Trial Outcomes & Findings for A 3-period Crossover Study With GSK573719 as Monotherapy in Adult Subjects With Asthma (NCT NCT01641692)

Results Overview

Dose-response was conducted for both QD and BID UMEC doses on trough FEV1 (measure of lung function, defined as the maximal amount of air that can be forcefully exhaled in 1 second) on D 15. Total daily dose of UMEC was used in the modeling. The null model was the final model. The null model is defined as: CFEV1,ij=(THETA1+ETA1j)\*meanBL+(THETA2+ETA1j)\*periodBL+EPSij, where CFEV1,ij represents the change from BL in trough FEV1 for participant j measured at period i. THETA1 and THETA2 were the slopes with respect to meanBL and periodBL, respectively. Omegas were the variance of the slopes on meanBL and periodBL (ETA1j, ETA2j) for each participant and Sigma was the variance of the residual errors (EPSij). MeanBL is the mean of the Baseline (BL) which is the FEV1 value recorded pre-dose on D 1 of each TP; periodBL is the difference between the BL and the meanBL in each TP for each participant.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

350 participants

Primary outcome timeframe

Day 15 of each treatment period (up to Study Day 71)

Results posted on

2017-03-09

Participant Flow

Participants were randomized to receive a sequence of 3 of 8 possible treatments over 3 treatment periods. There are 56 combinations of 3 treatments from the 8 study treatments, each of which can be ordered in 6 ways (totaling 336 possible sequences; 246 were randomly assigned). Participant Flow data are presented by treatment rather than sequence.

Participant milestones

Participant milestones
Measure	Placebo Participants received matching placebo in the morning via dry powder inhaler (DPI) A and in the evening via DPI B for 14 days.	UMEC 15.6 µg QD Participants received umeclidinium bromide (UMEC) 15.6 micrograms (µg) in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Treatment Period 1 STARTED	42	45	51	41	43	39	38	51
Treatment Period 1 COMPLETED	40	45	50	41	39	37	38	48
Treatment Period 1 NOT COMPLETED	2	0	1	0	4	2	0	3
Washout Period 1 (12-14 Days) STARTED	40	45	50	41	39	37	38	48
Washout Period 1 (12-14 Days) COMPLETED	36	44	47	39	35	37	36	47
Washout Period 1 (12-14 Days) NOT COMPLETED	4	1	3	2	4	0	2	1
Treatment Period 2 STARTED	33	46	40	41	37	45	43	36
Treatment Period 2 COMPLETED	30	46	40	41	37	43	43	35
Treatment Period 2 NOT COMPLETED	3	0	0	0	0	2	0	1
Washout Period 2 (12-14 Days) STARTED	30	46	40	41	37	43	43	35
Washout Period 2 (12-14 Days) COMPLETED	30	46	39	41	34	42	42	34
Washout Period 2 (12-14 Days) NOT COMPLETED	0	0	1	0	3	1	1	1
Treatment Period 3 STARTED	43	33	38	42	40	39	35	38
Treatment Period 3 COMPLETED	43	32	37	42	40	39	33	38
Treatment Period 3 NOT COMPLETED	0	1	1	0	0	0	2	0
Washout Period 3 or Follow-up STARTED	43	32	37	42	40	39	33	38
Washout Period 3 or Follow-up COMPLETED	42	32	36	41	40	37	32	38
Washout Period 3 or Follow-up NOT COMPLETED	1	0	1	1	0	2	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received matching placebo in the morning via dry powder inhaler (DPI) A and in the evening via DPI B for 14 days.	UMEC 15.6 µg QD Participants received umeclidinium bromide (UMEC) 15.6 micrograms (µg) in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Treatment Period 1 Adverse Event	1	0	0	0	0	0	0	0
Treatment Period 1 Lack of Efficacy	0	0	0	0	0	0	0	1
Treatment Period 1 Protocol Violation	1	0	0	0	2	0	0	0
Treatment Period 1 Protocol-defined Stopping Criteria	0	0	0	0	1	0	0	1
Treatment Period 1 Lost to Follow-up	0	0	1	0	0	0	0	0
Treatment Period 1 Physician Decision	0	0	0	0	1	0	0	0
Treatment Period 1 Withdrawal by Subject	0	0	0	0	0	2	0	1
Washout Period 1 (12-14 Days) Adverse Event	2	0	0	0	0	0	0	0
Washout Period 1 (12-14 Days) Protocol Violation	0	0	0	0	0	0	1	0
Washout Period 1 (12-14 Days) Protocol-defined Stopping Criteria	1	0	3	1	3	0	0	1
Washout Period 1 (12-14 Days) Withdrawal by Subject	1	1	0	1	1	0	1	0
Treatment Period 2 Lack of Efficacy	1	0	0	0	0	0	0	0
Treatment Period 2 Protocol-defined Stopping Criteria	1	0	0	0	0	0	0	0
Treatment Period 2 Lost to Follow-up	0	0	0	0	0	1	0	0
Treatment Period 2 Withdrawal by Subject	1	0	0	0	0	1	0	1
Washout Period 2 (12-14 Days) Protocol-defined Stopping Criteria	0	0	0	0	3	0	1	0
Washout Period 2 (12-14 Days) Withdrawal by Subject	0	0	1	0	0	1	0	1
Treatment Period 3 Adverse Event	0	0	0	0	0	0	1	0
Treatment Period 3 Protocol Violation	0	0	1	0	0	0	0	0
Treatment Period 3 Protocol-defined Stopping Criteria	0	0	0	0	0	0	1	0
Treatment Period 3 Lost to Follow-up	0	1	0	0	0	0	0	0
Washout Period 3 or Follow-up Protocol Violation	0	0	0	0	0	1	0	0
Washout Period 3 or Follow-up Protocol-defined Stopping Criteria	1	0	1	1	0	1	1	0

Baseline Characteristics

A 3-period Crossover Study With GSK573719 as Monotherapy in Adult Subjects With Asthma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Study Treatments n=350 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.
Age, Continuous	42.6 Years STANDARD_DEVIATION 14.84 • n=5 Participants
Sex: Female, Male Female	232 Participants n=5 Participants
Sex: Female, Male Male	118 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage (HER)	33 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	85 Participants n=5 Participants
Race/Ethnicity, Customized Asian-Japanese/East Asian HER/South East Asian HER	4 Participants n=5 Participants
Race/Ethnicity, Customized White	197 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native & White	31 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 15 of each treatment period (up to Study Day 71)

Population: Intent-To-Treat (ITT) Population: : all participants randomized to treatment and who received at least one dose of study medication. All participants with \>=1 post-Baseline assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 15.

Dose-response was conducted for both QD and BID UMEC doses on trough FEV1 (measure of lung function, defined as the maximal amount of air that can be forcefully exhaled in 1 second) on D 15. Total daily dose of UMEC was used in the modeling. The null model was the final model. The null model is defined as: CFEV1,ij=(THETA1+ETA1j)\*meanBL+(THETA2+ETA1j)\*periodBL+EPSij, where CFEV1,ij represents the change from BL in trough FEV1 for participant j measured at period i. THETA1 and THETA2 were the slopes with respect to meanBL and periodBL, respectively. Omegas were the variance of the slopes on meanBL and periodBL (ETA1j, ETA2j) for each participant and Sigma was the variance of the residual errors (EPSij). MeanBL is the mean of the Baseline (BL) which is the FEV1 value recorded pre-dose on D 1 of each TP; periodBL is the difference between the BL and the meanBL in each TP for each participant.

