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

Klaus F Rabea,*, Fernando J Martinezb, Gary T Fergusonc, Chen Wangd, Dave Singhe, Jadwiga A

Wedzichaf, Roopa Trivedig, Earl St Roseh, Shaila Ballalh, Julie McLareni, Patrick Darkenh,

Colin Reisnerh, Paul Dorinskyg

aLungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center

North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany

bJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA

cPulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA

dNational Clinical Research Centre for Respiratory Diseases, China-Japan Friendship Hospital,

Beijing, China

eMedicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation

Hospitals Trust, Manchester, UK

fRespiratory Division, National Heart and Lung Institute, London, UK

gAstraZeneca, Durham, NC, USA

hAstraZeneca, Morristown, NJ, USA

iAstraZeneca, Gaithersburg, MD, USA

*Corresponding author. Address: LungenClinic Grosshansdorf, Wöhrendamm 80, 22927

Großhansdorf, Germany. E-mail address: k.f.rabe@lungenclinic.de (KF Rabe).

Word count: 3188

Tables/figures: 5/2

1

Abbreviations: AE, adverse event; AUC0–4, area under the curve from 0 to 4 h; BDI, Baseline Dyspnea

Index; BDP, beclometasone dipropionate; BFF, budesonide/formoterol fumarate;

BGF, budesonide/glycopyrrolate/formoterol fumarate; BID, twice daily; CAT, COPD Assessment

Test; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler;

ECG, electrocardiogram; EXACT, Exacerbations of Chronic Pulmonary Disease Tool; FEV1, forced

expiratory volume in 1 s; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol;

FF/VI, fluticasone furoate/vilanterol; FVC, forced vital capacity; GFF, glycopyrrolate/formoterol

fumarate; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HCRU, healthcare resource

utilization; ICS, inhaled corticosteroid; IND/GLY, indacaterol/glycopyrronium; LABA, long-acting

β2-agonist; LAMA, long-acting muscarinic antagonist; MCID, minimum clinically important

difference; MDI, metered dose inhaler; mITT, modified intent-to-treat; PFT, pulmonary function test;

PP, per-protocol; QD, once daily; QID, four times daily; SABA, short-acting β2-agonist; SAMA,

short-acting muscarinic antagonist; SD, standard deviation; SGRQ, St. George’s Respiratory

Questionnaire; TDI, Transition Dyspnea Index; UMEC/VI, umeclidinium/vilanterol.

2

Originality and clinical relevance statement

This manuscript describes the study design and rationale for the ETHOS study, a pivotal

Phase III study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI),

one of three triple fixed-dose combinations that are in development or approved for the treatment of

chronic obstructive pulmonary disease (COPD). Studies thus far have shown that triple therapy can

improve lung function, symptoms, and reduce exacerbations versus dual therapies, with benefits

versus dual bronchodilators increasing at higher blood eosinophil levels. However, long-term inhaled

corticosteroid (ICS) use has been associated with potential safety concerns, although the risk of

adverse events may depend on the dose and duration of treatment, as well as the specific ICS used.

Further evidence is needed to identify which patients with COPD may benefit from ICS treatment,

and particularly whether a lower dose of ICS can still provide a benefit. With this in mind, the

ETHOS study will be the first to investigate a triple therapy with two doses of ICS (320 μg and

160 μg), in comparison to dual therapies. ETHOS enrolled patients with moderate-to-very severe

airflow obstruction (FEV1 < 65% predicted) who were symptomatic despite receiving ≥ 2 inhaled

maintenance therapies, and had a history of at least one COPD exacerbation in the previous year.

Furthermore, ETHOS is the first one-year triple therapy study to prospectively stratify randomization

by eosinophil count. These unique features of the study design will help clarify the appropriate role

for triple therapy in the management of COPD, and may provide support for the use of BGF MDI

with two doses of ICS, allowing for titration of COPD treatment to the lowest effective dose. Overall,

the findings are expected to help refine current treatment recommendations, with the ultimate goal of

improving outcomes and optimizing the benefit:risk ratio for patients with COPD.

3

ABSTRACT (250/250 words)

Background: Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting

muscarinic antagonist, and a long-acting β2-agonist (ICS/LAMA/LABAs) are an emerging treatment

option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding

the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment.

Methods: ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week

study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in

the previous year. Two doses of single inhaler triple therapy with

budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 μg and

160/18/9.6 μg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg and

budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, all formulated using co-suspension delivery

technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD

exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function

and cardiovascular safety.

Study population: From June 2015-July 2018, 16,044 patients were screened and 8572 were

randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥ 2

moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing

treatment at study entry, and 59.9% had blood eosinophil counts ≥ 150 cells/mm3.

Conclusions: ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and

safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose

combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS

will be compared to dual ICS/LABA and LAMA/LABA therapies.

Clinical trial registration number: NCT02465567

Keywords (3–6): BGF MDI, Chronic obstructive pulmonary disease, Exacerbations, Inhaled

corticosteroid, Study protocol, Triple therapy

4

1. Introduction

Triple fixed-dose combination therapies providing an inhaled corticosteroid (ICS), a long-

acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA) in a single inhaler are a

recent addition to the range of available treatment options for chronic obstructive pulmonary disease

(COPD) [1-5]. Studies investigating the efficacy of triple fixed-dose ICS/LAMA/LABA therapies

have found benefits on lung function, quality of life, and exacerbation rates versus dual

LAMA/LABA [4-6] and ICS/LABA therapies [1, 4, 6].

Nevertheless, the efficacy benefits of ICS therapy were called into question by the results of

one large study which reported that dual long-acting bronchodilator therapy was superior to

ICS/LABA therapy for the prevention of COPD exacerbations in patients with high exacerbation risk

[7]. Furthermore, stepping down from triple therapy to LAMA/LABA did not increase the overall risk

of exacerbations in two studies that enrolled patients with either ≤ 1 [8] or ≥ 1 [9] exacerbations in the

previous year, though increased exacerbations were detected in subgroups of patients with high blood

eosinophil levels [8, 10]. These findings, in addition to other recent studies showing that higher

eosinophil levels predict a greater treatment response to ICS-containing therapies versus

bronchodilator-only treatments [3-5, 11, 12], have led to new recommendations regarding eosinophils

in the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report [13]. Clinicians

are now encouraged to use blood eosinophil counts to guide treatment decisions for patients with

exacerbations, with triple therapy recommended for those who experience persistent exacerbations on

LAMA/LABA (if eosinophil counts are ≥ 100 cells/mm3) or ICS/LABA therapy [13].

Questions also remain regarding the benefit:risk ratio of ICS therapy due to the potential for

an increased risk of steroid-associated adverse events, including pneumonia [13, 14]. However, the

risk of pneumonia associated with ICS therapy may differ according to dose, duration of treatment,

and potentially the specific compound used [15, 16], in addition to demographic and clinical

characteristics such as prior exacerbation history, age, body mass index, and degree of airflow

limitation [17, 18]. Further investigation of patient responses to ICS-containing therapies, taking into

account modifying factors such as symptom burden, exacerbation history, pneumonia risk, and

5

eosinophil levels, will allow clinicians to identify those patients who are most likely to benefit from

triple fixed-dose combination maintenance treatments for COPD [19].

BGF MDI is a triple fixed-dose combination therapy of budesonide (ICS), glycopyrrolate

(LAMA), and formoterol fumarate (LABA), delivered via metered dose inhaler (MDI) using co-

suspension delivery technology. The first pivotal Phase III study, KRONOS, assessed the efficacy and

safety of BGF MDI 320/18/9.6 μg (equivalent to budesonide/glycopyrronium/formoterol fumarate

dihydrate 320/14.4/10 µg) in patients with COPD over 24 weeks compared to its corresponding

LAMA/LABA (glycopyrrolate/formoterol fumarate [GFF] MDI) and ICS/LABA

(budesonide/formoterol fumarate [BFF] MDI) therapies, as well as open-label budesonide/formoterol

dry powder inhaler (Symbicort® Turbuhaler®) [6]. Patients in KRONOS were required to be

symptomatic (COPD assessment test [CAT] score ≥ 10), but a history of exacerbations in the prior

year was not an entry requirement. BGF MDI showed benefits on lung function, symptoms, and

exacerbations versus both dual therapies, and had a safety profile comparable to LAMA/LABA and

ICS/LABA therapies, with a similar incidence of pneumonia observed across groups [6].

