Trial Outcomes & Findings for Study HZA106829: Efficacy/Safety Study of Fluticasone Furoate/Vilanterol (GW642444) in Adult and Adolescent Asthmatics (NCT NCT01134042)

Last Updated: 2017-01-11

Results Overview

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 measurement taken at the clinic visit while still on treatment. Pre-dose and pre-rescue albuterol/salbutamol trough FEV1 was measured electronically by spirometry in the evening at the Baseline (BL) through Week 24 clinic visits. The highest of 3 technically acceptable measurements was recorded. BL was the pre-dose value obtained at Visit 3. Change from BL was calculated as the Week 24 value minus the Baseline value. The analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of BL trough FEV1, country, sex, age, and treatment group.The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-BL on-treatment measurement at scheduled clinic visits was used to impute the missing measurements.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

587 participants

Primary outcome timeframe

Baseline and Week 24

Results posted on

2017-01-11

Participant Flow

Participants (par.) meeting eligibility criteria at the Screening visit entered a 4-week Run-in Period for completion of Baseline (BL) safety evaluations and to obtain BL measures of asthma status. Par. were then randomized to a 24-week Treatment Period. 1206 par. were screened, 587 were randomized, and 586 received \>=1 dose of study treatment.

Participant milestones

Participant milestones
Measure	FF 200 µg OD Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Overall Study STARTED	194	197	195
Overall Study COMPLETED	146	169	161
Overall Study NOT COMPLETED	48	28	34

Reasons for withdrawal

Reasons for withdrawal
Measure	FF 200 µg OD Participants received FF 200 microgram (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening plus placebo via the DISKUS/ACCUHALER twice daily (BID), for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD Participants received Fluticasone Furoate/Vilanterol (FF/VI) 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID Participants received Fluticasone Propionate (FP) 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Overall Study Adverse Event	3	7	2
Overall Study Lack of Efficacy	21	6	18
Overall Study Protocol Violation	5	3	5
Overall Study Lost to Follow-up	2	0	1
Overall Study Physician Decision	4	8	1
Overall Study Withdrawal by Subject	13	4	7

Baseline Characteristics

Study HZA106829: Efficacy/Safety Study of Fluticasone Furoate/Vilanterol (GW642444) in Adult and Adolescent Asthmatics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	Total n=586 Participants Total of all reporting groups
Age, Continuous	44.6 Years STANDARD_DEVIATION 14.33 • n=5 Participants	46.6 Years STANDARD_DEVIATION 15.05 • n=7 Participants	47.3 Years STANDARD_DEVIATION 14.06 • n=5 Participants	46.2 Years STANDARD_DEVIATION 14.51 • n=4 Participants
Gender Female	113 Participants n=5 Participants	116 Participants n=7 Participants	116 Participants n=5 Participants	345 Participants n=4 Participants
Gender Male	81 Participants n=5 Participants	81 Participants n=7 Participants	79 Participants n=5 Participants	241 Participants n=4 Participants
Race/Ethnicity, Customized African American/African Heritage (HER)	16 participants n=5 Participants	16 participants n=7 Participants	19 participants n=5 Participants	51 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Japanese/East Asian HER/South East Asian HER	12 participants n=5 Participants	15 participants n=7 Participants	13 participants n=5 Participants	40 participants n=4 Participants
Race/Ethnicity, Customized White	165 participants n=5 Participants	165 participants n=7 Participants	162 participants n=5 Participants	492 participants n=4 Participants
Race/Ethnicity, Customized African American/African Heritage and White	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of the study medication. Only those participants with non-missing covariates and a post-Baseline FEV1 measurement were analyzed.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=186 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=187 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=190 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period	0.201 Liters Standard Error 0.0303	0.394 Liters Standard Error 0.0302	0.183 Liters Standard Error 0.0300

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Weighted mean serial FEV1 was calculated in the subset of participants for whom serial FEV1 at Week 24 was performed.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry at the Baseline and Week 24 clinic visits. Weighted mean was calculated using the 24-hour serial FEV1 measurements that included the pre-dose assessment (within 5 minutes prior to dosing) and the post-dose assessments after 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours. At each time point, the highest of 3 technically acceptable measurements was recorded. Baseline was the value obtained at Visit 3. Change from Baseline was calculated as the average Week 24 FEV1 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=83 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=89 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=86 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in Weighted Mean Serial FEV1 Over 0-24 Hours Post-dose at Week 24	0.328 Liters Standard Error 0.0493	0.464 Liters Standard Error 0.0470	0.258 Liters Standard Error 0.0483

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants available at the specified time points were analyzed.

