web viewabstract word count: 245. text word count: 3,174. efficacy and safety of once-daily...

Abstract word count: 245

Text word count: 3,174

Efficacy and Safety of Once-Daily Fluticasone Furoate/Vilanterol

(100/25 mcg) versus Twice-Daily Fluticasone Propionate/Salmeterol

(250/50 mcg) in COPD Patients

Supplementary Tables and Figures

Mark T. Dransfield a,b*, Gregory Feldman c, Phillip Korenblat d, Craig F. LaForce e, Nicholas

Locantore f, Massimo Pistolesi g, Michael L. Watkins f, Courtney Crim f, Fernando J.

Martinez h

Affiliations:

a UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, 35294,

USA

b Birmingham VA Medical Center, Birmingham, AL, 35233, USA

c S. Carolina Pharmaceutical Research, Spartanburg, SC, 29303, USA

d Clinical Research Center LLB, St Louis, MO, 63141, USA

e North Carolina Clinical Research, Raleigh, NC, 27607, USA

f GlaxoSmithKline, Research Triangle Park, NC, 27709, USA

g University of Florence, Florence, 50121 Firenze, Italy

h University of Michigan, Ann Arbor, MI, 48109, USA

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Table E1– Demographic and clinical characteristics (intent-to-treat population)

Study 1 Study 2 Study 3

FF/VI 100/25mcg

N = 260

FP/SAL 250/50mcg

N = 259

FF/VI 100/25mcg

N = 259

FP/SAL 250/50mcg

N = 252

FF/VI 100/25mcg

N = 412

FP/SAL 250/50mcg

N = 416

Demographics

Age, years: mean (SD) 61 (8) 61 (8) 62 (10) 62 (9) 61 (8) 61 (8)

Sex, n (%): male 164 (63) 169 (65) 181 (70) 167 (66) 301 (73) 294 (71)

Race, n (%): white 254 (98) 250 (97) 242 (93) 238 (94) 403 (98) 410 (99)

BMI, kg/m2: mean (SD) 27 (6) 27 (6) 28 (6) 27 (5) 27 (6) 28 (6)

COPD duration <10 yrs, n

(%)177 (68) 193 (75) 165 (64) 160 (63) 321 (78) 317 (77)

Current smoker, n (%) 141 (54) 142 (55) 121 (47) 131 (52) 234 (57) 249 (60)

Pack-years, mean (SD) 40 (20) 39 (21) 41 (23) 44 (27) 44 (24) 43 (22)

Screening lung function (before 2-week placebo run-in)

Post- bronchodilator FEV1,

L mean (SD)1.46 (0.50) 1.45 (0.47) 1.48 (0.50) 1.46 (0.47) 1.51 (0.48) 1.51 (0.48)

Post-bronchodilator FEV1, 48 (12) 47 (12) 48 (12) 49 (12) 48 (13) 48 (12)

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% mean (SD)

Post-bronchodilator FEV1

reversibility, % mean (SD)11 (12) 11 (12) 12 (15) 12 (15) 12 (13) 12 (13)

Reversible to albuterol, n

(%)55 (21) 65 (25) 75 (29) 71 (28) 116 (28) 125 (30)

Post-bronchodilator

FEV1/FVC, L mean (SD)0.50 (0.11) 0.49 (0.10) 0.51 (0.10) 0.50 (0.10) 0.52 (0.10) 0.51 (0.10)

Baseline lung function (pre-dose on Day 1 of randomization)

Pre-bronchodilator FEV1,

L mean (SD)1.34 (0.48) 1.33 (0.47) 1.37 (0.52) 1.32 (0.47) 1.35 (0.5) 1.33 (0.5)

Pre-bronchodilator FEV1,

% mean (SD)44 (13) 43 (13) 45 (14) 44 (13) 43 (14) 42 (13)

BMI = body mass index; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 s; FF = fluticasone furoate; FP =

fluticasone propionate; FVC = forced vital capacity; SAL = salmeterol; SD = standard deviation; VI = vilanterol.

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Table E2– Other efficacy assessments (intent-to-treat population).