The potential to use a lower dose of budesonide in COPD maintenance therapy, while still

maintaining the benefits of ICS treatment, has been previously examined in a Phase III, 24-week dual-

therapy study, TELOS, which demonstrated that two doses of BFF MDI (320/9.6 μg and 160/9.6 μg)

both reduced the rate of moderate or severe COPD exacerbations (by 37% and 28%, respectively)

versus formoterol fumarate MDI 9.6 μg, with no evidence of a dose response for safety [20].

Given the findings of KRONOS and TELOS, it is important to assess the relative efficacy of

different doses of ICS in triple therapy with BGF MDI, when administered over a longer study period

in a population of patients at high risk of exacerbations. In ETHOS, we will evaluate the efficacy and

safety of two doses of BGF MDI (320/18/9.6 μg and 160/18/9.6 μg), relative to BFF MDI and

GFF MDI, over 52 weeks in symptomatic patients with moderate-to-very severe COPD and a

documented history of exacerbation(s) in the prior year. Among studies of ICS/LAMA/LABA triple

therapies, ETHOS will be the first to assess two different doses of ICS, and the first 52-week study to

stratify randomization by eosinophil levels. These unique features of the study design will help

6

provide evidence needed to optimize the benefit:risk ratio of triple therapy relative to dual

combination therapies in the management of COPD.

2. Material and methods

2.1. Study design and population

ETHOS (NCT02465567) is a randomized, double-blind, multicenter, parallel-group, 52-week

study conducted in patients with moderate-to-very severe COPD [21]. The study aims to assess the

effect of two doses of BGF MDI relative to BFF MDI and GFF MDI on the rate of moderate or severe

COPD exacerbations (primary objective), as well as symptoms, quality of life, and all-cause mortality

(secondary objectives). In addition, subsets of patients at designated study sites have participated in

sub-studies assessing lung function (4-h pulmonary function testing) and cardiovascular safety (24-h

Holter monitoring). Key inclusion and exclusion criteria are shown in Table 1 (full details are

provided in the supplementary material). Notably, enrollment in ETHOS required ≥ 1 moderate or

severe COPD exacerbation in the previous 12 months (if post-bronchodilator forced expiratory

volume in 1 s [FEV1] was < 50% predicted normal [i.e. severe or very severe airflow obstruction]); or,

for patients with FEV1 ≥ 50% predicted normal (i.e. moderate airflow obstruction), ≥ 2 moderate or

≥ 1 severe exacerbation(s) were required. Exacerbations were classified as moderate if they required

treatment with systemic corticosteroids and/or antibiotics for at least 3 days (or a single depot

injectable dose of corticosteroids), and as severe if they resulted in hospitalization. All moderate or

severe exacerbations were documented by the investigator using an electronic case report form.

Patients have been randomized 1:1:1:1 using an interactive web response system to receive

twice-daily BGF MDI 320/18/9.6 μg, BGF MDI 160/18/9.6 μg, BFF MDI 320/9.6 μg, or GFF MDI

18/9.6 μg. Randomization was stratified by exacerbation history (1 or ≥ 2 moderate or severe

exacerbations), post-bronchodilator FEV1 (25% to < 50% or 50% to < 65% predicted), blood

eosinophil count (< 150 or ≥ 150 cells/mm3), and country.

7

Inclusion criteria

Male/female, 40–80 years of age

Established clinical history of COPD with post-bronchodilator FEV1/FVC ratio < 0.70 and

FEV1 < 65% predicted normal

Current or former smokers with a smoking history of ≥ 10 pack-years

CAT score ≥ 10

On ≥ 2 inhaled maintenance therapies for COPD for ≥ 6 weeks prior to screening (could

include scheduled SABA and/or SAMA)

History of moderate or severe COPD exacerbations in the 12 months prior to screening

o If post-bronchodilator FEV1 < 50% of predicted normal: ≥ 1 moderate or severe

o If post-bronchodilator FEV1 ≥ 50% of predicted normal: ≥ 2 moderate or

≥ 1 severe

Exclusion criteria

Significant diseases or conditions other than COPD, including cardiac, respiratory,

neurological, renal, and endocrine disorders

Current diagnosis of asthma

COPD resulting from alpha-1 antitrypsin deficiency

Acute worsening of COPD in the 6 weeks prior to screening resulting in treatment with

oral corticosteroids or antibiotics

Failure to meet criteria for spirometry acceptability and repeatability

4-h PFT sub-study

Failure to meet criteria for spirometry baseline stability

24-h Holter monitoring sub-study

Current pacemaker/defibrillator device, or clinically significant abnormal baseline Holter

monitor findings

Table 1

Key inclusion/exclusion criteria.

CAT: COPD assessment test, COPD: chronic obstructive pulmonary disease, FEV1: forced expiratory

volume in 1 s, FVC: forced vital capacity, PFT: pulmonary function test, SABA: short-acting β2-

agonist, SAMA: short-acting muscarinic antagonist.

Full inclusion and exclusion criteria are provided in the supplementary material.

8

Fig. 1. ETHOS study design.

BFF: budesonide/formoterol fumarate, BGF: budesonide/glycopyrrolate/formoterol fumarate,

BID: twice daily, COPD: chronic obstructive pulmonary disease, GFF: glycopyrrolate/formoterol

fumarate, MDI: metered dose inhaler, SABA: short-acting β2-agonist, SAMA: short-acting muscarinic

antagonist.aThe screening period of 1–4 weeks could be extended to a maximum of 10 weeks if a patient

experienced a COPD exacerbation, in order to allow for treatment and recovery. bReversibility to a SABA (for classification) and a SAMA (for characterization) will be tested at

Visit 2 and 3, respectively.

Key study procedures including screening assessments and endpoint evaluations are shown in

Table 2. All patients completed a screening period of 1 to 4 weeks between Visit 1 and Visit 4

(randomization; Fig. 1). The screening period could be extended to a maximum of 10 weeks if a

patient experienced a COPD exacerbation, in order to allow for treatment, recovery, and a washout

period for any oral corticosteroid treatment. At Visit 1, the patients’ existing COPD maintenance

medications were adjusted as follows for the remainder of the screening period: all LAMA, LABA,

and LAMA/LABA therapies were discontinued; patients receiving an ICS/LABA discontinued the

ICS/LABA, but continued to receive the ICS component as monotherapy; all patients received open-

label ipratropium bromide four times daily, as well as albuterol sulfate for rescue use throughout the

screening period. Ipratropium bromide and ICS monotherapy were stopped at randomization while

albuterol sulfate was permitted for rescue use throughout the study.

9

Procedures

52-week treatment periodFollow-

up callScreeningV4

(Rand)V5 V6 V7 V8 V9 V10 V11 V12 V13 V14

V1 V2 V3

Week -4 to 0 (variable) 0 4 8 12 16 20 24 28 36 44 52 54

In-clinic X X X X X X X X X

Telephone contact X X X X X X

Informed consent, demographics,

medical/surgical history,

eDiary training, chest imaging

X

Spirometry X X X

Eligibility criteria, inhalation

device and dose indicator trainingX X X X

Smoking status, vital signs X X X X X X X X X

Prior/concomitant medications,

AEs, COPD exacerbationsX X X X X X X X X X X X X X X

CAT X X

12-lead ECG, clinical laboratory

testingaX X X X X

Study-drug dispensing, pregnancy X X X X X X X

10

test

Physical examination,

eDiary dispensing/collection,

adjust COPD medications

X X

Reversibility testing X X

eDiary reviewb X X X X X X X X

24-h Holter monitoring X X

Study-drug administration and

collection, BDI/TDI, SGRQ,

spirometry (PFT sub-study)c

X X X X X X

Verify continued eligibility X X X X X

HCRU X X X X X X X X X X X

Vital status check X

Table 2

Study procedures.

AE: adverse event, BDI/TDI: Baseline Dyspnea Index/Transition Dyspnea Index, CAT: COPD assessment test, COPD: chronic obstructive pulmonary

disease, ECG: electrocardiogram, eDiary: electronic diary, EXACT: Exacerbations of Chronic Pulmonary Disease Tool, HCRU: healthcare resource

utilization, PFT: pulmonary function test, Rand: randomization, SGRQ: St. George’s Respiratory Questionnaire, V: visit.aincluding blood eosinophilsbPatients will be asked to maintain a daily record of their study-drug dosing and rescue-medication use. EXACT will be reviewed at each visit as part of the

subject diary review.

11

cSpirometry assessments for patients participating in the 4-h PFT sub-study will be conducted at 60 min and 30 min prior to study-drug administration and at

5 min (Visit 4 only), 15, and 30 min; and 1, 2, and 4 h after study-drug administration.

