristics, study duration, and population size.
In conclusion, in this study of over 8500 patients with moderate-to-
very severe COPD and prior history of exacerbation, BGF, at both dose
levels, resulted in improvements versus both dual therapies in rescue
medication use, symptoms, and HRQoL, which were sustained over the 52
weeks of the study. These measures of overall HRQoL are important for
patients and complement the benefits previously seen with BGF vs both
dual therapies on reducing the rate of COPD exacerbations and improving
lung function in patients with moderate-to-very severe COPD.
Funding
This study was supported by AstraZeneca. The study’s funders had a
role in the study design, data analysis, data interpretation, and writing of
the report. Under the authors’ direction, medical writing support was
provided by Jake Casson, PhD, CMC Connect, McCann Health Medical
Communications, which was funded by AstraZeneca in accordance with
Good Publication Practice (GPP3) guidelines [21].
Author contributions
The authors meet criteria for authorship as recommended by the
International Committee of Medical Journal Editors, take responsibility
for the work’s integrity as a whole, contributed to the writing and
reviewing of the manuscript, and have given final approval for the
version to be published. All authors had full access to the data in this
study and take complete responsibility for the integrity of the data and
accuracy of the data analysis.
CRediT authorship contribution statement
Fernando J. Martinez: Investigation, Writing – review & editing.
Klaus F. Rabe: Investigation, Writing – review & editing. Gary T.
Ferguson: Investigation, Writing – review & editing. Jadwiga A.
Wedzicha: Investigation, Writing – review & editing. Roopa Trivedi:
Investigation, Writing – review & editing. Martin Jenkins: Formal
analysis, Methodology, Writing – review & editing. Patrick Darken:
Conceptualization, Methodology, Formal analysis, Writing – review &
editing, Supervision. Magnus Aurivillius: Investigation, Writing – re­
view & editing. Paul Dorinsky: Conceptualization, Methodology,
Investigation, Writing – review & editing, Supervision.
Declaration of interests
Fernando J Martinez reports grants from AstraZeneca during the
conduct of the study; personal fees and non-financial support from the
American College of Chest Physicians, AstraZeneca, Boehringer Ingel­
heim, Chiesi, Concert, Continuing Education, Genentech, Glax­
oSmithKline, Inova Fairfax Health System, Miller Communications, the
National Association for Continuing Education, Novartis, PeerView
Communications, Prime Communications, the Puerto Rican Respiratory
Society, Roche, Sunovion, and Theravance; non-financial support from
ProterixBio; personal fees from the American Thoracic Society,
Columbia University, Haymarket Communications, Integritas,
inThought Research, MD Magazine, Methodist Hospital Brooklyn, New
York University, Unity, UpToDate, WebMD/MedScape, and Western
Connecticut Health Network; and grants from the National Institutes of
Health, outside the submitted work.
Klaus F Rabe reports personal fees from AstraZeneca, Berlin-Chemie,
Boehringer Ingelheim, Chiesi Pharmaceuticals, InterMune, Novartis,
Sanofi, and Teva; and grants from the Ministry of Education and Science,
Germany, outside the submitted work.
Gary T Ferguson reports grants, personal fees, and non-financial
8
Respiratory Medicine 185 (2021) 106509
support from AstraZeneca during the conduct of the study; grants,
personal fees, and non-financial support from AstraZeneca, Boehringer
Ingelheim, Novartis, and Sunovion; grants and personal fees from
Theravance; and personal fees from Circassia, GlaxoSmithKline,
Innoviva, Mylan, and Verona, outside the submitted work.
Jadwiga A Wedzicha reports grants from AstraZeneca, Boehringer
Ingelheim, Chiesi, GlaxoSmithKline, Johnson & Johnson, and Novartis;
and meeting expenses from AstraZeneca, Boehringer Ingelheim, Glax­
oSmithKline, and Novartis, outside the submitted work.
Roopa Trivedi, Martin Jenkins, Patrick Darken, Magnus Aurivillius,
and Paul Dorinsky are AstraZeneca employees and hold stock and/or
stock options in the company.
Acknowledgments
The authors would like to thank all the patients, their families, and
the team of investigators, research nurses, and operations staff
involved in ETHOS. The authors also thank former AstraZeneca em­
ployees Shaila Ballal, Colin Reisner, and Earl St Rose for their valuable
contribution to the study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.rmed.2021.106509.
References
[1] Global Initiative for Chronic Obstructive Lung Disease, Global strategy for the
diagnosis, management, and prevention of chronic obstructive pulmonary disease,
report, 2021, https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REP
ORT-2021-v1.1-25Nov20_WMV.pdf, 2021. (Accessed 5 April 2021).
