Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in
patients with COPD. N Engl J Med 2018;378:1671-80. DOI: 10.1056/NEJMoa1713901
Supplementary Appendix

Table of contents
Figure S1. Patient Flow in the IMPACT Study. .................................................................. 2
Table S1. Summary of Reversibility and GOLD Grade at Screening.* ............................... 3
Table S2. Summary of COPD Duration at Screening.* ...................................................... 6
Table S3. Summary of Ethnicity Combinations.* ................................................................ 7
Table S4. Summary of COPD Concomitant Medication Combinations Taken at
Screening.* ........................................................................................................................ 8
Table S5. Analysis of Moderate/Severe COPD Exacerbations by Exacerbation History. . 10
Table S6. Analysis of On-treatment Moderate/Severe COPD Exacerbations Requiring
Systemic/Oral Corticosteroids. ........................................................................................ 11
Table S7. Analysis of On-treatment Moderate/Severe COPD Exacerbations Requiring .. 12
Antibiotics. ....................................................................................................................... 12
Table S8. Analysis of On-treatment Moderate/Severe COPD Exacerbations by Smoking
History. ............................................................................................................................ 13
Additional statistical information .......................................................................................... 14
Figure S2. Secondary endpoint hierarchy ........................................................................ 15
Protocol-Defined Secondary Endpoints ........................................................................... 15
Protocol-Defined Other Endpoints ................................................................................... 15
All-cause mortality including off-treatment information ........................................................ 16
Adjudicated causes of death ............................................................................................... 17
Table S9. Summary of On-Treatment Adjudicated Cause of Death.* ............................... 17
Table S10. Summary of Adjudicated Cause of Death Including Off-Treatment Data.* ..... 19
Additional safety information ............................................................................................... 21
Table S11. Overview of On-Treatment AEs.*................................................................... 21
Table S12. Most Frequent On-Treatment Serious Adverse Events (≥1%).* ..................... 23
Table S13. Summary of Adjudicated On-Treatment Fatal Serious Adverse Reports.* ..... 24
Table S14. Summary of Adverse Events Occurring in ≥2% of Patients. ........................... 28
Table S15. Adverse Events of Special Interest ................................................................ 30
Independent Data Monitoring Committee ........................................................................ 32

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Lipson et al_IMPACT ms

Figure S1. Patient Flow in the IMPACT Study.

NB: Patients may have had more than one sub-reason for discontinuation underneath a

single primary reason and were not required to indicate sub-reasons, therefore the

percentages may not sum to 100%.

2
Table S1. Summary of Reversibility and GOLD Grade at Screening.*

FF/UMEC/VI FF/VI UMEC/VI Total

(N=4151) (N=4134) (N=2070) (N=10,355)

GOLD grade (1–4)

No. 4145 4133 2069 10,347

Grade 1 (mild): percent predicted FEV1 ≥80% 10 (<1%) 8 (<1%) 4 (<1%) 22 (<1%)

Grade 2 (moderate): 50% percent predicted 1535 (37%) 1455 (35%) 729 (35%) 3719 (36%)

FEV1 <80%

Grade 3 (severe): 30% percent predicted FEV1 1934 (47%) 2031 (49%) 1017 (49%) 4982 (48%)

<50%

Grade 4 (very severe): percent predicted FEV1 666 (16%) 639 (15%) 319 (15%) 1624 (16%)

<30%

Reversible to salbutamol †

No. 4144 4133 2068 10,345

Reversible 734 (18%) 810 (20%) 366 (18%) 1910 (18%)

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Lipson et al_IMPACT ms

Not reversible 3410 (82%) 3323 (80%) 1702 (82%) 8435 (82%)

Exacerbation history

No. 4151 4134 2070 10,355

<2 moderate and no severe exacerbations in the 1198 (29%) 1242 (30%) 616 (30%) 3056 (30%)

past year

≥2 moderate or ≥1 severe exacerbation in the 2953 (71%) 2892 (70%) 1454 (70%) 7299 (70%)

past year

GOLD grade/exacerbation history

No. 4145 4133 2069 10,347

GOLD 1/2 with <2 moderate and no severe 17 (<1%) 21 (<1%) 10 (<1%) 48 (<1%)

exacerbations in the past year

GOLD 1/2 with ≥2 moderate or ≥1 severe 1528 (37%) 1442 (35%) 723 (35%) 3693 (36%)

exacerbation in the past year

GOLD 3/4 with <2 moderate and no severe 1180 (28%) 1220 (30%) 606 (29%) 3006 (29%)

exacerbations in the past year

4
Lipson et al_IMPACT ms

GOLD 3/4 with ≥2 moderate or ≥1 severe 1420 (34%) 1450 (35%) 730 (35%) 3600 (35%)

exacerbation in the past year

* FEV1 denotes forced expiratory volume in 1 second; † Reversible is an increase in FEV1 of ≥12% and >200mL following administration of

salbutamol. Not reversible is an increase in FEV1 of <200mL or a ≥200mL increase that is <12% of the pre-salbutamol FEV1. FF/UMEC/VI,

fluticasone furoate/umeclidinium/vilanterol; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