Study 1 Study 2 Study 3 Pooled data

FF/VI

100/25mcg

N = 260

FP/SAL

250/50mcg

N = 259

FF/VI

100/25mcg

N = 259

FP/SAL

250/50mcg

N = 252

FF/VI

100/25mcg

N = 412

FP/SAL

250/50mcg

N = 416

FF/VI

100/25mcg

N = 931

FP/SAL

250/50mcg

N = 927

Rescue use, occasions/24h Weeks 1–12

LS mean change from baseline

(SE)–0.49 (0.08) –0.48 (0.08) –0.61 (0.07) –0.50 (0.07) NA NA –0.58 (0.06) –0.52 (0.06)

LS mean treatment difference (95%

CI)

–0.01 (–0.20, 0.18)

P = 0.928

–0.11 (–0.30, 0.07) NA –0.06 (–0.19, 0.07)

P = 0.352

Rescue-free 24h periods, % Weeks 1–12

Percentage of rescue-free 24 h

periods48 47 59 51 NA NA 54 49

Pre-dose IC, mL on Day 84

LS mean change from baseline

(SE)106 (23) 73 (24) 104 (23) 72 (23) NA NA 105 (16) 72 (17)

LS mean treatment difference (95%

CI)

34 (–32, 99) 31 (–33, 96) NA 33 (–12, 79)

P = 0.154

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P = 0.310

wm (0–24h) FVC, mL on Day 84

LS mean change from baseline

(SE)152 (22) 59 (22) 45 (26) 45 (26) 148 (17) 126 (17) 120 (12) 86 (12)

LS mean treatment difference (95%

CI)

93 (32, 155)

P = 0.003

0 (–72, 73) 22 (–25, 69) 34 (0, 68)

P = 0.049

*Note: No inferences (P-values) provided for secondary/other endpoints in Study 2, as primary endpoint did not show an effect.

CI = confidence interval; FF = fluticasone furoate; FP = fluticasone propionate; FVC = forced vital capacity; IC = inspiratory capacity; LS = least

squares; SAL = salmeterol; SE = standard error; VI = vilanterol; wm = weighted mean.

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Table E3– Number (and %) of on-treatment AEs in individual studies (intent-to-treat population).

  Study 1 Study 2 Study 3 Pooled data

FF/VI 100/25mc

gN = 260

FP/SAL 250/50mcg

N = 259

FF/VI 100/25mcg

N = 259

FP/SAL 250/50mc

gN = 252

FF/VI 100/25mcg

N = 412

FP/SAL 250/50mcg

N = 416

FF/VI 100/25mc

gN = 931

FP/SAL 250/50mcg

N = 927

Cardiovascular effects 6 (2) 9 (3) 6 (2) 2 (<1) 10 (2) 10 (2) 22 (2) 21 (2)

Of which:                

Hypertension 0 3 (1) 2 (<1) 0 1 (<1) 2 (<1) 3 (<1) 5 (<1)

Blood pressure increased 1 (<1) 1 (<1) 1 (<1) 0 3 (<1) 1 (<1) 5 (<1) 2 (<1)

Chest pain 2 (<1) 0 2 (<1) 1 (<1) 2 (<1) 0 6 (<1) 1 (<1)

Atrial fibrillation 1 (<1) 1 (<1) 0 0 1 (<1) 0 2 (<1) 1 (<1)

Cardiac failure 0 1 (<1) 1 (<1) 0 0 1 (<1) 1 (<1) 2 (<1)

Cardiac failure congestive 0 1 (<1) 0 0 1 (<1) 1 (<1) 1 (<1) 2 (<1)

Oedema peripheral 1 (<1) 0 1 (<1) 0 1 (<1) 0 3 (<1) 0

Arrhythmia 0 1 (<1) 0 1 (<1) 0 0 0 2 (<1)

Myocardial infarction 0 0 1 (<1) 0 1 (<1) 0 2 (<1) 0

Palpitations 2 (<1) 0 0 1 (<1) 0 0 2 (<1) 0

Angina pectoris 0 0 0 0 0 1 (<1) 0 1 (<1)

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Angina unstable 0 0 1 (<1) 0 0 0 1 (<1) 0

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

Cardio-respiratory arrest 0 1 (<1) 0 0 0 0 0 1 (<1)

Cor pulmonale 0 0 0 0 0 1 (<1) 0 1 (<1)

Coronary artery disease 0 0 0 0 0 1 (<1) 0 1 (<1)

Sinus tachycardia 0 1 (<1) 0 0 0 0 0 1 (<1)

