Benefit/Risk Profile of Single-Inhaler Triple Therapy in COPD

Figures & data

Table 1 Exacerbation Rate, Lung Function, and Health-Related Quality of Life Outcomes in the TRILOGY, KRONOS, FULFIL, TRIBUTE, ETHOS, and IMPACT Trials

	Primary Endpoint: FEV1 and/or SGRQ				Primary Endpoint: Exacerbation Rate
	TRILOGY^Citation25	KRONOS^Citation20	FULFIL^Citation21,Citation87		TRIBUTE^Citation23	ETHOS^Citation24,Citation88	IMPACT^Citation22,Citation89
	52 Weeks	24 Weeks	24 Weeks	52 Weeks	52 Weeks	52 Weeks	52 Weeks
Study arms	BDP/FM/GLY BID (N=687) BDP/FM BID (N=680)	1. BUD/GLY/FM BID (N=639) 2. FM/GLY BID (N=625) 3. BUD/FM BID (N=314) 4. BUD/FM DPI open-label BID (N=318)	FF/UMEC/VI QD (N=911) BUD/FM BID (N=899)	FF/UMEC/VI QD (N=210) BUD/FM BID (N=220)	BDP/FM/GLY BID (N=764) IND/GLY QD (N=768)	1. BUD (320)/GLY/FM BID (N=2137) 2. BUD (160)/GLY/FM BID (N=2121) 3. FM/GLY BID (N=2120) 4. BUD/FM BID (N=2131)	1. FF/UMEC/VI QD (N=4151) 2. FF/VI QD (N=4134) 3. UMEC/VI QD (N=2070)
Run-in period	BDP/FM BID	Ipratropium bromide QID ICS use allowed if patient on a stable dose 4 weeks prior to screening	Current COPD medications		IND/GLY QD	Ipratropium bromide QID ICS use allowed if used prior to screening	Current COPD medications
Recruitment criteria (FEV1% predicted, exacerbations, and CAT score)	FEV1 <50% ≥1 moderate/severe exacerbation in the preceding year CAT ≥10	FEV1 ≥25–<80% No history of exacerbations required CAT ≥10	FEV1 <50%; or FEV1 ≥50–<80% plus ≥2 moderate or ≥1 severe exacerbation in the preceding year CAT ≥10		FEV1 <50% ≥1 moderate/severe exacerbation in the preceding year CAT ≥10	FEV1 ≥25–≤65% ≥1 moderate/severe (if FEV1 <50%), or ≥2 moderate or ≥1 severe (if FEV1 ≥50%) exacerbation in the preceding year CAT ≥10	FEV1 <50% plus ≥1 moderate or severe exacerbation in the preceding year; or FEV1 ≥50–<80% plus ≥2 moderate or ≥1 severe exacerbation in the preceding year CAT ≥10
Results (ITT population)
Moderate/severe exacerbation rate, per year	0.41 vs 0.53 Rate ratio: 0.77, 95% CI: 0.65, 0.92, P=0.005	0.46 vs 0.95 vs 0.56 vs 0.55 Rate ratio (1 vs 2): 0.48, 95% CI: 0.37, 0.64, P<0.0001 Rate ratio (1 vs 3): 0.82, 95% CI: 0.58, 1.17, P=0.2792 Rate ratio (1 vs 4): 0.83, 95% CI: 0.59, 1.18, P=0.3120	0.22 vs 0.34 Rate ratio: 0.65, 96% CI: 0.49, 0.86, P=0.002	0.20 vs 0.36 Rate ratio: 0.56, 95% CI: 0.37, 0.85, P=0.006	0.50 vs 0.59 Rate ratio: 0.848, 95% CI: 0.723, 0.995, P=0.043	1.08 vs 1.07 vs 1.42 vs 1.24 Rate ratio (1 vs 2): 1.00, 95% CI: 0.91, 1.10 (P-value not reported) Rate ratio (1 vs 3): 0.76, 95% CI: 0.69, 0.83, P<0.001 Rate ratio (1 vs 4): 0.87, 95% CI: 0.79, 0.95, P=0.003	0.91 vs 1.07 vs 1.21 Rate ratio (1 vs 2): 0.85, 95% CI: 0.80, 0.90, P<0.001 Rate ratio (1 vs 3): 0.75, 95% CI: 0.70, 0.81, P<0.001
