Extrafine triple therapy delays COPD clinically important deterioration vs ICS/LABA, LAMA, or LABA/LAMA

Figures & data

Table 1 Baseline characteristics (intention-to-treat population)

Characteristics	TRILOGY		TRINITY			TRIBUTE
	BDP/FF/G (N=687)	BDP/FF (N=680)	BDP/FF/G (N=1,077)	Tiotropium (N=1,074)	BDP/FF + tiotropium (N=538)	BDP/FF/G (N=764)	IND/GLY (N=768)
Gender
Male	509 (74.1%)	527 (77.5%)	829 (77.0%)	829 (77.2%)	398 (74.0%)	548 (71.7%)	552 (71.9%)
Race
White	684 (99.6%)	679 (99.9%)	1,067 (99.1%)	1,069 (99.5%)	533 (99.1%)	705 (92.3%)	708 (92.2%)
Other	3 (0.4%)	1 (0.1%)	10 (0.9%)	5 (0.5%)	5 (0.9%)	51 (6.7%)	52 (6.8%)
Missinga	0	0	0	0	0	8 (1.0)	8 (1.0)
Age (years)	63.3 (7.9)	63.8 (8.2)	63.4 (8.7)	63.3 (8.4)	62.6 (8.9)	64.4 (7.7)	64.5 (7.7)
Smoking status
Ex-smoker	364 (53.0%)	362 (53.2%)	560 (52.0%)	573 (53.4%)	271 (50.4%)	413 (54.1%)	436 (56.8%)
Current smoker	323 (47.0%)	318 (46.8%)	517 (48.0%)	501 (46.6%)	267 (49.6%)	351 (45.9%)	332 (43.2%)
FEV1% predictedb	36.9 (8.4)	36.2 (8.6)	36.6 (8.3)	36.6 (8.2)	36.7 (8.3)	36.4 (8.0)	36.4 (8.1)
≥30%	532 (77.4%)	525 (77.2%)	849 (78.8%)	845 (78.7%)	425 (79.0%)	610 (79.8%)	608 (79.2%)
<30%	155 (22.6%)	155 (22.8%)	228 (21.2%)	229 (21.3%)	113 (21.0%)	154 (20.2%)	160 (20.8%)
FEV1/FVC ratiob	0.42 (0.11)	0.41 (0.11)	0.42 (0.10)	0.43 (0.11)	0.42 (0.10)	0.41 (0.10)	0.42 (0.10)
Exacerbation rate in the previous year, mean (range)	1.2 (1, 5)	1.2 (1, 6)	1.3 (1, 11)	1.3 (1, 5)	1.2 (1, 7)	1.2 (1, 6)	1.2 (1, 4)
CAT total score	20.8 (5.9)	20.8 (5.7)	21.5 (5.8)	21.6 (5.8)	21.7 (6.0)	21.1 (5.7)	21.3 (5.5)
SGRQ total scorec	52.3 (16.8)	50.3 (16.5)	54.4 (16.6)	54.5 (16.8)	53.0 (16.3)	47.6 (14.3)	47.7 (15.1)
BDI focal scorec	5.3 (1.8)	5.5 (1.8)	–	–	–	–	–

Notes: Data are number of patients (percentage), mean (SD), or mean (range).

a Due to data collection restrictions in Portugal, this information was not collected in Portuguese sites;

b Post-salbutamol;

c At randomisation visit.

Abbreviations: BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; IND/GLY, indacaterol/glycopyrronium; CAT, COPD Assessment Test; SGRQ, St George’s Respiratory Questionnaire; BDI, Baseline Dyspnea Index.

