Safety of Once-Daily Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol in Japanese Patients with Asthma: A Long-Term (52-Week) Phase III Open-Label Study

Figures & data

Table 1 Study Treatment Assignment

	Inhaled Asthma Therapy and Control Status of Asthma During the Run-In Period^a	Study Treatment
Group 1	Not well controlled with ICS (mid-dose)+LABA or Controlled with ICS (mid-dose)+LABA+LAMA	FF/UMEC/VI 100/62.5/25mcg via ELLIPTA DPI, once-daily,1 inhalation/time, morning
Group 2	Not well controlled with ICS (high-dose)+LABA or Not well controlled with ICS (mid-dose)+LABA+LAMA or Controlled with ICS (high-dose)+LABA+LAMA	FF/UMEC/VI 200/62.5/25mcg via ELLIPTA DPI, once-daily, 1 inhalation/time, morning

Notes: ^aACQ-7 score (Week 0) was used for the assessment of control status of asthma: ACQ-7 ≤0.75 points=controlled; ACQ-7 >0.75 points=not well controlled.

Abbreviations: ACQ, Asthma Control Questionnaire; DPI, dry-powder inhaler; FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; UMEC, umeclidinium; VI, vilanterol.

Figure 1 Study design: 52-week, open-label Phase III safety study. ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg (selection of FF dose ([100 or 200mcg] depended on patients’ pre-screening therapy [ICS dose/prior use of LAMA] and control status [ACQ-7 total score ≤0.75 or >0.75] [Table 1]); ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25mcg at Week 24 if their ACQ-7 score was >0.75; this step up was at the investigator’s discretion; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg (selection of FF dose [100 or 200mcg] depended on patients’ pre-screening therapy [ICS dose/prior use of LAMA] and control status [ACQ-7 total score ≤0.75 or >0.75] (Table 1]).

Abbreviations: ACQ, Asthma Control Questionnaire; FF, fluticasone furoate; ICS, inhaled corticosteroid; ITT, intention-to-treat; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; UMEC, umeclidinium; VI, vilanterol.

Figure 2 Study disposition. ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg; ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25mcg at Week 24; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg.

Abbreviations: AE, adverse event; ITT, intention-to-treat.

Table 2 Baseline Demographics and Clinical Characteristics (ITT Population)

	Group 1^a (n=47)	Step-Up Group^b (n=9)	Group 2^c (n=55)	Total (N=111)
Demographics
Age, years, mean (SD)	48.0 (14.28)	48.4 (7.76)	53.8 (12.91)	50.9 (13.41)
Male, n (%)	24 (51)	4 (44)	19 (35)	47 (42)
BMI (kg/m^2), mean (SD)	23.8 (4.23)	24.3 (5.75)	24.4 (5.38)	24.2 (4.92)
Former smokers, n (%)	9 (19)	3 (33)	14 (25)	26 (23)
Clinical characteristics at screening
Asthma medications, n (%)^d
ICS	47 (100)	9 (100)	55 (100)	111 (100)
SABA	32 (68)	6 (67)	34 (62)	72 (65)
LABA (once per day)	17 (36)	1 (11)	25 (45)	43 (39)
LABA (twice per day)	30 (64)	8 (89)	30 (55)	68 (61)
LTRA	8 (17)	4 (44)	15 (27)	27 (24)
LAMA	0	0	14 (25)	14 (13)
Asthma duration, years, mean (SD)	17.3 (14.08)	17.8 (12.65)	19.6 (15.01)	18.5 (14.37)
Predicted FEV1 (%), mean (SD)	87.7 (14.77)	80.5 (14.82)	86.3 (18.29)	86.4 (16.58)
Exacerbations requiring OCS, n (%)^e
0	39 (83)	6 (67)	38 (69)	83 (75)
1	5 (11)	2 (22)	12 (22)	19 (17)
≥2	3 (6)	1 (11)	5 (9)	9 (8)
ACQ-6 score, mean (SD)	1.4 (0.45)	1.5 (0.63)	1.3 (0.59)	1.4 (0.54)

Notes: ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg; ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25mcg at Week 24; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg; ^dSummary of asthma concomitant medications before study treatment: a medication may be included in more than one respiratory class and thus may appear more than once; ^eSummary includes asthma exacerbations reported in the 12 months prior to the screening visit that required only OCS and did not involve hospitalization.

Abbreviations: ACQ, Asthma Control Questionnaire; FF, fluticasone furoate; ICS, inhaled corticosteroid; ITT, intention-to-treat; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroids; SABA, short-acting β₂-agonist; SD, standard deviation; UMEC, umeclidinium; VI, vilanterol.

