FLUTICASONE FUROATE/VILANTEROL (100/25; 200/25 µg)

IMPROVES LUNG FUNCTION IN COPD: A RANDOMISED

TRIAL

Supplementary online material

Fernando J. Martinez, Joseph Boscia, Gregory Feldman, Catherine Scott-

Wilson, Sally Kilbride, Leonardo Fabbri, Courtney Crim, Peter M.A. Calverley

Methods

Subjects

Reversibility to albuterol (400 µg administered via metered-dose inhaler with a

valved-holding chamber [AeroChamber Plus; Forest Laboratories, New York, NY,

USA]) was assessed at the screening visit; reversible and non-reversible subjects

were eligible.

Subjects were to be excluded from randomisation into the double-blind

treatment period if they exhibited any of the following: chronic obstructive pulmonary

disorder (COPD) exacerbation/lower respiratory tract infection during the run-in

period; an abnormal, clinically significant laboratory finding at screening or upon

repeat screening prior to randomisation; an abnormal, clinically significant 12-lead

electrocardiogram (ECG) finding at screening or pre-dose (visit 2, randomisation); an

abnormal, clinically significant 12-lead, 24-h Holter finding at screening (sub-set of

subjects); non-compliance, defined as failure to demonstrate adequate completion of

the daily diary card (defined as completion of all entries on at least 4 of the last 7

consecutive days), at least 80% compliance with single-blind run-in medication, and

the ability to withhold anti-COPD medications and keep clinic visit appointments.

A subject could voluntarily discontinue participation in the study at any time.

The investigator could also, at his/her discretion, discontinue a subject from the

study at any time. According to the study protocol, reasons for withdrawal from the

study, as recorded in the electronic case report form (eCRF), could include: adverse

event (AE), withdrawal of consent, lost to follow-up, protocol deviation, lack of

efficacy, subject reached protocol-defined stopping criteria, study closed/terminated,

and investigator discretion.

Subjects could also be withdrawn from the study if any of the following criteria

were met: a subject-provided positive serum pregnancy test, the subject was

repeatedly non-compliant (<80% or >120%) with double-blind study medication; the

subject experienced a COPD exacerbation (defined as worsening of COPD

symptoms requiring the use of any treatment other than study medication or rescue

albuterol; this included requiring the use of antibiotics, systemic corticosteroids,

and/or emergency treatment or hospitalisation); clinically important changes in

laboratory parameters; pneumonia (presumptive diagnosis or radiographically

confirmed); a clinically significant ECG abnormality (as defined in, but not limited to,

the protocol) identified during the study; a clinically significant 24-h Holter (sub-set of

subjects) abnormality (as defined in, but not limited to, the protocol) identified during

the study.

Study design and treatments

At visit 1 (screening visit, start of run-in period), subjects who met all of the

inclusion criteria and none of the exclusion criteria entered a 2-week run-in period to

obtain baseline assessments of albuterol use and symptom scores, to determine

eligibility and to evaluate the subject’s adherence with study treatment and

procedures, diary card completion and disease stability.

Subjects were eligible to be randomised provided that none of the following

occurred between visit 1 (screening) and visit 2 (randomisation): COPD exacerbation

or lower respiratory tract infection; abnormal clinically significant findings including

liver chemistry, biochemical or haematology screening tests; evidence of active,

clinically significant abnormalities in 12-lead ECG or 24-h Holter ECG (selected

subjects) at screening or pre-dose at visit 2; evidence of non-compliance with

prohibited medications and keeping clinic visit appointments. Post-randomisation

(which occurred at day 1), subjects attended 10 scheduled clinic visits on days 2, 7

14, 28, 56, 84, 112, 140, 168, and 169; subjects received a follow-up telephone call

7 days after their last clinic visit. All visits occurred in the morning, scheduled so that

the visits occurred within approximately 22 h following the previous morning’s study

medication administration, in order to obtain the 23- and 24-h post-dose trough

forced expiratory volume in 1 second (FEV1) measurements. Subjects withheld study

medication on the morning of clinic visits and rescue medication (and ipratropium

bromide if applicable) for at least 4 h prior to and during clinic visits.

A subject who had been assigned a subject identifier and had completed at

least one study procedure (in addition to signing a consent form), but had not

entered the run-in period and was not randomised was classified as a screen failure.