5
Lipson et al_IMPACT ms

Table S2. Summary of COPD Duration at Screening.*

FF/UMEC/VI FF/VI UMEC/VI Total

(N=4151) (N=4134) (N=2070) (N=10,355)

No. 4151 4134 2069 10,354

<1 year 213 (5%) 212 (5%) 117 (6%) 542 (5%)

≥1 to <5 years 1350 (33%) 1292 (31%) 705 (34%) 3347 (32%)

≥5 to <10 years 1370 (33%) 1400 (34%) 654 (32%) 3424 (33%)

≥10 to <15 years 747 (18%) 761 (18%) 363 (18%) 1871 (18%)

≥15 to <20 years 269 (6%) 280 (7%) 146 (7%) 695 (7%)

≥20 to <25 years 117 (3%) 112 (3%) 53 (3%) 282 (3%)

≥25 years 85 (2%) 77 (2%) 31 (1%) 193 (2%)

* COPD denotes chronic obstructive pulmonary disease; Table reflects time since diagnosis based on patient report

FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol.

6
Lipson et al_IMPACT ms

Table S3. Summary of Ethnicity Combinations.*

FF/UMEC/VI FF/VI UMEC/VI Total

(N=4151) (N=4134) (N=2070) (N=10,355)

No. 4151 4133 2070 10,354

American Indian or Alaska Native 87 (2%) 86 (2%) 45 (2%) 218 (2%)

Asian 668 (16%) 676 (16%) 335 (16%) 1679 (16%)

Central/South Asian Heritage 6 (<1%) 3 (<1%) 1 (<1%) 10 (<1%)

Japanese Heritage/East Asian Heritage/South 662 (16%) 673 (16%) 334 (16%) 1669 (16%)

East Asian Heritage

Black or African American 122 (3%) 99 (2%) 43 (2%) 264 (3%)

Native Hawaiian or other Pacific Islander 2 (<1%) 3 (<1%) 2 (<1%) 7 (<1%)

White 3231 (78%) 3224 (78%) 1628 (79%) 8083 (78%)

Multiple 41 (<1%) 45 (1%) 17 (<1%) 103 (<1%)

* FF/UMEC/VI denotes fluticasone furoate/umeclidinium/vilanterol.

7
Lipson et al_IMPACT ms

Table S4. Summary of COPD Concomitant Medication Combinations Taken at Screening.*

FF/UMEC/VI FF/VI UMEC/VI Total

(N=4151) (N=4134) (N=2070) N=10,355

No selected RMC medication combination 405 (10%) 411 (10%) 201 (10%) 1017 (10%)

No COPD medication reported 314 (8%) 316 (8%) 159 (8%) 789 (8%)

Other combination of RMC 91 (2%) 95 (2%) 42 (2%) 228 (2%)

ICS + LABA + LAMA 1396 (34%) 1433 (35%) 734 (35%) 3563 (34%)

ICS + LABA 1103 (27%) 1067 (26%) 523 (25%) 2693 (26%)

LABA + LAMA 330 (8%) 308 (7%) 163 (8%) 801 (8%)

LAMA 273 (7%) 331 (8%) 140 (7%) 744 (7%)

ICS + LABA + LAMA + Xanthine 142 (3%) 88 (2%) 67 (3%) 297 (3%)

ICS 109 (3%) 109 (3%) 55 (3%) 273 (3%)

ICS + LABA + Xanthine 109 (3%) 103 (2%) 51 (2%) 263 (3%)

LABA 98 (2%) 105 (3%) 42 (2%) 245 (2%)

ICS + LABA + LAMA + PDE4 inhibitors 39 (<1%) 41 (<1%) 21 (1%) 101 (<1%)

ICS + LAMA 42 (1%) 36 (<1%) 18 (<1%) 96 (<1%)

LABA + LAMA + Xanthine 23 (<1%) 16 (<1%) 15 (<1%) 54 (<1%)

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Lipson et al_IMPACT ms

Xanthine 16 (<1%) 24 (<1%) 7 (<1%) 47 (<1%)

