Web viewAbstract word count: 245. Text word count: 3,174. Efficacy and Safety of Once-Daily...
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Transcript of 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)
2
% 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.
3
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
4
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.
5
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:
7
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
14
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)
15
c)
FF = fluticasone furoate; FP = fluticasone propionate; LS = least squares; SAL = salmeterol; VI = vilanterol.
16