Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

Figures & data

Table 1 The 2016 stepwise approach to asthma treatment¹

Asthma step	As-needed SABA	Low-dose ICS preferred controller	Medium/high-dose ICS/LABA	LTRA or Theo	Tiotropium	Alternative
Step 1	+	+
Step 2	+	+		+
Step 3	+a	+b	+b	+		+c
Step 4	+a		+	+	+d	+e
Step 5	+a		+	+	+d	+f

Notes: Adapted from GINA 2016.¹

a May also include a single low-dose ICS/formoterol as a reliever medication for patients prescribed low-dose BUD/F for maintenance or low-dose BEC/F for those patients using BEC/F for maintenance.

b Preferred step 3 maintenance for children aged 6–11 years is medium-dose ICS; adolescent/adults, low-dose ICS/LABA option.

c Medium/high-dose ICS, low-dose ICS + LTRA, low-dose ICS + Theo are alternate options.

d Tiotropium (LAMA) by spring-driven mist (not indicated in children aged <12 years).

e Tiotropium (LAMA) by spring-driven mist, high-dose ICS and LTRA or Theo are alternate options.

f Refer to asthma specialist for add-on treatment options including tiotropium (LAMA), omalizumab, mepolizumab and/or oral corticosteroids.

Abbreviations: BEC/F, beclomethasone dipropionate/formoterol; BUD/F, budesonide/formoterol; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroids; LABA, long-acting beta₂ agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; SABA, short-acting beta₂ agonist; Theo, theophylline.

Table 2 Major handheld inhaler therapy in asthma and COPD

Category	Drug	Dose (μg)	Additional drug	Dose (μg)	Frequency	Type	Examples of brand name
SABA	Albuterol sulfate	90	None	N/A	prn, q6h	MDI	Proventil HFA^®
	Albuterol sulfate	90	None	N/A	prn, q6h	MDI	Ventolin HFA^®
	Albuterol sulfate	90	None	N/A	prn, q6h	MDI	ProAir HFA^®
	Albuterol sulfate	90	None	N/A	prn, q4–6h	DPI	ProAir RespliClick^®
	Albuterol sulfate (salbutamol)a	100 and 200	None	N/A	prn, q6h	DPI	Easyhaler Salbutamol^®
	Levalbuterol tartrate	45	None	N/A	prn, q6h	MDI	Xopenex HFA^®
LABA	Formoterol fumarateb	12	None	N/A	Twice daily	DPI	Foradil^®
	Formoterol fumaratec	12	None	N/A	Twice daily	DPI	Atimos Modulite^®
	SAL xinafoate	50	None	N/A	Twice daily	DPI	Serevent Diskus^®
	SAL xinafoatea	25	None	N/A	Twice daily	MDI	Neovent^®
	Indacaterol maleated	75	None	N/A	Daily	DPI	Arcapta^®
	Indacaterol maleatec	150 and 300	None	N/A	Once daily	DPI	Onbrez Breezhaler^®
	Olodaterol hydrochlorided	2.5	None	N/A	Daily	SDM	Striverdi Respimat^®
SAMA	Ipratropium bromided,e	21	None	N/A	q6h	MDI	Atrovent HFA^®
LAMA	Tiotropium bromided	18	None	N/A	Daily	DPF	Spiriva HandiHaler^®
	Tiotropium bromided	2.5	None	N/A	Daily	SDM	Spiriva Respimat^®
	Tiotropium bromide	1.25	None	N/A	Daily	SDM	Spiriva Respimat^®
	Aclidinium bromided	400	None	N/A	Twice daily	DPI	Tudorza Pressair^®
	UMEC bromided	62.5	None	N/A	Daily	DPI	Incruse Ellipta^®
	Glycopyrrolate bromidec	50	None	N/A	Daily	DPI	Seebri Breezhaler^®
Combination of SABA + SAMA	Albuterol sulfated,e	100	Ipratropium bromide	30	q6h	SDM	Combivent Respimat^®
Combination of LAMA + LABA	Tiotropium bromided	2.5	Olodaterol	2.5	Daily	SDM	Stiolto Respimat^®
	Aclidinium bromidec	400	Formoterol	12	Twice daily	DPI	Duaklir Genuair^®
	UMEC bromided	62.5	VI	25	Daily	DPI	Anora Ellipta^®
	Glycopyrrolate bromided	15.6	Indacaterol	27.5	Twice daily	DPI	Ultibro Neohaler^®
	Glycopyrrolate bromidec	50	Indacaterol	110	Daily	DPI	Ultibro Breezhaler^®
	Glycopyrrolate bromided	9	Formoterol	4.8	Twice daily	MDI	Bevespi Aerosphere^®
ICS	Beclomethasone dipropionate	40 and 80	None	N/A	Twice daily	MDI	QVAR HFA^®
	Budesonide	90 and 180	None	N/A	Twice daily	DPI	Pulmicort Flexhaler^®
	Ciclesonide	80 and 160	None	N/A	Twice daily	MDI	Alvesco HFA^®
	FP	50, 100 and 250	None	N/A	Twice daily	DPI	Flovent Diskus^®
	FP	44, 110 and 220	None	N/A	Twice daily	MDI	Flovent HFA^®
	FF	100 and 200	None	N/A	Daily	DPI	Arnuity Ellipta^®
	Mometasone furoate	110 and 220	None	N/A	Daily and twice daily	DPI	Asmanex Twisthaler^®
Combination of ICS + LABA	Budesonide	80 and 160	Formoterol fumarate	4.5	Twice daily	MDI	Symbicort^®
	Budesonidea	160 and 320	Formoterol fumarate	4.5/9	Twice daily	DPI	DuoResp SpiroMax^®
	FP	100, 250 and 500	SAL xinafoate	50	Twice daily	DPI	Advair Diskus^®
	FP	45, 115 and 500	SAL xinafoate	21	Twice daily	MDI	Advair HFA^®
	FF	100 and 200	VI	25	Daily	DPI	Breo Ellipta^®
	Mometasone furoate	100 and 200	Formoterol fumarate	5	Twice daily	MDI	Dulera^®