A subject who had been assigned a subject identifier, had completed at least one

study procedure (in addition to signing a consent form), and was given the single-

blind (placebo) run-in medication but was not randomised, was classified as a run-in

failure.

Subjects were provided with albuterol, to use as needed for symptomatic relief

during the 2-week run-in period and throughout the 6-month treatment period. In

addition, ipratropium bromide alone was permitted, provided that the subject was on

a stable dose from the screening visit and remained on the stable dose throughout

the study. Other permitted medications during the run-in and treatment periods

included: mucolytics (constant dosage); antibiotics (that were not strong inhibitors of

cytochrome P450 3A4) for short-term treatment (14 days) of acute non-respiratory

tract infections (e.g. erythromycin); over-the-counter cough suppressants for short-

term treatment (≤7 days); intranasal sodium cromoglycate or nedocromil sodium;

antihistamines and nasal decongestants; intranasal corticosteroids (provided the

subject was on a stable, daily dose for at least 4 weeks prior to screening and

remained on this dose throughout the study); topical (1% hydrocortisone in

strength) or ophthalmic corticosteroids; influenza and/or pneumonia vaccination;

tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs); diuretics;

treatment(s) for smoking cessation; and medications for other disorders as long as

the dose remained constant wherever possible and their use was not expected to

affect lung function.

Medications prohibited prior to and during the study included: depot

corticosteroids (12 weeks prior to screening); systemic, oral or parenteral

corticosteroids, antibiotics (for lower respiratory tract infection [LRTI]) and

cytochrome P450 3A4 strong inhibitors (6 weeks prior to screening); inhaled

corticosteroids alone or in combination with a long-acting β2-agonist (4 weeks prior to

screening); long-acting anticholinergics (1 week prior to screening); theophyllines,

long-acting β2-agonists (LABA; oral and inhaled) and oral leukotriene inhibitors (48 h

prior to screening); oral short-acting β2-agonists (SABA; 12 h prior to screening);

inhaled sodium cromoglycate or nedocromil sodium (24 h prior to screening); and

ipratropium/albuterol combination products, short-acting anticholinergics and inhaled

SABA (4 h prior to screening).

Efficacy measurements

Spirometry was performed using equipment that met or exceeded the

minimum performance recommendations of the ATS.S1 All sites were provided

training and standardised spirometric equipment (MasterScope® CT; manufactured

by Cardinal Health, Hoechberg, Germany) by an external vendor (eResearch

Technology [ERT]; formerly known as CareFusion, Cardinal Health Research

Services, and Viasys during the study). To ensure consistency and accuracy of the

data collected, independent from GlaxsoSmithKline, centralised over-read and

evaluation of the spirometric data was provided by certified staff at ERT (Respiratory

OverRead department in Yorba Linda, CA, USA).

All subjects had lung function performed at each scheduled clinic visit to

assess FEV1 and forced vital capacity (FVC). At each planned time point, at least

three valid spirometry efforts were attempted (with no more than eight) using the

American Thoracic Society guidelines.S1 Spirometry was initiated in the morning,

after withholding the morning dose of permitted scheduled COPD medications, after

withholding the morning dose of single-blind study drug and prior to administration of

double-blind study medication (day 1), after withholding the morning dose of double-

blind study medication (day 2 through day 168 visits), and at all visits after

withholding albuterol rescue medication and/or ipratropium for ≥4 h, after refraining

from exercising for 2 h or more, after refraining from smoking for 1 h, after exposure

to cold air for 15 min, and after refraining from drinks with high levels of caffeine (e.g.

coffee, tea). Measurements were to be made as close to the scheduled time points

as possible.

Serial FEV1 assessments were performed pre-dose and post-dose (5, 15 and

30 min and 1, 2 and 4 h) on days 1, 14, 56, 84, and 168. The pre-dose assessments

were performed 30 and 5 min prior to dosing on day 1 and 23 and 24 h after the

previous morning’s dose of study medication on days 14, 56, 84, and 168). Trough

FEV1 assessments were performed at all clinic visits, from day 2 through day 169.