12

Primary and secondary study endpoints as well as the primary sub-study endpoints are shown

in Table 3. Safety is being assessed via adverse-event monitoring, 12-lead electrocardiograms, clinical

laboratory testing, and vital-sign measurements. In addition to efficacy and safety endpoints,

healthcare resource utilization is also being evaluated.

The study is being conducted in accordance with Good Clinical Practice, including the

Declaration of Helsinki and applicable regulatory requirements. The protocol and informed consent

form have been approved by the appropriate institutional review boards or independent ethics

committees. All patients provided written informed consent prior to screening.

Primary endpoint

Rate of moderate or severe COPD exacerbations (efficacy estimand)

Secondary endpoints

Rate of moderate or severe COPD exacerbations (attributable estimand)

Time to first moderate or severe COPD exacerbation

Change from baseline in average daily rescue albuterol sulfate use over 24 weeks

TDI focal score over 24 weeks (ex-US only)

Change from baseline in EXACT total score over 52 weeks (ex-US only)

Change from baseline in SGRQ total score over 24 weeks (ex-US only)

Percentage of patients achieving a MCID of ≥ 4 units in SGRQ total score at Week 24 (US only)

Time to death (all cause)

Rate of severe COPD exacerbations

Primary sub-study endpoints

4-h PFT

Change from baseline in morning pre-dose trough FEV1 at Week 24 (US) and over 24 weeks

(ex-US) for the comparison of BGF MDI 320/18/9.6 μg versus GFF MDI 18/9.6 μg

FEV1 AUC0–4 at Week 24 (US) and over 24 weeks (ex-US) for the comparison of BGF MDI

320/18/9.6 μg versus BFF MDI 320/9.6 μg

24-h Holter monitoring

Change from baseline in mean heart rate averaged over 24 h

Table 3

Key study endpoints.

13

AUC0–4: area under the curve from 0 to 4 h, BFF: budesonide/formoterol fumarate,

BGF: budesonide/glycopyrrolate/formoterol fumarate, COPD: chronic obstructive pulmonary disease,

EXACT: Exacerbations of Chronic Pulmonary Disease Tool, FEV1: forced expiratory volume in 1 s,

GFF: glycopyrrolate/formoterol fumarate, MCID: minimum clinically important difference,

MDI: metered dose inhaler, PFT: pulmonary function test, SGRQ: St. George’s Respiratory

Questionnaire, TDI: Transition Dyspnea Index.

Endpoints that differ between approaches (US vs ex-US) are indicated in parentheses.

All endpoints to include the following comparisons unless otherwise indicated: BGF MDI 320/18/9.6

μg versus GFF MDI 18/9.6 μg, BGF MDI 320/18/9.6 μg versus BFF MDI 320/9.6 μg, BGF MDI

160/18/9.6 μg versus GFF MDI 18/9.6 μg, and BGF MDI 160/18/9.6 μg versus BFF MDI 320/9.6 μg

(all for superiority with the exception of BGF MDI 160/18/9.6 μg MDI to BFF MDI 320/9.6 μg,

which will be for non-inferiority first, followed by superiority).

2.2. Statistical analysis

A sample size of approximately 8400 patients was selected to provide 93% power to detect a

15% reduction in the rate of moderate or severe COPD exacerbations for BGF MDI 320/18/9.6 μg

compared to both GFF MDI and BFF MDI (96% power for each comparison), with Type I error

controlled at a one-sided alpha level of 0.025. This sample size reflects assumptions for parameter

estimates that were updated following a pre-specified blinded sample size re-estimation, which

resulted in an increase of 400 patients (100 per treatment arm) from the original 8000 based on an

interim assessment of the underlying rate of moderate or severe COPD exacerbations and prediction

of the negative binomial shape parameter. The updated estimates assume an average treatment

exposure of 0.83 years and yearly moderate or severe exacerbation rates of 1.142, 1.210, 1.344, and

1.344 for BGF MDI 320/18/9.6 μg, BGF MDI 160/18/9.6 μg, and GFF MDI, and BFF MDI,

respectively.

14

The primary estimand of interest is the efficacy estimand, i.e. the effect of the randomized

treatments in all patients assuming continuation of randomized treatments for the duration of the

study, regardless of actual compliance. This estimand will be assessed via analyses of the primary and

secondary endpoints (for superiority) in the modified intent-to-treat (mITT) population, containing all

post-randomization data obtained prior to discontinuation from treatment. A secondary analysis of the

primary endpoint will be performed (also using the mITT population) to estimate the attributable

estimand, i.e. the effect of treatment in patients that is attributable to the randomized treatment, by

unfavorably imputing missing data that are attributable to lack of efficacy or tolerability. An

additional estimand of interest is the treatment policy estimand, which is the effect of randomized

treatment over the study period regardless of whether randomized treatment is continued, and is

estimated by also including the data collected post-treatment discontinuation. Finally, the per-protocol

(PP) estimand will assess the effect of treatment on patients who are compliant with the protocol

(i.e. no major protocol deviations), including the use of randomized medication. The PP estimand will

use the PP population, which consists of all patients with post-randomization data obtained prior to

any major protocol deviations, and will be the primary estimand of interest for the non-inferiority

analyses of BGF 160/18/9.6 μg (lower ICS dose) versus BFF MDI 320/9.6 μg (higher ICS dose). The

safety population will include the same patients as the mITT population, analyzed according to

treatment received rather than randomized.

15

The rate of moderate or severe COPD exacerbations (primary endpoint) will be analyzed

using negative binomial regression, with exacerbations considered separate events when there are

> 7 days between the end date of the earlier event and the start date of the later event. The start date of

a moderate or severe exacerbation is defined as the first day of prescribed treatment with a systemic

corticosteroid or antibiotic, hospitalization, or date of death; the end date is defined as the end of

treatment or the end of hospitalization, whichever is later. Time at risk of experiencing an

exacerbation will be used as an offset variable in the model, and time during an exacerbation, or in the

7 days following an exacerbation, will not be included in its calculation. Treatments will be compared

adjusting for baseline post-bronchodilator % predicted FEV1, baseline exacerbation history, baseline

blood eosinophil count (logarithmically transformed and obtained from the mean of non-missing

values measured at screening [Visit 1] and at randomization [Visit 4]), region, and ICS use at

screening.

Treatment comparisons will be made in the following order, and for superiority: BGF MDI

320/18/9.6 μg versus GFF MDI, BGF MDI 320/18/9.6 μg versus BFF MDI, BGF MDI 160/18/9.6 μg

versus GFF MDI, and BGF MDI 160/18/9.6 μg versus BFF MDI (this comparison will be made for

non-inferiority first followed by superiority). For the primary endpoint, non-inferiority will be

declared based on a margin of 0.1, i.e. if the 95% confidence interval for the rate ratio is under 1.1.

These four treatment comparisons will be made for the efficacy estimand first, followed by the

attributable estimand before testing can proceed to the secondary efficacy variables for each

comparison of interest. Analyses by pre-specified subgroups, including exacerbation history and

eosinophil levels, will also be performed. In addition, nonparametric regression will be used to

evaluate the benefit of budesonide treatment relative to blood eosinophil levels (as a continuous

variable).

A pre-specified interim efficacy analysis was conducted following the blinded sample size re-

estimation, at which an independent Data Monitoring Committee reviewed unblinded efficacy data.

As the pre-specified stopping criteria for unequivocal efficacy and clarity regarding budesonide dose

were not met, the study will continue until all patients complete their final study visit.

16

3. Patient population

Enrollment and randomization were completed between June 30, 2015 and July 13, 2018,

with study completion expected in July 2019. In total, 16,044 patients were screened for participation

in ETHOS; of these, 8572 were randomized.

Preliminary baseline demographics for the safety population (n = 8539) are shown in Table 4

(treatment-group data remain blinded). At baseline, the majority of patients participating in ETHOS

had experienced ≥ 2 moderate or severe exacerbations in the previous 12 months (55.9%), and 21.2%

had experienced ≥ 1 severe exacerbation. Overall, 79.1% were receiving an ICS-containing treatment

at study entry. The mean (standard deviation) blood eosinophil count was 196.3 (132.9) cells/mm3,

with 59.9% of patients having a count ≥ 150 cells/mm3 and 14.7% having ≥ 300 cells/mm3. The

baseline distribution of patients’ eosinophil levels is shown in Fig. 2.