Notes:

a Approved in the UK and Europe for COPD and asthmatic patients.

b No longer manufactured and sold in the USA but still FDA approved, still available in the UK/Europe.

c Approved in the UK, Europe and Canada for COPD, not routinely used in asthmatic patients.

d Approved by the FDA only for COPD, not routinely used in asthmatic patients.

e Used in acute exacerbations of asthma. q6h, every 6 hours; prn, as needed.

Abbreviations: COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FDA, US Food and Drug Administration; FF, fluticasone furoate; FP, fluticasone propionate; ICS, inhaled corticosteroid; LABA, long-acting beta₂ agonist; LAMA, long-acting muscarinic antagonist; MDI, metered dose inhaler; N/A, not applicable; SABA, short-acting beta₂ agonist; SAL, salmeterol; SAMA, short-acting muscarinic antagonist; SDM, spring-driven mist; UMEC, umeclidinium; VI, vilanterol trifenatate.

Table 3 Major clinical trials with FF in asthma

Study	Trial number	N	Drugs (μg)	Design	Results (doses in μg)
Bateman et al^Citation61	NCT00603382	598	FF (25, 50, 100 or 200) qpm or FP (100) bid or P	≥12-year-old asthmatics; MC, R, DB, DD, PC, PG, ×8 weeks	A dose–response effect on FEV1 was seen (P<0.001) for FF. FF (50–200) significantly (P<0.05) improved FEV1 from baseline compared to P. FF non-inferior to FP
Woodcock et al^Citation13	NCT01431950	238	FF (100 or 200) daily	≥12-year-old asthmatics uncontrolled on mid–high-dose ICS; MC, R, DB, PG, ×24 weeks	Least-squares mean trough FEV1 was improved from baseline for both doses of FF. No significant difference between FF (100) and FF (200). Similar rates of AEs. No clinically relevant effects on 24-hour urinary cortisol excretion at week 24 by either FF dose
Lötvall et al^Citation62	NCT01159912	343	FF (100) qpm or FP (250) bid or P	≥12-year-old asthmatics uncontrolled on ICS; MC, R, DB, DD, PC, PG, ×24 weeks	Both FF and FP significantly (P=0.01) increased pre-dose evening FEV1 compared to P at week 24. Less use of rescue medications with FF compared to P (P<0.001). AEs were similar. Week 24 urinary cortisol levels were significantly reduced (P=0.036) by both FF and FP compared to P
Busse et al^Citation63	NCT01436110	347	FF (50) qpm or FP (100) bid or P	≥12-year-old asthmatics uncontrolled by non-ICS therapy; MC, R, DB, DD, PC, PG, ×24 weeks	Evening trough FEV1 at week 24 was not significantly increased with FF (50) but increased with FP (100) bid (P=0.03). No safety concerns were noted
O’Byrne et al^Citation64	NCT01436071	248	FF (50) or P qpm	≥12-year-old asthmatics; MC, R, DB, PC, PG, ×12 weeks	Significant (P=0.012) increase in evening trough FEV1 with FF compared to P. Significant increase in rescue-free 24-hour periods (P=0.004) with FF compared to P. Lower AEs with FF (31%) than P (38%)
Woodcock et al^Citation11	NCT00398645	646	FF (200 or 400) qam or FF (200 or 400) qpm or FF (200) or P bid all by DPI	≥12-year-old asthmatics; MC, R, DB, PC, ×8 weeks	All five FF dose groups produced significant (P<0.05) increases in pre-dose FEV1 compared to P. No difference between qd and bid dosing. Low incidence (0%–4%) of oral candidiasis and no differences in urinary cortisol excretion
Woodcock et al^Citation65	NCT00766090	190	All patients received bid dosing – if listed as qd – second daily dose was P. FF (100) bid or FF (200) qpm or FP (200) qpm or FP (100) bid or P bid	≥12-year-old asthmatics; MC, R, XO, PC, XO, ×4 weeks	Day 28 pre-dose FEV1 showed non-inferiority between FF (100) bid versus FF (200) qpm. All doses of FP and FF were superior to P (P<0.02). AEs were similar to P. Urinary cortisol excretion at day 28, lower for FF than for FP (P≤0.02)