Outcome measures

Outcome measures
Measure	All Study Treatments n=332 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) Theta1 (mean Baseline)	0.0363 unitless Interval 0.028 to 0.045	—	—	—	—	—	—	—
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) Theta2 (period Baseline)	-0.97 unitless Interval -1.06 to -0.881	—	—	—	—	—	—	—
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) Omega (mean Baseline)	0.00371 unitless Interval 0.002 to 0.005	—	—	—	—	—	—	—
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) Omega (period Baseline)	0.149 unitless Interval 0.0 to 0.298	—	—	—	—	—	—	—
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) Sigma (Variance of Residual error)	0.0393 unitless Interval 0.028 to 0.05	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Day 15 of each treatment period (up to Study Day 71)

Population: ITT Population. All participants with \>=1 post-Baseline assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 15.

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 on Treatment Day 15 is defined as the value obtained 24 hours after the morning dose administered on Day 14. Analysis was performed using a mixed model, including treatment, period, period Baseline FEV1 and mean Baseline FEV1 as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period; mean Baseline is the mean of the Baselines for each participant and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline for each treatment period is the trough FEV1 at Day 15 minus the Baseline value for that treatment period.

Outcome measures

Outcome measures
Measure	All Study Treatments n=110 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=120 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=124 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=122 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=113 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=117 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=113 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=118 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Trough FEV1 on Day 15 of Each Treatment Period	0.046 Liters Standard Error 0.0235	0.112 Liters Standard Error 0.0226	0.076 Liters Standard Error 0.0222	0.080 Liters Standard Error 0.0224	0.134 Liters Standard Error 0.0232	0.057 Liters Standard Error 0.0228	0.103 Liters Standard Error 0.0232	0.097 Liters Standard Error 0.0227

PRIMARY outcome

Timeframe: From Baseline until the end of Treatment Period 3 (up to Study Day 70)

Population: ITT Population

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of SAEs.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Any AE	15 Participants	12 Participants	13 Participants	21 Participants	26 Participants	28 Participants	16 Participants	12 Participants
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Any SAE	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Baseline until the end of Treatment Period 3 (up to Study Day 70)

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

Worsening of asthma symptoms is monitored throughout the study. Severe exacerbation (deterioration of asthma requiring use of systemic corticosteroids for 3 days, inpatient hospitalization or emergency department visit due to asthma) is an exclusion criterion and requires withdrawal from the study. Asthma symptoms were assessed daily using an electronic diary throughout study.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Number of Participants With Asthma Exacerbations During the Treatment Period	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

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

Blood pressure measurement included systolic blood pressure (SBP). Blood pressure was measured in a sitting position after the participant was kept at rest for at least 5 minutes. Analysis was performed using a mixed model, including treatment, period, period Baseline and mean Baseline for the measure as fixed effects and participant as a random effect. Baseline is the value recorded pre-dose on Day 1 of each treatment period; mean Baseline is the mean of the Baselines for each participant and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline was calculated as the assessment value at Day 14 minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=112 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=122 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=127 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=123 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=114 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=119 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=114 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=122 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Systolic Blood Pressure on Day 14 of Each Treatment Period	-0.4 Millimeters of mercury (mmHg) Standard Error 0.71	-0.6 Millimeters of mercury (mmHg) Standard Error 0.68	-1.0 Millimeters of mercury (mmHg) Standard Error 0.67	1.1 Millimeters of mercury (mmHg) Standard Error 0.68	-0.6 Millimeters of mercury (mmHg) Standard Error 0.71	0.0 Millimeters of mercury (mmHg) Standard Error 0.69	0.3 Millimeters of mercury (mmHg) Standard Error 0.71	-1.2 Millimeters of mercury (mmHg) Standard Error 0.69

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

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

Blood pressure measurement included diastolic blood pressure (DBP). Blood pressure was measured in a sitting position after the participant was kept at rest for at least 5 minutes. Analysis was performed using a mixed model, including treatment, period, period Baseline and mean Baseline for the measure as fixed effects and participant as a random effect. Baseline is the value recorded pre-dose on Day 1 of each treatment period; mean Baseline is the mean of the Baselines for each participant and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline was calculated as the assessment value at Day 14 minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=112 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=122 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=127 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=123 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=114 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=119 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=114 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=122 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Diastolic Blood Pressure on Day 14 of Each Treatment Period	-2.1 Millimeters of mercury (mmHg) Standard Error 0.57	-0.5 Millimeters of mercury (mmHg) Standard Error 0.55	-0.8 Millimeters of mercury (mmHg) Standard Error 0.53	-0.2 Millimeters of mercury (mmHg) Standard Error 0.54	0.3 Millimeters of mercury (mmHg) Standard Error 0.57	0.0 Millimeters of mercury (mmHg) Standard Error 0.55	0.6 Millimeters of mercury (mmHg) Standard Error 0.56	-0.7 Millimeters of mercury (mmHg) Standard Error 0.55

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

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

Pulse rate was measured in a sitting position after the participant was kept at rest for at least 5 minutes. Analysis was performed using a mixed model, including treatment, period, period Baseline and mean Baseline for the measure as fixed effects and participant as a random effect. Baseline is the value recorded pre-dose on Day 1 of each treatment period; mean Baseline is the mean of the Baselines for each participant and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Change from Baseline was calculated as the assessment value at Day 14 minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=112 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=122 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=127 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=123 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=114 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=119 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=114 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=122 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Pulse Rate on Day 14 of Each Treatment Period	-0.4 Beats per minute Standard Error 0.64	-0.1 Beats per minute Standard Error 0.62	1.2 Beats per minute Standard Error 0.60	0.2 Beats per minute Standard Error 0.61	0.2 Beats per minute Standard Error 0.64	1.1 Beats per minute Standard Error 0.62	-0.4 Beats per minute Standard Error 0.64	-1.1 Beats per minute Standard Error 0.62

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70))

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of albumin, total protein, and hemoglobin at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Albumin, Total Protein, and Hemoglobin on Day 14 of Each Treatment Period Albumin, n=111, 118, 120, 121, 112, 112, 112, 117	-1.1 Grams per liter (G/L) Standard Deviation 2.46	-1.0 Grams per liter (G/L) Standard Deviation 2.63	-0.8 Grams per liter (G/L) Standard Deviation 2.47	-0.9 Grams per liter (G/L) Standard Deviation 2.59	-1.1 Grams per liter (G/L) Standard Deviation 2.65	-1.0 Grams per liter (G/L) Standard Deviation 2.47	-0.6 Grams per liter (G/L) Standard Deviation 2.41	-0.7 Grams per liter (G/L) Standard Deviation 2.14
Change From Baseline in Albumin, Total Protein, and Hemoglobin on Day 14 of Each Treatment Period Total protein, n=111,118,120,121,112,112,112,117	-1.9 Grams per liter (G/L) Standard Deviation 3.63	-1.9 Grams per liter (G/L) Standard Deviation 3.83	-1.4 Grams per liter (G/L) Standard Deviation 3.82	-1.7 Grams per liter (G/L) Standard Deviation 3.48	-1.9 Grams per liter (G/L) Standard Deviation 4.02	-1.8 Grams per liter (G/L) Standard Deviation 3.58	-1.1 Grams per liter (G/L) Standard Deviation 3.58	-1.2 Grams per liter (G/L) Standard Deviation 3.09
Change From Baseline in Albumin, Total Protein, and Hemoglobin on Day 14 of Each Treatment Period Hemogloin, n=109,121,124,120,110,113,112,121	-2.2 Grams per liter (G/L) Standard Deviation 7.24	-2.8 Grams per liter (G/L) Standard Deviation 6.55	-1.6 Grams per liter (G/L) Standard Deviation 6.66	-2.3 Grams per liter (G/L) Standard Deviation 7.13	-1.8 Grams per liter (G/L) Standard Deviation 7.44	-1.4 Grams per liter (G/L) Standard Deviation 6.76	-1.3 Grams per liter (G/L) Standard Deviation 6.59	-2.0 Grams per liter (G/L) Standard Deviation 7.06

