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Efficacy and safety of fluticasone furoate 100µg once-daily in
patients with persistent asthma: a 24-week placebo and active-
controlled randomised trial
Jan Lötvall, Eugene R Bleecker, William W Busse, Paul M O’Byrne,
Ashley Woodcock, Edward M Kerwin, Sally Stone, Richard Forth, Loretta Jacques,
Eric D Bateman
ONLINE SUPPLEMENTARY MATERIAL
Additional methods
Study exclusion criteria
Exclusion criteria included a history of life-threatening asthma, clinically significant and
unresolved respiratory infection <4 weeks prior to screening, asthma exacerbation requiring
steroid treatment or resulting in hospitalisation within 6 months of screening, or other
clinically significant disease states.
Randomisation exclusion criteria
To be eligible for randomisation patients were required to exhibit evening pre-dose forced
expiratory volume in 1s (FEV1) of 40–90% predicted; the continued presence of symptoms
(combined daily asthma symptom score ≥1 or salbutamol use on four of the last 7 days of
run-in); and compliance with run-in inhaled corticosteroids and diary card entry (4 of the last
7 days of screening). Patients not meeting these criteria were excluded from randomisation,
as were those with abnormal laboratory tests, changes in asthma medication (excluding
inhaled albuterol/salbutamol), bacterial or viral infection, evidence of severe exacerbations,
or evidence of candidiasis.
Sample size and power calculations
A total of 330 patients were planned to be randomised (110 per arm). Assuming a 5%
withdrawal in the first 2 weeks of the study this would yield 104 patients per arm, which
would provide 94% power to detect a 200ml difference in pre-dose evening FEV1 between
fluticasone furoate (FF)100µg OD and placebo and 95% power to detect a 15% difference in
the percentage of rescue-free 24-h periods between FF100 µg and placebo. The power
calculations were based on a standard deviation for pre-dose evening FEV1 of 405ml and
30% for percentage of rescue-free 24-h periods at the two-sided 5% significance level,
based on prior studies.
Closed testing procedure
This entailed a hierarchy of comparisons where p≤0.05 was required for the prior
comparison to allow statistical significance to be inferred for the current comparison. The
order of testing for FF100µg versus placebo was (i) pre-dose evening FEV1, (ii) rescue-free
24-h periods, (iii) pre-dose evening PEF, (iv) morning PEF (v) symptom-free 24-h periods
and (vi) Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12). Thus, if the
difference for comparison (i), pre-dose evening FEV1, yielded a p-value >0.05 then no
significance could be inferred for subsequent comparisons within the hierarchy, regardless of
whether or not they yielded a p-value of ≤0.05. For that reason p-values are only presented
for comparisons of statistical significance, in other cases point estimates and 95%
confidence intervals only are presented.
Analysis populations
Analyses of efficacy and safety measures (except urine cortisol [UC]) are presented for the
intention-to-treat (ITT) population, comprising all randomised patients who received at least
one dose of study medication. The per-protocol population, comprising all patients in the ITT
population with no full protocol deviations, was used to confirm the findings in the ITT
population. Analysis of UC was conducted in the UC population, comprising all patients
whose urine samples did not have confounding factors that could affect interpretation of the
results.
Post-hoc analysis
A post-hoc sensitivity analysis of the pre-dose evening and morning PEF data was
conducted to assess the impact of a malfunctioning peak flow meter that resulted in one
patient exhibiting on-treatment PEF values that were much higher than those recorded
during run-in (the peak flow meter was replaced at randomisation).
Online Supplementary Table 1 Primary and powered secondary efficacy comparisons
(per-protocol population).
FF100µg OD vs.
placebo
FP250µg BD vs.
placebo
Pre-dose evening FEV1 (l): difference in
LS mean change from baseline (95% CI)
at week 24 (LOCF)
0.193
(0.068, 0.317)
0.179
(0.054, 0.304)
Rescue-free 24-h periods (%): difference
in LS mean change from baseline
(95% CI) over weeks 1–24
15.9
(7.3, 24.5)
17.1
(8.5, 25.7)
BD, twice daily; CI, confidence interval; FEV1, forced expiratory volume in 1s; FF, fluticasone furoate; FP, fluticasone propionate; LOCF, last observation carried forward; LS, least squares; OD, once daily.
Online Supplementary Table 2 Efficacy comparisons (intention-to-treat population) for
morning and evening PEF, initial analysis.
FF100µg OD vs.
placebo
FP250µg BD vs.
placebo
Evening PEF (l/min): difference in LS
mean change from baseline (95% CI)
over weeks 1–24
2.8 (-6.6, 12.2)
p=0.564
5.5 (-3.9, 15.0)
p=0.248
Morning PEF (l/min): difference in LS
mean change from baseline (95% CI)
over weeks 1–24
8.9 (-0.7, 18.5)
-
4.9 (-4.7, 14.5)
-
BD, twice daily; CI, confidence interval; FF, fluticasone furoate; FP, fluticasone propionate; LS, least
squares; OD, once daily; PEF, peak expiratory flow.
Online Supplementary Table 3 On-treatment drug-related adverse events occurring in
≥2 patients.
n (%) Placebo
N=115
FF100µg OD
N=114
FP250µg BD
N=114
Oral candidiasis 0 3 (3) 1 (<1)
Oropharyngeal candidiasis 0 3 (3) 1 (<1)
Dysphonia 0 1 (<1) 1 (<1)
Pruritis 1 (<1) 0 1 (<1)
Upper respiratory tract infection 0 2 (2) 0
BD, twice daily; FF, fluticasone furoate; FP, fluticasone propionate; OD, once daily.
Online Supplementary Figure 1 Pre-dose evening FEV1 treatment differences from
placebo over time.
BD, twice daily; CI, confidence interval; FF, fluticasone furoate; FP, fluticasone propionate; LS, least
squares; OD, once daily.
Online Supplementary Figure 2 Mean change from baseline in (a) evening and (b)
morning PEF (intention-to-treat population).
a
b
BD, twice daily; CI, confidence interval; FF, fluticasone furoate; FP, fluticasone propionate; OD, once
daily, PEF, peak expiratory flow.
Online Supplementary Figure 3. Cumulative incidence curve of time to withdrawal due to
lack of efficacy.
BD, twice daily; FF, fluticasone furoate; FP, fluticasone propionate; OD, once daily.
Online Supplementary Figure 4 24-h UC excretion at baseline and Week 24
(UC population): (a) individual patient data and (b) ratio of Week 24:baseline
BD, twice daily; CI, confidence interval; FF, fluticasone furoate; FP, fluticasone propionate; LS, least
squares; OD, once daily, UC, urinary cortisol.
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