Medley et al^Citation66	NCT01499446	575	FF (100) qam or FF (100) qpm or FF (250) qpm or P	Asthmatic patients aged 16–55 years; MC, R, DB, DD, PC, PG, ×4 weeks	Trough PEF improved with all doses of FF compared to P (P≤0.005). No difference in trough PEF with FF (100) qam or qpm. No serious AEs
Busse et al^Citation67	NCT00063746	627	FF (200, 400, 600 or 800) qpm, FP (500) bid, P qpm	≥12-year-old asthmatics uncontrolled on ICS; MC, R, DB, DD, PC, PG, ×8 weeks	No dose–response effect was seen across the FF doses studied. All FF doses improved PEF (P<0.001) compared to P. Incidence of oral candidiasis increased compared to P with the FF (800) dose. FP (500) bid also improved PEF
Lee et al^Citation14	NCT01573624	421	FF (100) qam or FF (100) + UMEC (15.6, 31.25, 62.5, 125 or 250) qam or FF (100) + VI (25) qam	≥18-year-old asthmatics on ICS; MC, R, DB, XO, ×2 weeks	Trough FEV1 improved with FF (100) alone but > with FF1 (100) + UMEC (125 or 250). FF/UMEC increased morning and evening PEF compared to FF (100) alone. AEs were similar across groups, and no laboratory parameter changes were noted
Kempsford et al^Citation12	NCT01808339	21	FF (100) qam + P qpm or P qam + FF (100) qpm or P qam + P qpm	18–70-year-old asthmatics on ICS; SC, R, DB, DD, PC, XO, ×2 weeks	FF (100) increased 24-hour weighted mean FEV1. The increases for FF dosed in the AM or PM were comparable. No serious AEs were reported
Bleecker et al^Citation68	NCT 00603278	622	FF (100, 200, 300 or 400) qpm or FP (250) bid or P bid	≥12-year-old asthmatics; MC, R, DB, DD, PC, PG, ×8 weeks	Significant (P<0.001) greater increase in FEV1 with all doses of FF and FP than P. Increases with qd FF were equal or greater than with bid FP. The 24-hour urinary cortisol levels were similar with all doses of FF, FP and P
van den Berge et al^Citation69	Not given	24	Single dose – P or FF (1,000) −2, 14 or 26 hours or FP (1,000) −14 or 26 hours before AmpCT	Asthmatic patients not on ICS; MC, R, DB, PC, XO	Threshold dose AmpCT increased by prior exposure to FF at 2, 14 or 26 hours compared to P. Prior FP exposure only increased AmpCT threshold at 14 hours not at 26 hours compared to P
Yang et al^Citation15	NCT01725685	18	Single dose – FF (400) or UMEC (500) or FF (400) plus UMEC (500)	18–65-year-old healthy volunteers; SC, R, DB, XO	Plasma FF concentrations peaked at 0.5 hours alone and with combined FF/UMEC inhaler. No clinically significant AEs, vital signs or laboratory parameters
Allen et al^Citation70	NCT01000597	80	FF (250) intravenous or FF (800) or FF (400) both by DPI	20–59-year-old healthy Caucasian, Japanese, Korean and Chinese subjects; OL, R, XO, single and daily repeat doses ×7 days; intravenous dose ×1 only	Higher FF systemic exposures were seen in Chinese, Japanese and Korean subjects compared to Caucasian subjects. Bioavailability was higher in Asian subjects than Caucasian. Japanese had on average 22% lower serum weighted mean cortisol levels than Caucasians, Chinese or Koreans. Serum weighted mean cortisol levels were similar in Caucasians, Chinese or Koreans. Well tolerated in all groups

Notes: References in bold are key studies; bid, twice daily; qam, daily morning; qd, once daily; qpm, daily evening.

Abbreviations: AEs, adverse events; AmpCT, adenosine 5¹-monophosphate (AMP) challenge test; DB, double blind; DD, double dummy; DPI, dry powder inhaler; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; FP, fluticasone propionate; ICS, inhaled corticosteroid; MC, multiple centers; NCT, clinicaltrials.gov study numbers, OL, open label; P, placebo; PC, placebo controlled; PEF, peak expiratory flow; PG, parallel group; R, randomized; SC, single center; UMEC, umeclidinium; VI, vilanterol trifenatate; XO, crossover.