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of ALP, ALT, AST, CK, GGT, and LDH at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period ALP, n=111, 118, 120, 121, 112, 112, 112, 117	-0.7 International Units/Liter (IU/L) Standard Deviation 16.13	-1.1 International Units/Liter (IU/L) Standard Deviation 14.35	-1.8 International Units/Liter (IU/L) Standard Deviation 13.55	-2.0 International Units/Liter (IU/L) Standard Deviation 10.73	-2.8 International Units/Liter (IU/L) Standard Deviation 14.16	-0.6 International Units/Liter (IU/L) Standard Deviation 10.90	-0.6 International Units/Liter (IU/L) Standard Deviation 14.05	-1.5 International Units/Liter (IU/L) Standard Deviation 9.88
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period ALT, n=111, 117, 120, 121, 112, 112, 112, 117	0.7 International Units/Liter (IU/L) Standard Deviation 12.15	0.6 International Units/Liter (IU/L) Standard Deviation 11.56	0.4 International Units/Liter (IU/L) Standard Deviation 11.24	-0.1 International Units/Liter (IU/L) Standard Deviation 7.18	-1.7 International Units/Liter (IU/L) Standard Deviation 8.44	1.4 International Units/Liter (IU/L) Standard Deviation 9.80	1.7 International Units/Liter (IU/L) Standard Deviation 16.17	-1.3 International Units/Liter (IU/L) Standard Deviation 8.73
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period AST, n=110, 118, 120, 120, 112, 112, 112, 117	0.6 International Units/Liter (IU/L) Standard Deviation 7.53	-0.3 International Units/Liter (IU/L) Standard Deviation 6.26	1.9 International Units/Liter (IU/L) Standard Deviation 18.69	-0.4 International Units/Liter (IU/L) Standard Deviation 6.31	-0.6 International Units/Liter (IU/L) Standard Deviation 7.51	0.7 International Units/Liter (IU/L) Standard Deviation 8.39	0.6 International Units/Liter (IU/L) Standard Deviation 7.24	-0.3 International Units/Liter (IU/L) Standard Deviation 9.59
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period CK, n=111, 118, 120, 121, 112, 112, 112, 117	5.2 International Units/Liter (IU/L) Standard Deviation 69.94	6.3 International Units/Liter (IU/L) Standard Deviation 70.20	143.0 International Units/Liter (IU/L) Standard Deviation 1486.66	-10.0 International Units/Liter (IU/L) Standard Deviation 73.53	-2.5 International Units/Liter (IU/L) Standard Deviation 147.85	7.7 International Units/Liter (IU/L) Standard Deviation 105.96	6.9 International Units/Liter (IU/L) Standard Deviation 100.44	19.8 International Units/Liter (IU/L) Standard Deviation 284.94
Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period GGT, n=111, 118, 120, 121, 112, 112, 112, 117	1.2 International Units/Liter (IU/L) Standard Deviation 15.06	0.7 International Units/Liter (IU/L) Standard Deviation 9.63	0.4 International Units/Liter (IU/L) Standard Deviation 10.63	0.0 International Units/Liter (IU/L) Standard Deviation 9.74	-0.6 International Units/Liter (IU/L) Standard Deviation 8.31	0.2 International Units/Liter (IU/L) Standard Deviation 12.15	2.0 International Units/Liter (IU/L) Standard Deviation 10.18	0.9 International Units/Liter (IU/L) Standard Deviation 10.61

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of direct bilirubin, indirect (ind) bilirubin, total bilirubin, and creatinine at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine on Day 14 of Each Treatment Period Direct bilirubin,n=111,118,120,121,112,112,112,117	-0.2 Micromoles/Liter (µM/L) Standard Deviation 1.10	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.10	-0.1 Micromoles/Liter (µM/L) Standard Deviation 0.99	-0.1 Micromoles/Liter (µM/L) Standard Deviation 0.95	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.15	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.15	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.08	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.10
Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine on Day 14 of Each Treatment Period Bilirubin, n=111,118,120,121,112,112,112,117	-1.0 Micromoles/Liter (µM/L) Standard Deviation 3.94	-0.9 Micromoles/Liter (µM/L) Standard Deviation 3.69	-0.7 Micromoles/Liter (µM/L) Standard Deviation 3.36	-0.9 Micromoles/Liter (µM/L) Standard Deviation 3.85	-1.1 Micromoles/Liter (µM/L) Standard Deviation 5.15	-0.9 Micromoles/Liter (µM/L) Standard Deviation 4.17	-0.8 Micromoles/Liter (µM/L) Standard Deviation 4.19	-0.9 Micromoles/Liter (µM/L) Standard Deviation 3.68
Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine on Day 14 of Each Treatment Period Ind Bilirubin, n=111,118,120,121,112,112,112,117	-0.8 Micromoles/Liter (µM/L) Standard Deviation 3.42	-0.8 Micromoles/Liter (µM/L) Standard Deviation 3.03	-0.6 Micromoles/Liter (µM/L) Standard Deviation 2.93	-0.8 Micromoles/Liter (µM/L) Standard Deviation 3.37	-1.1 Micromoles/Liter (µM/L) Standard Deviation 4.42	-0.8 Micromoles/Liter (µM/L) Standard Deviation 3.60	-0.7 Micromoles/Liter (µM/L) Standard Deviation 3.63	-0.8 Micromoles/Liter (µM/L) Standard Deviation 3.16
Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine on Day 14 of Each Treatment Period Creatinine, n=111,118,120,121,112,112,112,117	0.27 Micromoles/Liter (µM/L) Standard Deviation 9.218	-0.67 Micromoles/Liter (µM/L) Standard Deviation 8.037	-0.76 Micromoles/Liter (µM/L) Standard Deviation 6.242	0.94 Micromoles/Liter (µM/L) Standard Deviation 6.811	-0.24 Micromoles/Liter (µM/L) Standard Deviation 7.450	0.15 Micromoles/Liter (µM/L) Standard Deviation 6.826	0.30 Micromoles/Liter (µM/L) Standard Deviation 7.297	0.22 Micromoles/Liter (µM/L) Standard Deviation 7.671