Table 2 Number (%) of patients with a CID overall and by individual component

Endpoint	TRILOGY			TRINITY					TRIBUTE
	BDP/FF/G (N=687)	BDP/FF (N=680)	HR time to first event (95% CI)	BDP/FF/G (N=1,077)	Tiotropium (N=1,074)	BDP/FF + tiotropium (N=538)	HR time to first event (95% CI)		BDP/FF/G (N=764)	IND/GLY (N=768)	HR time to first event (95% CI)
							BDP/FF/G vs tiotropium	BDP/FF/G vs BDP/FF + tiotropium
FEV1a	276 (40.2)	402 (59.1)	0.55 (0.47, 0.64); P<0.001	483 (44.8)	598 (55.7)	225 (41.8)	0.69 (0.62, 0.78); P<0.001	1.11 (0.95, 1.30); P=0.197	448 (58.6)	460 (59.9)	0.98 (0.86, 1.12); P=0.748
SGRQ total scoreb	279 (40.6)	317 (46.6)	0.78 (0.67, 0.92); P=0.003	426 (39.6)	523 (48.7)	208 (38.7)	0.72 (0.63, 0.82); P<0.001	1.04 (0.88, 1.23); P=0.610	369 (48.3)	418 (54.4)	0.81 (0.71, 0.93); P=0.003
TDI focal scorec	175 (25.5)	204 (30.0)	0.81 (0.66, 0.99); P=0.040	–	–	–	–	–	–	–	–
COPD exacerbationd	214 (31.1)	240 (35.3)	0.80 (0.67, 0.97); P=0.020	351 (32.6)	383 (35.7)	167 (31.0)	0.84 (0.72, 0.97); P=0.015	1.06 (0.88, 1.27); P=0.569	273 (35.7)	288 (37.5)	0.90 (0.76, 1.06); P=0.219
Death	14 (2.0)	16 (2.4)	0.88 (0.43, 1.81); P=0.728	20 (1.9)	28 (2.6)	8 (1.5)	0.66 (0.37, 1.18); P=0.163	1.25 (0.55, 2.84); P=0.592	16 (2.1)	20 (2.6)	0.76 (0.39, 1.46); P=0.409
Composite, any event (excluding TDI)	480 (69.9)	569 (83.7)	0.61 (0.54, 0.70); P<0.001	800 (74.3)	883 (82.2)	394 (73.2)	0.72 (0.65, 0.79); P<0.001	1.06 (0.94, 1.20); P=0.326	623 (81.5)	668 (87.0)	0.82 (0.73, 0.91); P<0.001
Composite, any event (including TDI)	506 (73.7)	592 (87.1)	0.62 (0.55, 0.70); P<0.001	–	–	–	–	–	–	–	–

Notes:

a Patients with decrease from baseline ≥100 mL;

b patients with deterioration (ie, increase from baseline) ≥4 units;

c patients with TDI focal score ≤−1 unit;

d patients with a moderate/severe exacerbation. The composite CID was based on the occurrence of any of the following: decrease of ≥100 mL from baseline in FEV₁; increase of ≥4 units from baseline in SGRQ total score; TDI focal score ≤−1 unit (TRILOGY definition that included TDI only); occurrence of a moderate/severe exacerbation; or death. Data in bold are for the composite endpoint.

Abbreviations: IND/GLY, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire; BDP, beclometasone dipropionate; CID, clinically important deterioration; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index.

Figure 1 TRILOGY: Time to (A) first CID and (B) sustained CID (without TDI).

Notes: Time to first CID was based on the first occurrence of any of the following: decrease of ≥100 mL from baseline in FEV₁; increase of ≥4 units from baseline in SGRQ total score; occurrence of a moderate/severe exacerbation; or death. Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits, occurrence of a moderate/severe exacerbation, or death.
Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure 2 TRILOGY: Time to (A) first CID and (B) sustained CID (with TDI).

Notes: Time to first CID was based on the first occurrence of any of the following: decrease of ≥100 mL from baseline in FEV₁; increase of ≥4 units from baseline in SGRQ total score; TDI focal score ≤−1 unit; occurrence of a moderate/severe exacerbation; or death. Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score and/or TDI focal score maintained at all subsequent visits, occurrence of a moderate/severe exacerbation, or death.
Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure 3 TRINITY: Time to (A) first CID and (B) sustained CID.