All patients(N = 8539)

Mean age, years (SD) 64.7 (7.6)

Male, n (%) 5097 (59.7)

Race, n (%)WhiteAsianBlackAmerican Indian/Alaska NativeOther

7250 (84.9)651 (7.6)309 (3.6)140 (1.6)189 (2.2)

Mean body mass index, kg/m2 (SD) 27.5 (6.3)

Current smoker, n (%) 3508 (41.1)

Mean number of pack-years smokeda (SD) 47.7 (26.0)

Spirometric COPD severity, n (%)b

ModerateSevereVery severe

2437 (28.5)5169 (60.5)925 (10.8)

Mean COPD duration, years (SD) 8.3 (6.2)

17

COPD exacerbations in the past 12 months, n (%)c

0 moderate or severe1 moderate or severe≥ 2 moderate or severe≥ 1 severe

7 (0.1)3762 (44.1)4770 (55.9)1811 (21.2)

Blood eosinophil countd

nMean, cells/mm3 (SD)≥ 150 cells/mm3, n (%)≥ 300 cells/mm3, n (%)

8514196.3 (132.9)5109 (59.9)1252 (14.7)

Post-albuterol FEV1, % predicted nMean (SD)

851943.39 (10.34)

Reversibility to albuterold,e

nMean difference in FEV1 before and after albuterol, mL (SD)Reversible, n (%)

8500145.0 (151.4)2610 (30.6)

Use of ICS at screening, n (%) 6754 (79.1)

Mean CAT total score (SD) 19.6 (6.5)Table 4

Baseline demographics (safety population).

CAT: COPD Assessment Test, COPD: chronic obstructive pulmonary disease, FEV1: forced

expiratory volume in 1 s, ICS: inhaled corticosteroid, mITT: modified intent-to treat, SD: standard

deviation.aNumber of pack-years smoked = (number of cigarettes each day/20) x number of years smoked. bDefined by baseline post-bronchodilator FEV1 (moderate: 50% to 80% predicted normal; severe:

30% to <50% predicted normal; very severe: <30% predicted normal);13 note that the study only

enrolled patients with baseline post-bronchodilator FEV1 <65% predicted normal.cExacerbations were classified as moderate if they required treatment with systemic corticosteroids

and/or antibiotics for at least 3 days (or a single depot injectable dose of corticosteroids), and as

severe if they resulted in hospitalization. dmITT population. eReversible is defined as improvement in FEV1 post-albuterol administration compared with

pre-albuterol of ≥ 12% and ≥ 200 mL.

18

Fig. 2. Distribution of baseline eosinophil counts (mITT population).

mITT: modified intent-to-treat.

19

4. Discussion

20

The ETHOS study will provide important data comparing the effects of two doses of BGF

MDI (320/18/9.6 μg and 160/18/9.6 μg) with BFF MDI 320/9.6 μg and GFF MDI 18/9.6 μg on

moderate or severe COPD exacerbation rates over 52 weeks. A benefit of BGF MDI 320/18/9.6 μg

versus corresponding dual therapies on the rate of moderate or severe exacerbations has been shown

over 24 weeks in KRONOS, with a statistically significant and clinically meaningful improvement

versus GFF MDI and a numerical improvement versus BFF MDI [6]. A majority of the KRONOS

study population had not experienced an exacerbation in the year prior to study entry [6]. ETHOS will

determine whether similar benefits of BGF MDI are observed over a longer treatment period in a

larger population of patients at high risk of exacerbations, with adequate statistical power to detect

differences between BGF MDI and BFF MDI on the rate of moderate or severe COPD exacerbations.

21

ETHOS is the first study to include triple ICS/LAMA/LABA therapies with two different

doses of the ICS component, allowing an examination of the dose response of BGF MDI relative to

dual therapies. Studies of low/medium-dose ICS/LABA formulations have previously found

significant reductions in exacerbation rates versus LABA therapy alone [20, 22, 23]. ETHOS will

explore whether triple therapy with a lower dose of ICS could be an alternative treatment option for

patients with COPD by evaluating if BGF MDI 160/18/9.6 μg demonstrates comparable or better

efficacy versus a higher dose ICS/LABA (BFF MDI 320/9.6 μg) in reducing exacerbation rates while

also providing greater improvements in lung function. The availability of two BGF MDI formulations

would allow ICS treatment to be titrated to the lowest effective dose for individual patients based on

outcomes such as exacerbations. In addition, the two ICS doses will allow for an assessment of

possible interactions between ICS dose, eosinophil levels, and other modifying factors on treatment

response. Building on previous findings that eosinophils may be a useful biomarker of response to

ICS therapy [6, 11, 12, 24], randomization in ETHOS has been stratified by eosinophil count (from

values obtained prior to randomization); using pre-specified subgroups and visualizing relationships

with eosinophil count as a continuous variable in nonparametric regressions will help clarify the use

of this biomarker in COPD. This is especially important given recent updates to treatment

recommendations in the 2019 GOLD report, which now considers eosinophil counts in the initial and

follow-up treatment algorithms [13]. Eosinophil levels were assessed at several time points during the

study, and these measurements will allow for exploratory analyses of the consistency of eosinophil

levels over time across the treatment arms [25]. Overall, the unique features of ETHOS will provide

important data to inform the overall benefit:risk ratio of ICS treatment in COPD, enabling clinicians

to better identify patients who may be adequately managed without an ICS, or with a lower dose of

ICS, based on key background features including prior exacerbations and eosinophil levels.

As in previous studies that investigated the effect of fixed triple versus dual therapies on

exacerbation rates (IMPACT [4] and TRIBUTE [5]), all patients enrolled in ETHOS had a history of

exacerbation in the past year, and the majority had previous treatment with an ICS. However,

inclusion and exclusion criteria regarding the severity of airflow limitation, exacerbation history, and

22

prior medications, as well as the run-in treatments used, differ across studies (as summarized in

Table 5) [4, 5]. It should be noted that in TRIBUTE, any prior ICS use ceased at study entry, while in

IMPACT and ETHOS, patients on stable doses of ICS continued their treatment until the day prior to

randomization. Overall, these study-design differences will need to be considered when comparing

the results and subsequent analyses of these studies.

ETHOS will also provide additional data regarding the long-term safety of BGF MDI. Two

52-week extensions of the KRONOS study have been completed in the USA [26] and Japan [27] to

assess the safety and tolerability of BGF MDI compared to dual therapies. In US patients, BGF MDI

was found to be well tolerated over 52 weeks of treatment, with no evidence that the pattern or

frequency of adverse events changed appreciably with longer-term exposure [28]. In addition, BGF

MDI treatment did not have any clinically significant effects on bone mineral density or ocular safety

outcomes [28], which have been previously associated with long-term ICS use [29]. Results from the

Japanese safety extension study will also be published in 2019. ETHOS will provide safety data over

52 weeks in a substantially larger global population than the two completed extension studies, and

will characterize the safety profile of two doses of BGF MDI relative to both dual therapies in patients

with moderate-to-very severe COPD who had experienced at least one exacerbation in the previous

12 months (and > 50% of whom had reported ≥ 2 exacerbations during this time).

TRIBUTE [5]N = 1532

IMPACT [4]N = 10,355

ETHOS N = 8572

Treatmentsa

ICS/LAMA/LABA BDP/G/F MDI174/22/9.6 μg BID

FF/UMEC/VI DPI100/62.5/25 μg QD

BGF MDI 320/18/9.6 μg BID160/18/9.6 μg BID

LAMA/LABA IND/GLY DPI85/54 μg QD

UMEC/VI DPI62.5/25 μg QD

GFF MDI 18/9.6 μg BID

ICS/LABA – FF/VI DPI100/25 μg QD

BFF MDI 320/9.6 μg BID

Inclusion/exclusion criteria

23

Post-bronchodilatorFEV1 % predicted

< 50% < 80% < 65%

Moderate or severe exacerbations (last year)

≥ 1 ≥ 1 (if FEV1 < 50%);

≥ 2 (if FEV1 ≥ 50%)

≥ 1 (if FEV1 < 50%);

≥ 2 moderate / ≥ 1

severe (if FEV1 ≥ 50%)

Excluded patients on prior triple therapy

Yes No No

Run-in

Duration 2 weeks 2 weeks 1–4 weeksb

Maintenance treatment(s)

IND/GLY DPI85/54 μg

Patients’ own medications (LAMA, LABA, or ICS, alone or in combination)

Ipratropium bromide QID and patients’ own ICS (if on an ICS at screening)

Table 5

Studies assessing the rate of moderate or severe COPD exacerbations over 52 weeks with triple versus

dual fixed-dose combination therapies.

