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TRANSCRIPT
Once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI) versus FF/VI in inadequately controlled asthma:
the CAPTAIN studyAuthors: Ian Pavord1, Guy Peachey2, Huib Kerstjens3, Edward Kerwin4, Robert Nathan5,
Nicola A. Hanania6, Steven Pascoe7*, Andrew Fowler2, Zelie Bailes2, Dawn Edwards2,Neal Sule7, Neil Barnes8,9, Louis-Philippe Boulet10, Maggie Tabberer8, Laurie A. Lee7
Affiliations: 1University of Oxford, Oxford, UK; 2GSK, Stockley Park West, Uxbridge, Middlesex, UK; 3University of Groningen and University Medical Center Groningen, Groningen, the Netherlands;
4Crisor LLC Research, Clinical Research Institute of Southern Oregon, Medford, OR, USA; 5University of Colorado, Health Sciences Center, CO, USA;
6Baylor College of Medicine, Houston, TX, USA; 7GSK, Upper Providence, PA, USA; 8GSK, Brentford, Middlesex, UK; 9Barts and the London School of Medicine and Dentistry, London, UK;
10Laval University, Quebec, Canada
*Affiliation at time of study
A plain language summary and online version of this presentation can be accessed by scanning the QR code or via http://tago.ca/AAAAI_10The plain language summary is also available at the GSK Medical Information booth
Disclosures
• The presenting author, Ian Pavord, declares the following real or perceived conflicts of interest: received speaker’s fees, payments for organizing education events, honoraria for attending advisory panels, sponsorship to attend international scientific meetings, research grants or payments to support FDA approval meetings from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Genentech, GSK, Knopp, Merck, Novartis, Sanofi/Regeneron and Teva; acted as an expert witness for a patent dispute involving AstraZeneca and Teva; co-patent holder for the Leicester Cough Questionnaire, and received payments for use of the Leicester Cough Questionnaire in clinical trials from Bayer, Insmed and Merck
• Editorial support in the form of writing assistance (including assembling tables and figures, and slide formatting) was provided by Chloe Stevenson at Fishawack Indicia Ltd, UK, and was funded by GSK
• This study was funded by GSK (205715; clinicaltrials.gov ID: NCT02924688)
For many patients, ICS/LABA treatment does not lead to adequate asthma control
• Despite adherence to ICS/LABA therapy, at least 30% of patients with asthma remain symptomaticand poorly controlled1–4
• A smaller proportion – roughly 10–25% of GINA Step 3 or higher patients – experience exacerbations.5,6
The higher proportion comes from patients with healthcare contacts as part of their asthma definition
• ICS/LABA plus a LAMA, administered via either single or multiple inhalers, improves lung function and reduces exacerbation rates in patients with asthma7,8
• Single-inhaler triple therapy with the ICS/LAMA/LABA combination of FF/UMEC/VI is approved as QD treatment for COPD, but previously there were no studies investigating its use in patients with asthma
• CAPTAIN (Clinical study in Asthma Patients receiving Triple therapy in A single Inhaler) investigated the efficacy and safety of single-inhaler FF/UMEC/VI in patients with uncontrolled asthma on ICS/LABA
1. Sulaiman I, et al. Eur Respir J 2018;51(1):1701126; 2. Bernstein DI, et al. J Asthma 2015;52(10):1073–83; 3. Davis J, et al. J Asthma 2019;56(3):332–40; 4. Lee LK, et al. J Asthma 2018;55(2):208–19; 5. Suruki RY, et al. BMC Pulm Med 2017;17(1):74; 6. Zeiger RS, et al. J Allergy Clin Immunol Pract 2014;2:741–50; 7. Virchow JC, et al. Lancet 2019;394:1737–49; 8. Kerstjens HA, et al. N Engl J Med 2012;367(13):1198–207.COPD, chronic obstructive pulmonary disorder; FF, fluticasone furoate; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; QD, once daily; UMEC, umeclidinium; VI, vilanterol.
CAPTAIN study design: FF/UMEC/VI in patients with asthmacharacterized by airflow limitation and poor symptom control
FP/SAL provided BID as a fixed-dose via the Diskus DPI; FF/VI and FF/VI/UMEC provided QD as a fixed-dose via the Ellipta DPI.
*All patients in the study had a safety follow-up contact approximately 7 days after the End of Study Visit (dependent on actual transition date) or Early Withdrawal Visit.BID; twice daily; DPI, dry powder inhaler; FF, fluticasone furoate; FP, fluticasone propionate; ITT, intent-to-treat; QD, once daily; R, randomization; SAL, salmeterol; UMEC, umeclidinium; VI, vilanterol.
