ILA115938: Evaluate the Safety, Efficacy and Dose Response of GSK573719 in Combination With Fluticasone Furoate in Subjects With Asthma

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT01573624

Collaborator

(none)

421

Enrollment

Locations

Arms

10.1

Actual Duration (Months)

13.2

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Brief Summary: The purpose of this study is to characterize the dose response of GSK573719 in combination with Fluticasone furoate 100mcg in patients with asthma. Treatment with inhaled Fluticasone furoate and Fluticasone furoate/Vilanterol are included as an active control.

Detailed Description: Long acting muscarinic receptor antagonists (anti-cholinergic bronhcodilator) exert their effects via distinct and complementary bronchodilator mechanisms on large and small airways. Most of the experience with older anti-cholinergics had been with acute use and little is known about their effect in chronic use in asthma. This is a multicenter, randomized, double-blind, crossover study to evaluate 5 doses of inhaled GSK573719 inhaled over 14 days in patients with asthma. Fluticasone furoate (100 mcg) and Fluticasone furoate/Vilanterol (100/59mcg) will be included as an active comparator. Each eligible subject will receive a sequence of 3 of 7 potential treatments for a total of 3 treatment periods per subject. The total duration of subject participation is approximately 14 weeks.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: FF/GSK573719 Drug: FF/GSK573719 Drug: FF/GSK573719 Drug: FF/GSK573719 Drug: FF/GSK573719 Drug: FF Drug: FF/VI	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

421 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Diagnostic

Official Title:

A Multi-center, Randomized, Double-blind, Dose-ranging Study to Evaluate GSK573719 in Combination With Fluticasone Furoate, Fluticasone Furoate Alone, and an Active Control of Fluticasone Furoate/Vilanterol Combination in Subjects With Asthma

Actual Study Start Date :

Apr 3, 2012

Actual Primary Completion Date :

Feb 4, 2013

Actual Study Completion Date :

Feb 4, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fluticasone Furoate (FF) 100mcg, inhaled	Drug: FF 100
Active Comparator: Fluticasone Furoate /Vilanterol (VI) 100/25mcg inhaled	Drug: FF/VI 100/25
Experimental: Fluticasone Furoate/GSK573719 100/15.6-250mcg inhaled	Drug: FF/GSK573719 100/15.6 Drug: FF/GSK573719 100/31.25 Drug: FF/GSK573719 100/62.5 Drug: FF/GSK573719 100/125 Drug: FF/GSK573719 100/250

Arm

Intervention/Treatment

Active Comparator: Fluticasone Furoate (FF)

100mcg, inhaled

Drug: FF

100

Active Comparator: Fluticasone Furoate /Vilanterol (VI)

100/25mcg inhaled

Drug: FF/VI

100/25

Experimental: Fluticasone Furoate/GSK573719

100/15.6-250mcg inhaled

Drug: FF/GSK573719

100/15.6

Drug: FF/GSK573719

100/31.25

Drug: FF/GSK573719

100/62.5

Drug: FF/GSK573719

100/125

Drug: FF/GSK573719

100/250

Outcome Measures

Primary Outcome Measures

Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) [Baseline (Day 1) and Day 15 of each treatment period]
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 ante meridiem (AM) and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Slope-intercept on log dose model was used to predict trough FEV1 change from baseline for each of the FF+UMEC doses adjusted by FF 100 mcg alone. Mean value for the expected response and associated 95% confidence interval (CI) in change from baseline trough FEV1 is presented.
Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg [Baseline (Day 1) and Day 15 of each treatment period]
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Data is presented as percentage chance that FF 100 mcg alone corrected change from baseline trough FEV1 response would exceed a target response of 50 mL, 75 mL, 100 mL and 150 mL by doses of UMEC combined with FF 100 mcg.
Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods [Baseline (Day 1) and Day 15 of each treatment period]
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. The highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. The change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Analysis was done using a mixed model, including treatment, period, period baseline FEV1, and mean baseline FEV1 as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.