BDP/G/F: beclometasone dipropionate/glycopyrrolate/formoterol fumarate,

BFF: budesonide/formoterol fumarate, BGF: budesonide/glycopyrrolate/formoterol fumarate,

BID: twice daily, CAT: COPD Assessment Test, COPD: chronic obstructive pulmonary disease,

DPI: dry powder inhaler, FEV1: forced expiratory volume in 1 s, FF/UMEC/VI: fluticasone

furoate/umeclidinium/vilanterol, FF/VI: fluticasone furoate/vilanterol, FVC: forced vital capacity,

GFF: glycopyrrolate/formoterol fumarate, ICS: inhaled corticosteroid,

IND/GLY: indacaterol/glycopyrrolate, LABA: long-acting β2-agonist, LAMA: long-acting muscarinic

antagonist, MDI: metered dose inhaler, QD: once daily, QID: four times daily,

UMEC/VI: umeclidinium/vilanterol.

Note: all studies enrolled patients with a confirmed diagnosis of COPD who were symptomatic (CAT

score ≥ 10) and current/former smokers, with an FEV1/FVC ratio < 0.70. The use of rescue

medication (albuterol and/or terbutaline) was permitted throughout all three studies. aDoses represent the total amount per administered dose, which is the sum of two actuations for

BDP/G/F MDI, BGF MDI, GFF MDI, and BFF MDI. Doses are expressed as μg of glycopyrrolate

(glycopyrronium bromide) and formoterol fumarate. bCould be extended to a maximum of 10 weeks if a patient experienced a COPD exacerbation, in

order to allow for treatment and recovery.

5. Conclusions

The ETHOS study will investigate exacerbations, patient-reported outcomes, safety, and

24

mortality in a population of > 8500 symptomatic patients with moderate-to-very severe COPD

receiving triple and dual fixed-dose combination therapies. Sub-studies will also examine lung

function (in > 3000 patients) and cardiovascular safety (in > 700 patients). For the first time in a 52-

week study of triple therapy, randomization has been stratified by eosinophil count, and two different

ICS doses (320 μg and 160 μg) of ICS/LAMA/LABA triple therapy will be compared to

LAMA/LABA and ICS/LABA therapies. This may provide support for the use of triple therapies with

multiple ICS doses, increasing the versatility of prescribed treatments for COPD and allowing for

optimization of the benefit:risk profile for individual patients. Overall, the findings are expected to

add to the growing body of literature establishing an important role for single inhaler triple therapies,

thus helping to refine treatment recommendations with the ultimate goal of minimizing disease burden

and improving outcomes for patients with COPD.

25

Funding

The ETHOS study is supported by Pearl – a member of the AstraZeneca Group. The sponsor

was involved in the study design; the collection, analysis and interpretation of data; the writing of the

report; and in the decision to submit the article for publication.

Declarations of interest

KFR 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. FJM 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 Ingelheim, Chiesi, Concert, Continuing Education, Genentech,

GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, the National Association for

Continuing Education, Novartis, Pearl – a member of the AstraZeneca Group, 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. GTF reports grants, personal fees, and non-financial

support from AstraZeneca during the conduct of the study; grants, personal fees, and non-financial

support from AstraZeneca, Boehringer Ingelheim, Novartis, Pearl – a member of the AstraZeneca

Group, and Sunovion; grants and personal fees from Theravance; and personal fees from Circassia,

GlaxoSmithKline, Innoviva, Mylan, and Verona, outside the submitted work. CW declares no

competing interests. DS reports receiving personal fees from Apellis, Cipla, Genentech, Peptinnovate,

and Skyepharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi,

GlaxoSmithKline, Glenmark, Menarini, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva,

Therevance, and Verona, outside the submitted work. JAW reports receiving research grants from

26

AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Johnson & Johnson, and Novartis, outside the

submitted work. RT, ESR, SB, JM, PDa, CR, and PDo are employees of AstraZeneca.

Acknowledgements

We thank all the patients, their families and the team of investigators, research nurses, and

operations staff involved in ETHOS. Medical writing support, under the direction of the authors, was

provided by Julia King, PhD, of CMC Connect, a division of McCann Health Medical

Communications Ltd, Glasgow, UK, which was funded by AstraZeneca, Cambridge, UK in

accordance with Good Publication Practice (GPP3) guidelines [30].

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

27

REFERENCES

[1] D. Singh, A. Papi, M. Corradi, I. Pavlišová, I. Montagna, C. Francisco, G. Cohuet, S. Vezzoli, M.

Scuri, J. Vestbo, 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 (London, England) 388 (10048) (2016) 963-973.

[2] D.A. Lipson, H. Barnacle, R. Birk, N. Brealey, N. Locantore, D.A. Lomas, A. Ludwig-Sengpiel,

R. Mohindra, M. Tabberer, C.Q. Zhu, S.J. Pascoe, FULFIL trial: once-daily triple therapy for patients

with chronic obstructive pulmonary disease, Am J Respir Crit Care Med 196 (4) (2017) 438-446.

[3] J. Vestbo, A. Papi, M. Corradi, V. Blazhko, I. Montagna, C. Francisco, G. Cohuet, S. Vezzoli, M.

Scuri, D. Singh, 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 (London, England) 389 (10082) (2017) 1919-1929.

[4] D.A. Lipson, F. Barnhart, N. Brealey, J. Brooks, G.J. Criner, N.C. Day, M.T. Dransfield, D.M.G.

Halpin, M.K. Han, C.E. Jones, S. Kilbride, P. Lange, D.A. Lomas, F.J. Martinez, D. Singh, M.

Tabberer, R.A. Wise, S.J. Pascoe, Once-daily single-inhaler triple versus dual therapy in patients with

COPD, N Engl J Med 378 (18) (2018) 1671-1680.

[5] A. Papi, J. Vestbo, L. Fabbri, M. Corradi, H. Prunier, G. Cohuet, A. Guasconi, I. Montagna, S.

Vezzoli, S. Petruzzelli, M. Scuri, N. Roche, D. Singh, Extrafine inhaled triple therapy versus dual

bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel

group, randomised controlled trial, Lancet (London, England) 391 (10125) (2018) 1076-1084.

[6] G.T. Ferguson, K.F. Rabe, F.J. Martinez, L.M. Fabbri, C. Wang, M. Ichinose, E. Bourne, S.

Ballal, P. Darken, K. DeAngelis, M. Aurivillius, P. Dorinsky, C. Reisner, 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, The Lancet Respiratory medicine 6 (10) (2018) 747-

758.

[7] J.A. Wedzicha, D. Banerji, K.R. Chapman, J. Vestbo, N. Roche, R.T. Ayers, C. Thach, R. Fogel,

F. Patalano, C.F. Vogelmeier, Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD, N

Engl J Med 374 (23) (2016) 2222-2234.

28

[8] K.R. Chapman, J.R. Hurst, S.M. Frent, M. Larbig, R. Fogel, T. Guerin, D. Banerji, F. Patalano, P.

Goyal, P. Pfister, K. Kostikas, J.A. Wedzicha, Long-Term Triple Therapy De-escalation to

Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A

Randomized, Double-Blind, Triple-Dummy Clinical Trial, Am J Respir Crit Care Med 198 (3) (2018)

329-339.

[9] H. Magnussen, B. Disse, R. Rodriguez-Roisin, A. Kirsten, H. Watz, K. Tetzlaff, L. Towse, H.

Finnigan, R. Dahl, M. Decramer, P. Chanez, E.F. Wouters, P.M. Calverley, Withdrawal of inhaled

glucocorticoids and exacerbations of COPD, N Engl J Med 371 (14) (2014) 1285-1294.

[10] H. Watz, K. Tetzlaff, E.F.M. Wouters, A. Kirsten, H. Magnussen, R. Rodriguez-Roisin, C.

Vogelmeier, L.M. Fabbri, P. Chanez, R. Dahl, B. Disse, H. Finnigan, P.M.A. Calverley, Blood

eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal

of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial, The Lancet Respiratory medicine

4 (5) (2016) 390-398.

[11] M. Bafadhel, S. Peterson, M.A. De Blas, P.M. Calverley, S.I. Rennard, K. Richter, M. Fageras,

Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive

pulmonary disease: a post-hoc analysis of three randomised trials, The Lancet Respiratory medicine 6

(2) (2018) 117-126.

[12] S. Pascoe, N. Locantore, M.T. Dransfield, N.C. Barnes, I.D. Pavord, Blood eosinophil counts,

exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with

chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised

controlled trials, The Lancet Respiratory medicine 3 (6) (2015) 435-442.

