Triple Therapy in COPD: What We Know and What We Don't

Figures & data

Table 1. Patient disposition/enrollment criteria and key results from initial studies (pre-2016) demonstrating the efficacy of triple therapy combinations of LABA/ICS and LAMA administered using different inhaler devices.

				Inclusion/exclusion criteria
Study name						Number/
and patient	Run-in			Airflow		severity of	Prior
number	treatment	Duration	Comparators	limitation	Symptoms	exacerbations	medication	Key results
OPTIMAL (16) (N = 449)	N/A	52 weeks	SFC 25/250 µg two puffs BID plus TIO 18 µg QD TIO 18 µg QD plus SAL 25 µg two puffs BID TIO 18 µg QD	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	≥1 exacerbation requiring treatment with ICS or antibiotics in the previous 12 months	N/A	Primary outcome: No significant difference in the proportion of patients who experienced ≥1 COPD exacerbation (60.0%, 64.8% and 62.8% of patients in SFC + TIO, TIO + SAL and TIO groups, respectively) Secondary outcomes: No significant difference in TDI total score (mean scores 1.84, 1.40 and 1.78 units, respectively), rate of exacerbations (mean exacerbations per patient year 1.37, 1.75 and 1.61, respectively) or time-to-first exacerbation (217, 128 and 130 days, respectively) Triple therapy, compared with TIO, significantly improved pre-bronchodilator FEV1 (increase of 86 mL vs 27 mL;  p = 0.049) and SGRQ total score (change in score –8.6 units vs. –4.5 units; p = 0.01)
Singh et al. (17) (N = 41)	N/A	13 weeks	SFC 50/500 µg BID TIO 18 µg QD SFC 50/500 µg BID plus TIO 18 µg QD In a crossover study	Post-bronchodilator FEV1 30–75% predicted Post-bronchodilator FEV1/FVC 0.7	mMRC dyspnea scale minimum score of ≥2	Patients with COPD exacerbations were excluded	Patients who had used systemic CS within 4 weeks, or antibiotics within 8 weeks prior to randomization were excluded	Primary outcome: Triple therapy significantly improved AUC0–4h sGaw compared with TIO (ratio 1.22; 97.5% CI: 1.10–1.35;  p < 0.001) and SFC (ratio 1.27; 97.5% CI: 1.14–1.42;  p < 0.001) Secondary outcomes: Triple therapy significantly improved trough FEV1 (between-treatment differences: 212 mL; p < 0.001 and 110 mL; p = 0.017, respectively) and significantly reduced rescue medication use (1.0 occasion less; p < 0.001, and 0.6 of an occasion less; p = 0.013, respectively) compared with TIO and SFC
CLIMB (18) (N = 660)	TIO 18 µg QD plus reliever medication (2 weeks)	12 weeks	BUD/FOR 320/9 µg BID plus TIO 18 µg QD TIO 18 µg QD	Pre-bronchodilator FEV1 <50% predicted FEV1/FVC <0.7	N/A	≥1 exacerbation in the previous 12 months requiring treatment with systemic steroids and/or antibiotics Patients eligible for LABA/ICS combination therapy	Patients who had used ICS within 2 weeks or systemic CS within 4 weeks prior to visit 2 were excluded	Primary outcome: Triple therapy significantly improved pre-dose FEV1 compared with TIO (6% increase [65 mL]; p < 0.001) Secondary outcome: Triple therapy significantly improved post-dose FEV1 (11% increase [123 and 131 mL at 5 and 60 min post-dose, respectively]; both  p < 0.001) and reduced exacerbation rate vs TIO (rate ratio, 0.38; 95% CI: 0.25–0.57;  p < 0.001) Triple therapy significantly improved SGRQ total score (mean difference:  –2.3 units; p = 0.023) and symptoms (as measured by GCSQ [mean difference in scores for chest tightness and breathlessness ranging from –0.104 to –0.185 at 5 min and 15 min post-dose; all p < 0.05] and COPD symptoms rating scale [mean difference in scores ranging from –0.142 to –0.161 for breathlessness, chest tightness, nighttime awakenings and cough; all p < 0.001]) vs. TIO