Pre-dose FEV1 (mean change from baseline, mL)	71 vs 8 Mean difference: 63, 95% CI: 32, 94, P<0.001	147 vs 125 vs 73 vs 88 Mean difference (1 vs 2): 22, 95% CI: 4, 39, P=0.014 Mean difference (1 vs 3): 74, 95% CI: 52, 95, P<0.0001 Mean difference (1 vs 4): 59, 95% CI: 38, 80, P<0.0001^a	142 vs −29 Mean difference: 171, 95% CI: 148, 194, P<0.001	126 vs −53 Mean difference: 179, 95% CI: 131, 226, P<0.001	Mean difference: 19, NS [22, P<0.05 (overall)]	Mean difference (1 vs 3):^a,b 55, 95% CI: 30, 79, P<0.0001 Mean difference (1 vs 4): ^a,b,c 65, 95% CI: 40, 89 P<0.0001	94 vs −3 vs 40 Mean difference (1 vs 2): 97, 95% CI: 85, 109, P<0.001 Mean difference (1 vs 3): 54, 95% CI: 39, 69, P<0.001
TDI focal score	2.03 vs 1.81 Mean difference: 0.21, 95% CI: −0.10, 0.53, P=0.186	1.25 vs 1.07 vs 1.01 vs 0.78 Mean difference (1 vs 2): 0.18, 95% CI: −0.07, 0.43, P=0.1621 Mean difference (1 vs 3): 0.24, 95% CI: −0.07, 0.54, P=0.1283 Mean difference (1 vs 4): 0.46, 95% CI: 0.16, 0.77, P=0.0031	2.29 vs 1.72 Mean difference: 0.57, 95% CI: 0.30, 0.84, P<0.001	1.74 vs 1.39 Mean difference: 0.34, 95% CI: −0.28, 0.97, P=0.279	NR	1.3 vs 1.3 vs 0.9 vs 1.0 (over 24 weeks) Mean difference (1 vs 2): 0.03, 95% CI: −0.12, 0.19 (P-value not reported) Mean difference (1 vs 3): 0.40, 95% CI: 0.24, 0.55 (P-value not reported) Mean difference (1 vs 4): 0.31, 95% CI: 0.15, 0.46 (P-value not reported)	0.98 vs 0.71 vs 0.89^c Mean difference (1 vs 2): 0.27, 95% CI: 0.04, 0.49, P=0.020 Mean difference (1 vs 3): 0.09, 95% CI: −0.19, 0.37, P=0.522
SGRQ total score (mean change from baseline)	Mean difference: −1.69, 95% CI: −3.20, −0.17, P=0.029	−7.5 vs −6.3 vs −7.1 vs −6.3 Mean difference (1 vs 2): −1.22, 95% CI: −2.30, −0.15, P=0.0259^b Mean difference (1 vs 3): −0.45, 95% CI: −1.78, 0.87, P=0.5036 Mean difference (1 vs 4): −1.26, 95% CI: −2.58, 0.06, P=0.0617	−6.6 vs −4.3 Mean difference: -2.2, 95% CI: −3.5, −1.0, P<0.001	−4.6 vs −1.9 Mean difference: −2.7, 95% CI: −5.5, 0.2, P=0.065	Mean difference: −1.64, P<0.01 [−1.68, P<0.001 (overall)]	−6.5 vs −6.2 vs −4.9 vs −5.1 (over 24 weeks) Mean difference (1 vs 2): −0.34, 95% CI: −0.99, 0.30 (P-value not reported) Mean difference (1 vs 3): −1.62, 95% CI: −2.27, −0.97 (P-value not reported) Mean difference (1 vs 4): −1.38, 95% CI: −2.02, −0.73 (P-value not reported)	−5.5 vs −3.7 vs −3.7 Mean difference (1 vs 2): −1.8, 95% CI: −2.4, −1.1, P<0.001 Mean difference (1 vs 3): −1.8, 95% CI: −2.6, −1.0, P<0.001

