Trial Outcomes & Findings for A Study to Assess the Safety and Tolerability of Once Daily Inhaled Doses of GSK573719 Made With Magnesium Stearate in Subjects With Chronic Obstructive Pulmonary Disease(COPD)for 7 Days (NCT NCT00732472)

Last Updated: 2016-11-23

Results Overview

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An on-treatment adverse event is defined as an event that occurred between the start of investigational product and follow-up contact. Refer to the general SAE/non-serious AE module for a complete list of AEs reported in the study. 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, or is a congenital anomaly/birth defect.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

37 participants

Primary outcome timeframe

From start of treatment to study day 12

Results posted on

2016-11-23

Participant Flow

Participants=par.; umeclidinium=UMEC. A total of 37 unique par. were enrolled in the study; however, 1 par. was randomized and dosed on two separate occasions and is counted as two separate par. on all outputs (thus, 38 par. started study treatment).

Participants were assigned to one of two cohorts: UMEC 250 micrograms (μg) once daily (QD) or placebo (Cohort 1) and UMEC 1000 μg QD or placebo (Cohort 2) for 7 days. After reporting of Cohorts 1 and 2, it was found that par. in Cohort 2 received UMEC 250 μg in error. Cohort 3 was then recruited, in which par. received UMEC 1000 μg QD or placebo.

Participant milestones

Participant milestones
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Overall Study STARTED	9	10	10	9
Overall Study COMPLETED	9	7	9	6
Overall Study NOT COMPLETED	0	3	1	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 UMEC 250 µg Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Overall Study Adverse Event	1	1	1
Overall Study Protocol Violation	0	0	1
Overall Study Withdrawal by Subject	2	0	1

Baseline Characteristics

A Study to Assess the Safety and Tolerability of Once Daily Inhaled Doses of GSK573719 Made With Magnesium Stearate in Subjects With Chronic Obstructive Pulmonary Disease(COPD)for 7 Days

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.	Total n=38 Participants Total of all reporting groups
Age, Continuous	66.2 Years STANDARD_DEVIATION 4.47 • n=5 Participants	63.3 Years STANDARD_DEVIATION 8.21 • n=7 Participants	64.7 Years STANDARD_DEVIATION 6.31 • n=5 Participants	64.2 Years STANDARD_DEVIATION 7.97 • n=4 Participants	64.6 Years STANDARD_DEVIATION 6.72 • n=21 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	14 Participants n=21 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants	5 Participants n=4 Participants	24 Participants n=21 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	9 participants n=5 Participants	10 participants n=7 Participants	10 participants n=5 Participants	9 participants n=4 Participants	38 participants n=21 Participants

PRIMARY outcome

Timeframe: From start of treatment to study day 12

Population: All Subjects Population: all participants who received at least one dose of study medication

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Number of Participants With Any On-treatment Adverse Event (AE) or Any On-treatment Serious Adverse Event (SAE) Any on-treatment AE	6 participants	2 participants	8 participants	5 participants
Number of Participants With Any On-treatment Adverse Event (AE) or Any On-treatment Serious Adverse Event (SAE) Any on-treatment SAE	0 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: Day 1 (pre-dose and 15 minutes [min], 45 min, 1.5 hours [hr], 4 hr, and 8 hr post-dose) and Day 7 (pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr post-dose)

Population: All Subjects Population (ASP). Only participants with data available at the indicated time points were summarized. Different participants may have been summarized for different parameters/at different time points (reflected by n=X, X, X, X in the category titles), so the overall number of participants summarized reflects everyone in the ASP.

Blood pressure was measured in a semi-recumbent position at approximately 45 degrees after the participant was kept at rest for at least 5 minutes. SBP and DBP were obtained at pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, and 8 hr post-dose (PD) on Day 1 and at pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr PD on Day 7.