Subjects were provided a paper daily diary upon which they were instructed to

record their COPD symptoms (breathlessness [scale 0 (none) to 4 (severe)], cough

[scale 0 (none) to 3 (severe)] and sputum production [scale 0-3]), over the previous

24 h, the number of occasions that they used supplemental albuterol over the

previous 24 h, the number of night-time awakenings requiring albuterol during the

previous night, mean morning peak expiratory flow (AM PEF), and any medical

problems they may have experienced and any medications used to treat those

medical problems over the previous 24 h.

Safety evaluation

The safety endpoints for this study included: incidence of AEs; incidence of

COPD exacerbations; incidence of all pneumonias; change from baseline in pulse

rate, systolic blood pressure (BP) and diastolic BP on days 1 (10 min post-dose), 2,

7, 14, 28, 56 (pre-dose), 84 (pre-dose and 10 min post-dose post-dose) and 112,

140 and 168 (pre-dose) and 169; change from baseline in 12-lead ECG

assessments (heart rate and QT interval corrected using Friedericia’s formula

[QTcF]) on days 1 (10 min post-dose), 84 (pre-dose and 10 min post-dose) and 168

(pre-dose) and findings of potential clinical importance at each visit and time point;

change from baseline in clinical chemistry and haematology parameters at days 84

and 168 (including serum glucose and potassium at trough [pre-dose, non-fasting]

and 30 min post-dose [fasting]); change from baseline in oropharyngeal exam finding

at each treatment visit; Holter reading assessments in a subset of subjects (e.g.

measurements, important arrhythmias, findings of potential clinical importance) at

days 1, 84 and 168; and 24-h urinary cortisol (UC) excretion in a subset of subjects

at day 168.

All investigators were supplied with standardised 12-lead ECG equipment

(MasterScope® CT; manufactured by Cardinal Health) and standardised 12-lead

Holter monitoring equipment (conducted at selected sites) by eResearch Technology

(ERT; formerly known as CareFusion, Cardinal Health Research Services and

Viasys during the study). To ensure consistency and accuracy of the data collected,

independent from GlaxoSmithKline, centralised over-read and evaluation of the ECG

and Holter data was provided by certified staff at ERT (ECG and Holter over-reads

were conducted by staff through the Research Services Corlab in Hoechberg,

Germany). Standardised supplies and centralised analysis of chemistry and

haematology samples, 24-h urine samples (selected sites) and oropharyngeal swabs

were provided by Quest Diagnostics Clinical Trials (Heston, Middlesex, UK; Quest

Diagnostics Nichols Institute, San Juan Capistrano, CA, USA; Focus Diagnostics,

Inc, Cypress, CA, USA; and Tan Tock Seng Hospital, Department of Laboratory

Medicine, Tan Tock Seng, Singapore).

Statistical analyses

The intent to treat (ITT) population (defined as all randomised subjects who

received at least one dose of study medication) was the primary population for all

efficacy and safety analyses. The Per Protocol (PP) population was defined as

subjects in the ITT population who were not identified as full protocol deviators with

respect to reporting and analysis plan (RAP)-defined criteria that were considered to

impact the primary efficacy analysis. The PP population was used for confirmatory

analyses of the primary efficacy endpoints only. Twenty-four hour urine samples

were collected in a subset of subjects (approximately half) at selected sites. The UC

population was comprised of 407 subjects (33%) from the ITT population for whom a

urine sample was collected and whose samples were not considered to have

confounding factors that would affect the interpretation of the results. Twelve-lead,

24-h Holter monitoring was conducted in a subset of subjects (approximately half) at

selected sites. The Holter population was comprised of 541 subjects (44%) from the

ITT population for whom Holter monitoring was assessed.

Assuming a standard deviation (SD) of 210 ml derived from prior studies of

VIS2 and significance at the two-sided 5% level, a sample size of at least 146

evaluable subjects per arm was required for (1) 98% power to detect a 100 ml

difference between VI or FF/VI and placebo for wm or trough FEV1; (2) 98% power to

detect a 100 ml difference between FF/VI and FF for wm FEV1 (i.e. the contribution

of VI to the lung function effect of the combination); and (3) 90% power to detect a

80 ml difference between FF/VI and VI for trough FEV1 (i.e. the contribution of FF to

the lung function effect of the combination).