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of chloride, caron dioxide, glucose, potassium, sodium, and urea/BUN at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Chloride, n=111, 118, 120, 121, 112, 112, 112, 117	0.1 Micromoles/Liter (µM/L) Standard Deviation 2.11	0.4 Micromoles/Liter (µM/L) Standard Deviation 2.29	0.4 Micromoles/Liter (µM/L) Standard Deviation 2.29	0.3 Micromoles/Liter (µM/L) Standard Deviation 2.21	0.6 Micromoles/Liter (µM/L) Standard Deviation 2.18	0.3 Micromoles/Liter (µM/L) Standard Deviation 1.84	0.3 Micromoles/Liter (µM/L) Standard Deviation 2.22	0.3 Micromoles/Liter (µM/L) Standard Deviation 2.00
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Carbon dioxide, n=110,118,120,120,112,112,112,117	-0.6 Micromoles/Liter (µM/L) Standard Deviation 2.16	-0.4 Micromoles/Liter (µM/L) Standard Deviation 2.73	-0.6 Micromoles/Liter (µM/L) Standard Deviation 2.54	-0.2 Micromoles/Liter (µM/L) Standard Deviation 2.88	-0.4 Micromoles/Liter (µM/L) Standard Deviation 2.11	-0.0 Micromoles/Liter (µM/L) Standard Deviation 2.55	-0.5 Micromoles/Liter (µM/L) Standard Deviation 2.69	-0.6 Micromoles/Liter (µM/L) Standard Deviation 2.38
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Glucose, n=111, 118, 120, 121, 112, 112, 112, 117	0.01 Micromoles/Liter (µM/L) Standard Deviation 1.134	0.04 Micromoles/Liter (µM/L) Standard Deviation 0.975	-0.15 Micromoles/Liter (µM/L) Standard Deviation 0.950	0.01 Micromoles/Liter (µM/L) Standard Deviation 1.012	-0.29 Micromoles/Liter (µM/L) Standard Deviation 0.848	-0.08 Micromoles/Liter (µM/L) Standard Deviation 1.048	-0.09 Micromoles/Liter (µM/L) Standard Deviation 1.022	-0.14 Micromoles/Liter (µM/L) Standard Deviation 0.778
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Potassium, n=110, 118, 120, 120, 112, 112, 112,117	0.02 Micromoles/Liter (µM/L) Standard Deviation 0.400	0.05 Micromoles/Liter (µM/L) Standard Deviation 0.338	0.05 Micromoles/Liter (µM/L) Standard Deviation 0.416	0.03 Micromoles/Liter (µM/L) Standard Deviation 0.420	0.05 Micromoles/Liter (µM/L) Standard Deviation 0.353	0.02 Micromoles/Liter (µM/L) Standard Deviation 0.412	0.08 Micromoles/Liter (µM/L) Standard Deviation 0.387	0.09 Micromoles/Liter (µM/L) Standard Deviation 0.398
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Sodium, n=111, 118, 120, 121, 112, 112, 112, 117	-0.2 Micromoles/Liter (µM/L) Standard Deviation 1.78	0.2 Micromoles/Liter (µM/L) Standard Deviation 2.06	-0.0 Micromoles/Liter (µM/L) Standard Deviation 2.14	-0.2 Micromoles/Liter (µM/L) Standard Deviation 2.33	-0.1 Micromoles/Liter (µM/L) Standard Deviation 1.99	-0.3 Micromoles/Liter (µM/L) Standard Deviation 1.88	-0.2 Micromoles/Liter (µM/L) Standard Deviation 2.23	-0.4 Micromoles/Liter (µM/L) Standard Deviation 1.82
Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period Urea/BUN, n=111, 118, 120, 121, 112, 112, 112, 117	0.11 Micromoles/Liter (µM/L) Standard Deviation 1.382	0.34 Micromoles/Liter (µM/L) Standard Deviation 1.149	0.02 Micromoles/Liter (µM/L) Standard Deviation 1.197	0.11 Micromoles/Liter (µM/L) Standard Deviation 1.283	-0.04 Micromoles/Liter (µM/L) Standard Deviation 1.322	0.20 Micromoles/Liter (µM/L) Standard Deviation 1.303	0.02 Micromoles/Liter (µM/L) Standard Deviation 1.184	0.13 Micromoles/Liter (µM/L) Standard Deviation 1.265

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC - Absolute neutrophil \[neut\] count), platelet, and leucocytes count at Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Lymphocytes, n=109, 121, 124, 117,110,112,111,121	-0.038 10^9 cells/Liter (GI/L) Standard Deviation 0.5767	-0.064 10^9 cells/Liter (GI/L) Standard Deviation 0.5882	-0.050 10^9 cells/Liter (GI/L) Standard Deviation 0.5850	-0.033 10^9 cells/Liter (GI/L) Standard Deviation 0.4986	-0.043 10^9 cells/Liter (GI/L) Standard Deviation 0.5366	-0.152 10^9 cells/Liter (GI/L) Standard Deviation 0.5203	-0.156 10^9 cells/Liter (GI/L) Standard Deviation 0.5552	-0.069 10^9 cells/Liter (GI/L) Standard Deviation 0.6148
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Basophil, n=109, 121, 124, 117, 110, 112, 111, 121	0.003 10^9 cells/Liter (GI/L) Standard Deviation 0.0212	-0.001 10^9 cells/Liter (GI/L) Standard Deviation 0.0173	-0.000 10^9 cells/Liter (GI/L) Standard Deviation 0.0184	0.001 10^9 cells/Liter (GI/L) Standard Deviation 0.0178	0.006 10^9 cells/Liter (GI/L) Standard Deviation 0.0230	-0.001 10^9 cells/Liter (GI/L) Standard Deviation 0.0162	-0.002 10^9 cells/Liter (GI/L) Standard Deviation 0.0161	0.000 10^9 cells/Liter (GI/L) Standard Deviation 0.0184
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Eosinophils, n= 109, 121, 124, 117,110,112,111,121	0.097 10^9 cells/Liter (GI/L) Standard Deviation 0.2400	0.023 10^9 cells/Liter (GI/L) Standard Deviation 0.1988	0.029 10^9 cells/Liter (GI/L) Standard Deviation 0.1928	0.036 10^9 cells/Liter (GI/L) Standard Deviation 0.2056	0.036 10^9 cells/Liter (GI/L) Standard Deviation 0.1944	0.039 10^9 cells/Liter (GI/L) Standard Deviation 0.2583	0.040 10^9 cells/Liter (GI/L) Standard Deviation 0.1799	0.039 10^9 cells/Liter (GI/L) Standard Deviation 0.1862
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Monocytes, n=109, 121, 124, 117, 110, 112, 111,121	0.017 10^9 cells/Liter (GI/L) Standard Deviation 0.1278	0.029 10^9 cells/Liter (GI/L) Standard Deviation 0.1366	0.005 10^9 cells/Liter (GI/L) Standard Deviation 0.1173	0.017 10^9 cells/Liter (GI/L) Standard Deviation 0.1185	0.029 10^9 cells/Liter (GI/L) Standard Deviation 0.1348	0.030 10^9 cells/Liter (GI/L) Standard Deviation 0.1289	0.010 10^9 cells/Liter (GI/L) Standard Deviation 0.1168	-0.000 10^9 cells/Liter (GI/L) Standard Deviation 0.1060
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Total Neut, n= 109, 121, 124, 117, 110,112,111,121	-0.204 10^9 cells/Liter (GI/L) Standard Deviation 1.4615	0.032 10^9 cells/Liter (GI/L) Standard Deviation 1.2279	0.119 10^9 cells/Liter (GI/L) Standard Deviation 1.8710	-0.175 10^9 cells/Liter (GI/L) Standard Deviation 1.5228	-0.161 10^9 cells/Liter (GI/L) Standard Deviation 1.1780	0.107 10^9 cells/Liter (GI/L) Standard Deviation 1.8329	-0.133 10^9 cells/Liter (GI/L) Standard Deviation 1.2785	-0.080 10^9 cells/Liter (GI/L) Standard Deviation 1.1597
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Segmented Neut, n=109,121,124,117,110,112,111,121	-0.204 10^9 cells/Liter (GI/L) Standard Deviation 1.4615	0.032 10^9 cells/Liter (GI/L) Standard Deviation 1.2279	0.119 10^9 cells/Liter (GI/L) Standard Deviation 1.8710	-0.175 10^9 cells/Liter (GI/L) Standard Deviation 1.5228	-0.161 10^9 cells/Liter (GI/L) Standard Deviation 1.1780	0.107 10^9 cells/Liter (GI/L) Standard Deviation 1.8329	-0.133 10^9 cells/Liter (GI/L) Standard Deviation 1.2785	-0.080 10^9 cells/Liter (GI/L) Standard Deviation 1.1597
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Platelets,n=109, 121, 124, 119, 110, 112, 111, 119	-1.4 10^9 cells/Liter (GI/L) Standard Deviation 40.21	-0.7 10^9 cells/Liter (GI/L) Standard Deviation 30.35	-1.0 10^9 cells/Liter (GI/L) Standard Deviation 36.65	-2.3 10^9 cells/Liter (GI/L) Standard Deviation 36.32	-2.1 10^9 cells/Liter (GI/L) Standard Deviation 34.17	-8.4 10^9 cells/Liter (GI/L) Standard Deviation 40.89	-2.2 10^9 cells/Liter (GI/L) Standard Deviation 33.07	-1.0 10^9 cells/Liter (GI/L) Standard Deviation 39.34
Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period Leukocytes,n=109,121,124, 117, 110, 112, 111, 121	-0.12 10^9 cells/Liter (GI/L) Standard Deviation 1.740	0.01 10^9 cells/Liter (GI/L) Standard Deviation 1.385	0.10 10^9 cells/Liter (GI/L) Standard Deviation 1.867	-0.15 10^9 cells/Liter (GI/L) Standard Deviation 1.664	-0.14 10^9 cells/Liter (GI/L) Standard Deviation 1.400	0.02 10^9 cells/Liter (GI/L) Standard Deviation 1.913	-0.24 10^9 cells/Liter (GI/L) Standard Deviation 1.423	-0.11 10^9 cells/Liter (GI/L) Standard Deviation 1.402