Table 3 Summary of On-Treatment AEs (ITT Population)

	Group 1^a (n=47)	Step-Up Group^b (n=9)	Group 2^c (n=55)	Total (N=111)
AEs, n (%)	30 (63.8)	7 (77.8)	40 (72.7)	77 (69.4)
AEs leading to treatment discontinuation, n (%)	1 (2.1)	0	1 (1.8)^d	2 (1.8)
Common AEs, n (%)^e
Nasopharyngitis	13 (27.7)	2 (22.2)	18 (32.7)	33 (29.7)
Dysgeusia	3 (6.4)	2 (22.2)	6 (10.9)	11 (9.9)
Pharyngitis	5 (10.6)	2 (22.2)	4 (7.3)	11 (9.9)
Bronchitis	4 (8.5)	2 (22.2)	4 (7.3)	10 (9.0)
Influenza	3 (6.4)	1 (11.1)	5 (9.1)	9 (8.1)
Eczema	1 (2.1)	1 (11.1)	5 (9.1)	7 (6.3)
Dysphonia	2 (4.3)	0	3 (5.5)	5 (4.5)
Rhinitis	2 (4.3)	0	3 (5.5)	5 (4.5)
Treatment-related AEs, n (%)	6 (12.8)	2 (22.2)	8 (14.5)	16 (14.4)
Common treatment-related AEs, n (%)^f
Dysgeusia	2 (4.3)	1 (11.1)	4 (7.3)	7 (6.3)
Dysphonia	2 (4.3)	0	2 (3.6)	4 (3.6)

Notes: ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg; ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25 µg at Week 24; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg; ^dThe AE eosinophilic granulomatosis with polyangiitis led to treatment discontinuation and was also reported as an SAE (see Table 4); ^eAEs reported by 3 or more patients in any dose group, reported by descending frequency in the total population; ^fAEs reported by 3 or more patients in the total population, reported by descending frequency in the total population.

Abbreviations: AEs, adverse events; FF, fluticasone furoate; ITT, intention-to-treat; SAE, serious adverse event; UMEC, umeclidinium; VI, vilanterol.

Table 4 Summary of On-Treatment SAEs (ITT Population)

	Group 1^a (n=47)	Step-Up Group^b (n=9)	Group 2^c (n=55)	Total (N=111)
SAEs, n (%)	1 (2.1)	0	2 (3.6)	3 (2.7)
SAEs leading to treatment discontinuation, n (%)	0	0	1 (1.8)	1 (0.9)
Treatment-related SAEs, n (%)	0	0	0	0
Specific SAEs, n (%)
Eosinophilic granulomatosis with polyangiitis	0	0	1 (1.8)	1 (0.9)
Appendicitis	1 (2.1)	0	0	1 (0.9)
Spontaneous pneumothorax	0	0	1 (1.8)	1 (0.9)

Notes: ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg; ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25mcg at Week 24; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg.

Abbreviations: FF, fluticasone furoate; ITT, intention-to-treat; SAEs, serious adverse events; UMEC, umeclidinium; VI, vilanterol.

Table 5 Summary of On-Treatment AEs of Special Interest (ITT Population)

	Group 1^a (n=47)	Step-Up Group^b (n=9)	Group 2^c (n=55)	Total (N=111)
Adrenal suppression, n (%)	0	0	0	0
Anticholinergic syndrome (SMQ), n (%)	1 (2.1)	0	2 (3.6)	3 (2.7)
Dizziness	1 (2.1)	0	0	1 (0.9)
Dry eye	0	0	1 (1.8)	1 (0.9)
Pyrexia	0	0	1 (1.8)	1 (0.9)
Somnolence	0	0	1 (1.8)	1 (0.9)
Asthma/bronchospasm (SMQ), n (%)	0	0	1 (1.8)	1 (0.9)
Asthma	0	0	1 (1.8)	1 (0.9)
Cardiovascular effects, n (%)	1 (2.1)	0	4 (7.3)	5 (4.5)
Cardiac arrhythmia	1 (2.1)	0	2 (3.6)	3 (2.7)
Arrhythmia related investigations, signs, and symptoms (SMQ)	1 (2.1)	0	1 (1.8)	2 (1.8)
Palpitations	1 (2.1)	0	1 (1.8)	2 (1.8)
Supraventricular tachyarrhythmias	0	0	1 (1.8)	1 (0.9)
Atrial fibrillation	0	0	1 (1.8)	1 (0.9)
Cardiac failure (SMQ)	0	0	1 (1.8)	1 (0.9)
Edema	0	0	1 (1.8)	1 (0.9)
Hypertension (SMQ)	0	0	1 (1.8)	1 (0.9)
Hypertension	0	0	1 (1.8)	1 (0.9)
Decreased bone mineral density and associated fractures, n (%)	0	0	2 (3.6)	2 (1.8)
Osteoporosis	0	0	1 (1.8)	1 (0.9)
Rib fracture	0	0	1 (1.8)	1 (0.9)
Upper limb fracture	0	0	1 (1.8)	1 (0.9)
Dry mouth/drying of airway secretions (broad), n (%)^d,e	19 (40.4)	5 (55.6)	29 (52.7)	53 (47.7)
Nasopharyngitis	13 (27.7)	2 (22.2)	18 (32.7)	33 (29.7)
Dysgeusia	3 (6.4)	2 (22.2)	6 (10.9)	11 (9.9)
Pharyngitis	5 (10.6)	2 (22.2)	4 (7.3)	11 (9.9)
Bronchitis	4 (8.5)	2 (22.2)	4 (7.3)	10 (9.0)
Dysphonia	2 (4.3)	0	3 (5.5)	5 (4.5)
Cough	0	0	2 (3.6)	2 (1.8)
Gingivitis	0	0	2 (3.6)	2 (1.8)
Oropharyngeal discomfort	1 (2.1)	0	1 (1.8)	2 (1.8)
Stomatitis	0	0	1 (1.8)	1 (0.9)
Upper-airway cough syndrome	1 (2.1)	0	0	1 (0.9)
Dry mouth/drying of airway secretions (narrow), n (%)^d,f	0	0	0	0
Effects on glucose, n (%)	0	1 (11.1)	1 (1.8)	2 (1.8)
Hyperglycemia/new onset diabetes mellitus (SMQ)	0	1 (11.1)	1 (1.8)	2 (1.8)
Weight decreased	0	1 (11.1)	1 (1.8)	2 (1.8)
Effects on potassium, n (%)	0	0	0	0
Gastrointestinal obstruction (SMQ), n (%)	0	0	0	0
Hypersensitivity, n (%)	3 (6.4)	2 (22.2)	13 (23.6)	18 (16.2)
Eczema	1 (2.1)	1 (11.1)	5 (9.1)	7 (6.3)
Rhinitis allergic	2 (4.3)	0	3 (5.5)	5 (4.5)
Dermatitis	0	1 (11.1)	1 (1.8)	2 (1.8)
Urticaria	0	0	2 (3.6)	2 (1.8)
Blepharitis allergic	0	0	1 (1.8)	1 (0.9)
Conjunctivitis allergic	0	0	1 (1.8)	1 (0.9)
Eosinophilic granulomatosis with polyangiitis	0	0	1 (1.8)	1 (0.9)
Rash	1 (2.1)	0	0	1 (0.9)
Swelling of eyelid	0	0	1 (1.8)	1 (0.9)
Infective pneumonia (SMQ), n (%)	0	0	1 (1.8)	1 (0.9)
Pneumonia	0	0	1 (1.8)	1 (0.9)
LRTI excluding infective pneumonia (SMQ), n (%)	4 (8.5)	2 (22.2)	4 (7.3)	10 (9.0)
Bronchitis	4 (8.5)	2 (22.2)	4 (7.3)	10 (9.0)
Local steroid effects, n (%)	3 (6.4)	1 (11.1)	5 (9.1)	9 (8.1)
Dysphonia	2 (4.3)	0	3 (5.5)	5 (4.5)
Oropharyngeal discomfort	1 (2.1)	0	1 (1.8)	2 (1.8)
Oral candidiasis	0	1 (11.1)	0	1 (0.9)
Stomatitis	0	0	1 (1.8)	1 (0.9)
Ocular effects, n (%)	0	0	0	0
Tremor, n (%)	0	0	1 (1.8)	1 (0.9)
Tremor	0	0	1 (1.8)	1 (0.9)
Urinary retention, n (%)	0	0	0	0

Notes: ^aPatients allocated to receive FF/UMEC/VI 100/62.5/25mcg; ^bPatients switching medication from FF/UMEC/VI 100/62.5/25mcg to 200/62.5/25mcg at Week 24; ^cPatients allocated to receive FF/UMEC/VI 200/62.5/25mcg; ^dSpecial interest groups related to LAMAs; ^eDefined using 37 preferred terms including nasopharyngitis; ^fDefined using seven preferred terms excluding nasopharyngitis.

Abbreviations: AEs, adverse events; FF, fluticasone furoate; ITT, intention-to-treat; LAMA, long-acting muscarinic antagonist; LRTI, lower respiratory tract infection; SMQ, standard Medical Dictionary for Regulatory Activities (MedDRA) queries; UMEC, umeclidinium; VI, vilanterol.