Table 4 Major clinical trials with VI in asthma

Study	Trial number	N	Drugs (μg)	Design	Results (doses in μg)
Kempsford et al^Citation17	NCT00469040; NCT00463697; NCT00519376; NCT00702910	36, 22 and 24	VI (25) or VI (50) or VI (100) or P all daily and VI (25) or VI (50) or VI (100) or P single dose and VI (6.25) or VI (25) or VI (100) or P all single dose, all by DPI	Healthy subjects (36) between 18 and 55 years old, SC, PC, R, DB, PG, ×14 days and persistent asthmatics (22) ≥18 years old, MC, R, DB, PC, XO, single dose and persistent asthmatics (24) between 18 and 55 years old, MC, R, DB, PC, XO, single dose	VI rapidly absorbed maximal concentration between 5 and 10 minutes. No significant changes in vital signs, 12-lead ECG or blood chemistry changes were noted with VI. All doses of VI resulted in increases in FEV1 within 5 minutes and lasted at least 24 hours
Lötvall et al^Citation21	NCT01181895	347	VI (25) daily SAL (50) bid or P, all by DPI	Adult asthmatics uncontrolled by ICS alone; MC, R, PC, DB, DD, ×12 weeks	VI, SAL and P all showed substantial improvement in 24-hour weighted mean FEV1 after 12 weeks without statistically significant differences. Low rates of AEs compared to P
Oliver et al^Citation20	NCT01573767	456	VI (6.25, 12.5 or 25) or P Daily, all by DPI, all replaced their ICS with FP (100) bid during 4-week run-in phase	Children aged 5–11 years with persistent asthma on ICS; MC, R, DB, PC, PG, ×4- and 1-week follow-up	The adjusted mean change from baseline in evening PEF averaged over the 4-week treatment phase showed no significant difference between VI and P. No difference was also seen in trough FEV1 between VI and P. VI resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week compared to P. AEs were slightly higher with VI (28%–33%) versus P (22%)
Lötvall et al^Citation18	NCT00600171	614	VI (3, 6.25, 12.5, 25 or 50) or P qpm, by DPI	≥12-year-old symptomatic asthmatics on stable ICS dose; MC, R, DB, P, dose-ranging study, ×28 days	A VI dose–response effect (P=0.037) was seen on improving trough FEV1. Statistically significant (P≤0.016) increases in mean FEV1 relative to P were seen for VI doses (12, 25 and 50). Prolonged bronchodilation was seen for at least 24 hours with VI
Sterling et al^Citation19	NCT00980200	75	VI (6.25) daily or VI (6.25) bid or VI (12.5) daily or VI (25) daily or P, all by DPI	≥18-year-old asthmatics on stable dose ICS; MC, R, DB, PC, XO, ×7 days	All VI doses had significant (P<0.001) increase in weighted mean 24-hour FEV1 compared to P. Low incidence of AEs with VI (5%–9%) without evidence of dose dependence. P AEs were 18%
Oliver et al^Citation71	NCT01453296	28	VI (25) or P single dose and VI (25) or P daily, all by DPI	Children aged 5–11 years with persistent asthma on ICS; MC, R, DB, PC, XO, single dose then 7 days later, once-daily dosing, ×7 days	All ages showed similar VI pharmacokinetics. No laboratory or ECG abnormalities. No change in PEF from day 1 to day 14

Notes: References in bold are key studies; bid, twice daily; qpm, daily evening.

Abbreviations: AEs, adverse events; DB, double blind; DD, double dummy; DPI, dry powder inhaler; ECG, electrocardiogram; FEV₁, forced expiratory volume in 1 second; FP, fluticasone propionate; ICS, inhaled corticosteroid; MC, multicenter; P, placebo; PC, placebo controlled; PEF, peak expiratory flow; PG, parallel group; R, randomized; SAL, salmeterol; SC, single center; VI, vilanterol trifenatate; XO, crossover.

Table 5 Pharmacokinetics of FF and VI

Drug	Mean absorption time (IN) (hours)	Absolute bioavailability (IN) (%)	tmax (IN) (hours)	t1/2 beta (hours)	VD (IN) (L)
FF	10.53 (8.52–13.01)	6.3–18.4; 15.2 (12.6–18.4)	1.0 (0.08–4.00) to 0.08 (0.08–1.50)	23.7 (20.8–26.9) (IN); 15.4 (13.1–18.2) (IV)	661 (546–800)
VI	0.659 (0.286–1.517)	10–12; 27.3 (21.6–34.6)	0.150 (0.08–0.17) to 0.100 (0.08–0.18)	2.47 (1.65–3.70) (IN); 2.40 (1.65–3.48) (IV)	165 (129–211)

Notes: Data are mean (90% CI); t_max, time to maximum observed concentration (inhaled); t_1/2 beta, terminal elimination half-life. Data from.^10,70,72,73

Abbreviations: CI, confidence interval; FF, fluticasone furoate; IN, inhaled dose; IV, intravenous dose; L, liters; VD, volume of distribution at steady state; VI, vilanterol trifenatate.