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Blood samples were collected for the measurement of the percentage of basophils, eosinophils, lymphocytes, monocytes, and segmented neutrophils (neut) at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Eosinophils, n= 109,121,124,117,110,112,111,121	1.45 Percentage of cells in blood Standard Deviation 3.380	0.30 Percentage of cells in blood Standard Deviation 2.782	0.32 Percentage of cells in blood Standard Deviation 2.896	0.68 Percentage of cells in blood Standard Deviation 3.100	0.56 Percentage of cells in blood Standard Deviation 2.403	0.55 Percentage of cells in blood Standard Deviation 3.142	0.65 Percentage of cells in blood Standard Deviation 2.537	0.56 Percentage of cells in blood Standard Deviation 2.481
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Lymphocytes, n=109,121,124,117,110,112,111,121	-0.00 Percentage of cells in blood Standard Deviation 6.861	-0.64 Percentage of cells in blood Standard Deviation 7.590	-0.29 Percentage of cells in blood Standard Deviation 7.485	0.62 Percentage of cells in blood Standard Deviation 8.069	-0.06 Percentage of cells in blood Standard Deviation 6.996	-1.97 Percentage of cells in blood Standard Deviation 8.203	-0.76 Percentage of cells in blood Standard Deviation 8.001	-0.46 Percentage of cells in blood Standard Deviation 7.650
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Monocytes, n=109,121,124,117,110,112,111,121	0.30 Percentage of cells in blood Standard Deviation 1.735	0.45 Percentage of cells in blood Standard Deviation 1.941	0.04 Percentage of cells in blood Standard Deviation 1.798	0.41 Percentage of cells in blood Standard Deviation 1.787	0.52 Percentage of cells in blood Standard Deviation 1.719	0.45 Percentage of cells in blood Standard Deviation 1.622	0.43 Percentage of cells in blood Standard Deviation 2.626	0.07 Percentage of cells in blood Standard Deviation 1.585
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Neutrophils, n=109,121,124,117,110,112,111,121	-1.80 Percentage of cells in blood Standard Deviation 8.264	-0.11 Percentage of cells in blood Standard Deviation 8.872	-0.04 Percentage of cells in blood Standard Deviation 8.739	-1.73 Percentage of cells in blood Standard Deviation 9.048	-1.11 Percentage of cells in blood Standard Deviation 8.107	0.96 Percentage of cells in blood Standard Deviation 9.319	-0.30 Percentage of cells in blood Standard Deviation 9.252	-0.17 Percentage of cells in blood Standard Deviation 8.676
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Segmented Neut, n=109,121,124,117,110,112,111,121	-1.80 Percentage of cells in blood Standard Deviation 8.264	-0.11 Percentage of cells in blood Standard Deviation 8.872	-0.04 Percentage of cells in blood Standard Deviation 8.739	-1.73 Percentage of cells in blood Standard Deviation 9.048	-1.11 Percentage of cells in blood Standard Deviation 8.107	0.96 Percentage of cells in blood Standard Deviation 9.319	-0.30 Percentage of cells in blood Standard Deviation 9.252	-0.17 Percentage of cells in blood Standard Deviation 8.676
Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period Basophils, n=109,121,124,117,111,112,111,121	0.05 Percentage of cells in blood Standard Deviation 0.302	-0.01 Percentage of cells in blood Standard Deviation 0.240	-0.02 Percentage of cells in blood Standard Deviation 0.273	0.03 Percentage of cells in blood Standard Deviation 0.286	0.08 Percentage of cells in blood Standard Deviation 0.318	0.00 Percentage of cells in blood Standard Deviation 0.212	-0.02 Percentage of cells in blood Standard Deviation 0.248	0.00 Percentage of cells in blood Standard Deviation 0.268

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

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

Blood samples were collected for the measurement of hematocrit (proportion of red blood cells in blood) at Baseline and Day 14. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=109 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=121 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=124 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=120 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=110 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=113 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=112 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=121 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Hematocrit on Day 14 of Each Treatment Period	-0.0093 Proportion of red blood cells in blood Standard Deviation 0.02298	-0.0118 Proportion of red blood cells in blood Standard Deviation 0.02180	-0.0075 Proportion of red blood cells in blood Standard Deviation 0.02271	-0.0092 Proportion of red blood cells in blood Standard Deviation 0.02198	-0.0082 Proportion of red blood cells in blood Standard Deviation 0.02452	-0.0079 Proportion of red blood cells in blood Standard Deviation 0.02053	-0.0084 Proportion of red blood cells in blood Standard Deviation 0.02259	-0.0087 Proportion of red blood cells in blood Standard Deviation 0.02279

PRIMARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70))