Notes: Time to first CID was based on the first occurrence of any of the following: decrease of ≥100 mL from baseline in FEV₁, increase of ≥4 units from baseline in SGRQ total score, occurrence of a moderate/severe exacerbation, or death. Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits, occurrence of a moderate/severe exacerbation, or death.
Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Figure 4 TRIBUTE: Time to (A) first CID and (B) sustained CID.

Notes: Time to first CID was based on the first occurrence of any of the following: decrease of ≥100 mL from baseline in FEV₁, increase of ≥4 units from baseline in SGRQ total score, occurrence of a moderate/severe exacerbation, or death. Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits, occurrence of a moderate/severe exacerbation, or death.
Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; IND/GLY, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Figure S1 TRILOGY: Time to sustained CID (without TDI), alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure S2 TRILOGY: Time to sustained CID (with TDI), alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score and/or TDI focal score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score and/or TDI focal score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure S3 TRINITY: Time to sustained CID, alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Figure S4 TRIBUTE: Time to sustained CID, alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; IND/GLY, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Table S1 Number (%) of patients with a sustained CID overall and by individual component

Endpoint	TRILOGY			TRINITY					TRIBUTE
	BDP/FF/G (N=687)	BDP/FF (N=680)	HR time to first event (95% CI)	BDP/FF/G (N=1,077)	Tiotropium (N=1,074)	BDP/FF + tiotropium (N=538)	HR time to first event (95% CI)		BDP/FF/G (N=764)	IND/GLY (N=768)	HR time to first event (95% CI)
							BDP/FF/G vs tiotropium	BDP/FF/G vs BDP/FF + tiotropium
Main definition
FEV1 a	80 (11.6)	158 (23.2)	0.45 (0.35, 0.59); P<0.001	146 (13.6)	190 (17.7)	70 (13.0)	0.72 (0.58, 0.89); P=0.003	1.07 (0.81, 1.43); P=0.624	170 (22.3)	189 (24.6)	0.88 (0.72, 1.09); P=0.241
SGRQ total scoreb	88 (12.8)	112 (16.5)	0.74 (0.56, 0.98); P=0.034	142 (13.2)	164 (15.3)	62 (11.5)	0.82 (0.65, 1.03); P=0.081	1.16 (0.86, 1.56); P=0.338	95 (12.4)	127 (26.5)	0.73 (0.56, 0.95); P=0.021
TDI focal scorec	27 (3.9)	45 (6.6)	0.58 (0.36, 0.93); P=0.024	–	–	–	–	–	–	–	–
COPD exacerbationd	214 (31.1)	240 (35.3)	0.80 (0.67, 0.97); P=0.020	351 (32.6)	383 (35.7)	167 (31.0)	0.84 (0.72, 0.97); P=0.015	1.06 (0.88, 1.27); P=0.569	273 (35.7)	288 (37.5)	0.90 (0.76, 1.06); P=0.219
Death	14 (2.0)	16 (2.4)	0.88 (0.43, 1.81); P=0.728	20 (1.9)	28 (2.6)	8 (1.5)	0.66 (0.37, 1.18); P=0.163	1.25 (0.55, 2.84); P=0.592	16 (2.1)	20 (2.6)	0.76 (0.39, 1.46); P=0.409
Composite, any event (excluding TDI)	305 (44.4)	395 (58.1)	0.64 (0.55, 0.74); P<0.001	532 (49.4)	584 (54.4)	256 (47.6)	0.80 (0.71, 0.90); P<0.001	1.06 (0.92, 1.23); P=0.425	437 (57.2)	457 (59.5)	0.90 (0.79, 1.02); P=0.107
Composite, any event (including TDI)	316 (46.0)	405 (59.6)	0.65 (0.56, 0.75); P<0.001	–	–	–	–	–	–	–	–
Alternative definition
FEV1a	80 (11.6)	158 (23.2)	0.45 (0.35, 0.59); P<0.001	146 (13.6)	190 (17.7)	70 (13.0)	0.72 (0.58, 0.89); P=0.003	1.07 (0.81, 1.43); P=0.624	170 (22.3)	189 (24.6)	0.88 (0.72, 1.09); P=0.241
SGRQ total scoreb	88 (12.8)	112 (16.5)	0.74 (0.56, 0.98); P=0.034	142 (13.2)	164 (15.3)	62 (11.5)	0.82 (0.65, 1.03); P=0.081	1.16 (0.86, 1.56); P=0.338	95 (12.4)	127 (26.5)	0.73 (0.56, 0.95); P=0.021
TDI focal scorec	27 (3.9)	45 (6.6)	0.58 (0.36, 0.93); P=0.024	–	–	–	–	–	–	–	–
COPD exacerbation (excluding TDI)e	102 (14.8)	144 (21.2)	0.64 (0.50, 0.83); P<0.001	159 (14.8)	227 (21.1)	85 (15.8)	0.64 (0.52, 0.79); P<0.001	0.92 (0.70, 1.19); P=0.510	164 (21.5)	189 (24.6)	0.81 (0.66, 1.00); P=0.052
COPD exacerbation (including TDI)e	110 (16.0)	148 (21.8)	0.67 (0.52, 0.86); P=0.002	–	–	–	–	–	–	–	–
Death	14 (2.0)	16 (2.4)	0.88 (0.43, 1.81); P=0.728	20 (1.9)	28 (2.6)	8 (1.5)	0.66 (0.37, 1.18); P=0.163	1.25 (0.55, 2.84); P=0.592	16 (2.1)	20 (2.6)	0.76 (0.39, 1.46); P=0.409
Composite, any event (excluding TDI)	204 (29.7)	309 (45.4)	0.56 (0.47, 0.67); P<0.001	353 (32.8)	440 (41.0)	183 (34.0)	0.72 (0.62, 0.82); P<0.001	0.97 (0.81, 1.16); P=0.754	340 (44.5)	370 (48.2)	0.86 (0.74, 1.00); P=0.051
Composite, any event (including TDI)	222 (32.3)	325 (47.8)	0.58 (0.49, 0.69); P<0.001	–	–	–	–	–	–	–	–