ICS + Xanthine 16 (<1%) 18 (<1%) 5 (<1%) 39 (<1%)

LAMA + Xanthine 14 (<1%) 15 (<1%) 4 (<1%) 33 (<1%)

LABA + LAMA + PDE4 inhibitors 8 (<1%) 7 (<1%) 9 (<1%) 24 (<1%)

LABA + Xanthine 10 (<1%) 5 (<1%) 5 (<1%) 20 (<1%)

ICS + LABA + PDE4 Inhibitors 8 (<1%) 7 (<1%) 1 (<1%) 16 (<1%)

ICS + LABA + LAMA + PDE4 inhibitors + Xanthine 4 (<1%) 1 (<1%) 4 (<1%) 9 (<1%)

ICS + LAMA + Xanthine 1 (<1%) 3 (<1%) 1 (<1%) 5 (<1%)

ICS + LAMA + PDE4 inhibitors 2 (<1%) 2 (<1%) 0 4 (<1%)

PDE4 inhibitors 1 (<1%) 3 (<1%) 0 4 (<1%)

LABA + PDE4 inhibitors 1 (<1%) 1 (<1%) 1 (<1%) 3 (<1%)

LAMA + PDE4 inhibitors 1 (<1%) 0 2 (<1%) 3 (<1%)

ICS + LABA + PDE4 inhibitors + Xanthine 0 0 1 (<1%) 1 (<1%)

* COPD denotes chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol; ICS, inhaled corticosteroid;

LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; PDE4, phosphodiesterase type 4; RMC, respiratory medicine class.

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Lipson et al_IMPACT ms

Table S5. Analysis of Moderate/Severe COPD Exacerbations by Exacerbation History.

≤1 Moderate/Severe Exacerbations In Prior ≥2 Moderate/Severe Exacerbations In Prior

Year Year

FF/UMEC/VI FF/VI UMEC/VI FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070) (N=4151) (N=4134) (N=2070)

Number of patients in each subgroup 1855 1912 933 2296 2222 1137

Number of patients 1853 1911 932 2292 2222 1137

Model estimated exacerbation rate 0.86 1.08 1.08 0.94 1.06 1.32

(95% CI) (0.80 to 0.92) (1.01 to 1.15) (0.98 to 1.19) (0.89 to 1.00) (1.00 to 1.12) (1.21 to 1.43)

FF/UMEC/VI vs. column

Percentage reduction in annual 20%*** 21%*** 11%** 28%***

rate (95% CI) (13% to 28%) (11% to 29%) (3% to 18%) (21% to 35%)

CI denotes confidence interval; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol

**P<0.01; ***P<0.001

10
Table S6. Analysis of On-treatment Moderate/Severe COPD Exacerbations Requiring

Systemic/Oral Corticosteroids.

FF/VI UMEC/VI

(N=4134) (N=2070)

FF/UMEC/VI vs. column

Percentage reduction in annual rate 17%*** 33%***

(95% CI) (11% to 23%) (27% to 38%)

CI denotes confidence interval; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol

***P<0.001

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Table S7. Analysis of On-treatment Moderate/Severe COPD Exacerbations Requiring

Antibiotics.

FF/VI UMEC/VI

(N=4134) (N=2070)

FF/UMEC/VI vs. column

Percentage reduction in annual rate 13%*** 13%***

(95% CI) (7% to 18%) (6% to 20%)

CI denotes confidence interval; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol

***P<0.001

12
Table S8. Analysis of On-treatment Moderate/Severe COPD Exacerbations by Smoking History.

Current Smoker Former Smoker

FF/UMEC/VI FF/VI UMEC/VI FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070) (N=4151) (N=4134) (N=2070)

Number of patients in each subgroup 1436 1423 728 2715 2711 1342

Number of patients 1433 1423 728 2712 2710 1341

Model estimated 0.92 1.09 1.07 0.89 1.06 1.28

exacerbation rate (95% CI) (0.86 to 0.99) (1.01 to 1.17) (0.96 to 1.19) (0.85 to 0.95) (1.00 to 1.12) (1.18 to 1.38)

FF/UMEC/VI vs. column

Percentage reduction in rate 15%** 14%* 15%*** 30%***

(95% CI) (6% to 24%) (2% to 24%) (9% to 22%) (23% 36%)

CI denotes confidence interval; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol

*P<0.05; **P<0.01; ***P<0.001

13
Additional statistical information

Blinded exacerbation rates were examined after 12 and 18 months (approximately 5000 and

7500 patients, respectively), to determine if any adjustment to sample size was necessary.