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Urinalysis parameters included: Urine Bilirubin (UB), Urine Occult Blood (UOB), Urine Glucose (UG), Urine Ketones (UK), Urine Nitrite (UN), Urine Protein (UP), and Urine Leukocyte Esterase test for detecting White Blood Cell (UWBC). The dipstick was a strip used to detect the presence or absence of these parameters in the urine sample. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative (Neg), Trace (T), 1+, 2+, and 3+, and for UG the result can be read as Neg, T, T or 1/10 G/dL, 1+ or 1/4 G/dL, 3+ or 1 G/dL, indicating proportional concentrations in the urine sample. Data are reported as the number of participants who had neg, T, 1+, 2+ and 3+ levels at Day 14.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UB, Neg, n=109,121,125,120,112, 113,112,119	109 Participants	121 Participants	125 Participants	120 Participants	112 Participants	112 Participants	112 Participants	119 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UOB, T, n=109,121,125,120,112,113,112,119	8 Participants	8 Participants	14 Participants	12 Participants	13 Participants	11 Participants	8 Participants	13 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UOB, 1+, n=109,121,125,120,112,113,112,119	5 Participants	8 Participants	4 Participants	5 Participants	5 Participants	7 Participants	5 Participants	2 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UOB, 2+, n=109,121,125,120,112,113,112,119	5 Participants	1 Participants	3 Participants	2 Participants	0 Participants	1 Participants	3 Participants	2 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UOB, 3+, n=109,121,125,120,112,113,112,119	6 Participants	3 Participants	1 Participants	1 Participants	4 Participants	3 Participants	2 Participants	3 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UOB, Neg, n=109,121,125,120,112,113,112,119	85 Participants	101 Participants	103 Participants	100 Participants	90 Participants	91 Participants	94 Participants	99 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UG, T, n=109,121,125,120,112,113,112,119	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UG, T or 1/10, n=109,121,125,120,112,113,112,119	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UG, 1+ or 1/4, n=109,121,125,120,112,113,112,119	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UG, 3+ or 1, n=109,121,125,120,112,113,112,119	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UG, Neg, n=109,121,125,120,112,113,112,119	107 Participants	118 Participants	124 Participants	119 Participants	112 Participants	112 Participants	111 Participants	119 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UK, T, n=109,121,125,120,112,113,112,119	4 Participants	3 Participants	5 Participants	2 Participants	8 Participants	0 Participants	2 Participants	3 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UK, Neg, n=109,121,125,120,112,113,112,119	103 Participants	118 Participants	119 Participants	116 Participants	104 Participants	112 Participants	110 Participants	113 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UK, 1+, n=109,121,125,120,112,113,112,119	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UK, 2+, n=109,121,125,120,112,113,112,119	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UK, 3+, n=109,121,125,120,112,113,112,119	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UN, Neg, n=109,121,125,120,112,113,112,119	97 Participants	113 Participants	116 Participants	108 Participants	108 Participants	109 Participants	103 Participants	105 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UN, Pos, n=109,121,125,120,112,113,112,119	12 Participants	8 Participants	9 Participants	12 Participants	4 Participants	4 Participants	9 Participants	14 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UP, Neg, n=109,121,125,120,112,113,112,119	99 Participants	112 Participants	110 Participants	116 Participants	102 Participants	108 Participants	107 Participants	111 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UP, T, n=109,121,125,120,112,113,112,119	4 Participants	6 Participants	8 Participants	2 Participants	6 Participants	3 Participants	4 Participants	4 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UP, 1+, n=109,121,125,120,112,113,112,119	4 Participants	2 Participants	6 Participants	1 Participants	4 Participants	2 Participants	1 Participants	4 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UP, 2+, n=109,121,125,120,112,113,112,119	2 Participants	1 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UWBC, Neg, n=109,121,125,120,112,113,112,119	88 Participants	96 Participants	100 Participants	90 Participants	82 Participants	88 Participants	89 Participants	85 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UWBC, T, n=109,121,125,120,112,113,112,119	6 Participants	5 Participants	6 Participants	11 Participants	8 Participants	5 Participants	5 Participants	11 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UWBC, 1+, n=109,121,125,120,112,113,112,119	6 Participants	9 Participants	12 Participants	12 Participants	12 Participants	12 Participants	4 Participants	10 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UWBC, 2+, n=109,121,125,120,112,113,112,119	4 Participants	8 Participants	5 Participants	3 Participants	5 Participants	8 Participants	11 Participants	12 Participants
Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period UWBC, 3+, n=109,121,125,120,112,113,112,119	5 Participants	3 Participants	2 Participants	3 Participants	5 Participants	0 Participants	3 Participants	1 Participants

PRIMARY outcome

Timeframe: Day 14 of each treatment period (up to Study Day 70)

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

Urine samples were collected for the measurement of urine pH by dipstick method at Day 14. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

Outcome measures

Outcome measures
Measure	All Study Treatments n=109 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=121 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=125 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=120 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=112 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=113 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=112 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=119 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Urine pH on Day 14 of Each Treatment Period	5.89 Scores on a scale Standard Deviation 0.635	5.97 Scores on a scale Standard Deviation 0.709	6.05 Scores on a scale Standard Deviation 0.718	6.07 Scores on a scale Standard Deviation 0.743	5.90 Scores on a scale Standard Deviation 0.678	5.99 Scores on a scale Standard Deviation 0.720	5.89 Scores on a scale Standard Deviation 0.690	5.90 Scores on a scale Standard Deviation 0.684

PRIMARY outcome

Timeframe: Day 14 of each treatment period (up to Study Day 70)

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

Urine samples were collected for the measurement of urine specific gravity by dipstick method at Day 14. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. A urinary specific gravity measurement is a routine part of urinalysis. The reference range is 1.002-1.030.

Outcome measures

Outcome measures
Measure	All Study Treatments n=109 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=121 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=125 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=120 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=112 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=113 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=112 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=118 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Urine Specific Gravity on Day 14 of Each Treatment Period	1.0194 Ratio Standard Deviation 0.00703	1.0198 Ratio Standard Deviation 0.00628	1.0194 Ratio Standard Deviation 0.00732	1.0185 Ratio Standard Deviation 0.00653	1.0201 Ratio Standard Deviation 0.00780	1.0192 Ratio Standard Deviation 0.00707	1.0189 Ratio Standard Deviation 0.00734	1.0193 Ratio Standard Deviation 0.00671

PRIMARY outcome

Timeframe: Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data at the indicated time points were analyzed.

Electrocardiograph measurements performed at Screening (Visit 1) and at Day 1 and Day 14 (pre-dose, 10 minutes post-dose and 2 hours post-dose.of each treatment period). Any clinically significant findings were identified during participant monitoring.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Number of Participants With the Indicated Abnormal Electrocardiogram Findings Conduction	14 Participants	17 Participants	10 Participants	12 Participants	10 Participants	11 Participants	7 Participants	12 Participants
Number of Participants With the Indicated Abnormal Electrocardiogram Findings Depolarisation/Repolarisation(QRS-T)	21 Participants	20 Participants	26 Participants	20 Participants	32 Participants	25 Participants	22 Participants	28 Participants
Number of Participants With the Indicated Abnormal Electrocardiogram Findings Myocardial Infarction	2 Participants	3 Participants	1 Participants	2 Participants	1 Participants	0 Participants	1 Participants	2 Participants
Number of Participants With the Indicated Abnormal Electrocardiogram Findings P-Wave and QRS Morphology	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants	0 Participants
Number of Participants With the Indicated Abnormal Electrocardiogram Findings Rhythm	12 Participants	13 Participants	15 Participants	12 Participants	13 Participants	15 Participants	17 Participants	21 Participants

PRIMARY outcome

Timeframe: Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only participants with sufficient data (at least 16 hours of recorded data) at the specified time points were analyzed.

