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.