No adjustment to the sample size was required.

The primary analysis of on-treatment moderate/severe COPD exacerbations was

performed using a generalized linear model assuming a negative binomial distribution and

covariates of treatment group, sex, smoking status at screening, geographical region, and

post-bronchodilator percent predicted FEV1 at screening. The percentage reduction in

annual rate was calculated as (1-rate ratio)*100. For time-to-first analyses hazard ratio and

95% CI are from a Cox proportional hazards model with covariates of treatment group, sex,

exacerbation history (1, ≥2 moderate/severe), smoking status at screening, geographical

region, and post-bronchodilator percent predicted FEV1 at screening. The percentage

reduction in risk was calculated as (1-hazard ratio)*100. Time to all-cause mortality was

analyzed using a Cox proportional hazards model with covariates of treatment group, age,

and sex. Due to patient withdrawals from investigational therapy 7991 patients (77%)

provided on-treatment vital status. In order to minimize data loss, patients were encouraged

to stay in the study even if they discontinued investigational therapy.

For the co-primary treatment comparisons (pairwise comparison of FF/UMEC/VI with

FF/VI and FF/UMEC/VI with UMEC/VI for the annual rate of on-treatment moderate/severe

exacerbations), both comparisons were declared statistically significant if the unadjusted p-

value for both comparisons were significant at the 0.04 level. Additionally, multiplicity across

selected treatment comparisons and key secondary endpoints were controlled using a

hierarchical, closed testing procedure. The secondary hypothesis tests were grouped

sequentially in two blocks of two comparisons each, grouped according to specific clinical

concepts (lung function and symptoms, and time to first exacerbation event). Each block of

comparisons were also adjusted for multiplicity using the truncated Hochberg method as

described for the primary endpoint analysis.

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Lipson et al_IMPACT ms

Figure S2. Secondary endpoint hierarchy

Since all treatment comparisons in the testing hierarchy demonstrated adjusted p-

values of <0.001 all further efficacy endpoints/treatment comparisons not in the above

testing hierarchy are considered statistically significant at the 0.05 reference level.

Protocol-Defined Secondary Endpoints

• Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with FF/VI

• Change from baseline SGRQ Total Score at Week 52 comparing FF/UMEC/VI with FF/VI

• Time to first on-treatment moderate or severe exacerbation comparing FF/UMEC/VI with

FF/VI and with UMEC/VI

• Annual rate of on-treatment moderate and severe exacerbations comparing FF/UMEC/VI

with UMEC/VI in the subset of subjects with a blood eosinophil count ≥150 cells/µl

• Time to first on-treatment moderate or severe exacerbation comparing FF/UMEC/VI with

UMEC/VI in the subset of subjects with a blood eosinophil count ≥150 cells/µl

• Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with FF/VI and

with UMEC/VI

Protocol-Defined Other Endpoints

• Change from baseline in post-bronchodilator FEV1

• Time to death from any cause

• Responder rate based on the SGRQ Total Score

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Lipson et al_IMPACT ms

• Annual rate of all on-treatment exacerbations (mild, moderate, severe)

• Annual rate of on-treatment moderate exacerbations

• Time to first on-treatment COPD hospitalization and COPD re-hospitalization

• Annual rate of exacerbations requiring systemic/oral corticosteroids

• Annual rate of exacerbations requiring antibiotics

• Transitional Dyspnea Index (TDI) focal score comparing FF/UMEC/VI with FF/VI

• Use of rescue albuterol/salbutamol (percentage of rescue-free days and occasions/day)

• Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with UMEC/VI

• Change from baseline in SGRQ Total Score comparing FF/UMEC/VI with UMEC/VI

• CAT score (change from baseline and responder rate)

• Subject Global Rating of Activity Limitation and Subject Global Impression of Change in

Activity Limitation

• Subject Global Rating of Severity of COPD and Change in COPD

• Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with UMEC/VI

in the subset of subjects with a blood eosinophil count ≥ 150 cells/µl

All-cause mortality including off-treatment information

There were 89 on- and off-treatment deaths (2.14%) in the FF/UMEC/VI arm, 97 deaths

(2.35%) in the FF/VI arm, and 60 deaths (2.90%) in the UMEC/VI arm. This corresponds to a

statistically significant 28.6% reduction in the risk of time to all-cause mortality on

FF/UMEC/VI versus UMEC/VI (HR, 0.71; 95% CI, 0.51 to 0.99; unadjusted P=0.043) and a

non-statistically significant reduction of 20.6% for FF/VI versus UMEC/VI (HR, 0.79; 95% CI,

0.58 to 1.10; P=0.164). There was no difference in the risk of all-cause mortality including

off-treatment data for FF/UMEC/VI versus FF/VI (10.3%; HR, 0.90; 95% CI, 0.67 to 1.20;

P=0.458). When off-treatment data are included in the analysis, vital status is available for

9781 (94.4%) of the total study population at Week 52. Data for the remaining 5.6% of

patients are currently being sought.