Twenty-four hour Holter ECG measurements were obtained using a 12-lead Holter monitor. The Holter monitor is worn by the participant for 24 hours, and the monitor continuously records the heart's rhythm while the monitor is worn. Following the 24-hour period, the data from the monitor were downloaded and transmitted to the centralized vendor for analysis and interpretation by a licensed cardiologist. The 24-hour Holter ECG measurements were obtained at during the screening period and on Day 14 of each treatment period. The number of participants with clinically significant change (abnormal or normal) were reported.

Outcome measures

Outcome measures
Measure	All Study Treatments n=41 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=41 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=51 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=46 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=46 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=42 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=39 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=49 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Number of Participants With the Indicated 24 Hour Holter Findings Abnormal	6 Participants	3 Participants	7 Participants	7 Participants	8 Participants	8 Participants	7 Participants	7 Participants
Number of Participants With the Indicated 24 Hour Holter Findings Normal	35 Participants	38 Participants	44 Participants	39 Participants	38 Participants	34 Participants	32 Participants	42 Participants

SECONDARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

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

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. Baseline is the 0h value obtained prior to the AM dose on Day 14 of the treatment period. Change from BL at a was calculated as WM at the evaluated time point minus BL. Analysis was performed using a mixed model, including treatment, period, period Baseline FEV1, and mean Baseline FEV1 as fixed effects and participant as a random effect.

Outcome measures

Outcome measures
Measure	All Study Treatments n=33 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=35 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=49 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=42 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=45 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=38 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=35 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=43 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline (BL) in the Weighted Mean (WM) 0-24 Hour FEV1 Obtained Post-AM Dose on Day 14 of Each Treatment Period	-0.025 Liters Standard Error 0.0255	0.060 Liters Standard Error 0.0249	0.077 Liters Standard Error 0.0222	0.092 Liters Standard Error 0.0232	0.094 Liters Standard Error 0.0229	0.048 Liters Standard Error 0.0243	0.097 Liters Standard Error 0.0252	0.043 Liters Standard Error 0.0231

SECONDARY outcome

Timeframe: Baseline and Day 14 of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Serial FEV1 measurements were taken electronically by spirometry. Serial FEV1 was measured at 5, 15, 30 minutes (min), 1, 3, 6, 9, 12, 16, 20, 23 and 24 hours (h) post-dose. Baseline is the 0h value obtained prior to the AM dose on Day 14 of the treatment period. Change from Baseline was calculated as FEV1 value at the evaluated time point minus Baseline. Analysis was preformed using a repeated measures model with terms for period, treatment, time, mean Baseline, period Baseline, and time by mean Baseline, time by period Baseline, and time by treatment interactions.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 5 min, n=41, 39, 49, 46, 44, 42, 38, 48	0.024 Liters Standard Error 0.0329	0.095 Liters Standard Error 0.0330	0.110 Liters Standard Error 0.0296	0.077 Liters Standard Error 0.0309	0.123 Liters Standard Error 0.0312	0.042 Liters Standard Error 0.0326	0.141 Liters Standard Error 0.0338	0.118 Liters Standard Error 0.0301
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 15 min, n=41, 41, 51, 46, 46, 42, 39, 49	0.002 Liters Standard Error 0.0322	0.082 Liters Standard Error 0.0322	0.124 Liters Standard Error 0.0290	0.090 Liters Standard Error 0.0303	0.115 Liters Standard Error 0.0305	0.038 Liters Standard Error 0.0320	0.160 Liters Standard Error 0.0331	0.108 Liters Standard Error 0.0294
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 30 min, n=45, 42, 39, 49, 45, 42, 39, 49	0.012 Liters Standard Error 0.0318	0.109 Liters Standard Error 0.0317	0.115 Liters Standard Error 0.0285	0.092 Liters Standard Error 0.0299	0.149 Liters Standard Error 0.0301	0.040 Liters Standard Error 0.0315	0.158 Liters Standard Error 0.0326	0.110 Liters Standard Error 0.0290
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 1 h, n=41, 41, 51, 46, 46, 42, 39, 49	0.025 Liters Standard Error 0.0319	0.127 Liters Standard Error 0.0318	0.161 Liters Standard Error 0.0286	0.143 Liters Standard Error 0.0300	0.165 Liters Standard Error 0.0302	0.113 Liters Standard Error 0.0316	0.164 Liters Standard Error 0.0327	0.168 Liters Standard Error 0.0291
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 3 h, n=41, 41, 51, 46, 46, 42, 39, 49	0.000 Liters Standard Error 0.0353	0.141 Liters Standard Error 0.0353	0.175 Liters Standard Error 0.0317	0.156 Liters Standard Error 0.0332	0.143 Liters Standard Error 0.0335	0.143 Liters Standard Error 0.0350	0.182 Liters Standard Error 0.0362	0.165 Liters Standard Error 0.0322
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 6 h, n=41, 40, 51, 46, 46, 42, 39, 48	0.007 Liters Standard Error 0.0368	0.099 Liters Standard Error 0.0369	0.089 Liters Standard Error 0.0330	0.108 Liters Standard Error 0.0346	0.134 Liters Standard Error 0.0349	0.076 Liters Standard Error 0.0365	0.157 Liters Standard Error 0.0378	0.100 Liters Standard Error 0.0337
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 9 h, n=41, 40, 51, 46, 46, 42, 39, 49	-0.049 Liters Standard Error 0.0354	0.043 Liters Standard Error 0.0356	0.061 Liters Standard Error 0.0318	0.118 Liters Standard Error 0.0333	0.117 Liters Standard Error 0.0335	0.081 Liters Standard Error 0.0351	0.072 Liters Standard Error 0.0363	0.075 Liters Standard Error 0.0323
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 12 h, n=41, 41, 51, 46, 46, 41, 39, 49	-0.044 Liters Standard Error 0.0395	0.015 Liters Standard Error 0.0394	0.021 Liters Standard Error 0.0354	0.060 Liters Standard Error 0.0372	0.056 Liters Standard Error 0.0374	0.016 Liters Standard Error 0.0393	0.050 Liters Standard Error 0.0405	0.056 Liters Standard Error 0.0360
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 16 h, n=40, 40, 51, 46, 46, 42, 38, 49	-0.074 Liters Standard Error 0.0408	0.006 Liters Standard Error 0.0407	0.022 Liters Standard Error 0.0364	0.052 Liters Standard Error 0.0382	0.035 Liters Standard Error 0.0384	0.008 Liters Standard Error 0.0402	0.053 Liters Standard Error 0.0419	0.009 Liters Standard Error 0.0370
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 20 h, n=40, 41, 51, 45, 46, 41, 39, 49	-0.149 Liters Standard Error 0.0441	-0.046 Liters Standard Error 0.0438	-0.003 Liters Standard Error 0.0393	0.057 Liters Standard Error 0.0415	0.029 Liters Standard Error 0.0416	-0.050 Liters Standard Error 0.0437	-0.005 Liters Standard Error 0.0450	-0.012 Liters Standard Error 0.0400
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 23 h, n=40, 40, 51, 46, 46, 42, 39, 48	0.013 Liters Standard Error 0.0391	0.033 Liters Standard Error 0.0390	0.056 Liters Standard Error 0.0349	0.107 Liters Standard Error 0.0366	0.087 Liters Standard Error 0.0369	0.058 Liters Standard Error 0.0386	0.081 Liters Standard Error 0.0399	0.037 Liters Standard Error 0.0356
Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period 24 h, n=41, 41, 51, 45, 46, 42, 39, 49	0.039 Liters Standard Error 0.0387	0.105 Liters Standard Error 0.0386	0.110 Liters Standard Error 0.0347	0.143 Liters Standard Error 0.0366	0.139 Liters Standard Error 0.0366	0.088 Liters Standard Error 0.0384	0.187 Liters Standard Error 0.0397	0.124 Liters Standard Error 0.0353