[13] D. Singh, A. Agusti, A. Anzueto, P.J. Barnes, J. Bourbeau, B.R. Celli, G.J. Criner, P. Frith,

D.M.G. Halpin, M. Han, M.V. Lopez Varela, F. Martinez, M. Montes de Oca, A. Papi, I.D. Pavord,

N. Roche, D.D. Sin, R. Stockley, J. Vestbo, J.A. Wedzicha, C. Vogelmeier, Global Strategy for the

Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD Science

Committee Report 2019, Eur Respir J pii: 1900164. doi: 10.1183/13993003.00164-2019. [Epub ahead

of print] (2019).

[14] European Medicines Agency, Inhaled corticosteroids (ICS) containing medicinal products

indicated in the treatment of chronic obstructive pulmonary disease (COPD), 2016.

https://www.ema.europa.eu/en/documents/referral/inhaled-corticosteroids-article-31-referral-prac-

assessment-report_en.pdf. (Accessed 9 April 2019).

29

[15] S. Suissa, V. Patenaude, F. Lapi, P. Ernst, Inhaled corticosteroids in COPD and the risk of

serious pneumonia, Thorax 68 (11) (2013) 1029-1036.

[16] K.M. Kew, A. Seniukovich, Inhaled steroids and risk of pneumonia for chronic obstructive

pulmonary disease, Cochrane Database Syst Rev (3) (2014) CD010115.

[17] C. Crim, M.T. Dransfield, J. Bourbeau, P.W. Jones, N.A. Hanania, D.A. Mahler, J. Vestbo, A.

Wachtel, F.J. Martinez, F. Barnhart, S. Lettis, P.M. Calverley, Pneumonia risk with inhaled

fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD, Ann Am

Thorac Soc 12 (1) (2015) 27-34.

[18] D.D. Sin, D. Tashkin, X. Zhang, F. Radner, U. Sjobring, A. Thoren, P.M. Calverley, S.I.

Rennard, Budesonide and the risk of pneumonia: a meta-analysis of individual patient data, Lancet

(London, England) 374 (9691) (2009) 712-9.

[19] B. Lipworth, C.R. Kuo, S. Jabbal, Current appraisal of single inhaler triple therapy in COPD, Int

J Chron Obstruct Pulmon Dis 13 (2018) 3003–3009.

[20] G.T. Ferguson, A. Papi, A. Anzueto, E.M. Kerwin, C. Cappelletti, E.A. Duncan, J. Nyberg, P.

Dorinsky, Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS

study, The European respiratory journal 52 (3) (2018) pii: 1801334.

[21] ClinicalTrials.gov, Study to Assess the Efficacy and Safety of PT010 Relative to PT003 and

PT009 in Subjects With Moderate to Very Severe COPD (Ethos), 2017.

https://clinicaltrials.gov/ct2/show/NCT02465567. (Accessed 9 April 2019).

[22] G.T. Ferguson, A. Anzueto, R. Fei, A. Emmett, K. Knobil, C. Kalberg, Effect of fluticasone

propionate/salmeterol (250/50 µg) or salmeterol (50 µg) on COPD exacerbations, Respir Med 102 (8)

(2008) 1099-1108.

[23] A. Anzueto, G.T. Ferguson , G. Feldman, K. Chinsky, A. Seibert, A. Emmett, K. Knobil, D.

O'Dell, C. Kalberg, G. Crater, Effect of fluticasone propionate/salmeterol (250/50) on COPD

exacerbations and impact on patient outcomes, Copd 6 (5) (2009) 320-329.

[24] G. Brusselle, I.D. Pavord, S. Landis, S. Pascoe, S. Lettis, N. Morjaria, N. Barnes, E. Hilton,

Blood eosinophil levels as a biomarker in COPD, Respir Med 138 (2018) 21-31.

[25] N.C. Barnes, R. Sharma, S. Lettis, P.M. Calverley, Blood eosinophils as a marker of response to

inhaled corticosteroids in COPD, The European respiratory journal 47 (5) (2016) 1374-82.

30

[26] ClinicalTrials.gov, Study to Assess the Safety and Tolerability of PT010, PT009 and PT003 in

Subjects With Moderate to Very Severe Chronic Obstructive Pulmonary Disease, 2018.

https://clinicaltrials.gov/ct2/show/NCT02536508. (Accessed 9 April 2019).

[27] ClinicalTrials.gov, Study to Assess the Safety and Efficacy of PT010, PT003, and PT009 in

Japanese Subjects With COPD Compared With Symbicort® Turbohaler®, 2017.

https://clinicaltrials.gov/ct2/show/NCT03262012. (Accessed 9 April 2019).

[28] E.M. Kerwin, G.T. Ferguson, M. Mo, K. DeAngelis, P. Dorinsky, Bone mineral density and

ocular safety after 52 weeks' treatment with budesonide/glycopyrrolate/formoterol fumarate metered

dose inhaler (BGF MDI) using co-suspension delivery technology in COPD, 2019.

https://www.abstractsonline.com/pp8/#!/5789/presentation/19649. (Accessed 9 April 2019).

[29] D. Price, B. Yawn, G. Brusselle, A. Rossi, Risk-to-benefit ratio of inhaled corticosteroids in

patients with COPD, Prim Care Respir J 22 (1) (2013) 92-100.

[30] W.P. Battisti, E. Wager, L. Baltzer, D. Bridges, A. Cairns, C.I. Carswell, L. Citrome, J.A. Gurr,

L.A. Mooney, B.J. Moore, T. Peña, C.H. Sanes-Miller, K. Veitch, K.L. Woolley, Y.E. Yarker, Good

publication practice for communicating company-sponsored medical research: GPP3, Ann Intern Med

163 (6) (2015) 461-464

31

Supplemental material

Methods

The ETHOS study is being conducted in the following countries: Argentina, Australia, Austria,

Belgium, Canada, Chile, China, Czech Republic, France, Germany, Hungary, Italy, Japan, Mexico,

the Netherlands, New Zealand, Peru, Poland, Russia, Serbia, South Africa, Spain, Sweden, Taiwan,

the United Kingdom and the United States of America.

Inclusion criteria

Each patient must meet the following criteria to be enrolled in this study:

1. Give their signed, written, informed consent to participate.

2. Are at least 40 years of age and no older than 80 years at Visit 1.

3. A female is eligible to enter and participate in the study if she is of:

a. Non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including

any female who is 2 years post-menopausal)

b. Childbearing potential, has a negative serum pregnancy test at Visit 1, and agrees to an

acceptable contraceptive method used consistently and correctly (i.e. in accordance with the

approved product label and the instructions of the physician for the duration of the study –

from Visit 1 [screening] until 14 days after the final visit).

4. Have an established clinical history of chronic obstructive pulmonary disease (COPD) as

defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) [1] or

by locally applicable guidelines, e.g. Japanese Respiratory Society (JRS) Guidelines [2],

characterized by progressive airflow limitation associated with an abnormal inflammatory

response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.

5. Tobacco use: Current or former smokers with a history of at least 10 pack-years of cigarette

smoking. [Number of pack-years = (number of cigarettes per day / 20) x number of years

32

smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years represent

10 pack-years)].

6. COPD severity: An established clinical history of COPD and severity defined as:

At Visit 1, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio must

be < 0.70 and FEV1 must be < 65% predicted normal value.

At Visit 2, post-bronchodilator FEV1/FVC ratio of < 0.70 and post-bronchodilator FEV1

must be ≥ 25% to < 65% predicted normal value.

At Visit 4, the average of the -60 min and -30 min pre-dose FEV1 assessments must be

< 65% predicted normal value. Note: This criterion applies to patients in the pulmonary

function test (PFT) sub-study only.

Note: All values calculated using the National Health and Nutrition Examination Survey III

reference equations (or reference norms applicable to other regions, e.g. for Japan, use JRS

reference equations [2])

Symptomatic (COPD assessment test score ≥ 10) at screening (Visit 1).

7. Required COPD maintenance therapy: All patients must have been on two or more inhaled

maintenance therapies for the management of their COPD for at least 6 weeks prior to

screening. Scheduled short-acting β2-agonists and/or short-acting muscarinic antagonists are

considered inhaled maintenance therapies.

8. History of exacerbations:

Patients with a post-bronchodilator FEV1 < 50% of predicted normal must have a

documented history of ≥ 1 moderate or severe COPD exacerbation in the 12 months

prior to screening (Visit 1).