16
Adjudicated causes of death

Table S9. Summary of On-Treatment Adjudicated Cause of Death.*

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Total duration at risk — patient-years 3780.6 3523.3 1730.9

Primary cause of death

Total 50 (1%), 13.2 [50] 49 (1%), 13.9 [49] 39 (2%), 22.5 [39]

Cardiovascular 16 (<1%), 4.2 [16] 21 (<1%), 6.0 [21] 15 (<1%), 8.7 [15]

Respiratory 15 (<1%), 4.0 [15] 12 (<1%), 3.4 [12] 9 (<1%), 5.2 [9]

Cancer 4 (<1%), 1.1 [4] 4 (<1%), 1.1 [4] 2 (<1%), 1.2 [2]

Unknown 11 (<1%), 2.9 [11] 8 (<1%), 2.3 [8] 11 (<1%), 6.4 [11]

Other 4 (<1%), 1.1 [4] 4 (<1%), 1.1 [4] 2 (<1%), 1.2 [2]

Death associated with COPD

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Lipson et al_IMPACT ms

Yes 18 (<1%), 4.8 [18] 14 (<1%), 4.0 [14] 15 (<1%), 8.7 [15]

No 20 (<1%), 5.3 [20] 24 (<1%), 6.8 [24] 11 (<1%), 6.4 [11]

Inadequate information 7 (<1%), 1.9 [7] 6 (<1%), 1.7 [6] 9 (<1%), 5.2 [9]

Indeterminate 5 (<1%), 1.3 [5] 5 (<1%), 1.4 [5] 4 (<1%), 2.3 [4]

* COPD denotes chronic obstructive pulmonary disease; [#] = number of events; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol.

Data were adjudicated by an independent adjudication committee unaware of treatment assignment.

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Lipson et al_IMPACT ms

Table S10. Summary of Adjudicated Cause of Death Including Off-Treatment Data.*

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Total duration at risk — patient-years 4088.3 4030.1 1999.3

Primary cause of death

Total 88 (2%), 21.5 [88] 92 (2%), 22.8 [92] 58 (3%), 29.0 [58]

Cardiovascular 26 (<1%), 6.4 [26] 31 (<1%), 7.7 [31] 20 (<1%), 10.0 [20]

Respiratory 25 (<1%), 6.1 [25] 26 (<1%), 6.5 [26] 18 (<1%), 9.0 [18]

Cancer 13 (<1%), 3.2 [13] 7 (<1%), 1.7 [7] 6 (<1%), 3.0 [6]

Unknown 14 (<1%), 3.4 [14] 14 (<1%), 3.5 [14] 11 (<1%), 5.5 [11]

Other 10 (<1%), 2.4 [10] 14 (<1%), 3.5 [14] 3 (<1%), 1.5 [3]

Death associated with COPD

Yes 34 (<1%), 8.3 [34] 36 (<1%), 8.9 [36] 25 (1%), 12.5 [25]

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Lipson et al_IMPACT ms

No 40 (<1%), 9.8 [40] 37 (<1%), 9.2 [37] 16 (<1%), 8.0 [16]

Inadequate information 9 (<1%), 2.2 [9] 14 (<1%), 3.5 [14] 12 (<1%), 6.0 [12]

Indeterminate 5 (<1%), 1.2 [5] 5 (<1%), 1.2 [5] 5 (<1%), 2.5 [5]

* COPD denotes chronic obstructive pulmonary disease; [#] = number of events; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol.