The number of inhalations of rescue bronchodilator, albuterol/salbutamol inhalation aerosol, used during the day and night was recorded by the participants in a daily electronic diary (eDiary). Similarly, asthma symptoms were recorded in a daily eDairy by the participants every day in the morning and evening before taking any rescue or study medication and before the peak expiratory flow measurement. A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no use of rescue medication/symptoms was considered to be rescue free/symptom free. The Baseline value was derived from the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=193 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=194 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in the Percentage of Rescue-free and Symptom-free 24-hour Periods at the End of the 24-week Treatment Period Rescue-free 24-hour periods	26.6 Percentage of periods Standard Error 2.45	38.2 Percentage of periods Standard Error 2.42	31.9 Percentage of periods Standard Error 2.45
Change From Baseline in the Percentage of Rescue-free and Symptom-free 24-hour Periods at the End of the 24-week Treatment Period Symptom-free 24-hour periods	21.0 Percentage of periods Standard Error 2.32	29.3 Percentage of periods Standard Error 2.29	24.5 Percentage of periods Standard Error 2.31

SECONDARY outcome

Timeframe: Baseline, Week 12, and Week 24/Early Withdrawal

Population: ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

The AQLQ is a disease-specific, self-administered quality of life questionnaire used to evaluate the impact of asthma treatments on the quality of life of asthma sufferers. The AQLQ for 12 years and older (AQLQ \[+12\]) is a modified version of the AQLQ for use in asthma patients between the age of 12 and 70. The AQLQ contains 32 items in 4 domains: activity limitation (11 items), symptoms (12 items), emotional function (5 items), and environmental stimuli (4 items). For the 32 items on the questionnaire, the response format consists of a seven-point scale, where a value of 1 indicates "total impairment" and a value of 7 indicates "no impairment." The AQLQ total score is defined as the average of the scores from all 32 questions; thus, the total score ranges from 1 (indicates "total impairment") to 7 (indicates "no impairment"). Baseline was the total score obtained at Visit 3. Change from Baseline was calculated as the total score at Weeks 12 and 24 minus the total score at Baseline.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in the Total Asthma Quality of Life Questionnaire (AQLQ) (+12) Score at Week 12 and Week 24/Early Withdrawal Week 12, n=154, 180, 163	0.66 Scores on a scale Standard Error 0.061	0.74 Scores on a scale Standard Error 0.056	0.74 Scores on a scale Standard Error 0.059
Change From Baseline in the Total Asthma Quality of Life Questionnaire (AQLQ) (+12) Score at Week 12 and Week 24/Early Withdrawal Week 24, n=140, 167, 156	0.88 Scores on a scale Standard Error 0.071	0.93 Scores on a scale Standard Error 0.065	0.90 Scores on a scale Standard Error 0.068

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT Population. 12-hour post-dose FEV1 was analyzed in the subset of participants for whom serial FEV1 at Week 24 was performed.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. 12-hour post-dose FEV1 measurements were taken electronically by spirometry at the Week 24 clinic visit. The highest of 3 technically acceptable measurements was recorded.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=82 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=93 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=87 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Clinic Visit 12-hour Post-dose FEV1at Week 24	2.611 Liters Standard Deviation 0.8437	2.683 Liters Standard Deviation 0.9758	2.262 Liters Standard Deviation 0.7786