Table 6 Major clinical trials with FF/VI in asthma

Study	Trial number	N	Drugs (μg)	Design	Results (doses in μg)
Allen et al^Citation74	NCT01086410	185	FF (100)/VI (25) or FF (200)/VI (25) or P by DPI or P by DPI plus 10 mg Pred oral last 7 days	12–65-year-old asthmatic patients; MC, R, PC, DB, PG, DD, all daily doses ×6 weeks	No differences (non-inferior) in 24-hour weighted mean serum or urinary cortisol levels between FF/VI at either dose and P. Pred substantially reduced 24-hour weighted mean serum cortisol compared to P
Woodcock et al^Citation36	NCT01147848	806	FF (100)/VI (25) qpm or FP (250)/SAL (50) bid by DPI	≥12-year-old asthmatic patients on stable ICS; MC, R, DB, DD, PG, ×24 weeks	Significant improvement from baseline seen in 0–24-hour weighted mean FEV1 after 24-week treatment with both FF/VI qpm or FP/SAL bid. No difference in asthma control measures or exacerbations
Busse et al^Citation34	NCT01018186	503	FF (100)/VI (25) qpm or FF (200)/VI (25) qpm or FP (500) bid by DPI	≥12-year-old asthmatic patients on ICS; MC, R, DB, DD, PG, ×52 weeks	Exacerbation rates were FF (100)/VI (25) (1%), FF (200)/VI (25) (3%) and FP (500) (3%) during the study. Statistically significant (P≤0.006) cortical suppression seen with FP compared to both FF/VI doses at weeks 12 and 28 but not at week 52. No clinically important glucose, potassium, ECG or ophthalmic changes were noted
O’Byrne et al^Citation32	NCT01134042	586	FF (200)/VI (25) qpm or FF (200) qpm or FP (500) bid by DPI	≥12-year-old asthmatic patients on ICS; MC, R, DB, DD, PG, ×24 weeks	FF/VI significantly (P<0.001) improved both trough and weighted mean (0–24 hours) FEV1 compared to both FF and FP alone. AEs were similar between groups
Bateman et al^Citation31	NCT01086384	2,019	FF (100)/VI (25) or FF (100) daily qpm by DPI	≥12-year-old asthmatic patients on ICS; MC, R, DB, PG, ×24–78 weeks	FF/VI compared to FF alone delayed onset of first severe asthma experience exacerbation (P≤0.05). Significantly (P<0.001) greater trough FEV1 improvement with FF/VI than FF alone. Both were well tolerated with similar AEs
Bernstein et al^Citation29	NCT01686633	1,039	FF (100) or FF (100)/VI (25) or FF (200)/VI (25) qpm daily by DPI	≥12-year-old asthmatic patients on ICS; MC, R, DB, stratified, PG, ×12 weeks	Weighted mean FEV1 (0–24 hours) was significantly (P<0.01) increased by both doses of FF/VI compared to FF alone. Trough FEV1 percentage of rescue-free 24-hour periods and morning/evening PEF were also improved. Small numerical improvements occurred with FF (200)/VI (25) compared to FF (100)/VI (25). All treatments were well tolerated
Kempsford et al^Citation35	NCT01287065	26	FF (100)/VI (25) qpm or FF (100)/VI (25) qam or P by DPI	18–70-year-old asthmatic patients on stable ICS; SC, R, DB, PC, XO, daily dose of FF/VI given qam or qpm with P given the opposite qam/qpm or P given bid ×14 days	Both, morning and evening FF/VI, increased weighted mean FEV1. Both dosing times produced comparable improvements in lung function
Allen et al^Citation25	NCT01266941 and NCT01266980	35	FF (200)/VI (25) or FF (100)/VI (25) by DPI	Two studies, OL, PG, daily doses in: 1) mild to moderate hepatic impaired patients or healthy matched patients, all daily dose ×7 days; 2) severe renal impaired (CrCl <30 mL/min) patients or healthy matched patients, all daily dose ×7 days	No effect on VI maximal concentrations or area under the concentration curve for 24 hours in liver or renal impaired patients. No difference in heart rate, serum potassium or 24 hour serum cortisol levels seen
Oliver et al^Citation75	NCT01128569	52	FF (100) or FF (100)/VI (25) or P by DPI	18–65-year-old asthmatics; MC, R, DB, PC, XO, daily dose ×28 days	Weighted mean FEV1 for the 2-hour post-allergen challenge was improved by FF and FF/VI compared to P. No difference was seen between FF and FF/VI
Kempsford et al^Citation24	NCT01165125 and NCT00866515	20 and 18	1) Keto 400 mg or P oral daily ×6 days on day 5 VI (25) ×1 dose by DPI and 2) Keto 400 mg or P oral daily ×11 days with FF (200)/VI (25) daily days 4–11 by DPI	18–52-year-old healthy subjects; SC, R, DB, XO, all doses were daily	Oral Keto is known as CYP3A4 and PgP inhibitors. No major effect of Keto on VI pharmacodynamics was seen. Maximal levels and area under the curve (0–24 hours) were increased approximately twofold by Keto on FF (36%) and VI (65%). No effect on maximal heart rate or minimal potassium levels was seen when Keto was given with FF/VI. A 27% decrease in 24-hour weighted mean serum cortisol levels was noted