For both co-primary endpoints, the primary analysis for was performed using

mixed models repeated measures (MMRM) analysis. For weighted mean (wm) FEV1

(0–4 h), the analysis included covariates of baseline FEV1, smoking status (stratum),

day, center grouping, treatment, day by baseline interaction and day by treatment

interaction, where day is nominal. The model used all available wm FEV1 (0–4 h)

values recorded on days 1, 14, 56, 84, and 168. Missing data were not directly

imputed in this analysis; however, all non-missing data for a subject was used within

the analysis to estimate the treatment effect for wm FEV1 (0–4 h) on day 168. Two

models were fitted; one with a response variable of wm FEV1 (0–4 h), and one with a

response variable of change from baseline wm FEV1 (0–4 h). Change from baseline

trough FEV1 was analysed using the same MMRM model as described for wm FEV1

(0–4 h). All available trough FEV1 values, recorded at each clinic visit, were used in

the analysis. The primary analysis for both co-primary endpoints was repeated for

the PP population.

References

S1. Miller MR, Hankinson J, Brusaco V, et al. Standardisation of spirometry. Eur

Respir J 2005;26(2):319–38.

S2. Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel

long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-

controlled trial. Chest 2012;142(1):119–27.

Supplementary Tables

Table E1 Other endpoints – all comparisons analysed.

Comparison

Endpoint

FF 100/25 µg vs. PBO

FF 200/25 µg vs. PBO

VI vs. PBO FF 100 µg vs. PBO

FF 200 µg vs. PBO

FF 100/25 µg vs. VI

FF 200/25 µg vs. VI

FF 100/25 µg vs. FF 100

µg

FF 200/25 µg vs. FF 200

µg

Diary card: cough - weeks 1–24 (score)

–0.13a

(–0.22, –0.03)–0.15a

(–0.24, –0.06)–0.07

(–0.16, 0.02)–0.03

(–0.12, 0.06)–0.06

(–0.15, 0.04)–0.06

(–0.15, 0.03)–0.08

(–0.17, 0.01)–0.10a

(–0.19, –0.01)–0.09

(–0.19, –0.00)

Diary card: sputum - weeks 1–24 (score)

–0.14a

(–0.23, –0.05)–0.12a

(–0.20, –0.03)–0.02

(–0.11, 0.06)–0.03

(–0.12, 0.06)–0.07

(–0.16, 0.01)–0.12a

(–0.21, –0.03)–0.09a

(–0.18, –0.01)–0.11a

(–0.20, –0.02)–0.04

(–0.13, 0.04)

Diary card: breathlessness - weeks 1–24 (score)

–0.31a

(–0.42, –0.20)–0.32a

(–0.43, –0.21)–0.19a

(–0.30, –0.08)–0.09

(–0.20, 0.01)–0.13a

(–0.23, –0.02)–0.12a

(–0.23, –0.01)–0.13a

(–0.24, –0.02)–0.21a

(–0.32, –0.11)–0.19a

(–0.30, –0.08)

Diary card: rescue use - weeks 1–24 (occasions/24 h)

–0.71a

(–0.92, –0.49)–0.49

(–0.71, 0.28)–0.43a

(–0.65, –0.22)–0.17

(–0.39, 0.04)–0.15

(–0.37, 0.06)–0.27a

(–0.49, –0.06)–0.06

(–0.27, 0.15)–0.53a

(–0.75, –0.32)–0.34a

(–0.55, –0.13)

Diary card: night-time awakenings requiring rescue use - weeks 1–24 (occasions)

–0.20a

(–0.29, –0.11)–0.15a

(–0.23, –0.06)–0.11a

(–0.20, –0.02)–0.11a

(–0.20, –0.02)–0.03

(–0.12, 0.06)–0.08

(–0.17, 0.00)–0.03

(–0.12, 0.06)–0.08

(–0.17, 0.00)–0.11a

(–0.20, –0.02)

Diary card: night-time awakenings requiring rescue use in subjects with ≥ 1 awakening during baseline period - weeks 1–24 (occasions)

–0.36a

(–0.57, –0.16)–0.22a

(–0.44, –0.01)–0.16

(–0.38, 0.05)–0.21

(–0.42, 0.01)0.01

(–0.21, 0.23)–0.20

(–0.41, 0.01)–0.06

(–0.28, 0.16)–0.16

(–0.36, 0.05)–0.23a

(–0.45, –0.01)