SECONDARY outcome

Timeframe: Baseline (Day 7 prior to each treatment period) and the last 7 days of each treatment period (up to Study Day 70)

Population: ITT Population. Only those participants remaining in the study and contributing evaluable data for the indicated parameter were indicated by "n=X, X" in the category title and the overall number of participants analyzed reflects everyone in the ITT Population.

PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants daily in the morning and evening just prior to each dose, using an electronic peak flow meter, throughout the 14-day Treatment Period. Only the averaged daily AM and PM PEF over Days 7 to 14 was analyzed. The analysis was performed using a mixed effects analysis of covariance model with fixed effect terms for treatment and period; Baseline PEF AM and PM, gender and age fitted as covariates; and participant as a random effect.

Outcome measures

Outcome measures
Measure	All Study Treatments n=126 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=131 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=138 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in Mean Morning (AM) and Evening (PM) Pre-treatment Peak Expiratory Flow (PEF) Over Day 7 to Day 14 of Each Treatment Period AM, n=112, 120, 125, 122, 113, 116, 110, 122	0.8 Liters per minute Standard Deviation 31.98	5.2 Liters per minute Standard Deviation 42.17	1.7 Liters per minute Standard Deviation 37.95	1.1 Liters per minute Standard Deviation 31.23	6.4 Liters per minute Standard Deviation 32.31	6.4 Liters per minute Standard Deviation 43.24	5.0 Liters per minute Standard Deviation 35.82	5.8 Liters per minute Standard Deviation 33.00
Change From Baseline in Mean Morning (AM) and Evening (PM) Pre-treatment Peak Expiratory Flow (PEF) Over Day 7 to Day 14 of Each Treatment Period PM, n=116, 123, 123, 119, 115, 118, 108, 121	-5.1 Liters per minute Standard Deviation 34.43	10.0 Liters per minute Standard Deviation 43.47	1.5 Liters per minute Standard Deviation 37.95	-0.9 Liters per minute Standard Deviation 31.32	9.8 Liters per minute Standard Deviation 31.25	9.3 Liters per minute Standard Deviation 40.03	2.5 Liters per minute Standard Deviation 35.89	8.7 Liters per minute Standard Deviation 30.55

SECONDARY outcome

Timeframe: Baseline (Day 7 prior to each treatment period) and the last 7 days of each treatment period (up to Study Day 70)

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

The mean number of puffs per day of rescue salbutamol at Baseline (i.e. run-in or washout data) and on-treatment were recorded. Total puffs was calculated as (Number of Puffs + (2 x number of Nebules)). Only the 7 days proceeding each treatment period were included in the Baseline calculations. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	All Study Treatments n=109 Participants The treatment phase was comprised of three 14-day treatment periods. Treatment Period 1 and 2 were followed by a 12-14 day washout period. Treatment Period 3 was followed by a 5 to 9 day washout period before the Follow-up visit. Participants were randomly assigned to receive a sequence of 3 of the 8 active treatments : UMEC 15.6, 31.25, 62.5, 125, 250 µg QD and UMEC 15.6, 31.25 µg BID, placebo.	UMEC 15.6 µg QD n=117 Participants Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.25 µg QD n=119 Participants Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=114 Participants Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=108 Participants Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=111 Participants Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=105 Participants Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=118 Participants Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Change From Baseline in the Mean Number of Puffs Per Day of Rescue Albuterol/Salbutamol Over Day 7 to Day 14 of Each Treatment Period	-0.3 Number of puffs Standard Deviation 1.25	-0.4 Number of puffs Standard Deviation 1.42	-0.2 Number of puffs Standard Deviation 1.06	-0.3 Number of puffs Standard Deviation 1.14	-0.4 Number of puffs Standard Deviation 1.19	-0.3 Number of puffs Standard Deviation 1.31	-0.6 Number of puffs Standard Deviation 1.49	-0.3 Number of puffs Standard Deviation 1.04

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

UMEC 15.6 µg QD

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

UMEC 31.5 µg QD

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

UMEC 62.5 µg QD

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

UMEC 125 µg QD

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

UMEC 250 µg QD

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

UMEC 15.6 µg BID

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

UMEC 31.25 µg BID

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=126 participants at risk Participants received matching placebo in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 15.6 µg QD n=131 participants at risk Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.5 µg QD n=138 participants at risk Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 participants at risk Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 participants at risk Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 participants at risk Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 participants at risk Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 participants at risk Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Pregnancy, puerperium and perinatal conditions Spontaneous abortion	0.00% 0/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/131 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/138 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/128 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.74% 1/135 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.

Other adverse events

Other adverse events
Measure	Placebo n=126 participants at risk Participants received matching placebo in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 15.6 µg QD n=131 participants at risk Participants received UMEC 15.6 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 31.5 µg QD n=138 participants at risk Participants received UMEC 31.25 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 62.5 µg QD n=133 participants at risk Participants received UMEC 62.5 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 125 µg QD n=128 participants at risk Participants received UMEC 125 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 250 µg QD n=135 participants at risk Participants received UMEC 250 µg in the morning via DPI A and placebo in the evening via DPI B for 14 days.	UMEC 15.6 µg BID n=126 participants at risk Participants received UMEC 15.6 µg in the morning via DPI A and in the evening via DPI B for 14 days.	UMEC 31.25 µg BID n=133 participants at risk Participants received UMEC 31.25 µg in the morning via DPI A and in the evening via DPI B for 14 days.
Nervous system disorders Headache	1.6% 2/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.8% 5/131 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	2.9% 4/138 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.8% 5/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.1% 4/128 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	4.4% 6/135 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	1.6% 2/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	4.5% 6/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.
Infections and infestations Nasopharyngitis	0.79% 1/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	2.3% 3/131 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/138 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.75% 1/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	2.3% 3/128 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.74% 1/135 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.2% 4/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	1.5% 2/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.
Infections and infestations Pharyngitis	0.79% 1/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/131 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.72% 1/138 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.8% 5/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/128 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.74% 1/135 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.79% 1/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.
General disorders Product taste abnormal	0.00% 0/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/131 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	1.4% 2/138 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.75% 1/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.1% 4/128 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	3.7% 5/135 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.79% 1/126 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.	0.00% 0/133 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to Study Day 70). On-treatment SAEs and non-serious AEs were collected in members of the ITT Population, comprised of all participants who had received at least one dose of randomized study medication during treatment period. Provision was made for the collection of any SAEs during the 9 - 14 days screening (pre-treatment) period. None was reported.

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