OD
N=2436 (ITT population)
Wk 52
Up to 5 on-treatment clinic visitsVisit 3:
Randomization
Wk 24
Primary endpoint
1-week safety
follow-up*
Visit 2:
Enrollment
Visit 1:
Screening
3-week
run-in period
2-week
stabilization period
R
FF/UMEC/VI 200/62.5/25 mcg, N=408
FF/UMEC/VI 200/31.25/25 mcg, N=404
FF/VI 200/25 mcg, N=406
FF/VI 100/25 mcg, N=407
FF/UMEC/VI 100/31.25/25 mcg, N=405
FF/UMEC/VI 100/62.5/25 mcg, N=406FP/SAL
250/50 mcg
FF/VI
100/25 mcg
Fixed treatment period: 0–24 weeks
Variable treatment period: 24–52 weeks
Wk 0Wk -2Wk -5
Eligible adults had inadequately controlled asthma symptoms
Key inclusion criteria Key exclusion criteria
• Maintenance therapy with medium-to-high dose ICS/LABAfor ≥12 weeks
• ACQ-6 score ≥1.5 (at both screening and enrollment)
• Healthcare contact or temporary change in asthma therapy for acute asthma symptoms within 1 year of screening
• Best pre-bronchodilator FEV1 ≥30–<85% predicted at screening
• Increase in FEV1 of ≥12% and ≥200 mL 20–60 minutes following 4 albuterol inhalations
• COPD
• Pneumonia or pneumonia risk factors
• Any other concurrent respiratory disorders
• Current and former smokers with a smoking history of ≥10 pack years
ACQ, Asthma Control Questionnaire; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.
Primary endpoint: Change from baseline in trough FEV1 at Week 24
Note: All doses are mcg. *Responder threshold of ≥0.5-points improvement from baseline; †Responder threshold of ≥4-points improvement from baseline.1. Hanania NA, et al. AAAAI 2020 poster presentation: #072.ACQ, Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; SGRQ, St. George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.
Primary (at Week 24)
• Change from baseline in trough FEV1
Key secondary
• Annualized rate of moderate/severe asthma exacerbations
Secondary/Other (at Week 24)
• Clinic FEV1: Change from baseline 3 hours post-dose
• ACQ-7: Change from baseline & proportion of responders*
• SGRQ: Change from baseline & proportion of responders†
Endpoints
Spirometry endpoints FF/VI 100/25 vs FF/UMEC/VI 100/31.25/25 and
vs FF/UMEC/VI 100/62.5/25
FF/VI 200/25 vs FF/UMEC/VI 200/31.25/25 and vs FF/UMEC/VI 200/62.5/25
Non-spirometry endpoints FF/VI 100&200/25 vs
FF/UMEC/VI 100&200/31.25/25and vs FF/UMEC/VI 100&200/62.5/25
Primary analysis
• A step-down closed-testing hierarchy was used to account for multiplicity across UMEC doses and efficacy endpoints
• Results of the effect of increasing FF dose in CAPTAIN are reported separately1
Patient demographics and clinical characteristics at screening and baseline were generally similar across treatment arms
Total(N=2436)
Age, years, mean (SD) 53.2 (13.11)
Male, n (%) 922 (38)
BMI (kg/m2), mean (SD) 29.4 (6.64)
Total number of exacerbations in 12 months prior to screening, n (%)
01≥2
364 (15)1390 (57)682 (28)
Former smokers, n (%) 470 (19)
Pre-bronchodilator FEV1, % predicted at screening, mean (SD)
n=242358.5 (12.79)
Mean reversibility to salbutamol at screening,% mean (SD)
n=241829.9 (18.12)
ACQ-7 score at screening, mean (SD) n=2410
2.8 (0.61)
FF/VI100/25(N=407)
FF/UMEC/VI100/31.25/25
(N=405)
FF/UMEC/VI100/62.5/25
(N=406)
FF/VI200/25(N=406)
FF/UMEC/VI200/31.25/25
(N=404)
FF/UMEC/VI200/62.5/25
(N=408)
53.3 (13.03) 51.7 (13.27) 52.9 (13.39) 53.9 (13.30) 53.5 (13.12) 53.7 (12.50)
153 (38) 143 (35) 158 (39) 154 (38) 164 (41) 150 (37)
29.3 (6.08) 29.1 (6.80) 29.2 (6.65) 29.4 (6.29) 29.4 (7.07) 29.7 (6.93)
62 (15)219 (54)126 (31)
67 (17)227 (56)111 (27)
59 (15)234 (58)113 (28)
62 (15)251 (62)93 (23)
66 (16)224 (55)114 (28)
48 (12)235 (58)125 (31)
69 (17) 78 (19) 81 (20) 69 (17) 80 (20) 93 (23)
n=40258.2 (13.06)
n=40558.8 (11.73)
n=40458.8 (12.74)
n=40158.7 (13.20)
n=40457.4 (12.70)
n=40758.98 (13.26)
n=40229.5 (18.08)
n=40530.6 (17.62)
n=40230.2 (18.30)
n=40029.4 (18.29)
n=40330.0 (18.08)
n=40629.88 (18.45)
n=4012.8 (0.59)
n=4002.8 (0.60)
n=4032.8 (0.62)
n=4042.8 (0.63)
n=4012.8 (0.60)
n=4012.8 (0.60)
Note: N=patients with analyzable data. All doses are mcg. ACQ-7, asthma control questionnaire-7; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; SD, standard deviation; UMEC, umeclidinium; VI, vilanterol.
0
50
100
150
200
250
300
350
0 2 4 6 8
Clin
ic t
rou
gh F
EV1
(mL)
, mea
n
chan
ge f
rom
scr
een
ing
Imp
rove
me
nt
Screening Enrollment Randomization
Trough FEV1 and ACQ-7 showed clinically meaningful improvements during pre-randomization phases
FP/SAL provided BID as a fixed-dose via the Diskus DPI; FF/VI and FF/VI/UMEC provided QD as a fixed-dose via the Ellipta DPI.
ACQ-7, asthma control questionnaire-7; FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; FP/SAL, fluticasone propionate/salmeterol; SD, standard deviation; VI, vilanterol.
Any changes seen during the treatment phase of the study following randomization are on top of these improvements
Change in clinic trough FEV1 (N=2436)
FP/SAL
250/50 mcg
FF/VI
100/25 mcg
Changes in ACQ-7 score (N=2436)
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0 2 4 6 8
Imp
rovem
ent
Screening Enrollment Randomization
AC
Q-7
to
tal s
core
, m
ean
ch
ange
fro
m s
cree
nin
g
FP/SAL
250/50 mcg
FF/VI
100/25 mcg
Addition of UMEC to FF/VI resulted in dose-related improvements in lung function
Trough FEV1 (primary endpoint)
Note: P-values were not adjusted for multiplicity unless marked with an asterisk. Baseline values were last value prior to randomization. n=patients with analyzable data at Week 24. All doses are mcg. CI, confidence interval; LS, least squares; FEV1, forced expiratory volume in 1 second; FF, fluticasone furoate; UMEC, umeclidinium; SD, standard deviation; VI, vilanterol.
0
20
40
60
80
100
120
140
160
180
200
n=381 n=390n=379 n=384 n=391n=385
120(89, 151)
134(104, 165)
24(-6, 55)
157(127, 188)
168(137, 198)
76(45, 106)
Difference: 92(95% CI: 49, 135); P <0.001*
Difference: 82(95% CI: 39, 125); P <0.001
LS m
ean
(9
5%
CI)
ch
ange
fr
om
bas
elin
e at
Wee
k 2
4 (
mL)
Difference: 96(95% CI: 52, 139); P <0.001
Difference: 110(95% CI: 66, 153); P<0.001*
FEV1 3 hours post-dose
LS m
ean
(9
5%
CI)
ch
ange
fr
om
bas
elin
e at
Wee
k 2
4 (
mL)
0
50
100
150
200
250
300
350
220(189, 251)
243(212, 274)
132(100, 163)
256(225, 288)
286(255, 317)
168(137, 199)
n=375 n=379n=369 n=371 n=378n=377
Difference: 88(95% CI: 44, 132); P <0.001
Difference: 118(95% CI: 74, 162); P <0.001
Difference: 88(95% CI: 44, 132); P <0.001
Difference: 111(95% CI: 67, 155); P <0.001
Moderate/severe exacerbations (unpooled)
0.0
0.2
0.4
0.6
0.8
1.0
n=405 n=406n=407 n=404 n=408n=406
0.76(0.64, 0.92) 0.68
(0.56, 0.82)
0.87(0.73, 1.04)
0.61(0.50, 0.74)
0.55(0.45, 0.67)
0.57(0.47, 0.69)
Adjusted RR: 0.78(95% CI: 0.61, 1.01); P=0.060
Adjusted RR: 0.88(95% CI: 0.68, 1.13); P=0.321
Adjusted RR: 1.08(95% CI: 0.82, 1.42); P=0.602
Adjusted RR: 0.97(95% CI: 0.73, 1.28); P=0.818
Mea
n (
95
% C
I)
ann
ual
ized
rat
e
Moderate/severe exacerbations (pooled)
Trends for reducing moderate/severe exacerbations with FF/UMEC/VI
Note: P-values were not adjusted for multiplicity. All doses are mcg. CI, confidence interval; FF, fluticasone furoate; RR, rate ratio; UMEC, umeclidinium; VI, vilanterol.