Diary card: rescue-free 24 h periods - weeks 1–24 (periods) post-

13.54a

(7.91, 19.17)11.36a

(5.77, 16.96)4.90

(–0.72, 10.51)–0.08

(–5.70, 5.54)1.74

(–3.88, 7.35)8.64a

(3.02, 14.27)6.46a

(0.86, 12.07)13.62a

(7.98, 19.25)9.62a

(4.02, 15.23)

hoc analysis

Diary card: AM PEF - weeks 1–24 (l/min)

21.7a

(14.9, 28.6)20.1a

(13.3, 26.9)15.9a

(9.1, 22.8)9.0a

(2.2, 15.9)9.7a

(2.9, 16.5)5.8

(–1.0, 12.6)4.1

(–2.7, 10.9)12.7a

(5.9, 19.5)10.4a

(3.6, 17.2)CRQ-SAS: fatigue domain - day 168 (units)

0.23a

(0.03, 0.43)0.14

(–0.05, 0.34)0.16

(–0.04, 0.35)0.01

(–0.19, 0.20)0.04

(–0.16, 0.24)0.08

(–0.12, 0.28)–0.01

(–0.21, 0.18)0.23a

(0.03, 0.43)0.10

(–0.09, 0.30)

CRQ-SAS: emotional function domain - day 168 (units)

0.20a

(0.01, 0.39)0.10

(–0.09, 0.29)0.06

(–0.13, 0.25)–0.15

(–0.34, 0.04)–0.01

(–0.19, 0.18)0.14

(–0.05, 0.33)0.04

(–0.14, 0.23)0.35a

(0.16, 0.54)0.11

(–0.08, 0.29)

CRQ-SAS: mastery domain - day 168 (units)

0.21(–0.01, 0.44)

0.16(–0.06, 0.38)

0.13(–0.09, 0.35)

0.02(–0.20, 0.24)

0.01(–0.21, 0.23)

0.08(–0.14, 0.30)

0.03(–0.19, 0.24)

0.19(–0.03, 0.42)

0.15(–0.07, 0.37)

CRQ-SAS: total score - day 168 (units)

0.21a

(0.04, 0.38)0.11

(–0.06, 0.28)0.09

(–0.07, 0.26)–0.09

(–0.26, 0.08)–0.01

(–0.18, 0.16)0.12

(–0.05, 0.29)0.02

(–0.15, 0.18)0.30a

(0.13, 0.47)0.12

(–0.05, 0.28)

The median time to achievement of ≥12% improvement in FEV1 from baseline on day 1 was 35 min for VI 25 µg, 33 min for FF/VI 100/25 µg and 61 min for

FF 200/25 µg. No median time could be determined for placebo or either dose of FF as less than 50% of subjects in each arm had achieved the improvement

by 4 h on day 1. As the comparisons were conducted by log-rank analysis, which generates only p-values, and due to the statistical hierarchy meaning p-

values <0.05 cannot be inferred to be significant for comparisons at level 2 and below, no data are presented in the table. Diary card symptoms are scaled

from 0 to 4 (breathlessness) or 0 to 3 (cough, sputum), with 0 indicating no impairment. CRQ-SAS is scaled from 0 to 7, with 0 indicating no impairment; AM

PEF = mean morning peak expiratory flow, CRQ-SAS = Chronic Respiratory Questionnaire Self-Administered Standardized, FF = fluticasone furoate, PBO =

placebo, VI = vilanterol.

a Indicates comparisons where the 95% CI excludes zero. These data are interpreted descriptively and not as inferential findings due to the statistical

hierarchy used in the analysis.

Table E2: All on-treatment drug-related adverse events.