Secondary Outcome Measures

Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period [Baseline (Week 0) and last 7 days of each treatment period]
PEF is a measure of lung function and measures how fast a person can breathe out. Morning PEF was measured pre-dose and pre- rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline morning PEF and mean baseline morning PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period [Baseline (Week 0) and last 7 days of each treatment period]
PEF is a measure of lung function and measures how fast a person can breathe out. Evening PEF was measured pre-dose and pre-rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and seven days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline evening PEF and mean baseline evening PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. [Baseline (Week 0) and last 7 days of each treatment period]
Short-Acting Beta2-Agonists albuterol/salbutamol was provided to participants as rescue medication, to use in morning and evening. Participants recorded number of puffs of salbutamol MDI used in last 24 hours (sum of night time and day time puffs) daily for relief of symptoms in eDiary. Mean change from baseline was calculated where, baseline was defined as measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 (for night time puffs) and seven days (for day time puffs) for each treatment period. Change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and the baseline week. Analysis was done using a mixed model, including treatment, period, period baseline rescue albuterol use, and mean baseline rescue albuterol use as fixed effects and participant as random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Outpatient
18 years of age or older at Visit 1
Diagnosis of Asthma
Male or eligible Female
Pre-bronchodilator FEV1 of 40-80% of the predicted normal value at Visit 1
Demonstrated reversibility by ≥12% and ≥200mL of FEV1 within 40 minutes following albuterol at Visit 1
A need for regular controller therapy (i.e., inhaled corticosteroids alone or in combination with a long-acting beta-agonist, or leukotriene modifier etc.,) for a minimum of 8 weeks prior to Visit 1.

Exclusion Criteria:

History of Life threatening asthma
Respiratory infection not resolved
Asthma exacerbation
Concurrent respiratory disease
Current Smokers
Other diseases that are uncontrolled disease or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study
A positive Hepatitis B surface antigen or positive Hepatitis C antibody and/or HIV
Visual clinical evidence of oropharyngeal candidiasis
Drug or milk protein allergies
Concomitant medications affecting course of asthma
Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer)
Previous use of GSK573719
Any disease preventing use of anticholinergics
Any condition that impairs compliance with study protocol including visit schedule and completion of daily diaries
Any subject with a history of alcohol or substance abuse
Any affiliation with Investigator's site

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Saint Louis	Missouri	United States	63141
2	GSK Investigational Site	Medford	Oregon	United States	97504
3	GSK Investigational Site	Orangeburg	South Carolina	United States	29118
4	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
5	GSK Investigational Site	Buenos Aires		Argentina	C1424BSF
6	GSK Investigational Site	Ciudad Autonoma de Buenos Aires		Argentina	C1425BEN
7	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
8	GSK Investigational Site	Mendoza		Argentina	M5500CCG
9	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
10	GSK Investigational Site	Tucumán		Argentina	T4000DGF
11	GSK Investigational Site	Puente Alto - Santiago	Región Metro De Santiago	Chile	8207257
12	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500551
13	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500800
14	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	8880465
15	GSK Investigational Site	Talca	Región Metro De Santiago	Chile	3460001
16	GSK Investigational Site	Valparaiso	Valparaíso	Chile	2341131
17	GSK Investigational Site	Santiago		Chile	8380453
18	GSK Investigational Site	Barnaul		Russian Federation	656038
19	GSK Investigational Site	Kazan		Russian Federation	420015
20	GSK Investigational Site	Klin		Russian Federation	141600
21	GSK Investigational Site	Moscow		Russian Federation	115 280
22	GSK Investigational Site	Moscow		Russian Federation	123367
23	GSK Investigational Site	Saint-Petersburg		Russian Federation	194354
24	GSK Investigational Site	St. Petersburg		Russian Federation	194356
25	GSK Investigational Site	Tomsk		Russian Federation	634001
26	GSK Investigational Site	Tomsk		Russian Federation	634055
27	GSK Investigational Site	Ufa		Russian Federation	450071
28	GSK Investigational Site	Yaroslavl		Russian Federation	150003
29	GSK Investigational Site	Bangkok		Thailand	10330
30	GSK Investigational Site	Bangkok		Thailand	10400
31	GSK Investigational Site	Khon Kaen		Thailand	40002
32	GSK Investigational Site	Nonthaburi		Thailand	11000

