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