Syncope 0 1 (<1) 0 0 0 0 0 1 (<1)

Tachycardia 0 0 0 0 1 (<1) 0 1 (<1) 0

Troponin increased 0 0 0 0 1 (<1) 0 0 1 (<1)

Local steroid effects 4 (2) 10 (4) 10 (4) 21 (8) 13 (3) 15 (4) 27 (3) 46 (5)

Of which:                

Oral candidiasis 1 (<1) 5 (2) 2 (<1) 7 (3) 5 (1) 7 (2) 8 (<1) 19 (2)

Oropharyngeal candidiasis 0 2 (<1) 4 (2) 7 (3) 3 (<1) 2 (<1) 7 (<1) 11 (1)

Oropharyngeal pain 3 (<1) 2 (<1) 1 (<1) 3 (<1) 5 (1) 4 (<1) 9 (<1) 9 (<1)

Dysphonia 0 1 (<1) 1 (<1) 3 (1) 0 2 (<1) 1 (<1) 6 (<1)

Throat irritation 0 0 2 (<1) 1 (<1) 0 0 2 (<1) 1 (<1)

Candidiasis 0 0 0 1 (<1) 0 0 0 1 (<1)

Pneumonia 1 (<1) 0 3 (1) 0 4 (<1) 4 (<1) 8 (<1) 4 (<1)

Of which:                

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Pneumonia 0 0 2 (<1) 0 2 (<1) 4 (<1) 4 (<1) 4 (<1)

Bronchopneumonia 0 0 0 0 1 (<1) 0 1 (<1) 0

Lobar pneumonia 0 0 0 0 1 (<1) 0 1 (<1) 0

Lung consolidation 0 0 1 (<1) 0 0 0 1 (<1) 0

Tuberculosis 1 (<1)a 0 0 0 0 0 1 (<1)a 0

Hypersensitivity 3 (1) 2 (<1) 1 (<1) 2 (<1) 3 (<1) 0 7 (<1) 4 (<1)

LRTI excluding pneumonia 2 (<1) 2 (<1) 0 1 (<1) 0 4 (<1) 2 (<1) 7 (<1)

Bone disorders 1 (<1) 1 (<1) 2 (<1) 4 (2) 4 (<1) 2 (<1) 7 (<1) 7 (<1)

Effects on glucose 1 (<1) 1 (<1) 1 (<1) 0 3 (<1) 3 (<1) 5 (<1) 4 (<1)

Effects on potassium 1 (<1) 0 1 (<1) 0 1 (<1) 0 3 (<1) 0

Tremor 1 (<1) 0 0 0 0 0 1 (<1) 0

Ocular effects 0 0 0 1 (<1) 0 0 0 1 (<1)a Was an adverse event of tuberculosis.

FF = fluticasone furoate; FP = fluticasone propionate; LRTI = lower respiratory tract infection; SAL = salmeterol; VI = vilanterol.

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SUPPLEMENTARY FIGURES

Figure E1. CONSORT flowcharts for a) Study 1, b) Study 2, c) Study 3.

a)

aComprised: withdrew consent (n=7), investigator discretion (n=5), adverse event (n=1), protocol deviation (n=1).bTwo patients were randomized but did not receive any double-blind study medication and were therefore not included in the intent-to-treat population.

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b)

aComprised: withdrew consent (n =12), investigator discretion (n=7), lost to follow-up (n=1), protocol deviation (n=1).

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c)

aComprised: withdrew consent (n=15), investigator discretion (n=4), adverse event (n=4), lost to follow-up (n=2).

FF = fluticasone furoate; FP = fluticasone propionate; SAL = salmeterol; VI = vilanterol.

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Figure E2. LS mean FEV1 Day 84 change from baseline in a) Study 1, b) Study 2, c) Study 3 (intent-to-treat population).

a)

12

b)

13

c)

FF = fluticasone furoate; FP = fluticasone propionate; LS = least squares; SAL = salmeterol; VI = vilanterol

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Figure E3. Cumulative proportions of patients reaching an increase in FEV1 ≥100mL from 0–4 h on Day 1 in a) Study 1, b) Study 2, c) Study 3 (intent-to-treat population).

a)

b)

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c)

FF = fluticasone furoate; FP = fluticasone propionate; LS = least squares; SAL = salmeterol; VI = vilanterol.

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