Notes: ^aNominally significant; ^bpulmonary function test sub-study population (total N=3088); ^cTDI population (FF/UMEC/VI N=2029; FF/VI N=2014; UMEC/VI N=1015).

Abbreviations: BDP, beclometasone dipropionate; BID, twice daily; BUD, budesonide; CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate: FM, formoterol; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol; ITT, intent-to-treat; NR, not reported; NS, not significant; QD, once daily; QID, four times daily; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index; UMEC, umeclidinium; VI, vilanterol.

Table 2 Patient Characteristics in the TRILOGY, KRONOS, FULFIL, TRIBUTE, ETHOS, and IMPACT Trials

Baseline Characteristics (at Study Entry)	TRILOGY^Citation25	KRONOS^Citation20	FULFIL^Citation21,Citation87a	TRIBUTE^Citation23b	ETHOS^Citation24,Citation90	IMPACT^Citation22
Sex
Female	24%	29%	26%	28%	40%	34%
Male	76%	71%	74%	72%	60%	66%
Ethnicity
White	>99%	50%	85%	92%^c	85%^b	78%
Other	<1%	50%	15%	7%^c	15%^b	22%
Age, mean (years)	63.3–63.8	64.9–65.9	63.9	64.4–64.5	64.6–64.8	65.3
BMI, mean (kg/m^2)	26.3–26.4	26.1–26.3	26.9	25.7–26.6	27.5^b	26.6
GOLD classification
GOLD B	0%	NR	46%	NR	NR	30%
GOLD D	100%	NR	54%	NR	NR	70%
FEV1, % predicted^d
Mean	36.2–36.9	50.0–50.7	45.3%	36.4	43.1–43.6	45.5
≥80%	0%	NR (inclusion criteria: <80%)	<1%	0%	0%	<1%
50% to <80%	0%	NR	33%	0%	29%	36%
30% to <50%	77%	NR	54%	80%	60%	48%
<30%	23%	NR	13%	20%	11%	16%
CAT score, mean	20.8	18.0–18.7	19.1	NR (inclusion criteria: ≥10)	19.5–19.7	20.1
Moderate/severe exacerbations in the preceding year
0	NR (inclusion criteria: ≥1)	74%	35%	0%	<1%	<1%
1	NR	19%	28%	81%	43%	45%
≥2	NR	7%	37%	19%	57%	55%
Raw calculated annual rate	1.2	0.3–0.4	NR	1.2	1.7	NR
Prior ICS use
ICS at study entry (alone or as any combination)	74%	72%	66%	66%	80%	71%
Triple therapy (ICS/LABA/LAMA)	0%	27%^a	28%	0%	39%^b	38%

Notes: Unless otherwise indicated, data are % of patients in the intention-to-treat population. Mean values are given as a range over the treatment arms when data for the overall population were not provided. ^aData presented for the ITT population (24 weeks); ^bdata presented are for the safety population; ^cdata missing for a total of 16 patients in the study; ^dpost-salbutamol administration.

Abbreviations: BMI, body mass index; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; NR, not reported.

Table 3 Pneumonia Incidence in the TRILOGY, KRONOS, FULFIL, TRIBUTE, ETHOS, and IMPACT Trials

	TRILOGY^Citation25	KRONOS^Citation20	FULFIL^Citation21,Citation87		TRIBUTE^Citation23	ETHOS^Citation24	IMPACT^Citation22,Citation89
	52 Weeks	24 Weeks	24 Weeks	52 Weeks	52 Weeks	52 Weeks	52 Weeks
Study arms	BDP/FM/GLY BID (N=687) BDP/FM BID (N=680)	1. BUD/GLY/FM BID (N=639) 2. FM/GLY BID (N=625) 3. BUD/FM BID (N=314) 4. BUD/FM DPI open-label BID (N=318)	FF/UMEC/VI QD (N=911) BUD/FM BID (N=899)	FF/UMEC/VI QD (N=210) BUD/FM BID (N=220)	BDP/FM/GLY BID (N=764) IND/GLY QD (N=768)	1. BUD (320)/GLY/FM BID (N=2137) 2. BUD (160)/GLY/FM BID (N=2121) 3. FM/GLY BID (N=2120) 4. BUD/FM BID (N=2131)	1. FF/UMEC/VI QD (N=4151) 2. FF/VI QD (N=4134) 3. UMEC/VI QD (N=2070)
Pneumonia AE	3.3% vs 2.6%	1.9% vs 1.6% vs 1.9% vs 1.3% (over 24 weeks)^a	2.2% vs 0.8%^c	1.9% vs 1.8%^c	3.7% vs 3.5%	4.2% vs 3.5% vs 2.3% vs 4.5%^a	7.6% vs 7.1% vs 4.7%^c
Pneumonia AE incidence in ICS- vs non-ICS-containing treatment arms	N/A	Fold difference: 1 vs 2: 1.2-fold 3 vs 2: 1.2-fold 4 vs 2: 0.8-fold	N/A	N/A	Fold difference: 1.0-fold	Fold difference: 1 vs 3: 1.9-fold 2 vs 3: 1.6-fold 4 vs 3: 2.0-fold	Fold difference: 1 vs 3: 1.6-fold 2 vs 3: 1.5-fold
Pneumonia SAE	2.2% vs 1.0%	1.3 vs 1.0 vs 0.3 vs 0 (over 24 weeks)^a,b	1.2% vs 0.3%^d	1.9% vs 1.8%^d	2.4% vs 2.2%	3.0% vs 2.5% vs 1.3% vs 2.4%^a	4.4% vs 3.7% vs 2.6%
Pneumonia SAE incidence in ICS- vs non-ICS- containing treatment arms	N/A	Fold difference: 1 vs 2: 1.3-fold 3 vs 2: 0.3-fold 4 vs 2: N/A	N/A	N/A	Fold difference: 1.1-fold	Fold difference: 1 vs 3: 2.3-fold 2 vs 3: 1.9-fold 4 vs 3: 1.8-fold	Fold difference: 1 vs 3: 1.7-fold 2 vs 3: 1.4-fold