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Weighted mean serial FEV1 was calculated in the subset of participants for whom serial FEV1 at Week 24 was performed.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry at Baseline. Weighted mean was calculated using the 4-hour serial FEV1 measurements that included the pre-dose assessment (within 5 minutes prior to dosing) and post-dose assessments after 5, 15, and 30 minutes and 1, 2, 3, and 4 hours. At each time point, the highest of 3 technically acceptable measurements was recorded. Baseline was the value obtained at Visit 3. Change from Baseline was calculated as the average Week 24 FEV1 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=83 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=89 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=86 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in Weighted Mean Serial FEV1 Over 0 to 4 Hours Post-dose at Week 24	0.363 Liters Standard Deviation 0.4690	0.492 Liters Standard Deviation 0.5671	0.256 Liters Standard Deviation 0.4679

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline up to Week 12 and Week 24

PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Trough PEF is the PEF measured approximately 24 hours after the last administration of study drug. Change from Baseline (defined as the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily trough AM/PM PEF over 12 weeks and 24 weeks of the 24-week Treatment Period (at Weeks 12 and 24) minus the Baseline value.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Mean Change From Baseline in Daily Morning Trough (AM) and Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the First 12 Weeks and 24 Weeks of the 24-week Treatment Period AM PEF, Week 1 to 12, n=193, 197, 195	15.1 Liters/minute (L/min) Standard Error 2.82	48.1 Liters/minute (L/min) Standard Error 2.78	17.1 Liters/minute (L/min) Standard Error 2.80
Mean Change From Baseline in Daily Morning Trough (AM) and Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the First 12 Weeks and 24 Weeks of the 24-week Treatment Period AM PEF, Week 1 to 24, n=193, 197, 195	18.2 Liters/minute (L/min) Standard Error 2.97	51.8 Liters/minute (L/min) Standard Error 2.94	18.8 Liters/minute (L/min) Standard Error 2.95
Mean Change From Baseline in Daily Morning Trough (AM) and Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the First 12 Weeks and 24 Weeks of the 24-week Treatment Period PM PEF, Week 1 to 12, 192, 197, 194	7.5 Liters/minute (L/min) Standard Error 2.80	36.6 Liters/minute (L/min) Standard Error 2.75	12.6 Liters/minute (L/min) Standard Error 2.78
Mean Change From Baseline in Daily Morning Trough (AM) and Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the First 12 Weeks and 24 Weeks of the 24-week Treatment Period PM PEF, Week 1 to 24, 192, 197, 194	9.1 Liters/minute (L/min) Standard Error 2.98	39.8 Liters/minute (L/min) Standard Error 2.93	13.6 Liters/minute (L/min) Standard Error 2.96

OTHER_PRE_SPECIFIED outcome

Timeframe: From the first dose of the study medication up to Week 24/Early Withdrawal

Population: ITT Population

The number of participants whose primary reason for withdrawal was lack of efficacy was analyzed.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
The Number of Participants Who Withdrew Due to Lack of Efficacy During the 24-week Treatment Period	21 participants	6 participants	18 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 12, and Week 24/Early Withdrawal

The ACT is a 5-item questionnaire developed as a measure of the participant's asthma control. Questions are designed to be self-completed by the participant and include the following: In the past 4 weeks, "How much of the time did your asthma keep you from getting as much done at work, school or at home?", "How often have you had shortness of breath?", "How often did your asthma symptoms wake you up at night or earlier than usual in the morning?", "How often have you used your rescue inhaler or nebulizer medication (such as albuterol)?" and "How would you rate your asthma control"? The ACT total score is defined as the sum of the scores from all 5 questions, provided all questions have been answered; thus, the total score ranges from 5 (poor control of asthma) to 25 (complete control of asthma). A score of 20 or higher indicates well-controlled asthma. Change from Baseline was calculated as the total score at Week 12 and Week 24/Early Withdrawal minus the total score at Baseline.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Change From Baseline in the Asthma Control Test (ACT) Scores at Week 12 and Week 24 Week 12, n=164, 183, 169	3.9 Scores on a scale Standard Error 0.29	4.8 Scores on a scale Standard Error 0.27	3.9 Scores on a scale Standard Error 0.28
Change From Baseline in the Asthma Control Test (ACT) Scores at Week 12 and Week 24 Week 24, n=147, 170, 162	5.2 Scores on a scale Standard Error 0.30	5.5 Scores on a scale Standard Error 0.28	4.7 Scores on a scale Standard Error 0.29