Nakahara et al^Citation23	NCT00625196; NCT00964249; NCT00972673	48, 32 and 16	FF (200, 400 or 800) or P and VI (12.5 or 25) and FF (800) or VI (50) or FF (800)/VI (50) by DPI	Healthy adult Japanese males, single dose; then 4-day washout; then daily dose days 5–11 (7 days) and single dose daily ×7 days and single dose	Peak serum concentrations of FF and VI were up to two times higher compared to single doses. No clinically significant difference in VI or FF levels when administered together compared to alone. Repeat doses of FF affected weighted mean (0–24 hours) serum cortisol with FF (200, 400 and 800) resulting in respective reductions from placebo of 32%, 38% and 97% respectively. No safety concerns were seen
Oliver et al^Citation26	NCT01128595	26	FF (100) or VI (25) or FF (100)/VI (25) or P by DPI	18–65-year-old asthmatic patients; MC, R, DB, PC, XO, daily dose qam ×21 days; allergen challenge test and MCT	Treatment with FF, VI or FF/VI all reduced the early decrease in FEV1 with allergen challenge test 0–2 hours and 24 hours compared to P on day 21. Same protection was seen with MCT for FF, VI or FF/VI on day 22
Oliver et al^Citation33	None given	26	FF (100)/VI (25) or FF (100) daily by DPI	5–11-year-old patients with mild asthma controlled by ICS, R, DB, XO, stratified by age, ×14 days	No difference was seen in primary outcomes including AEs, laboratory measures, heart rate, blood pressure, PEF or ECG between FF/VI and FF
Bleecker et al^Citation30	NCT01165138	609	FF (100)/VI (25) or FF (100) or P all daily qpm by DPI	≥12-year-old asthmatic patients; MC, R, DB, PG, ×12 weeks	Both FF/VI and FF significantly (P<0.003) increased trough and weighted mean (0–24 hours) FEV1 compared to P. No statistical difference between FF/VI and FF in FEV1. The percentage of rescue inhaler-free 24-hour periods 10.6% greater with FF/VI than FF alone and 19.3% greater with FF/VI than P
Lin et al^Citation38	NCT10498653	309	FF (200)/VI (25) qpm or FP (500) bid by DPI	≥12-year-old asthmatic patients from the People’s Republic of China, South Korea and the Philippines; MC, R, DB, DD, PG, ×12 weeks	Significantly greater change from baseline on evening PEF by FF/VI compared to FP (P<0.001). No difference in AEs
Chen et al^Citation22	NCT01711463	16	FF (50)/VI (25) or FF (100)/VI (25) or FF (200)/VI (25) or P qam daily by DPI	18–45-year-old healthy Chinese subjects; SC, R, DB, PC, XO, ×7 days	Reductions compared to P in weighted mean serum cortisol (0–24 hour) levels for day 7 were seen for FF (100)/VI (25) and FF (200)/VI (25) compared to P. FF/VI was safe and well tolerated
Lin et al^Citation37	NCT01498679	307	FF (100)/VI (25) or P daily all by DPI	≥12-year-old patients with Asian ancestry and asthmatics on ICS; MC, R, DB, PC, PG, ×12 weeks	Significant (P<0.001) improvement in change from baseline for FF/VI versus P in evening PEF. Greater percentage of symptom-free 24-hour periods with FF/VI than P. ADEs were 35% for FF/VI and 31% for P
Hozawa et al^Citation40	None given	30	BUD (320)/F (9) bid plus as-needed BUD (160)/F (4.5) or FF (100)/VI (25) qpm plus as-needed procaterol, all by DPI	≥20-year-old Japanese asthmatics on ICS; SC, R, OL, ×4 weeks	BUD/F and FF/VI both showed improvement in airway inflammation, FEV1, resonance frequency exhaled nitric oxide and asthma control scores, but FF/VI improvement seemed to plateau, while BUD/F did not. The use of a single as-needed dose of BUD/F was well tolerated
Dal Negro et al^Citation39	None given	117	BEC (100)/F (6) bid or FF (92)/VI (22) daily, all by DPI	Adult asthmatic patients; observational, retrospective with propensity score matching, ×12 weeks	The number of relapses per patient was 0.53 (±0.12) for the BEC/F treatment group and 0.28 (±0.07) for the FF/VI group (P=0.12). Less hospitalizations (P=0.11), specialist visits (P<0.001) and general physician visits (P<0.001) were seen in the FF/VI group compared to the BEC/F-treated group. The mean cost of hospitalizations per patient was less but not significant for the FF/VI group
Ishiura et al^Citation42	None given	16	FF (200)/VI (25) qam or FP (500)/SAL (50) bid, all by DPI	Adult 59–87-year-old Japanese patients with ACOS; OL, R, XO, ×12 weeks	The trough FEV1 was significantly (P<0.01) higher after FF/VI than at baseline. No significant change in FEV1 was seen with FP/SAL treatment. Each spirometry parameter was significantly (P<0.05) higher after FF/VI treatment than values found with FP/SAL