• Improvements were dose related when UMEC was added to FF/VI 100/25, but no improvements were seen when
adding UMEC to FF/VI 200/25
• Hierarchy was broken, all subsequent analyses were not adjusted for multiplicity
0.0
0.2
0.4
0.6
0.8
1.0
n=809 n=814n=813
0.68(0.60, 0.78) 0.61
(0.53, 0.70)
0.70(0.61, 0.80)
Adjusted RR: 0.97(95% CI: 0.81, 1.17); P=0.778
Adjusted RR: 0.87(95% CI: 0.72, 1.05); P=0.151
Mea
n (
95
% C
I)an
nu
aliz
ed r
ate
Greater odds of response on ACQ-7 with FF/UMEC 62.5 mcg/VI than FF/VI
Note: P-values were not adjusted for multiplicity; baseline values were taken at randomization; n=patients with analyzable data at Week 24. All doses are mcg. *Patients reaching a responder threshold of ≥0.5-points (the MCID) improvement from baseline. 1. Juniper EF, et al. Respir Med 2005;99(5):553–8ACQ, asthma control questionnaire; CI, confidence interval; FF, fluticasone furoate; MCID, minimal clinically important difference; OR, odds ratio; SGRQ, St. George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.
ACQ-7 responders* (pooled)
These results were supported by similar findings in the analysis of ACQ-5 responders
ACQ-7 responders* (unpooled)
0
10
20
30
40
50
60
70
n=396 n=399 n=400 n=397 n=396 n=395
5257
6258 60
64
Adjusted OR: 1.28(95% CI: 0.95, 1.72); P=0.102
Adjusted OR: 1.06(95% CI: 0.79, 1.42); P=0.710
Adjusted OR: 1.26(95% CI: 0.94, 1.68); P=0.124
Adjusted OR: 1.59(95% CI: 1.18, 2.13); P=0.002
Res
po
nd
er r
ate
at W
eek
24
(%
)
0
10
20
30
40
50
60
70
FF/VI FF/UMEC 31.25/VI FF/UMEC 62.5/VI
n=793 n=795 n=795
5558
63
Adjusted OR: 1.15 (95% CI: 0.94, 1.42); P=0.179
Adjusted OR: 1.43(95% CI: 1.16, 1.76); P<0.001
Res
po
nd
er r
ate
at W
eek
24
(%
)
Improvements over time exceeding the MCID for ACQ-7 and SGRQ were seen in all treatment groups (pooled)
Note: Baseline values were taken at randomization. All doses are mcg. n=number of subjects with analyzable data for one or more time points.1. Juniper EF, et al. Respir Med 2005;99(5):553–8; 2. Jones PW. COPD 2005;2(1):75–9. ACQ-7, asthma control questionnaire-7; FF, fluticasone furoate; LS, least squares; MCID, minimal clinically important difference; SGRQ, St. George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.
Adding UMEC to FF/VI resulted in small improvements in ACQ-7 change from baseline, but no differences were observed between treatment groups in SGRQ
MCID1
-15
-13
-11
-9
-7
-5
-3
-1
Baseline Week 12 Week 24
FF/VI (n=784)
FF/UMEC 31.25/VI (n=782)
FF/UMEC 62.5/VI (n=795)
MCID2
SGR
Q (
95
% C
I) t
ota
l sco
re
LS m
ean
ch
ange
fro
m b
asel
ine
AC
Q-7
(9
5%
CI)
to
tal s
core
LS
mea
n c
han
ge f
rom
bas
elin
e
-1.00
-0.90
-0.80
-0.70
-0.60
-0.50
-0.40
-0.30
-0.20
-0.10
0.00
0 5 10 15 20 25
FF/VI (n=784)
FF/UMEC 31.25/VI (n=784)
FF/UMEC 62.5/VI (n=790)
Baseline Week 4 Week 12 Week 24
FF/UMEC/VI safety profile is similar to FF/VI
Note: n=patients with analyzable data. *Special interest groups related to LAMAs. All doses are MCG. AE, adverse event; AESI; adverse event of special interest; CV, cardiovascular; FF, fluticasone furoate; MACE, major adverse cardiovascular event; LTRI, lower respiratory tract infection; MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event; SMQ, standardized MedDRA queries; UMEC, umeclidinium; VI, vilanterol.
FF/VI100/25(N=407)
FF/UMEC/VI100/31.25/25
(N=405)
FF/UMEC/VI100/62.5/25
(N=406)
FF/VI200/25(N=406)
FF/UMEC/VI200/31.25/25
(N=404)
FF/UMEC/VI200/62.5/25
(N=408)
AEs, n (%) 258 (63) 232 (57) 239 (59) 210 (52) 233 (58) 217 (53)
AEs leading to treatment discontinuation, n (%) 11 (3) 5 (1) 7 (2) 5 (1) 6 (1) 3 (<1)
Treatment-related AEs, n (%) 21 (5) 16 (4) 29 (7) 17 (4) 20 (5) 19 (5)
AESIs CV effects
Supraventricular tachyarrhythmias (SMQ)Tachyarrhythmia terms, nonspecific (SMQ)Ventricular tachyarrhythmias (SMQ)
Infective pneumonia (SMQ)Dry mouth/drying of airway secretions (not including nasopharyngitis)*Gastrointestinal obstruction (SMQ)*LRTI excluding infective pneumonia SMQ*
22 (5)000
7 (2)1 (<1)
1 (<1)20 (5)
21 (5)2 (<1)
02 (<1)4 (<1)1 (<1)
023 (6)
27 (7)000
5 (1)2 (<1)
1 (<1)24 (6)
24 (6)3 (<1)
00
7 (2)0
025 (6)
15 (4)2 (<1) 1 (<1)
09 (2)
2 (<1)
026 (6)
18 (4)3 (<1)
00
4 (<1)1 (<1)
023 (6)
SAEs, n (%) 25 (6) 18 (4) 23 (6) 21 (5) 23 (6) 21 (5)
MACE, n (%) 5 (1) 3 (<1) 4 (<1) 2 (<1) 3 (<1) 3 (<1)
AEs leading to death, n (%) 0 2 (<1) 0 1 (<1) 0 0
Key findings for FF/UMEC/VI in patients with asthma characterized by airflow limitation and poor symptom control
• Addition of UMEC 62.5 mcg to both doses of FF/VI offered significant improvements in lung function; similar improvements were seen with addition of UMEC 31.25 mcg
• Addition of UMEC to FF/VI resulted in dose-related improvements in asthma control
• Dose-related trends for reductions in annualized moderate/severe exacerbation rate were observed when adding UMEC to FF/VI 100/25 mcg
• FF/UMEC/VI had a similar safety profile to FF/VI with no dose-related findings for UMEC
• The CAPTAIN study shows that FF/UMEC/VI is a safe and effective once-daily single inhaler treatment option for those uncontrolled on ICS/LABA
AE, adverse event; FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long acting muscarinic antagonist; UMEC, umeclidinium; VI, vilanterol.
A plain language summary and online version of this presentation can be accessed by scanning the QR code or via http://tago.ca/AAAAI_10
The plain language summary is also available at the GSK Medical Information booth
All author disclosures
• ZB, NB, DE, AF, LL, GP, NS and MT are employees of GSK and hold stocks or shares in GSK
• SP was an employee of GSK at the time of study and owns stocks in GSK
• LPB has received research grants for participation in multicentre clinical research trials and support for research projects from AstraZeneca, Boston Scientific, GSK, Hoffman La Roche, Ono Pharma, Novartis, Sanofi, Takeda, Boehringer Ingelheim and Merck. LPB has also received fees for consulting and advisory boards, conference fees, and support for participation in conferences and meetings from AstraZeneca, GSK, Merck, Metapharm, Novartis, and Takeda, and non-profit grants for the production of educational materials from AstraZeneca, Boehringer-Ingelheim, GSK, Merck and Novartis
• NAH reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Genentech, Genzyme, GSK, Mylan, Novartis, Regeneron,Sanofi, Sunovion, and for serving as an advisor or consultant. He also received research support from Astra Zeneca, Boehringer Ingelheim and GSK
• HK has received research grants and served on advisory boards for Boehringer Ingelheim, GSK, and Novartis
• EK is an employee of Crisor LLC Research and has served on advisory boards, speaker panels or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Forest, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance.EK has also conducted multicentre clinical research trials for approximately 40 pharmaceutical companies
• RN is an employee of the University of Colorado Health Sciences Center, and is a consultant or scientific advisor and received speaker’s fees from Boehringer Ingelheim and GSK.
• AP has received research grants and personal fees from Chiesi, GSK and Teva, and personal fees from AstraZeneca, Boehringer Ingelheim, Menarini, Merck Sharp & Dohme, Mundipharma, Novartis, Sanofi and Zambon