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Lipson et al_IMPACT ms

Additional safety information

Table S11. Overview of On-Treatment AEs.*

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Total duration at risk — patient-years 3714.9 3457.9 1698.3

Any on-treatment AEs 2897 (70%), 2628.6 2800 (68%), 2593.7 [8969] 1429 (69%), 2580.3 [4382]

[9765]

Any on-treatment drug-related AEs 478 (12%), 181.7 [675] 492 (12%), 207.9 [719] 214 (10%), 175.5 [298]

Any on-treatment AEs leading to permanent 252 (6%), 92.1 [342] 327 (8%), 128.7 [445] 187 (9%), 144.3 [245]

discontinuation of study treatment or withdrawal from

study

Any on-treatment SAEs 895 (22%), 431.8 [1604] 850 (21%), 423.7 [1465] 470 (23%), 443.4 [753]

Any on-treatment non-fatal SAEs 847 (20%), 405.4 [1506] 801 (19%), 395.9 [1369] 433 (21%), 405.1 [688]

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Lipson et al_IMPACT ms

Any on-treatment fatal SAEs 68 (2%), 26.4 [98] 76 (2%), 27.8 [96] 49 (2%), 38.3 [65]

Any on-treatment drug-related SAEs 64 (2%), 21.8 [81] 57 (1%), 21.1 [73] 27 (1%), 22.4 [38]

Any on-treatment drug-related fatal SAEs 3 (<1%), 1.3 [5] 3 (<1%), 0.9 [3] 1 (<1%), 1.2 [2]

Any on-treatment adjudicated serious adverse reports 891 (21%), 323.3 [1201] 850 (21%), 326.8 [1130] 469 (23%), 353.9 [601]

Any on-treatment adjudicated non-fatal serious 834 (20%), 304.5 [1131] 791 (19%), 304.2 [1052] 429 (21%), 324.4 [551]

adverse reports

Any on-treatment adjudicated fatal serious adverse 70 (2%), 18.8 [70] 78 (2%), 22.6 [78] 50 (2%), 29.4 [50]

reports

* AE denotes adverse event; [#] = number of events; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol; SAE, serious adverse event.

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Lipson et al_IMPACT ms

Table S12. Most Frequent On-Treatment Serious Adverse Events (≥1%).*

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Preferred term

Chronic obstructive pulmonary disease 443 (11%), 149.1 [554] 450 (11%), 164.5 [569] 269 (13%), 198.4 [337]

Pneumonia 184 (4%), 53.3 [198] 152 (4%), 47.7 [165] 54 (3%), 32.4 [55]

* FF/UMEC/VI denotes fluticasone furoate/umeclidinium/vilanterol. [#] = number of events

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Lipson et al_IMPACT ms

Table S13. Summary of Adjudicated On-Treatment Fatal Serious Adverse Reports.*

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Total duration at risk (patient-years) 3714.9 3457.9 1698.3

Primary cause of death

Total 70 (2%), 18.8 [70] 78 (2%), 22.6 [78] 50 (2%), 29.4 [50]

Cardiovascular 20 (<1%), 5.4 [20] 27 (<1%), 7.8 [27] 16 (<1%), 9.4 [16]

Respiratory 20 (<1%), 5.4 [20] 22 (<1%), 6.4 [22] 14 (<1%), 8.2 [14]

Cancer 12 (<1%), 3.2 [12] 7 (<1%), 2.0 [7] 5 (<1%), 2.9 [5]

Unknown 11 (<1%), 3.0 [11] 10 (<1%), 2.9 [10] 11 (<1%), 6.5 [11]

Other 7 (<1%), 1.9 [7] 12 (<1%), 3.5 [12] 4 (<1%), 2.4 [4]

Death associated with COPD

Yes 25 (<1%), 6.7 [25] 30 (<1%), 8.7 [30] 20 (<1%), 11.8 [20]

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Lipson et al_IMPACT ms

No 32 (<1%), 8.6 [32] 35 (<1%), 10.1 [35] 16 (<1%), 9.4 [16]

Inadequate information 8 (<1%), 2.2 [8] 8 (<1%), 2.3 [8] 10 (<1%), 5.9 [10]

Indeterminate 5 (<1%), 1.3 [5] 5 (<1%), 1.4 [5] 4 (<1%), 2.4 [4]

Cardiovascular

Any event 20 (<1%), 5.4 [20] 27 (<1%), 7.8 [27] 16 (<1%), 9.4 [16]

Sudden death 12 (<1%), 3.2 [12] 16 (<1%), 4.6 [16] 11 (<1%), 6.5 [11]

Myocardial infarction/ischemic heart disease 1 (<1%), 0.3 [1] 2 (<1%), 0.6 [2] 1 (<1%), 0.6 [1]

Congestive heart failure 0 2 (<1%), 0.6 [2] 1 (<1%), 0.6 [1]

Stroke 3 (<1%), 0.8 [3] 7 (<1%), 2.0 [7] 1 (<1%), 0.6 [1]