Patients with a post-bronchodilator FEV1 ≥ 50% of predicted normal must have a

documented history of ≥ 2 moderate exacerbations or a documented history of ≥ 1 severe

COPD exacerbation in the 12 months prior to screening (Visit 1).

33

Note: Prior use of antibiotics and/or oral corticosteroids alone does not qualify as a COPD

exacerbation history unless the use was associated with treatment of worsening symptoms of

COPD (e.g. increased dyspnea, increased sputum volume, or a change in sputum purulence

[color]). Patient verbal reports are not acceptable.

Antibiotics or corticosteroids used for the treatment of upper respiratory infections with

no lower respiratory symptoms do not qualify for the treatment of COPD exacerbation.

9. Patient is willing and, in the opinion of the investigator, able to adjust current COPD therapy,

as required by the protocol.

10. Screening clinical laboratory tests must be acceptable to the investigator.

11. Screening electrocardiogram (ECG) must be acceptable to the investigator.

12. Chest X-ray or computed tomography (CT) scan of the chest/lungs within 6 months prior to

Visit 1 must be acceptable to the investigator. Patients who have a chest X-ray that reveals

clinically significant abnormalities not believed to be due to the presence of COPD should not

be included. A chest X-ray must be conducted if the most recent chest X-ray or CT scan are

more than 6 months old at the time of Visit 1, except in countries with restrictive radiology

assessment practice where only patients who have had an chest X-ray or CT scan (thorax)

performed outside of the study in the last 6 months are allowed to be enrolled. Alternatively,

in these countries, magnetic resonance imaging may be used instead of a CT scan or chest X-

ray as per local practice assessment.

13. Compliance: Patients must be willing to remain at the study center as required per protocol to

complete all visit assessments.

Exclusion criteria

Patients who meet any of the following criteria will be excluded from the study.

34

1. Significant diseases or conditions other than COPD, which, in the opinion of the investigator,

may put the patient at risk because of participation in the study or may influence either the

results of the study or the patient’s ability to participate in the study.

2. Women who are pregnant or lactating, or are planning to become pregnant during the course

of the study, or women of childbearing potential who are not using an acceptable method of

contraception.

3. Respiratory:

a. Asthma: Patients who, in the opinion of the investigator, have a current diagnosis of

asthma.

b. Alpha-1 antitrypsin deficiency: Patients who have alpha-1 antitrypsin deficiency as the

cause of COPD.

c. Other respiratory disorders: Patients who have other active pulmonary disease such as

active tuberculosis, lung cancer, significant bronchiectasis (high-resolution CT evidence

of bronchiectasis that causes repeated acute exacerbations), sarcoidosis, idiopathic

interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep

apnea (i.e. in the opinion of the investigator the severity of the disorder would impact the

conduct of the study). Note: Allergic rhinitis is not exclusionary.

d. Lung volume reduction: Patients who have undergone lung volume reduction surgery,

lobectomy, or bronchoscopic lung volume reduction (endobronchial blockers, airway

bypass, endobronchial valves, thermal vapor ablation, biological sealants, and airway

implants) within 6 months of Visit 1.

e. Hospitalization: Patients who have been hospitalized due to poorly controlled COPD

within 6 weeks prior to Visit 1 (screening) with less than a 4-week washout of

corticosteroids and/or antibiotics prior to Visit 1 (screening).

f. Poorly controlled COPD: Patients who have poorly controlled COPD, defined as acute

worsening of COPD that requires treatment with oral corticosteroids or antibiotics within

6 weeks prior to Visit 1 (screening) with less than a 4-week washout of corticosteroids

and/or antibiotics prior to Visit 1 (screening).

35

g. Lower respiratory tract infection: Patients who had lower respiratory tract infections that

required antibiotics within 6 weeks prior to Visit 1 (screening) with less than a 4-week

washout of antibiotics prior to Visit 1 (screening).

h. Other respiratory tract infections (e.g. upper respiratory tract infection) that have not

resolved at least 7 days prior to screening.

i. Chest X-ray (frontal and lateral) with suspicion of pneumonia or other

condition/abnormality that will require additional investigation/treatment, or put the

patient at risk because of participation in the study.

j. Risk factors for pneumonia: Immune suppression (e.g. human immunodeficiency virus),

severe neurological disorders affecting control of the upper airway or other risk factors

that, in the opinion of the investigator, would put the patient at substantial risk of

pneumonia.

k. Pneumonia not clinically resolved within 14 days of Visit 1.

l. Spirometry performance:

Acceptability: Patients who cannot perform acceptable spirometry (i.e. meet

ATS/ERS acceptability criteria).

Repeatability: Patients who cannot perform technically acceptable spirometry with

at least three acceptable flow-volume curves with two or more meeting ATS

repeatability criteria for FEV1 during at least one of the pre-bronchodilator

assessments at Visit 2 (-60 min or -30 min) and at the post-bronchodilator

assessment at Visit 2.

Note: Patients who have met all of the inclusion criteria, but have failed to meet

acceptability or repeatability criteria at Visit 1, may continue to Visit 2. Provided these

patients meet all spirometry criteria at Visit 2, including acceptability and repeatability,

they are eligible for inclusion in the main study but they are excluded from participating

in the PFT sub-study. Patients who fail to meet acceptability and repeatability criteria at

Visit 2 must be screen failed.

36

FEV1 baseline stability (for PFT sub-study only): Patients who cannot meet

protocol-specified baseline stability criteria. FEV1 baseline stability is defined as

the average of the -60 min and -30 min pre-dose FEV1 assessments at Visit 4 being

within ± 20% or 200 mL of the mean of the pre-bronchodilator FEV1 assessments

obtained at the two preceding visits (average of pre-dose FEV1 assessments

obtained at Visit 2 and Visit 3).

m. Oxygen: Patients receiving long-term-oxygen therapy or nocturnal oxygen therapy

required for > 15 h a day. Note: As-needed oxygen use is not exclusionary.

n. Patient use of any non-invasive positive pressure ventilation device. Note: Patients using

continuous positive airway pressure or bi-level positive airway pressure for sleep apnea

syndrome are allowed in the study if not used for ventilatory support.

o. Change in smoking status (i.e. start or stop smoking) or initiation of a smoking-cessation

program within 6 weeks of Visit 1 and throughout the screening period (Visit 1 to

Visit 4).

p. Pulmonary rehabilitation: Patients who have participated in the acute phase of a

pulmonary rehabilitation program within 4 weeks prior to Visit 1 (screening) or who are

scheduled to enter the acute phase of a pulmonary rehabilitation program during the

study. These patients will be allowed to rescreen after completion of the acute phase of

pulmonary rehabilitation. Patients who are in the maintenance phase of a pulmonary

rehabilitation program are not to be excluded.

q. Patients who have initiated or altered the dose regimen of intranasal corticosteroids,

intranasal antihistamines, or a combination thereof within 7 days prior to Visit 1 or

during the screening period (Visit 1 to Visit 4).

4. Cardiac disease:

a. Patients who have unstable ischemic heart disease, left ventricular failure, or documented

myocardial infarction within 6 months of enrollment. Patients with a recent history of

acute coronary syndrome, or who have undergone percutaneous coronary intervention or

coronary artery bypass graft within the past 3 months are to be excluded.

37

b. Patients with congestive heart failure (New York Heart Association Class III/IV).

c. Clinically significant abnormal ECG, defined as (but not limited to) any of the following:

Clinically significant conduction abnormalities (e.g. left bundle branch block,

Wolff-Parkinson-White syndrome, or evidence of second-degree [Mobitz Type II]

or third-degree atrioventricular block [unless a pacemaker or defibrillator has been

inserted]).

Clinically significant arrhythmias (e.g. atrial fibrillation with irregular ventricular

response, atrial flutter, ventricular tachycardia). Note: Atrial fibrillation that has

been clinically stable for at least 6 months and that has been appropriately treated

with anticoagulation and controlled with a rate control strategy (i.e. selective β-

blocker, calcium channel blocker, digoxin, or ablation therapy) for at least

6 months is allowed for inclusion. In such patients, if atrial fibrillation is present at

Visit 1, resting ventricular rate must be < 100 beats per min (bpm).

QT interval corrected for heart rate (using Fridericia’s formula; QTcF) ≥ 500

milliseconds (msec) in patients with QRS < 120 msec and QTcF ≥ 530 msec in

patients with QRS ≥ 120 msec.

Ventricular rate < 45 bpm.

ST-T wave abnormalities deemed to be clinically significant by the investigator.