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT01573624

Other Study ID Numbers:

115938

First Posted:

Apr 9, 2012

Last Update Posted:

Oct 6, 2017

Last Verified:

Sep 1, 2017

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

Additional relevant MeSH terms:

Asthma

Study Results

Participant Flow

Recruitment Details	The study was conducted across 33 centres of 5 countries from 03 April 2012 to 04 February 2013 in adults aged 18 to 50 years with persistent asthma. Participants were randomized for 3 treatment periods of 2 weeks each.
Pre-assignment Detail	A total of 706 participants were screened for this study designed in 3 period crossover, incomplete block manner; 523 participants entered 2-week open label run-in period where they received fluticasone furoate (FF) 100 micrograms (mcg) dry powder inhalation once daily. A total of 421 participants were randomized to double-blind treatment period.

Arm/Group Title	FF 100 mcg First	FF 100 mcg + UMEC 15.6 mcg First	FF 100 mcg + UMEC 31.25 mcg First	FF 100 mcg + UMEC 62.5 mcg First	FF 100 mcg + UMEC 125 mcg First	FF 100 mcg + UMEC 250 mcg First	FF 100 mcg + VI 25 mcg First
Arm/Group Description	Participants received a dose of FF 100 mcg via a dry powder inhaler (DPI) once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol metered-dose inhaler (MDI) was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and umeclidinium bromide (UMEC) 15.6 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and vilanterol (VI) 25 mcg via a DPI once daily in the morning for 14 days during the first treatment period of the 3 treatment periods as per their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	64	62	60	63	58	55	59
COMPLETED	58	59	51	61	56	51	57
NOT COMPLETED	6	3	9	2	2	4	2
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	58	59	51	61	56	51	57
COMPLETED	57	58	48	56	56	48	55
NOT COMPLETED	1	1	3	5	0	3	2
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	57	58	48	56	56	48	55
COMPLETED	50	52	45	55	53	43	55
NOT COMPLETED	7	6	3	1	3	5	0
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	50	52	45	55	53	43	55
COMPLETED	49	48	43	53	52	41	52
NOT COMPLETED	1	4	2	2	1	2	3
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	49	48	43	53	52	41	52
COMPLETED	46	47	43	53	51	39	48
NOT COMPLETED	3	1	0	0	1	2	4
Period Title: Period 1 : Treatment Period 1 (14 Days)
STARTED	46	47	43	53	51	39	48
COMPLETED	45	47	43	53	49	38	48
NOT COMPLETED	1	0	0	0	2	1	0

Baseline Characteristics

Arm/Group Title	All Treatments Combined
Arm/Group Description	The participants received 3 of the 7 possible treatments during the 3 double blind treatment periods. Participants received study treatments in a crossover manner according to their randomization sequence. The 7 treatment regimens were, FF 100 mcg, FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + UMEC 125 mcg, FF 100 mcg + UMEC 250 mcg and FF 100 mcg + VI 25 mcg. The study treatments were administered via a DPI taken once daily in the morning for 14 days during each study period. The treatment periods were separated by 2 washout periods of 12-14 days each. During the two week run-in period and during the two washout period, participants were administered open-label FF 100 mcg once daily in the morning via a DPI. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Overall Participants	421
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	47.5 (13.84)
Sex: Female, Male (Count of Participants)
Female	289 68.6%
Male	132 31.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	36 8.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	18 4.3%
White	367 87.2%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1)
Description	FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 ante meridiem (AM) and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Slope-intercept on log dose model was used to predict trough FEV1 change from baseline for each of the FF+UMEC doses adjusted by FF 100 mcg alone. Mean value for the expected response and associated 95% confidence interval (CI) in change from baseline trough FEV1 is presented.
Time Frame	Baseline (Day 1) and Day 15 of each treatment period