Notes: References in bold are key studies; bid, twice daily; qam, daily morning; qpm, daily evening.

Abbreviations: ACOS, asthma–COPD overlap syndrome; ADE, adverse drug event; AEs, adverse events; BEC/F, beclomethasone dipropionate/formoterol; BUD/F, budesonide/formoterol; COPD, chronic obstructive pulmonary disease; CYP, cytochrome P450; DB, double blind; DD, double dummy; DPI, dry powder inhaler; ECG, electrocardiogram; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; FP, fluticasone propionate; ICS, inhaled corticosteroid; Keto, ketoconazole; MC, multicenter; MCT, methacholine challenge test; OL, open label; PC, placebo controlled; PEF, peak expiratory flow; PG, parallel group; PgP, P-glycoprotein; Pred, prednisolone; R, randomized; SAL, salmeterol; SC, single center; VI, vilanterol trifenatate; XO, crossover.

Asthma GINA Guidelines [homepage on the Internet]Pocket Guide for Asthma Management and Prevention2016 Available from: www.ginasthma.orgAccessed September 1, 2016

 Google Scholar

BatemanEDBleeckerERLotvallJDose effect of once-daily fluticasone furoate in persistent asthma: a randomized trialRespir Med2012106564265022342538

 PubMed Web of Science ®Google Scholar

WoodcockALotvallJBusseWWEfficacy and safety of fluticasone furoate 100 mug and 200 mug once daily in the treatment of moderate-severe asthma in adults and adolescents: a 24-week randomised studyBMC Pulm Med20141411325007865

 PubMed Web of Science ®Google Scholar

LötvallJBleeckerERBusseWWEfficacy and safety of fluticasone furoate 100 mug once-daily in patients with persistent asthma: a 24-week placebo and active-controlled randomised trialRespir Med20141081414924295556

 PubMed Web of Science ®Google Scholar

BusseWWBatemanEDO’ByrnePMOnce-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trialAllergy201469111522153025040613

 PubMed Web of Science ®Google Scholar

O’ByrnePMWoodcockABleeckerEREfficacy and safety of once-daily fluticasone furoate 50 mcg in adults with persistent asthma: a 12-week randomized trialRespir Res2014158825108545

 PubMed Web of Science ®Google Scholar

WoodcockABatemanEDBusseWWEfficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trialRespir Res20111213221977941

 PubMed Web of Science ®Google Scholar

WoodcockABleeckerERBusseWWFluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthmaRespir Res20111216022188590

 PubMed Web of Science ®Google Scholar

MedleyHOrozcoSAllenAEfficacy and safety profile of fluticasone furoate administered once daily in the morning or evening: a randomized, double-blind, double-dummy, placebo-controlled trial in adult and adolescent patients with persistent bronchial asthmaClin Ther20123481683169522796247

 PubMed Web of Science ®Google Scholar

BusseWWBleeckerERBatemanEDFluticasone furoate demonstrates efficacy in patients with asthma symptomatic on medium doses of inhaled corticosteroid therapy: an 8-week, randomised, placebo-controlled trialThorax2012671354121828231

 PubMed Web of Science ®Google Scholar

LeeLAYangSKerwinETrivediREdwardsLDPascoeSThe effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging studyRespir Med20151091546225452139

 PubMed Web of Science ®Google Scholar

KempsfordRDBalJBainesARenauxJRavindranathRThomasPSThe efficacy of fluticasone furoate administered in the morning or evening is comparable in patients with persistent asthmaRespir Med2016112182426823210

 PubMed Web of Science ®Google Scholar

BleeckerERBatemanEDBusseWWOnce-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroidsAnn Allergy Asthma Immunol20121095353e354358e35423062392

 PubMed Web of Science ®Google Scholar

van den BergeMLuijkBBareillePDallowNPostmaDSLammersJWProlonged protection of the new inhaled corticosteroid fluticasone furoate against AMP hyperresponsiveness in patients with asthmaAllergy201065121531153520560909

 PubMed Web of Science ®Google Scholar

YangSLeeLMallettSAyerJWolstenholmeAPascoeSA randomized, crossover study to investigate the pharmacokinetics and safety of inhaled fluticasone furoate and umeclidinium, administered separately and in combination via dry powder inhaler in healthy adult volunteersAdv Ther201532215717125700806

 PubMed Web of Science ®Google Scholar

AllenABalJCheesbroughAHamiltonMKempsfordRPharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjectsBr J Clin Pharmacol201477580882024152086

 PubMed Web of Science ®Google Scholar

KempsfordRNorrisVSiedererSVilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPDPulm Pharmacol Ther201326225626423232038

 PubMed Web of Science ®Google Scholar

LötvallJBatemanEDBusseWWComparison of vilanterol, a novel long-acting beta2 agonist, with placebo and a salmeterol reference arm in asthma uncontrolled by inhaled corticosteroidsJ Negat Results Biomed2014131924928338

 PubMedGoogle Scholar

OliverAJCovarRAGoldfradCHRandomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapyRespir Res2016173727044326

 PubMed Web of Science ®Google Scholar

LötvallJBatemanEDBleeckerER24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroidsEur Respir J201240357057922362859

 PubMed Web of Science ®Google Scholar

SterlingRLimJFrithLSnowiseNGJacquesLHaumannBEfficacy and optimal dosing interval of the long-acting beta(2) agonist, vilanterol, in persistent asthma: a randomised trialRespir Med201210681110111522520084