Notes: AESIs/serious AESIs were defined as AEs/SAEs that are pharmacologically related to ICS, LAMA, or LABA. ^aConfirmed by clinical endpoint committee; ^bincidence based on unadjudicated cases of pneumonia classified by the investigator as serious; ^creported as pneumonia AESI; ^dreported as pneumonia serious AESI.

Abbreviations: AE, adverse event; AESI, adverse event of special interest; ICS, inhaled corticosteroid; N/A, not applicable; NR, not reported; SAE, serious adverse event.

Table 4 Capture and Assessment of Pneumonia in the TRILOGY, KRONOS, FULFIL, TRIBUTE, ETHOS, and IMPACT Trials

Pneumonia Capture and Assessment	TRILOGY^Citation25	KRONOS^Citation20	FULFIL^Citation21,Citation87	TRIBUTE^Citation23	ETHOS^Citation24	IMPACT^Citation22,Citation89
Assessment method	NR	According to a clinical diagnosis of pneumonia by the investigator and confirmatory radiography within 14 days of diagnosis and treatment with antibiotics and at least two clinical signs, symptoms, or laboratory findings^a	A diagnosis of pneumonia was assigned according to the clinical judgement of the investigator. All suspected pneumonias were required to be confirmed by the presence of new infiltrate(s) on chest imaging and at least two signs or symptoms^a	In cases of clinical features suggesting a diagnosis of pneumonia, investigators were asked to undertake, whenever possible, further investigations based on their clinical experience and judgement; over 80% of pneumonia cases were diagnosed based on medical imaging	According to a clinical diagnosis of pneumonia by the investigator and confirmatory radiography within 14 days of diagnosis and treatment with antibiotics and increased respiratory symptoms^a	A diagnosis of pneumonia was assigned according to the clinical judgement of the investigator. All suspected pneumonias were required to be confirmed by the presence of new infiltrate(s) on chest imaging and at least two signs or symptoms^a
Capture and analysis/presentation method	Events reported as AEs, according to MedDRA v16.0 preferred terms: pneumonia, bronchopneumonia, and pneumonia aspiration	Events reported as AEs	Events reported as AEs and analyzed/presented as AESIs (according to a selection of 69 MedDRA preferred terms)	Events reported as AEs, according to MedDRA v18.0 preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, pneumonia bacterial, pneumonia streptococcal, pneumonia viral, and interstitial lung disease^b	Events reported as AEs	Events reported as AEs and analyzed/presented as AESIs (according to a selection of MedDRA preferred terms)
Adjudication	No	All AEs reported as pneumonia were reviewed by an independent clinical endpoint committee	All SAEs were adjudicated by an independent clinical endpoint committee	No	All AEs reported as pneumonia were reviewed by an independent clinical endpoint committee	All SAEs were adjudicated by an independent adjudication committee blinded to treatment assignment

Notes: AESIs/serious AESIs were defined as AEs/SAEs that are pharmacologically related to the use of ICS, LAMA, or LABA. ^aIncreased cough, increased sputum purulence or production, adventitious breath sounds on auscultation, dyspnea or tachypnoea, fever, elevated white blood cell counts, hypoxemia; ^bin addition, one event of pulmonary tuberculosis was considered, since the investigator reported that this was a tuberculous pneumonia; other events belonging to the pulmonary tuberculosis preferred term were not considered.

Abbreviations: AE, adverse event; AESI, adverse event of special interest; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MedDRA, Medical Dictionary for Regulatory Activities; NR, not reported; SAE, serious adverse event.