System organ class, n (%) Placebo N = 205

FF 100 µg N = 204

FF 200 µg N = 203

VI 25 µg N = 203

FF/VI 100/25 µg N = 204

FF/VI 200/25 µg N = 205

Any 20 (10) 13 (6) 27 (13) 13 (6) 21 (10) 18 (9)

Infections and infestations 6 (3) 7 (3) 14 (7) 3 (1) 13 (6) 10 (5)

Cardiac disorders 3 (1) 4 (2) 3 (1) 3 (1) 3 (1) 1 (<1)

Respiratory, thoracic and mediastinal disorders 2 (<1) 1 (<1) 4 (2) 1 (<1) 3 (1) 4 (2)

Gastrointestinal disorders 3 (1) 0 1 (<1) 3 (1) 1 (<1) 2 (<1)

Investigations 2 (<1) 0 1 (<1) 3 (1) 1 (<1) 1 (<1)

Nervous system disorders 2 (<1) 1 (<1) 1 (<1) 2 (<1) 1 (<1) 1 (<1)

General disorders and administrative site conditions 2 (<1) 0 1 (<1) 1 (<1) 0 1 (<1)

Psychiatric disorders 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 0

Musculoskeletal and connective tissue disorders 0 0 1 (<1) 1 (<1) 1 (<1) 0

Skin and subcutaneous tissue disorders 1 (<1) 0 0 0 1 (<1) 1 (<1)

Blood and lymphatic disorders 1 (<1) 0 1 (<1) 0 0 0

Metabolism and nutrition disorders 1 (<1) 0 0 1 (<1) 0 0

Injury, poisoning and procedural complications 0 0 0 0 1 (<1) 0

Vascular disorders 0 0 1 (<1) 0 0 0FF = fluticasone furoate, VI = vilanterol.

Table E3 All on-treatment serious adverse events.n (%) Placebo

N = 205FF 100 µg N = 204

FF 200 µg N = 203

VI 25 µg N = 203

FF/VI 100/25 µg N = 204

FF/VI 200/25 µg N = 205

COPD 5 (2) 0 2 (<1) 5 (2) 5 (2) 5 (2)

Pneumothorax 0 0 0 1 (< 1) 0 1 (<1)

Bronchiectasis 0 0 0 1 (< 1) 0 0

Pleural effusion 0 0 0 0 0 1 (<1)

Pneumonia 0 0 2 (<1) 2 (<1) 0 3 (1)

Infective exacerbation of COPD 1 (<1) 0 1 (<1) 1 (<1) 0 0

Appendicitis 0 0 0 0 1 (<1) 1 (<1)

Sepsis 0 1 (<1) 0 1 (<1) 0 0

Myocardial infarction 1 (<1) 1 (<1) 0 1 (<1) 0 1 (<1)

Acute myocardial infarction 0 1 (<1) 0 0 0 0

Atrial fibrillation 0 0 1 (<1) 0 0 0

Atrioventricular block first degree 0 0 1 (<1) 0 0 0

Bradycardia 0 0 1 (<1) 0 0 0

Cardiac failure chronic 0 0 0 0 0 1 (<1)

Cardiac failure congestive 0 0 0 1 (<1) 0 0

Myocardial ischaemia 1 (<1) 0 0 0 0 0

Supraventricular extrasystoles 0 0 0 0 1 (<1) 0

Abdominal hernia 0 0 0 1 (<1) 0 0

Enteritis 0 0 0 0 1 (<1) 0

Hiatus hernia 0 0 0 1 (<1) 0 0

Inguinal hernia 0 0 0 1 (<1) 0 0

Oesophagitis 0 1 (<1) 0 0 0 0

Pancreatitis 0 1 (<1) 0 0 0 0

Peritonitis 0 0 0 0 0 1 (<1)

Rectal haemmorhage 1 (<1) 0 0 0 0 0

Accidental poisoning 0 0 0 1 (<1) 0 0

Fibula fracture 0 0 1 (<1) 0 0 0

Incisional hernia 0 0 0 0 1 (<1) 0

Joint dislocation 0 0 0 1 (<1) 0 0

Subdural haematoma 0 0 0 0 1 (<1) 0

Tibia fracture 0 0 1 (<1) 0 0 0

COPD = chronic obstructive pulmonary disorder, FF = fluticasone furoate, VI = vilanterol.

Table E4 Adverse events and serious adverse events leading to permanent discontinuation of study drug or withdrawal from

the study.