 PubMed Web of Science ®Google Scholar

OliverAVanBurenSAllenASafety, tolerability, pharmacokinetics, and pharmacodynamics of vilanterol, a novel inhaled long-acting beta-agonist, in children aged 5–11 years with persistent asthma: a randomized trialClin Pharmacol Drug Dev20143321522126097789

 PubMed Web of Science ®Google Scholar

AllenABareillePJRousellVMFluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung absorption kinetics in man compared with inhaled fluticasone propionateClin Pharmacokinet2013521374223184737

 PubMed Web of Science ®Google Scholar

AllenRAWuWYaoMNerve regeneration and elastin formation within poly(glycerol sebacate)-based synthetic arterial grafts one-year post-implantation in a rat modelBiomaterials201435116517324119457

 PubMed Web of Science ®Google Scholar

CalzettaLRinaldiBCazzolaMMateraMGPharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthmaExpert Opin Drug Metab Toxicol201612781382227253498

 PubMed Web of Science ®Google Scholar

AllenASchenkenbergerITrivediRInhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled studyClin Respir J20137439740623578031

 PubMed Web of Science ®Google Scholar

WoodcockABleeckerERLotvallJEfficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma: a randomized trialChest201314441222122923846316

 PubMed Web of Science ®Google Scholar

BusseWWO’ByrnePMBleeckerERSafety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the beta2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trialThorax201368651352023440247

 PubMed Web of Science ®Google Scholar

O’ByrnePMBleeckerERBatemanEDOnce-daily fluticasone furoate alone or combined with vilanterol in persistent asthmaEur Respir J201443377378224136330

 PubMed Web of Science ®Google Scholar

BatemanEDO’ByrnePMBusseWWOnce-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF aloneThorax201469431231924253831

 PubMed Web of Science ®Google Scholar

BernsteinDIBatemanEDWoodcockAFluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthmaJ Asthma201552101073108326291137

 PubMed Web of Science ®Google Scholar

KempsfordRDOliverABalJTombsLQuinnDThe efficacy of once-daily fluticasone furoate/vilanterol in asthma is comparable with morning or evening dosingRespir Med2013107121873188024200619

 PubMed Web of Science ®Google Scholar

AllenADavisAHardesKTombsLKempsfordRInfluence of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate and vilanterol in combinationClin Ther201234122316233223200625

 PubMed Web of Science ®Google Scholar

OliverAQuinnDGoldfradCvan HeckeBAyerJBoyceMCombined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trialClin Transl Allergy2012211122738148

 PubMedGoogle Scholar

KempsfordRAllenABalJRubinDTombsLThe effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjectsBr J Clin Pharmacol20137561478148723116485

 PubMed Web of Science ®Google Scholar

NakaharaNWakamatsuAKempsfordRThe safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjectsInt J Clin Pharmacol Ther201351866067123735179

 PubMed Web of Science ®Google Scholar

OliverABjermerLQuinnDModulation of allergen-induced bronchoconstriction by fluticasone furoate and vilanterol alone or in combinationAllergy20136891136114223924233

 PubMed Web of Science ®Google Scholar

OliverAVanBurenSAllenATolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthmaClin Ther2014366928e921939e92124793536

 PubMed Web of Science ®Google Scholar

BleeckerERLotvallJO’ByrnePMFluticasone furoate-vilanterol 100-25 mcg compared with fluticasone furoate 100 mcg in asthma: a randomized trialJ Allergy Clin Immunol Pract20142555356125213048

 PubMed Web of Science ®Google Scholar

LinJKangJLeeSHFluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: a randomized trialRespir Med20151091445325524507

 PubMed Web of Science ®Google Scholar

ChenXZhengXJiangJPharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjectsPharmacotherapy201535658659926059225

 PubMed Web of Science ®Google Scholar

LinJTangHChenPEfficacy and safety evaluation of once-daily fluticasone furoate/vilanterol in Asian patients with asthma uncontrolled on a low- to mid-strength inhaled corticosteroid or low-dose inhaled corticosteroid/long-acting beta2-agonistAllergy Asthma Proc201637430231027401316

 PubMed Web of Science ®Google Scholar

HozawaSTeradaMHarutaYHozawaMComparison of early effects of budesonide/formoterol maintenance and reliever therapy with fluticasone furoate/vilanterol for asthma patients requiring step-up from inhaled corticosteroid monotherapyPulm Pharmacol Ther201637152326850307

 PubMed Web of Science ®Google Scholar

Dal NegroRWDistanteCBonadimanLTurcoPIannazzoSFluticasone furoate/vilanterol 92/22 mug once-a-day vs beclomethasone dipropionate/formoterol 100/6 mug b.i.d.: a 12-week cost analysis in mild-to-moderate asthmaMultidiscip Respir Med2016112027275384

 PubMedGoogle Scholar

IshiuraYFujimuraMShibaYOhkuraNHaraJKasaharaKA comparison of the efficacy of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in asthma-COPD overlap syndromePulm Pharmacol Ther201535283326497109

 PubMed Web of Science ®Google Scholar