Hoshino and Ohtawa (19) (N = 30)	N/A	12 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1/FVC <0.7	N/A	Patients with >1 exacerbation in the 12 weeks prior to the study were excluded	N/A	Primary outcome: Triple therapy significantly decreased airway wall area corrected for body surface area; percentage wall area and absolute wall thickness (p < 0.05;  p < 0.01 and p < 0.01, respectively) and increased luminal area corrected for body surface area (p < 0.01) Secondary outcome: Triple therapy significantly improved SGRQ total score vs. TIO
Hanania et al. (20) (N = 342)	Open-label TIO 18 µg QD (4 weeks)	24 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1 40–80% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	<7% of patients suffered from >1 exacerbation in the previous 12 months	N/A	Primary outcome: Triple therapy significantly improved pre-dose FEV1 compared with TIO (LSM difference: 115 mL; p < 0.001) Secondary outcome: Triple therapy significantly improved rescue medication use compared with TIO (LSM difference: −0.6 [SE 0.24]; p  =  0.01) There were no significant differences in health status (LSM differences in CRQ-SAS domain scores ranging from 0.02 to 0.2) or exacerbation rate (0.14 vs. 0.17 for SFC + TIO and TIO, respectively)
Jung et al. (21) (N = 479)	Treatment not specified (2 weeks)	24 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	N/A	Patients were excluded if they had used systemic CS or immuno-suppressants ≤ 4 weeks prior to study entry	Primary outcome: Triple therapy significantly improved pre-bronchodilator FEV1 vs. TIO (90 mL vs. 38 mL; p = 0.005) Secondary outcome: Triple therapy significantly improved SGRQ-C scores vs TIO (mean change in score: −6.6 units vs. −1.5 units; p =  0.001)
NHS database study (22) (N = 2,853)	N/A	5 years	ICS plus LABA plus TIO ICS plus LABA	Post-bronchodilator FEV1 < 80% predicted (77) Post-bronchodilator FEV1/FVC <0.70 (77)	Dyspnea, chronic cough or sputum production, and/or a history of exposure to disease risk factors (77)	N/A	N/A	Triple therapy has benefits in reducing all-cause mortality (HR 0.65; 95% CI: 0.57–0.75; p < 0.001) and hospital admissions (HR 0.85; 95% CI: 0.73–0.99; p  =  0.04) compared with LABA/ICS
GLISTEN (23) (N = 773)	SFC 50/500 µg BID (one week)	12 weeks	SFC 50/500 µg BID plus GLY 50 µg QD SFC 50/500 µg BID plus TIO 18 µg QD SFC 50/500 µg BID	Post-bronchodilator FEV1 30– <80% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	Patients were excluded if they experienced a COPD exacerbation within 6 weeks before screening		Primary outcome: GLY + SFC was non-inferior to TIO + SFC in terms of trough FEV1 Secondary outcome: Compared with SFC plus placebo, triple therapy with SFC plus GLY significantly improved trough FEV1 (101 mL increase; p < 0.001), SGRQ total score (LSM treatment difference: −2.15 units; p = 0.02) and rescue medication use (between-group mean difference: −0.72 puffs/day; p < 0.001) No significant differences in SGRQ total score (LSM treatment difference: −1.1 units) or rescue medication use (between-group mean difference: 0.098 puffs/day) were reported between SFC plus GLY and SFC plus TIO groups

 

AUC, area under the curve; BID, twice daily; BUD, budesonide; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRQ-SAS, Chronic Respiratory Disease Questionnaire-Self-Administered Standardized; CS, corticosteroids; FEV₁, forced expiratory volume in 1 second; FEV₁/FVC, forced expiratory ratio; FOR, formoterol; GCSQ, Global Chest Symptoms Questionnaire; GLY, glycopyrronium; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LSM, least squares mean; mMRC, modified Medical Research Council dyspnea scale; N/A, not applicable/not reported; NHS, National Health Service; QD, once daily; SAL, salmeterol; SE, standard error; SFC, salmeterol/fluticasone; sGaw, specific airway conductance; SGRQ, St George's Respiratory Questionnaire; SGRQ-C, St George's Respiratory Questionnaire for COPD patients; TDI, Transition Dyspnea Index; TIO, tiotropium

Table 2. Patient disposition/enrollment criteria and key results from modern recent studies (2016 onwards), and studies yet to be published, demonstrating the efficacy of fixed-dose triple therapy combinations.

						Inclusion/exclusion criteria
Study name						Degree of		Number and
and patient			Run-in			airflow		severity of	Prior medication
number			treatment	Duration	Comparators	limitation	Symptoms	exacerbations	use	Key results/primary endpoint
TRILOGY (24) (N = 1,368)			BDP/FOR 100/6 µg two puffs BID (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/12.5 µg two puffs BID BDP/FOR 100/6 µg two puffs BID	Post-bronchodilator FEV1 <50%; Post-bronchodilator FEV1/FVC <0.7	CAT score ≥10 and BDI score ≤ 10	≥1 moderate or severe exacerbation in the previous 12 months	LABA/ICS Or ICS/LAMA Or LAMA monotherapy As open or fixed combinations for ≥2 months prior to screening	Primary outcome: Triple therapy significantly improved pre-dose FEV1 (adjusted mean difference: 81 mL; p < 0.001) and 2-hour post-dose FEV1 (adjusted mean difference: 117 mL; p < 0.001) compared with BDP/FOR Triple therapy did not significantly improve TDI total score compared with BDP/FOR (mean treatment difference: 0.21 units) Secondary outcomes: Triple therapy significantly improved SGRQ total score at Weeks 4, 12 and 52 vs. BDP/FOR (mean treatment difference at Week 52: –1.69 units; p = 0.029) Triple therapy significantly reduced the rate of moderate-to-severe exacerbations vs. BDP/FOR (rate ratio 0.77; 95% CI: 0.65–0.92; p  = 0.005) In patients with >1 exacerbation, triple therapy significantly reduced the rate of moderate-to-severe exacerbation vs. BDP/FOR (rate ratio 0.67; 95% CI: 0.48–0.94; p  =  0.019)
TRINITY (25) (N = 2,691)			TIO 18 µg QD (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/12.5 µg two puffs BID TIO 18 µg QD BDP/FOR 100/6 µg BID plus TIO 18 µg two puffs QD	Post-bronchodilator FEV1 <50% predicted	CAT score ≥10	≥1 moderate or severe exacerbation in the previous 12 months	LABA/ICS Or ICS plus LAMA Or LABA/LAMA Or LAMA monotherapy As open or fixed combinations for ≥2 months prior to screening	Primary outcome: BDP/FOR/GLY significantly reduced the rate of moderate or severe exacerbations compared with TIO (rate ratio 0.80; 95% CI: 0.69–0.92; p  =  0.0025) Secondary outcomes: BDP/FOR/GLY significantly improved pre-dose FEV1 compared with TIO (mean difference 61 mL; p < 0.0001) BDP/FOR/GLY was non-inferior to BDP/FOR plus TIO in terms of lung function (adjusted mean difference –3 mL) BDP/FOR/GLY significantly improved SGRQ total score compared with TIO at all time-points except Week 26 BDP/FOR/GLY and BDP/FOR plus TIO resulted in similar rates of moderate or severe exacerbations (rate ratio 1.01; 95% CI 0.85–1.21) and provided a similar mean change from baseline in SGRQ total score at all time-points except Weeks 26 and 52
FULFIL (26) (N = 1,810)			Medications at screening unchanged (2 weeks)	52 weeks	FF/UMEC/VI 100/62.5/25 µg QD BUD/FOR 400/12 µg BID	Post-bronchodilator FEV1 <50% or 50–80% predicted	CAT score ≥10	2 moderate or 1 severe exacerbation in the previous year	Daily maintenance treatment for COPD for ≥3 months prior to screening	Primary outcome: At Week 24, triple therapy significantly improved trough FEV1 (between- treatment difference: 171 mL; p < 0.001) and SGRQ total score (between-treatment difference:  –2.2 units; p < 0.001) compared with BUD/FOR Secondary outcomes: At Week 52, triple therapy significantly improved trough FEV1 compared with BUD/FOR (between- treatment difference: 179 mL; p < 0.001) No significant difference in SGRQ total score at Week 52 (between-treatment difference:  –2.7 units) Triple significantly reduced the rate of moderate or severe exacerbations (up to 24 weeks and 52 weeks) compared with BUD/FOR (35% reduction in rate; p  = 0.002 and 44% reduction in rate p = 0.006, respectively)
	Studies yet to be completed
IMPACT (27) (N = 10,000^*)			Treatment not specified (2 weeks)	52 weeks	FF/UMEC/VI 100/62.5/25 µg QD UMEC/VI 62.5/25 µg QD FF/VI 100/25 µg QD	Severe COPD Post-bronchodilator FEV1 <50% predicted and a documented history of >1 moderate or severe COPD exacerbation in the previous 12 months (GOLD B) Or post-bronchodilator 50–80% FEV1 predicted and a documented history of >2 moderate exacerbations in the previous 12 months (GOLD D) Or documented history of >1 severe COPD exacerbation in the previous 12 months			Daily maintenance treatment for COPD for ≥3 months prior to screening	Primary outcome: Rate of moderate and severe exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate and severe exacerbations Rate of moderate and severe exacerbations in patients with blood eosinophil count ≥150 cells/µL Time to first moderate and severe exacerbation in patients with blood eosinophil count ≥150 cells/µL Change from baseline in trough FEV1 Change from baseline in SGRQ
TRIBUTE (28) (N = 2,192^*)			IND/GLY 85/43 µg QD (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/ 12.5 µg BID IND/GLY 85/43 µg QD	Post-bronchodilator FEV1 <50% predicted Post-bronchodilator FEV1/FVC <0.7	CAT score ≥10	≥1 exacerbation in the previous 12 months	LABA/ICS Or ICS/LAMA Or LABA/LAMA For ≥2 months prior to screening	Primary outcome: Rate of moderate and severe COPD exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate or severe exacerbation Rate of severe COPD exacerbations over 52-weeks of treatment Rate of moderate COPD exacerbations over 52-weeks of treatment Change from baseline in trough FEV1
ETHOS (29) (N = 8,000^*)			N/A	52 weeks	BUD/FOR/GLY 320/9.6/ 14.4 µg FOR/GLY 9.6/14.4 µg BUD/FOR 320/9.6 µg (Dosing frequency not specified)	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	History of exacerbation	N/A	Primary outcome: Rate of moderate and severe COPD exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate or severe exacerbation Change from baseline in rescue medication use Time to death (all cause)

 

^*Estimated enrollment. AB,antibiotics, BDP, beclomethasone dipropionate; BDI, baseline dyspnea index; BID, twice daily; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; CS, corticosteroids; FEV₁, forced expiratory volume in 1 second; FEV₁/FVC, forced expiratory ratio; FF, fluticasone furoate; FOR, formoterol fumarate; GOLD, Global initiative for chronic Obstructive Lung Disease; GLY, glycopyrronium bromide; IND/GLY, indacaterol/glycopyrronium; N/A, not applicable/not reported; QD, once daily; SFC, salmeterol/fluticasone; SGRQ-C, St George's Respiratory Questionnaire for COPD patients; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol

Figure 1. A proposed algorithm for ICS withdrawal adapted from Kaplan A, et al. (46). ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Figure 2. A two-step treatment algorithm for the treatment of COPD from Miravitlles and Anzueto. Eur Respir J 2017 (14). Reproduced with permission from the ©ERS 2017. European Respiratory Journal Feb, 2017, 49 (2) 1602200; DOI: 10.1183/13993003.02200–2016, At the Step 2: in patients with >1 exacerbation on LABA/LAMA, comorbidities and compliance to treatment should be assessed in order to determine additional treatment according to individual patient phenotype. COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale.

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