Outcome Measure Data

Analysis Population Description
The primary endpoint was analyzed using Intent -to -Treat (ITT) Population defined as all participants randomized to treatment and who received at least one dose of study medication. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg
Arm/Group Description	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	154	146	150	155	150
Mean (95% Confidence Interval) [Litres (L)]	0.0260	0.0320	0.0385	0.0444	0.0510

2. Primary Outcome

Title	Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg
Description	FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Data is presented as percentage chance that FF 100 mcg alone corrected change from baseline trough FEV1 response would exceed a target response of 50 mL, 75 mL, 100 mL and 150 mL by doses of UMEC combined with FF 100 mcg.
Time Frame	Baseline (Day 1) and Day 15 of each treatment period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg
Arm/Group Description	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	154	146	150	155	150
Target response of 50 mL	9	17	27	37	52
Target response of 75 mL	0.5	1	2	5	10
Target response of 100 mL	0	0	0	0.2	0.2
Target response of 150 mL	0	0	0	0	0

3. Primary Outcome

Title	Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods
Description	FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. The highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. The change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Analysis was done using a mixed model, including treatment, period, period baseline FEV1, and mean baseline FEV1 as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time Frame	Baseline (Day 1) and Day 15 of each treatment period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg	FF 100mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg	FF 100 mcg + VI 25 mcg
Arm/Group Description	Participants received a dose of FF 100 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and VI 25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	146	154	146	150	155	150	147
Least Squares Mean (Standard Error) [Litres (L)]	0.120 (0.0175)	0.145 (0.0170)	0.152 (0.0174)	0.145 (0.0172)	0.174 (0.0170)	0.175 (0.0172)	0.198 (0.0174)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95% -0.019 to 0.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 62.5 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.165
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.033
	Confidence Interval	(2-Sided) 95% -0.013 to 0.079
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 125 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95% -0.020 to 0.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.055
	Confidence Interval	(2-Sided) 95% 0.010 to 0.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.055
	Confidence Interval	(2-Sided) 95% 0.010 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + VI 25 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.078
	Confidence Interval	(2-Sided) 95% 0.032 to 0.124
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.052
	Confidence Interval	(2-Sided) 95% -0.097 to -0.007
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.045
	Confidence Interval	(2-Sided) 95% -0.091 to 0.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 125 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.053
	Confidence Interval	(2-Sided) 95% -0.098 to -0.007
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.306
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95% -0.068 to 0.021
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.330
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.023
	Confidence Interval	(2-Sided) 95% -0.068 to 0.023
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period
Description	PEF is a measure of lung function and measures how fast a person can breathe out. Morning PEF was measured pre-dose and pre- rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline morning PEF and mean baseline morning PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time Frame	Baseline (Week 0) and last 7 days of each treatment period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg	FF 100 mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg	FF 100 mcg + VI 25 mcg
Arm/Group Description	Participants received a dose of FF 100 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and VI 25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	159	159	156	155	158	159	156
Least Squares Mean (Standard Error) [Litres per min (L/min)]	-2.9 (2.44)	13.0 (2.44)	14.5 (2.46)	15.7 (2.47)	20.0 (2.44)	19.0 (2.44)	24.1 (2.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	15.9
	Confidence Interval	(2-Sided) 95% 9.5 to 22.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 62.5 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	17.4
	Confidence Interval	(2-Sided) 95% 10.9 to 23.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 125 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	18.6
	Confidence Interval	(2-Sided) 95% 12.1 to 25.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	22.9
	Confidence Interval	(2-Sided) 95% 16.5 to 29.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.0
	Confidence Interval	(2-Sided) 95% 15.5 to 28.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + VI 25 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	27.0
	Confidence Interval	(2-Sided) 95% 20.6 to 33.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11.2
	Confidence Interval	(2-Sided) 95% -17.6 to -4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.6
	Confidence Interval	(2-Sided) 95% -16.1 to -3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 125 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.4
	Confidence Interval	(2-Sided) 95% -14.9 to -1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.209
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95% -10.6 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95% -11.6 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period