Figure 1 Disease severity and exacerbation history are strongly correlated with pneumonia risk whereas ICS only adds a small additional risk.

Abbreviations: BMI, body mass index; CAP, community-acquired pneumonia; CI, confidence interval; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; OCS, oral corticosteroid; OR, odds ratio. The graph has been independently created from the original data.⁴⁹

Table 5 Severe Exacerbations and All-Cause Mortality in the TRIBUTE, ETHOS, and IMPACT Trials

	TRIBUTE^Citation23		ETHOS^Citation24				IMPACT^Citation22,Citation89
Study arms	BDP/FM/GLY BID (N=764)	IND/GLY QD (N=768)	BUD (320)/GLY/FM BID (N=2137)	BUD (160)/GLY/FM BID (N=2121)	FM/GLY BID (N=2120)	BUD/FM BID (N=2131)	FF/UMEC/VI QD (N=4151)	FF/VI QD (N=4134)	UMEC/VI QD (N=2070)
On-treatment severe exacerbations
Rate, per year	0.07	0.09	0.13	0.14	0.15	0.16	0.13	0.15	0.19
Rate ratio (95% CI), SITT vs dual therapy	–	0.787 (0.551, 1.125), P=0.189	–	–	BUD 320 µg SITT: 0.84 (0.69, 1.03), P=0.09 BUD 160 µg SITT: 0.88 (0.72, 1.08), P-value not reported	BUD 320 µg SITT: 0.80 (0.66, 0.97), P=0.02 BUD 160 µg SITT: 0.83 (0.69, 1.01), P-value not reported	–	0.87 (0.76, 1.01), P=0.06	0.66 (0.56, 0.78), P<0.001
On-/off-treatment death from any cause^a
Deaths, n (%)	16 (2.09%)^b	21 (2.73%)^b	28 (1.31%)	39 (1.84%)	49 (2.31%)	34 (1.60%)	89 (2.14%)	97 (2.35%)	60 (2.90%)
Relative risk reduction, SITT vs dual therapy: HR (95% CI)	–	NR	–	–	BUD 320 µg SITT: 0.54 (0.34, 0.87)^c BUD 160 µg SITT: 0.79 (0.52, 1.20)	BUD 320 µg SITT: 0.78 (0.47, 1.30) BUD 160 µg SITT: 1.13 (0.72, 1.80)	–	0.90 (0.67, 1.20), P=0.458	0.71 (0.51, 0.99), P=0.043
Absolute risk difference, SITT vs dual therapy	–	0.64%^b	–	–	BUD 320 µg SITT: 1.00% BUD 160 µg SITT: 0.47%	BUD 320 µg SITT: 0.29% BUD 160 µg SITT: −0.24%	–	0.21%	0.76%

Notes: Data are over 52 weeks in the ITT population, unless otherwise indicated. ^aETHOS: analysis performed with the use of a treatment policy estimand, which included all observed data regardless of whether patients continued to receive their assigned treatment,²⁴ IMPACT: on- and off-treatment deaths included all observed data regardless of whether patients continued to receive their assigned treatment and are those which occurred between study treatment start date and 7 days after study treatment stop date (inclusive) for study treatment completers or up to the projected Week 52 date + 7 days for patients who prematurely discontinued study treatment;⁸⁹ bAEs leading to a fatal outcome (safety population); ^cno statistical inferences can be made due to hierarchy broken on severe exacerbations.

Abbreviations: BDP, beclometasone dipropionate; BUD, budesonide; CI, confidence interval; FF, fluticasone furoate: FM, formoterol; GLY, glycopyrronium; HR, hazard ratio; IND, indacaterol; NR, not reported; SITT, single-inhaler triple therapy; UMEC, umeclidinium; VI, vilanterol.

Figure 2 All-cause mortality benefits with SITT are similar to, or better than, smoking cessation and cardioprotective treatments. ^aPooled analysis of AEs leading to a fatal outcome (safety population); ^bon- and off-treatment deaths in post hoc analysis with additional vital status follow-up (vital status available for 99.6% of patients at nominal Week 52); ^canalysis included all observed data regardless of whether patients continued to receive their assigned treatment.

Abbreviations: BDP, beclometasone dipropionate; BUD, budesonide; FF, fluticasone furoate: FM, formoterol; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol; SITT, single-inhaler triple therapy; UMEC, umeclidinium; VI, vilanterol. The graph has been independently created from the original data.

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