. 2021 Mar 1;16:499–517. doi: 10.2147/COPD.S291967

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
	TRILOGY²⁵	KRONOS²⁰	FULFIL²¹^,⁸⁷		TRIBUTE²³	ETHOS²⁴^,⁸⁸	IMPACT²²^,⁸⁹
	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.