System organ class, n (%) Placebo N = 205

FF 100 µg N = 204

FF 200 µg N = 203

VI 25 µg N = 203

FF/VI 100/25  µg N = 204

FF/VI 200/25  µg N = 205

Cardiac disorders 8 (4) 8 (4) 4 (2) 3 (1) 7 (3) 7 (3)

Infections and infestations 5 (2) 3 (1) 8 (4) 3 (1) 4 (2) 9 (4)

Respiratory, thoracic and mediastinal disorders 6 (3) 0 2 (<1) 3 (1) 5 (2) 6 (3)

Psychiatric disorders 3 (1) 0 1 (<1) 1 (<1) 0 0

Neoplasms benign, malign and unspecified (including cysts and polyps) 0 1 (<1) 0 2 (<1) 1 (<1) 0

Gastrointestinal disorders 0 0 1 (<1) 1 (<1) 1 (<1) 0

Investigations 1 (<1) 1 (<1) 0 0 1 (<1) 0

Nervous system disorders 0 0 0 0 2 (<1) 1 (<1)

Injury, poisoning and procedural complaint 0 0 0 2 (<1) 0 0

Blood and lymphatic disorders 0 1 (<1) 0 0 0 0

General disorders and administrative site conditions 0 0 0 1 (<1) 0 0

Immune system disorders 0 0 0 1 (<1) 0 0

Metabolism and nutrition disorders 0 0 1 (<1) 0 0 0

FF = fluticasone furoate, VI = vilanterol.

Table E5 On-treatment COPD exacerbations and pneumonias.

n (%) Placebo N = 205 FF 100 µg N = 204

FF 200 µg N = 203

VI 25 µg N = 203

FF/VI 100/25 µg N = 204

FF/VI 200/25 µg N = 205

COPD exacerbations

Subjects with 1 or more exacerbations

21 (10) 4 (2) 10 (5) 18 (9) 13 (6) 14 (7)

Total number of exacerbations, of which:

Moderatea Severeb

21

15 (71)6 (29)

4

4 (100)0

10

7 (70)3 (30)

18

11 (61)7 (39)

13

8 (62)5 (38)

14

8 (57)6 (43)

OutcomeResolved FatalNot resolved at discharge from study

20 (95)0

1 (5)

4 (100)00

10 (100)00

18 (100)00

12 (92)0

1 (8)

13 (93)0

1 (7)

Pneumonias

Total number of subjects with pneumonia recorded as an AE, of which: Pneumonia

recorded as an SAE

0

0

2 (<1)

0

3 (1)

2

2 (<1)

2

1 (<1)

0

4 (2)

3

aModerate exacerbations required systemic corticosteroids and/or antibiotics; bSevere exacerbations required hospitalisation. AE = adverse event, FF =

fluticasone furoate, SAE = serious adverse event, VI = vilanterol.

Supplementary Figures

Figure E1 Study design.

F = follow-up visit, FF = fluticasone furoate, R = randomisation visit, S = screening visit, VI = vilanterol.

Figure E2. Least squares weighted mean (0-4 h) FEV1 from day 1 to day 168: differences from (a) placebo and differences for

(b) FF/VI from FF.

(a)

(b)

CI = confidence interval, FEV1 = forced expiratory volume in 1 second, FF = fluticasone furoate, LS = least squares , VI = vilanterol, wm = weighted mean.

Figure E3 Least square means trough FEV1, change from baseline from day 2 to day 169: differences from (a) placebo and

differences for (b) FF/VI 200/25 µg and FF/VI 100/25 µg from VI 25 µg.

(a)

(b)

CI = confidence interval, FEV1 = forced expiratory volume in 1 second, FF = fluticasone furoate, LS = least squares, VI = vilanterol.

Figure E4 Serial FEV1 over the first 4 h post-dose on (a) day 1 and (b) day 168.

FEV1 = forced expiratory volume in first second, FF = fluticasone furoate, SD = standard deviation, VI = vilanterol.

Figure E5 24 h UC excretion ratio to baseline at day 168 (UC population).

FF = fluticasone furoate, UC = urinary cortisol, VI = vilanterol.

Figure E6 Change from baseline in pre-dose QTcF at day 168 (ITT population).

CI = confidence interval, FF = fluticasone furoate, ITT =

intent to treat, LS = ,least squares QTcF = QT interval corrected using Fridericia’s formula , VI = vilanterol.

Figure E7 Change from baseline in pre-dose ECG heart rate at day 168 (ITT population).

bpm = beats per minute, CI = confidence interval, ECG = electrocardiogram, FF = fluticasone furoate, ITT = intent to treat, LS = least squares, VI = vilanterol.