[2] World Health Organization, Disease burden and mortality estimates. https://www.
who.int/healthinfo/global_burden_disease/estimates/en/. (Accessed 20 January
2021).
[3] St George’s University of London, St George’s Respiratory Questionnaire (SGRQ).
http://www.healthstatus.sgul.ac.uk/, 2016. (Accessed 25 January 2021).
[4] D.A. Mahler, J. Ward, G. Fierro-Carrion, et al., Development of self-administered
versions of modified baseline and transition dyspnea indexes in COPD, COPD 1
(2004) 165–172.
[5] N.K. Leidy, L.T. Murray, Patient-reported outcome (PRO) measures for clinical
trials of COPD: the EXACT and E-RS, COPD 10 (2013) 393–398.
[6] N.K. Leidy, L.T. Murray, B.U. Monz, et al., Measuring respiratory symptoms of
COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three
clinical trials, Respir. Res. 15 (2014) 124.
[7] K.F. Rabe, F.J. Martinez, G.T. Ferguson, et al., Triple inhaled therapy at two
glucocorticoid doses in moderate-to-very-severe COPD, N. Engl. J. Med. 383
(2020) 35–48.
[8] F.J. Martinez, K.F. Rabe, G.T. Ferguson, et al., Reduced all-cause mortality in the
ETHOS trial of budesonide/glycopyrrolate/formoterol for COPD: a randomized,
double-blind, multi-center parallel-group study, Am. J. Respir. Crit. Care Med. 203
(2021) 553–564.
[9] K.F. Rabe, F.J. Martinez, G.T. Ferguson, et al., A Phase III study of triple therapy
with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/
18/9.6 μg and 160/18/9.6 μg using co-suspension delivery technology in
moderate-to-very severe COPD: the ETHOS study protocol, Respir. Med. 158
(2019) 59–66.
[10] P.W. Jones, St. George’s Respiratory Questionnaire: MCID, COPD 2 (2005) 75–79.
[11] D.A. Mahler, T.J. Witek Jr., The MCID of the transition dyspnea index is a total
score of one unit, COPD 2 (2005) 99–103.
[12] Y. Hochberg, A sharper Bonferroni procedure for multiple tests of significance,
Biometrika 75 (1988) 800–802.
[13] A. Rehman, M. Hassali, S. Harun, et al., Validation and clinical interpretation of the
St George’s Respiratory Questionnaire for COPD (SGRQ-C) after adaptation to
Malaysian language and culture, in patients with COPD, Health Qual. Life Outcome
18 (2020) 138.
[14] M. Miravitlles, A. Ribera, Understanding the impact of symptoms on the burden of
COPD, Respir. Res. 18 (2017) 67.
[15] G.T. Ferguson, K.F. Rabe, F.J. Martinez, et al., Triple therapy with budesonide/
glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus
dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-
blind, parallel-group, multicentre, phase 3 randomised controlled trial, Lancet
Respir. Med. 6 (2018) 747–758.
F.J. Martinez et al.
[16] J. Vestbo, A. Papi, M. Corradi, et al., Single inhaler extrafine triple therapy versus
long-acting muscarinic antagonist therapy for chronic obstructive pulmonary
disease (TRINITY): a double-blind, parallel group, randomised controlled trial,
Lancet 389 (2017) 1919–1929.
[17] D. Singh, A. Papi, M. Corradi, et al., Single inhaler triple therapy versus inhaled
corticosteroid plus long-acting β2-agonist therapy for chronic obstructive
pulmonary disease (TRILOGY): a double-blind, parallel group, randomised
controlled trial, Lancet 388 (2016) 963–973.
[18] M. Tabberer, C.E. Jones, S. Kilbride, et al., Single-inhaler triple therapy and health-
related quality of life in COPD: the IMPACT study, Adv. Ther. 37 (2020)
3775–3790.
Respiratory Medicine 185 (2021) 106509
[19] D.A. Lipson, F. Barnhart, N. Brealey, et al., Once-daily single-inhaler triple versus
dual therapy in patients with COPD, N. Engl. J. Med. 378 (2018) 1671–1680.
[20] A. Papi, J. Vestbo, L. Fabbri, et al., Extrafine inhaled triple therapy versus dual
bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a
double-blind, parallel group, randomised controlled trial, Lancet 391 (2018)
1076–1084.
[21] W.P. Battisti, E. Wager, L. Baltzer, et al., Good publication practice for
communicating company-sponsored medical research: GPP3, Ann. Intern. Med.
163 (2015) 461–464.