Note: Patients with non-specific ST-T wave abnormalities that are not deemed

clinically significant (per investigator) are allowed.

Any other ECG abnormalities not listed above that, in the opinion of the

investigator, are clinically significant.

d. Patients who have clinically significant uncontrolled hypertension.

5. Neurological:

a. Patients with seizures requiring anticonvulsants within 12 months prior to Visit 1

(Screening). Note: Patients treated with anticonvulsant medication for 12 months or more

with no seizure events are eligible.

38

b. Patients taking selective serotonin reuptake inhibitors or serotonin-norepinephrine

reuptake inhibitors whose dose has not been stable for at least 4 weeks prior to Visit 1 or

is altered at any point during the screening period (Visit 1 to Visit 4), or exceeds the

maximum recommended dose.

c. Patients who have experienced a cerebrovascular accident within 6 months prior to

Visit 1.

6. Renal:

a. Patients with symptomatic prostatic hypertrophy that is clinically significant and not

adequately controlled with appropriate therapy in the opinion of the investigator. Patients

with a trans-urethral resection of prostate or full resection of the prostate within 6 months

prior to Visit 1 are excluded from the study.

b. Patients with bladder neck obstruction or urinary retention that is clinically significant in

the opinion of the investigator.

c. Patients with a calculated creatinine clearance ≤ 30 mL/min using the Chronic Kidney

Disease Epidemiology Collaboration formula [3] at Visit 1 and on repeat testing prior to

Visit 2.

Note: Patients with overactive bladder syndrome treated with oral anticholinergics who have

been on treatment for at least 1 month are allowed in the study.

7. Endocrine:

a. Patients who, in the opinion of the investigator, have uncontrolled hypo- or

hyperthyroidism, hypokalemia, or hyperadrenergic state.

b. Patients who, in the opinion of the investigator, have uncontrolled Type I or II diabetes.

8. Liver: Patients with abnormal liver function tests defined as aspartate transaminase, alanine

transaminase, or total bilirubin ≥ 1.5 times upper limit of normal at Visit 1 and on repeat

testing prior to Visit 2. Note: Chronic stable hepatitis B and C are acceptable if the patient

otherwise meets study entry criteria.

39

9. Cancer: Patients who have cancer that has not been in complete remission for at least 5 years.

Note: Patients with squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or

localized prostate cancer are eligible if, in the opinion of the investigator, the condition has

been adequately worked up, is clinically controlled, and the patient’s participation in the study

would not represent a safety concern.

10. Glaucoma: Patients with a diagnosis of narrow-angle glaucoma, which, in the opinion of the

investigator, has not been adequately treated. All medications approved for control of

intraocular pressure are allowed, including topical ophthalmic non-selective β-blockers (such

as betaxolol, carteolol, levobunolol, metipranolol, and timolol), and prostaglandin analogs.

11. Drug allergy: Patients who have a history of hypersensitivity to β2-agonists, budesonide or

any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or

any component of the metered dose inhaler (MDI).

12. Substance abuse: Patients who, in the opinion of the investigator, significantly abuse alcohol

or drugs.

13. Medication prior to spirometry: Patients who are medically unable to withhold their short-

acting bronchodilators for the 6-h period required prior to spirometry testing at each study

visit will be ineligible to participate in the PFT sub-study.

14. Prohibited medications: Patients who, in the opinion of the investigator, would be unable to

abstain from protocol-defined prohibited medications during the screening period and

treatment phases of this study.

15. Patients using any herbal inhalation and nebulizer products within 2 weeks prior to Visit 1

(screening) and do not agree to stop using them during the study-drug treatment.

Note: Nebulized products (e.g. albuterol/salbutamol, ipratropium) are acceptable, but require

a minimum of a 6-h washout prior to Visit 1 and must be discontinued at Visit 1 and

throughout the study.

16. Vaccinations: Patients who received a live attenuated vaccination within 7 days prior to

Visit 1 (screening).

40

17. Non-compliance: Patients unable to comply with study procedures including non-compliance

with diary completion (i.e. < 70% completion of diary assessments in the last 7 days

preceding Visit 4).

18. Affiliations with investigator site: Study investigators, sub-investigators, study coordinators,

employees of a participating investigator, or immediate family members of the

aforementioned are excluded from participation in this study.

19. Questionable validity of consent: Patients with a history of psychiatric disease, intellectual

deficiency, poor motivation, substance abuse (including drug and alcohol), or other conditions

that will limit the validity of informed consent to participate in the study.

20. Use of prohibited COPD medications following Visit 1 (see Supplemental Table S1).

21. Investigational drugs or devices: Treatment with an investigational study drug or device in

another clinical study within the last 30 days or five half-lives prior to Visit 1 (screening),

whichever is longer. Note: Participation in observational studies (i.e. studies that do not

require change to medication or an additional intervention) is not exclusionary.

22. Hand-to-breath coordination: Patients who require the use of a spacer device to compensate

for poor hand-to-breath coordination with a MDI. Note: Use of a nebulizer to deliver

maintenance COPD medications is prohibited throughout the study.

23. Previous participation: Patients who were previously enrolled in any budesonide/formoterol

fumarate MDI or budesonide/glycopyrrolate/formoterol fumarate MDI study conducted or

funded by the sponsor of this study.

41

24-h Holter monitoring sub-study exclusion criteria

Patients with a pacemaker or implantable cardioverter-defibrillator/cardiac resynchronization

therapy/cardiac resynchronization therapy-defibrillator devices will not be allowed into the Holter

monitor sub-study. Clinically significant abnormal findings during the baseline Holter monitor

recording are defined as (but not limited to) any of the following:

1. Average heart rate ≤ 40 bpm for any 1 h.

2. Atrioventricular block (second degree, Type 2, or third degree).

3. Sinus pause of:

2.5 s duration during daytime.

3.0 s duration during night-time.

4. Any episode of ventricular flutter and/or ventricular fibrillation.

5. Any episode of non-sustained ventricular tachycardia (VT) with symptoms of hypotension or

syncope or asymptomatic non-sustained VT > 15 ventricular premature beats in a row.

6. Sustained VT (> 30 s in duration).

7. Five or more episodes of non-sustained VT/24 h.

8. Greater than 500 ventricular premature beats/h.

REFERENCES

[1] B.R. Celli, W. MacNee, and ATS/ERS Task Force, Standards for the diagnosis and treatment of

patients with COPD: a summary of the ATS/ERS position paper, Eur Respir J 23 (6) (2004) 932-946.

[2] The Japanese Respiratory Society, Guidelines for the Diagnosis and Treatment of COPD, 4th

Edition, 2013. http://www.jrs.or.jp/. (Accessed 9 April 2019).

[3] A.S. Levey, L.A. Stevens, C.H. Schmid, Y.L. Zhang, A.F. Castro, 3rd, H.I. Feldman, J.W. Kusek,

P. Eggers, F. Van Lente, T. Greene, J. Coresh, CKD-EPI (Chronic Kidney Disease Epidemiology

Collaboration), A new equation to estimate glomerular filtration rate, Ann Intern Med 150 (9) (2009)

604-612.

42

Class of medication Minimum washout period prior to Visit 2

LAMAs Tiotropium: 14 days

Aclidinium: 7 days

Glycopyrronium: 7 days

Umeclidinium: 7 days

SAMAsa 6 h

LABAs (inhaled) 7 days (14 days for indacaterol and olodaterol)

Fixed combinations of LABA/LAMA 7 days (14 days for indacaterol/glycopyrronium and

olodaterol/tiotropium)

Fixed combinations of LABA/ICS 7 days

Fixed combinations of SABAs and SAMAs 6 h

SABAsb 6 h

Oral β-agonists 2 days

Theophylline (total daily dose

> 400 mg/day)c

7 days

Supplemental Table S1

Prohibited COPD medications and required washout periods prior to Visit 2.

COPD: chronic obstructive pulmonary disease; ICS: inhaled corticosteroid; LABA: long-acting β2-

agonist; LAMA: long-acting muscarinic antagonist; SABA: short-acting β2-agonist; SAMA: short-

acting muscarinic antagonists.

Note: Roflumilast (or any phosphodiesterase-4 inhibitor) is allowed provided the subject has been on

a stable dose of therapy for at least 2 months prior to randomization.aDiscontinue and use only sponsor-provided ipratropium bromide during screening. bDiscontinue and use only sponsor-provided rescue salbutamol throughout the study.cTheophylline (< 400 mg/day) is permitted provided the subject has been on a stable dose of therapy

for at least 4 weeks prior to randomization.

43