Notes:

a Patients with decrease from baseline ≥100 mL maintained at all subsequent visits;

b patients with deterioration (ie, increase from baseline) ≥4 units maintained at all subsequent visits;

c patients with deterioration (ie, TDI focal score ≤−1 unit) maintained at all subsequent visits;

d patients with a moderate/severe exacerbation;

e patients with a moderate/severe exacerbation who also met one of the following features: a clinically important deterioration in FEV₁ and/or SGRQ at all subsequent visits (and/or TDI focal score in the additional TRILOGY analysis), or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation. In the main definition, the composite sustained CID was: a CID in FEV₁ and/or SGRQ total score (and/or TDI focal score in TRILOGY) maintained at all subsequent visits; a moderate/severe exacerbation; or death. In the alternative definition, the composite sustained CID was: a CID in FEV₁ and/or SGRQ total score (and/or TDI focal score in TRILOGY) maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score (and/or TDI focal score in TRILOGY) at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death. Data in bold are for the composite endpoints.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; IND/GLY, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Data availability

Chiesi commits to sharing with qualified scientific and medical researchers, conducting legitimate research, the anonymized patient-level data, the study-level data, the clinical protocol and the full CSR of Chiesi Farmaceutici SpA-sponsored interventional clinical trials in patients for medicines and indications approved by the European Medicines Agency and/or the US Food and Drug Administration after 1 January 2015.

Chiesi commits to sharing the clinical data of TRILOGY (NCT1917331) and TRINITY (NCT1911364) studies starting from 1 January 2019, following the approval of any received research proposal and the signature of a Data Sharing Agreement. Chiesi provides access to clinical trial information consistently with the principle of safeguarding commercially confidential information and patient privacy. To date, TRIBUTE (NCT2579850) is out of scope of the Chiesi policy on clinical data sharing.

Other information on Chiesi’s data sharing commitment, access, and research request’s approval process will be available from 1 January 2019 in the Clinical Trial Transparency section of this webpage page: http://www.chiesi.com/en/research-and-development/.