Description	PEF is a measure of lung function and measures how fast a person can breathe out. Evening PEF was measured pre-dose and pre-rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and seven days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline evening PEF and mean baseline evening PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time Frame	Baseline (Week 0) and last 7 days of each treatment period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg	FF 100 mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg	FF 100 mcg + VI 25 mcg
Arm/Group Description	Participants received a dose of FF 100 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and VI 25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	160	157	156	154	157	157	153
Least Squares Mean (Standard Error) [L/min]	-5.2 (2.51)	11.1 (2.53)	12.1 (2.54)	16.0 (2.56)	23.7 (2.52)	17.7 (2.52)	21.4 (2.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	16.2
	Confidence Interval	(2-Sided) 95% 9.5 to 22.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 62.5 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95% 10.5 to 24.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 125 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	21.2
	Confidence Interval	(2-Sided) 95% 14.4 to 28.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	28.8
	Confidence Interval	(2-Sided) 95% 22.1 to 35.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	22.9
	Confidence Interval	(2-Sided) 95% 16.2 to 29.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + VI 25 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	26.6
	Confidence Interval	(2-Sided) 95% 19.8 to 33.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.3
	Confidence Interval	(2-Sided) 95% -17.2 to -3.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-9.3
	Confidence Interval	(2-Sided) 95% -16.2 to -2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 125 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.126
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95% -12.3 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.523
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.2
	Confidence Interval	() 95% -4.6 to 9.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.290
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95% -10.5 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period.
Description	Short-Acting Beta2-Agonists albuterol/salbutamol was provided to participants as rescue medication, to use in morning and evening. Participants recorded number of puffs of salbutamol MDI used in last 24 hours (sum of night time and day time puffs) daily for relief of symptoms in eDiary. Mean change from baseline was calculated where, baseline was defined as measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 (for night time puffs) and seven days (for day time puffs) for each treatment period. Change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and the baseline week. Analysis was done using a mixed model, including treatment, period, period baseline rescue albuterol use, and mean baseline rescue albuterol use as fixed effects and participant as random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time Frame	Baseline (Week 0) and last 7 days of each treatment period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	FF 100 mcg	FF 100 mcg + UMEC 15.6 mcg	FF 100 mcg + UMEC 31.25 mcg	FF 100 mcg + UMEC 62.5 mcg	FF 100 mcg + UMEC 125 mcg	FF 100 mcg + UMEC 250 mcg	FF 100 mcg + VI 25 mcg
Arm/Group Description	Participants received a dose of FF 100 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.	Participants received fixed dose of FF 100 mcg and VI 25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
Measure Participants	158	151	152	151	153	157	151
Least Squares Mean (Standard Error) [Number of puffs]	-0.2 (0.09)	-0.4 (0.09)	-0.4 (0.09)	-0.3 (0.09)	-0.5 (0.09)	-0.4 (0.09)	-0.6 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95% -0.5 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 62.5 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95% -0.5 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 125 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.335
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95% -0.3 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95% -0.5 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 250 mcg
	Comments	No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95% -0.5 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + VI 25 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95% -0.7 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.104
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% 0.0 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% 0.0 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 125 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95% 0.1 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.217
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -0.1 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	FF 100 mcg + UMEC 250 mcg, FF 100 mcg + VI 25 mcg
	Comments	No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.143
	Comments
	Method	Mixed Models Analysis
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95% -0.1 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	FF 100 mcg		FF 100 mcg + UMEC 15.6 mcg		FF 100 mcg + UMEC 31.25 mcg		FF 100 mcg + UMEC 62.5 mcg		FF 100 mcg + UMEC 125 mcg		FF 100 mcg + UMEC 250 mcg		FF 100 mcg + VI 25 mcg
Time Frame	Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment (Visit 3) up to the follow-up (Visit 12, held 7 days from the Day 15 of treatment period 3 [Visit 11]). AE's and SAE's were reported for the treatment period only ( Visit 11 [up to Day 15 of the treatment period 3]).
Adverse Event Reporting Description	ITT Population was used.