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 4, Week 12, and Week 24/Early Withdrawal

At the end of Week 4, Week 8, and Week 24/Early Withdrawal, the Global Assessment of Change Questionnaire that assesses changes in asthma symptoms (AS) and rescue medication use (RMU) was completed by the participants. The number of participants who chose the following answers to the questionnaire were determined: much better, somewhat better, a little better, the same, a little worse, somewhat worse, much worse (to assess the changes in asthma symptoms); much less often, somewhat less often, a little less often, the same, a little more often, somewhat more often, much more often (to assess the changes in the frequency of rescue medication use).

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: Much worse, n=162, 183, 165	1 participants	0 participants	0 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: Much better, n=174, 191, 180	37 participants	58 participants	35 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: Somewhat better, n=174, 191, 180	47 participants	65 participants	49 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: A little better, n=174, 191, 180	43 participants	34 participants	40 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: The same, n=174, 191, 180	35 participants	25 participants	44 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: A little worse, n=174, 191, 180	8 participants	7 participants	6 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: Somewhat worse, n=174, 191, 180	2 participants	2 participants	3 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, AS: Much worse, n=174, 191, 180	2 participants	0 participants	3 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: Much less often, n=174, 191, 180	49 participants	71 participants	42 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: Somewhat less often, n=174, 191, 180	29 participants	48 participants	41 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: A little less often, n=174, 191, 180	42 participants	38 participants	45 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: The same, n=174, 191, 180	34 participants	27 participants	37 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: A little more often, n=174, 191, 180	14 participants	4 participants	9 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: Somewhat more often, n=174, 191, 180	5 participants	2 participants	3 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 4, RMU: Much more often, n=174, 191, 180	1 participants	1 participants	3 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: Much better, n=162, 183, 165	60 participants	78 participants	54 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: Somewhat better, n=162, 183, 165	43 participants	51 participants	52 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: A little better, n=162, 183, 165	27 participants	33 participants	34 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: The same, n=162, 183, 165	23 participants	15 participants	16 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: A little worse, n=162, 183, 165	8 participants	5 participants	6 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, AS: Somewhat worse, n=162, 183, 165	0 participants	1 participants	3 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: Much less often, n=162, 183, 164	66 participants	90 participants	59 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: Somewhat less often, n=162, 183, 164	31 participants	36 participants	37 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: A little less often, n=162, 183, 164	28 participants	24 participants	40 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: The same, n=162, 183, 164	26 participants	24 participants	20 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: A little more often, n=162, 183, 164	7 participants	8 participants	6 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: Somewhat more often, n=162, 183, 164	2 participants	0 participants	1 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 12, RMU: Much more often, n=162, 183, 164	2 participants	1 participants	1 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: Much better, n=146, 168, 162	64 participants	89 participants	62 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: Somewhat better, n=146, 168, 162	43 participants	37 participants	52 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: A little better, n=146, 168, 162	22 participants	23 participants	17 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: The same, n=146, 168, 162	11 participants	14 participants	23 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: A little worse, n=146, 168, 162	3 participants	4 participants	4 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: Somewhat worse, n=146, 168, 162	2 participants	1 participants	2 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, AS: Much worse, n=146, 168, 162	1 participants	0 participants	2 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: Much less often, n=146, 168, 162	68 participants	87 participants	69 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: Somewhat less often, n=150, 187, 18	33 participants	38 participants	37 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: A little less often, n=150, 187, 18	29 participants	22 participants	26 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: The same, n=146, 168, 162	12 participants	16 participants	19 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: A little more often, n= 142, 168, 16	1 participants	3 participants	8 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: Somewhat more often, n=146, 168, 162	3 participants	1 participants	1 participants
Number of Participants With the Indicated Global Assessment of Change Questionnaire Responses at Weeks 4, 12, and 24 Week 24, RMU: Much more often, n=146, 168, 162	0 participants	1 participants	2 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline up to Week 24/Withdrawal Visit

Population: ITT Population

All unscheduled asthma-related visits to a physician's office, visits to urgent care, visits to the emergency department, and hospitalizations (ICU=intensive care unit; GW=general ward) associated with severe asthma exacerbations or other asthma-related healthcare issues were recorded.

Outcome measures

Outcome measures
Measure	FF 200 µg OD n=194 Participants Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 Participants Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 Participants Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Home Visits (Day)	0.0 Number of visits Standard Deviation 0.07	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Home Visits (Night)	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Physician Office/Practice Visits	0.0 Number of visits Standard Deviation 0.10	0.0 Number of visits Standard Deviation 0.00	0.1 Number of visits Standard Deviation 0.45
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Urgent Care/Outpatient Clinic Visits	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Emergency Room Visits	0.0 Number of visits Standard Deviation 0.07	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Inpatient Hospitalization Days (ICU)	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00
Number of the Indicated Unscheduled Asthma-related Healthcare Visits During the Treatment Period Number of Inpatient Hospitalization (GW) Days	0.0 Number of visits Standard Deviation 0.29	0.0 Number of visits Standard Deviation 0.00	0.0 Number of visits Standard Deviation 0.00

Adverse Events

FF 200 µg OD

Serious events: 1 serious events

Other events: 66 other events

Deaths: 0 deaths

FF/VI 200/25 µg OD

Serious events: 6 serious events

Other events: 62 other events

Deaths: 0 deaths

FP 500 µg BID

Serious events: 2 serious events

Other events: 73 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	FF 200 µg OD n=194 participants at risk Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 participants at risk Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 participants at risk Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Injury, poisoning and procedural complications Limb traumatic amputation	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Respiratory, thoracic and mediastinal disorders Asthma	0.52% 1/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Cardiac disorders Atrial fibrillation	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Gastrointestinal disorders Inguinal hernia	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Pneumonia	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Renal and urinary disorders Haematuria	0.00% 0/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.00% 0/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.

Other adverse events

Other adverse events
Measure	FF 200 µg OD n=194 participants at risk Participants received FF 200 µg inhalation powder via a Dry Powder Inhaler DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FF/VI 200/25 µg OD n=197 participants at risk Participants received FF/VI 200/25 µg inhalation powder via a DPI OD in the evening plus placebo via the DISKUS/ACCUHALER BID, for 24 weeks. Additionally participants were provided with albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.	FP 500 µg BID n=195 participants at risk Participants received FP 500 µg inhalation powder via the DISKUS/ACCUHALER BID plus placebo via a DPI OD in the evening, for 24 weeks. Additionally participants were provided albuterol/salbutamol inhalation aerosol to be used as rescue medication as needed.
Infections and infestations Nasopharyngitis	13.9% 27/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	12.7% 25/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	20.0% 39/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Respiratory tract infection viral	3.6% 7/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Influenza	4.1% 8/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	2.5% 5/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Bronchitis	3.1% 6/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.1% 6/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Sinusitis	3.6% 7/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	1.5% 3/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	2.1% 4/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Pharyngitis	1.0% 2/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	2.0% 4/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.1% 6/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Infections and infestations Rhinitis	1.0% 2/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	0.51% 1/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Respiratory, thoracic and mediastinal disorders Cough	3.1% 6/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	1.5% 3/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	6.7% 13/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.1% 8/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	2.0% 4/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.6% 7/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Respiratory, thoracic and mediastinal disorders Dysphonia	1.0% 2/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	3.0% 6/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	2.1% 4/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.
Nervous system disorders Headache	6.7% 13/194 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	5.6% 11/197 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.	7.7% 15/195 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 24). An on-therapy AE or SAE is defined as an AE with an onset on or after the start date of study medication, but not later than one day after the last date of study medication. SAEs and AEs were collected in members of the ITT Population, comprised of all participants randomized to treatment, who received at least one dose of the study medication.

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