Hemorrhagic 1 (<1%), 0.3 [1] 2 (<1%), 0.6 [2] 0

Thromboembolic 0 1 (<1%), 0.3 [1] 0

Indeterminate 2 (<1%), 0.5 [2] 4 (<1%), 1.2 [4] 1 (<1%), 0.6 [1]

Other cardiovascular cause 4 (<1%), 1.1 [4] 0 2 (<1%), 1.2 [2]

Respiratory

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Lipson et al_IMPACT ms

Any event 20 (<1%), 5.4 [20] 22 (<1%), 6.4 [22] 14 (<1%), 8.2 [14]

COPD exacerbation 17 (<1%), 4.6 [17] 17 (<1%), 4.9 [17] 12 (<1%), 7.1 [12]

With evidence of pneumonia 8 (<1%), 2.2 [8] 7 (<1%), 2.0 [7] 7 (<1%), 4.1 [7]

Without evidence of pneumonia 9 (<1%), 2.4 [9] 10 (<1%), 2.9 [10] 5 (<1%), 2.9 [5]

Pneumonia/respiratory tract infection without COPD 3 (<1%), 0.8 [3] 1 (<1%), 0.3 [1] 2 (<1%), 1.2 [2]

exacerbation

Asthma associated 0 0 0

Pulmonary embolism 0 0 0

Other respiratory cause 0 4 (<1%), 1.2 [4] 0

Cancer 12 (<1%), 3.2 [12] 7 (<1%), 2.0 [7] 5 (<1%), 2.9 [5]

Lung 7 (<1%), 1.9 [7] 4 (<1%), 1.2 [4] 2 (<1%),1.2 [2]

Breast 0 0 0

Colorectal 0 0 1 (<1%), 0.6 [1]

Unknown Primary 1 (<1%), 0.3 [1] 1 (<1%), 0.3 [1] 0

26
Lipson et al_IMPACT ms

Other Cancer Cause 4 (<1%),1.1 [4] 2 (<1%), 0.6 [2] 2 (<1%), 1.2 [2]

Unknown 11 (<1%), 3.0 [11] 10 (<1%), 2.9 [10] 11 (<1%), 6.5 [11]

Inadequate Information 9 (<1%), 2.4 [9] 7 (<1%), 2.0 [7] 7 (<1%), 4.1 [7]

Indeterminate 2 (<1%), 0.5 [2] 3 (<1%), 0.9 [3] 4 (<1%), 2.4 [4]

* COPD, chronic obstructive pulmonary disease; [#] = number of events; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol.

27
Lipson et al_IMPACT ms

Table S14. Summary of Adverse Events Occurring in ≥2% of Patients.

FF/UMEC/VI FF/VI UMEC/VI

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Adverse events occurring

in ≥2% of patients*

Viral URTI 521 (13), 191.9 [713] 479 (12), 190.3 [658] 223 (11), 186.7 [317]

URTI 299 (7), 108.5 [403] 283 (7), 111.0 [384] 117 (6), 95.4 [162]

Pneumonia 298 (7), 88.6 [329] 264 (6), 86.8 [300] 93 (4), 57.7 [98]

Bronchitis 152 (4), 47.1 [175] 130 (3), 47.1 [163] 73 (4), 50.6 [86]

Oral candidiasis 161 (4), 54.6 [203] 146 (4), 50.9 [176] 41 (2), 29.4 [50]

Influenza 117 (3), 34.7 [129] 102 (2), 31.5 [109] 50 (2), 34.2 [58]

Sinusitis 104 (3), 32.0 [119] 98 (2), 33.3 [115] 45 (2), 27.7 [47]

Urinary tract infection 92 (2), 30.1 [112] 86 (2), 30.1 [104] 35 (2), 25.3 [43]

Pharyngitis 82 (2), 29.1 [108] 81 (2), 25.7 [89] 48 (2), 34.7 [59]

Rhinitis 89 (2), 26.4 [98] 69 (2), 22.0 [76] 33 (2), 23.0 [39]

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Lipson et al_IMPACT ms

COPD 455 (11), 152.9 [568] 472 (11), 172.1 [595] 279 (13), 207.3 [352]

Cough 145 (3), 45.2 [168] 117 (3), 37.0 [128] 58 (3), 44.2 [75]

Dyspnea 82 (2), 26.6 [99] 95 (2), 31.8 [110] 52 (3), 37.1 [63]

Oropharyngeal pain 99 (2), 29.1 [108] 71 (2), 23.7 [82] 39 (2), 28.3 [48]

Back pain 148 (4), 49.0 [182] 140 (3), 48.0 [166] 83 (4), 59.5 [101]

Arthralgia 122 (3), 36.6 [136] 86 (2), 27.8 [96] 46 (2), 34.2 [58]

Diarrhoea 88 (2), 25.6 [95] 72 (2), 22.0 [76] 46 (2), 28.9 [49]

Constipation 65 (2), 18.6 [69] 63 (2), 21.7 [75] 16 (<1), 11.2 [19]

Nausea 37 (<1), 10.8 [40] 46 (1), 13.6 [47] 32 (2), 19.4 [33]

Headache 233 (6), 103.6 [385] 198 (5), 96.3 [333] 103 (5), 83.0 [141]

Hypertension 91 (2), 26.1 [97] 79 (2), 24.0 [83] 41 (2), 24.7 [42]

* Based on analysis of preferred terms; [#] = number of events; COPD denotes chronic obstructive pulmonary disease; FF/UMEC/VI,

fluticasone furoate/umeclidinium/vilanterol; URTI, upper respiratory tract infection.

29
Table S15. Adverse Events of Special Interest

FF/UMEC/VI FF/VI UMEC/VI

100/62.5/25 µg 100/25 µg 62.5/25 µg

(N=4151) (N=4134) (N=2070)

n (%), Rate [#] n (%), Rate [#] n (%), Rate [#]

Anticholinergic syndrome 184 (4), 60.8 140 (3), 47.1 70 (3), 47.7

[226] [163] [81]

Asthma/bronchospasm 27 (<1), 7.5 34 (<1), 10.1 16 (<1), 9.4

[28] [35] [16]

Cardiovascular effects 450 (11), 167.2 430 (10), 157.0 224 (11), 166.6

[621] [543] [283]

Cardiac arrhythmia 153 (4), 50.9 161 (4), 51.5 81 (4), 51.2

[189] [178] [87]

Cardiac failure 138 (3), 42.5 126 (3), 42.8 68 (3), 44.8

[158] [148] [76]

Central nervous system hemorrhages 41 (<1), 12.1 28 (<1), 9.3 11 (<1), 6.5

and cerebrovascular conditions [45] [32] [11]

Hypertension 113 (3), 35.5 115 (3), 35.0 54 (3), 34.2

[132] [121] [58]

Ischemic heart disease 80 (2), 26.1 57 (1), 18.5 47 (2), 30.6

[97] [64] [52]

Decreased bone mineral density and 98 (2), 32.6 85 (2), 26.9 37 (2), 24.7

associated fractures [121] [93] [42]

Effects on potassium 34 (<1), 9.2 25 (<1), 7.5 8 (<1), 4.7 [8]

[34] [26]

Gastrointestinal obstruction 9 (<1), 2.7 10 (<1), 2.9 2 (<1), 1.2 [2]

[10] [10]

30
Lipson et al_IMPACT ms

Hyperglycemia/new onset diabetes 152 (4), 47.4 117 (3), 37.9 73 (4), 46.5

mellitus [176] [131] [79]

Hypersensitivity 196 (5), 61.4 195 (5), 64.8 95 (5) 59.5

[228] [224] [101]

LRTI excluding pneumonia 200 (5), 63.0 199 (5), 69.7 108 (5), 76.0

[234] [241] [129]

Local steroid effects 337 (8), 114.4 301 (7), 107.3 108 (5), 80.1

[425] [371] [136]

Ocular effects 55 (1), 16.7 45 (1), 14.7 26 (1), 15.3

[62] [51] [26]

Pneumonia 317 (8), 95.8 292 (7), 96.6 97 (5), 61.2

[356] [334] [104]

Tremor 8 (<1), 2.2 [8] 4 (<1%) 1.2 6 (<1), 3.5 [6]

[4]

Urinary retention 8 (<1), 2.7 [10] 12 (<1), 3.5 9 (<1), 5.3 [9]

[12]

Adverse events of special interest are based on analysis of a group of prespecified AEs

associated with ICS, LAMA, or LABA use; [#] = number of events;

COPD denotes chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone

furoate/umeclidinium/vilanterol; LTRI, lower respiratory tract infection; URTI, upper
respiratory tract infection

31
Independent Data Monitoring Committee

An independent data monitoring committee (IDMC) reviewed unblinded safety information at

regular intervals during the conduct of the trial to ensure patient safety. The members of the

IDMC were Fernando J. Martinez (chair), Vernon Chinchilli, Martin Denvir, and Robert Wise.

The IDMC was supported by a Statistics Data Analysis Center (PAREXEL International

LLC), Derek H. Coombs was the independent statistician. The sponsor was excluded from

all IDMC deliberations/closed portions of the meetings.

32