Arm/Group Title	FF 100 mcg		FF 100 mcg + UMEC 15.6 mcg		FF 100 mcg + UMEC 31.25 mcg		FF 100 mcg + UMEC 62.5 mcg		FF 100 mcg + UMEC 125 mcg		FF 100 mcg + UMEC 250 mcg		FF 100 mcg + VI 25 mcg
Arm/Group Description	Participants received a dose of FF 100 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and UMEC 15.6 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and UMEC 31.25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and UMEC 62.5 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and UMEC 125 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and UMEC 250 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.		Participants received fixed dose of FF 100 mcg and VI 25 mcg via a DPI once daily in the morning for 14 days in any one of the 3 treatment periods according to their randomization sequence. The 3 treatment periods were separated by 2 washout periods of 12-14 days each. Participants were administered with open-label FF 100 mcg once daily in the morning via a DPI while on washout period. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/187 (0%)		0/183 (0%)		0/179 (0%)		0/180 (0%)		0/176 (0%)		0/186 (0%)		0/172 (0%)
Serious Adverse Events
	FF 100 mcg		FF 100 mcg + UMEC 15.6 mcg		FF 100 mcg + UMEC 31.25 mcg		FF 100 mcg + UMEC 62.5 mcg		FF 100 mcg + UMEC 125 mcg		FF 100 mcg + UMEC 250 mcg		FF 100 mcg + VI 25 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/187 (0%)		0/183 (0%)		1/179 (0.6%)		0/180 (0%)		0/176 (0%)		0/186 (0%)		1/172 (0.6%)
Hepatobiliary disorders
Cholecystitis acute	0/187 (0%)		0/183 (0%)		0/179 (0%)		0/180 (0%)		0/176 (0%)		0/186 (0%)		1/172 (0.6%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/187 (0%)		0/183 (0%)		1/179 (0.6%)		0/180 (0%)		0/176 (0%)		0/186 (0%)		0/172 (0%)
Other (Not Including Serious) Adverse Events
	FF 100 mcg		FF 100 mcg + UMEC 15.6 mcg		FF 100 mcg + UMEC 31.25 mcg		FF 100 mcg + UMEC 62.5 mcg		FF 100 mcg + UMEC 125 mcg		FF 100 mcg + UMEC 250 mcg		FF 100 mcg + VI 25 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/187 (1.6%)		4/183 (2.2%)		2/179 (1.1%)		5/180 (2.8%)		4/176 (2.3%)		7/186 (3.8%)		6/172 (3.5%)
Nervous system disorders
Headache	3/187 (1.6%)		4/183 (2.2%)		2/179 (1.1%)		5/180 (2.8%)		4/176 (2.3%)		7/186 (3.8%)		6/172 (3.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT01573624

Other Study ID Numbers:

115938

First Posted:

Apr 9, 2012

Last Update Posted:

Oct 6, 2017

Last Verified:

Sep 1, 2017

ILA115938: Evaluate the Safety, Efficacy and Dose Response of GSK573719 in Combination With Fluticasone Furoate in Subjects With Asthma

Study Details

Study Description

Brief Summary

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

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Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Statistical Analysis 11

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Statistical Analysis 11

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Statistical Analysis 11

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Statistical Analysis 11

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats