Table 3 Overview of key clinical trials comparing single or dual bronchodilator therapies with ICS/LABA combination therapy

Calverley et al. (2007) [87]

NCT00268216 TORCH

MC, R, DB, PG, PC, AC

3 years

FEV₁ < 60% predicted and FEV₁/ FVC ≤ 0.7

SALM 50 μg b.i.d.

FP 500 μg b.i.d.

SFC 500/50 μg b.i.d.

PBO^a

1,542

1,551

1,546

1,545

Symptomatic deterioration

requiring treatment with AB agents, systemic CS, hospitalization or a combination of these

• Annual rate of moderate or severe exac: 0.97 (SALM), 0.93 (FP), 0.85 (FP/SALM), 1.13 (PBO)

• Combination therapy reduced the rate of moderate or severe exac; RR:

 o FP/SALM vs SALM: 0.88 (95% CI 0.81, 0.95, p = 0.002)

 o FP/SALM vs FP: 0.91 (95% CI 0.84, 0.99, p = 0.02)

• Hospitalization for exac did not differ significantly between FP/SALM and monotherapies

Ohar et al. (2014) [129]

NCT01110200

ADC113874

MC, R, DB, PG, AC

26 weeks

FEV₁ < 70% predicted and FEV₁/ FVC < 0.7 plus recent (≤ 14 days) history of exac requiring hospitalization for ≤ 10 days; ER observation for ≥ 24 h during which OCS/ OCS + AB administered; or physician’s office/ER visit of < 24 h with OCS/OCS + AB and 6-month history of exac-related hospitalization

SALM 50 μg b.i.d.

SFC 250/50 μg b.i.d.

(1:1)

325

314

Worsening for ≥2 documented consecutive days of at least two of: dyspnea, sputum volume, sputum purulence, or at least one of these combined with sore throat, cold symptoms, fever or increased cough or wheeze

• No significant difference between FP/SALM vs SALM in rates of recurrent severe (ratio 0.92; 95% CI 0.58, 1.45) or moderate/severe (ratio 0.82; 95% CI 0.64, 1.06) exac

• No difference between FP/SALM vs SALM in time to first moderate/severe exac (HR 0.83; 95% CI 0.63, 1.09)

• Annualized exac rates in patient subgroup^b lower with FP/SALM (1.54) vs SALM (2.28); ratio 0.68 (95% CI 0.47, 0.97)

Calverley et al. (2010) [130]

NCT476099

MC, R, DB, DD, PG, AC

48 weeks

Severe stable COPD (FEV₁ 30–50% predicted and FEV₁/FVC ≤ 0.7) plus ≥ 1 exac requiring medical intervention (OCS and/or AB and/or ER visit and/or hospitalization) within 2–12 months before screening and to be clinically stable for 2 months before study entry

FOR 12 μg b.i.d.

BDP/FOR 200/12 μg b.i.d. BUD/FOR 400/12 μg b.i.d. (1:1:1)

239

237

242

Need for treatment with OCS and/or AB and/or visit/admission to hospital.

• ≥1 exac and mean rate/pt/yr similar between groups; corresponding data were

 o BDP/FOR: 27.6% and 0.414

 o BUD/FOR: 26.9% and 0.423

 o FOR: 28.3% and 0.431

• Hospitalizations for exac: 5.6% for BDP/FOR, 2.9% for BUD/FOR and 3.4% for FOR (p < 0.001 and p = 0.008 vs BDP/FOR, respectively)

Dransfield et al. (2013) [88]

Pooled analysis

Study 1

NCT01009463

HZC102871

Study 2

NCT01017952

HZC102970

2 x MC, R, DB, PG, AC

1 year

FEV₁ ≤ 70% predicted and FEV₁/FEV ≤ 0.7 plus a documented history of ≥ 1 exac requiring treatment (systemic/OCS/AB/hospitalization) in the preceding year

VI 25 μg q.d.

FF/VI 50/25 μg q.d.

FF/VI 100/25 μg q.d.

FF/VI 200/25 μg q.d.

(1:1:1:1)

818

820

806

811

Worsening symptoms of COPD (≥2 consecutive days) necessitating treatment with OCS or AB or both; severe exac were similar events that necessitated hospital admission

• Mean annual rate of moderate and severe exac was significantly lower with FF/VI vs VI alone; yearly ratios vs VI were

 o 0.8 (p = 0.0398) FF/VI 50/25 μg

 o 0.8 (p = 0.0244) FF/VI 100/25 μg

 o 0.7 (p = 0.0004) FF/VI 200/25 μg

• Time to first moderate or severe exac longer with FF/VI 100/25 and 200/25 μg vs VI

 o HR 0.8 (95% CI, 0.7, 1.0, p = 0.0365) and 0.7 (95% CI, 0.5, 0.8, p = 0.0001), respectively

• Exac necessitating treatment with CS significantly lower with FF/VI vs VI alone (p < 0.05 for 100/25 μg and p = 0.0009 for 200/25 μg)

Martinez et al. 2016 [89]

NCT01313676 SUMMIT

(post hoc analysis)

MC, R, DB, PG, PC

Event-driven, mortality^c

Moderate COPD (FEV₁ ≥ 50– ≤ 70% predicted; FEV₁/FEV ≤ 0.7) and a history of/multiple risk factors for CV disease^d

FF/VI 100/25 μg q.d.

FF 100 μg q.d.

VI 25 μg q.d.

PBO^a

4121

4135

4118

4111

Moderate exac: treated with AB and/or systemic CS; severe exac: required hospitalization

• % reduction in moderate/severe exacerbations compared with PBO: 12% (95% CI 4, 19) for FF; 10% (95% CI 2, 18) for VI; and 29% (95% CI 22, 35) for FF/VI

• % reduction in exacerbations requiring hospital admissions compared with PBO: 18% (95% CI 3, 31) for FF; 20% (95% CI 5, 32) for VI; and 27% (95% CI 13, 39) for FF/VI

• FF/VI reduced the rate of moderate/severe exacerbations by 19% vs FF (95% CI 12, 26, p < 0.001) and by 21% vs VI (95% CI 14, 28, p < 0.001)

• FF/VI reduced the % of exacerbations requiring hospital admissions by 11% vs FF (95% CI –6, 25, p = 0.204) and by 9% vs VI (95% CI –8, 25, p = 0.282)

Wedzicha et al. (2008) [54]

NCT00361959 INSPIRE

MC, R, DB, DD, PG

2 years

Severe and very severe COPD (FEV₁ < 50% predicted) and mMRC score ≥ 2

TIO 18 μg q.d.

SFC 500/50 μg b.i.d.

665

658

Defined by HCRU: episodes that required treatment with OCS and/or AB or hospitalization

• No difference in overall rate between FP/SALM (1.28/yr) and TIO (1.32/yr)

• Exac requiring AB with FP/SALM vs TIO: 0.97 vs 0.82/yr (p = 0.028)

• Exac requiring systemic CS with FP/SALM vs TIO: 0.69 vs 0.85/yr (p = 0.039)

• Hospitalizations: 16% with FP/SALM vs 13% with TIO (p = NS)

Study title

Study design

Duration

Patient population

Treatment arms

N

Exacerbation definition

Key exacerbation results

Bateman et al. and Banerji et al. (2014) [90, 131]

NCT01315249 ILLUMINATE (post hoc analysis)

MC, R, DB, DD, PG

26 weeks

Moderate-to-severe COPD (FEV₁ ≥ 40%– < 80% predicted and FEV₁/FEV < 0.7)

IND/GLY 110/50 μg q.d.

SFC 500/50 μg b.i.d.

258

264

Defined by modified Anthonisen criteria^e (increased dyspnea, sputum production and sputum purulence)

• No significant difference between treatments; RR (IND/GLY vs FP/SALM) of moderate/severe exac: 0.80 (95% CI 0.41, 1.56) and all exac: 0.69 (95% CI 0.44, 1.07)

• IND/GLY reduced risk of time to first exac by 35% vs FP/SALM (HR 0.65; 95% CI 0.44, 0.96, p = 0.03)

Zhong et al. (2015) [28]

NCT01709903 LANTERN

MC, R, DB, DD, PG

26 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30– < 80% predicted and FEV₁/FEV < 0.7), mMRC score ≥ 2 and history of ≤ 1 exac in the previous year

IND/GLY 110/50 μg q.d.

SFC 500/50 μg b.i.d.

372

372

Worsening of symptoms captured via eDiary; defined by Anthonisen criteria^e. Moderate exac: requiring treatment with systemic CS and/or AB; severe exac: requiring hospitalization/ER visit > 24 hours

• Annualized rate of moderate or severe exac significantly lower with IND/GLY vs FP/SALM (31% reduction; p = 0.048)

• IND/GLY prolonged time to first moderate or severe exac by 35% (p = 0.028)

• In patients with a history of moderate or severe exac, annualized rate

Wedzicha et al. (2016) [29]

NCT01782326 FLAME

MC, R, DB, DD, PG, NI

52 weeks

Moderate-to-very severe COPD (FEV₁ ≥ 25– < 60% predicted and FEV₁/FEV < 0.7), mMRC score ≥ 2 and documented history of ≥ 1 exac treated with systemic CS and/or AB in previous year

IND/GLY 110/50 μg q.d.

SFC 500/50 μg b.i.d.

1,680

1,682

Defined according to Anthonisen criteria^e. Categorized as mild (worsening of symptoms for >2 consecutive days but not requiring treatment), moderate (treated with systemic CS and/or AB) or severe (requiring hospital \admission/ER visit of >24 h plus systemic CS and/or AB)

• Annual rate of all exac: IND/GLY (3.59) was non-inferior to FP/SALM (4.03): representing an 11% lower rate (RR, 0.89, 95% CI 0.83, 0.96, p = 0.003)

• IND/GLY showed superiority to FP/SALM as the upper limits of the 95% CIs for the primary endpoint RRs were less than 1

• IND/GLY had a longer time to first exac than the FP/SALM group (median, 71 days [95% CI 60, 82] vs. 51 days [95% CI 46, 57]: HR 0.84 (95% CI 0.78, 0.91, representing a 16% lower risk; p < 0.001)

Vogelmeier et al. (2015) [132]

NCT01908140

AFFIRM

MC, R, DB, DD, AC

24 weeks

Symptomatic pts with FEV₁ < 80%, FEV₁/FVC < 0.7 and CAT ≥ 10

A/F 400/12 μg b.i.d.

SFC 500/50 μg b.i.d.

468

463

Defined by HCRU or identified using EXACT

• ≥1 exac: comparable between treatment groups:

 o HCRU: 15.8% (A/F) vs 16.6% (FP/SALM); OR 0.95

 o EXACT: 37.8% (A/F) vs 39.5% (FP/SALM); OR 0.94

Donohue et al. (2015) [26]

Study 1

NCT01817764

DB2114930

Study 2

NCT01879410

DB2114951

MC, R, DB, DD, PG

12 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30– ≤ 70% predicted), mMRC score ≥ 2, no exacerbations in the previous year

UMEC/VI 62.5/25 μg q.d.

SFC 250/50 μg b.i.d.

353 and 349

353 and 348

Captured only as a safety event. Defined as an acute worsening of COPD symptoms requiring use of AB, systemic CS, and/or emergency treatment or hospitalization

NCT01817764

• Exac rate was the same in each treatment group:

 o 3% (UMEC/VI) vs 3% (FP/SALM)

NCT01879410

• Exac rate was the same in each treatment group:

 o 3% (UMEC/VI) vs 3% (FP/SALM)

Singh et al. (2015) [92]

NCT01822899

MC, R, DB, DD, PG

12 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30– ≤ 70% predicted and FEV₁/FVC < 0.7), mMRC score ≥ 2, no exacerbations in the previous year

UMEC/VI 62.5/25 μg q.d.

SFC 500/50 μg b.i.d.

358

358

Captured only as a safety event. Not defined

• Exac rate was similar between treatment groups:

 o 2% (UMEC/VI) vs <1% (FP/SALM)

Beeh et al. (2016) [133]

NCT01969721 ENERGITO

MC, R, DB, DD, PG

12 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30– < 80% predicted and FEV₁/FEV < 0.7), no exacerbations in the previous 3 months

TIO/OLO

5/5 μg q.d.

TIO/OLO

5/2.5 μg q.d.

SFC 500/50 μg b.i.d.

SFC 250/50 μg b.i.d.

221

215

219

212

Captured only as a safety event as ‘COPD worsening’

• Exac rate was similar among each of the high- and low-dose groups:

 o 9.0% (TIO/OLO 5/5 μg) and 8.7% (FP/SALM 500/50 μg)

 o 5.6% (TIO/OLO 5/2.5 μg) and 4.2% (FP/SALM 250/50 μg)