Outcome measures

PRIMARY outcome

Timeframe: Day 1 (pre-dose and 15 minutes [min], 45 min, 1.5 hours [hr], 4 hr, and 8 hr post-dose) and Day 7 (pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr post-dose)

Population: All Subjects Population. Only participants with data available at the indicated time points were summarized. Different participants may have been summarized for different parameters/at different time points (reflected by n=X, X, X, X in the category titles), so the overall number of participants summarized reflects everyone in the ASP.

HR was measured in a semi-recumbent position at approximately 45 degrees after the participant was kept at rest for at least 5 minutes. HR was obtained at pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, and 8 hr post-dose (PD) on Day 1 and at pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr PD on Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 15 min PD, n=9, 7, 9, 6	67.0 Beats per minute Standard Deviation 6.61	69.4 Beats per minute Standard Deviation 12.16	68.9 Beats per minute Standard Deviation 12.19	74.8 Beats per minute Standard Deviation 9.39
Mean Heart Rate (HR) on Days 1 and 7 Day 1, pre-dose, n=9, 10, 10, 9	70.9 Beats per minute Standard Deviation 11.09	68.3 Beats per minute Standard Deviation 10.42	72.8 Beats per minute Standard Deviation 11.69	64.7 Beats per minute Standard Deviation 10.34
Mean Heart Rate (HR) on Days 1 and 7 Day 1, 15 min PD, n=9, 9, 10, 8	68.2 Beats per minute Standard Deviation 10.28	67.4 Beats per minute Standard Deviation 11.28	71.4 Beats per minute Standard Deviation 9.86	72.3 Beats per minute Standard Deviation 13.56
Mean Heart Rate (HR) on Days 1 and 7 Day 1, 45 min PD, n=9, 9, 10, 9	66.0 Beats per minute Standard Deviation 9.33	62.3 Beats per minute Standard Deviation 10.90	70.2 Beats per minute Standard Deviation 11.95	66.4 Beats per minute Standard Deviation 14.78
Mean Heart Rate (HR) on Days 1 and 7 Day 1, 1.5 hr PD, n=9, 9, 10, 9	63.3 Beats per minute Standard Deviation 9.42	60.7 Beats per minute Standard Deviation 12.06	65.8 Beats per minute Standard Deviation 10.30	64.2 Beats per minute Standard Deviation 11.05
Mean Heart Rate (HR) on Days 1 and 7 Day 1, 4 hr PD, n=9, 9, 10, 9	64.0 Beats per minute Standard Deviation 10.37	62.0 Beats per minute Standard Deviation 10.31	70.2 Beats per minute Standard Deviation 10.74	65.7 Beats per minute Standard Deviation 10.20
Mean Heart Rate (HR) on Days 1 and 7 Day 1, 8 hr PD, n=9, 9, 10, 9	72.6 Beats per minute Standard Deviation 9.93	67.4 Beats per minute Standard Deviation 9.62	77.2 Beats per minute Standard Deviation 11.73	74.4 Beats per minute Standard Deviation 7.35
Mean Heart Rate (HR) on Days 1 and 7 Day 7, pre-dose, n=9, 7, 9, 6	70.1 Beats per minute Standard Deviation 7.90	71.3 Beats per minute Standard Deviation 12.64	71.4 Beats per minute Standard Deviation 14.01	69.7 Beats per minute Standard Deviation 10.51
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 45 min PD, n=9, 6, 9, 6	66.8 Beats per minute Standard Deviation 9.16	66.3 Beats per minute Standard Deviation 11.88	66.6 Beats per minute Standard Deviation 10.98	70.0 Beats per minute Standard Deviation 10.00
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 1.5 hr PD, n=9, 7, 9, 6	65.3 Beats per minute Standard Deviation 7.86	64.0 Beats per minute Standard Deviation 10.92	63.8 Beats per minute Standard Deviation 8.96	67.7 Beats per minute Standard Deviation 11.13
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 4 hr PD, n=9, 7, 9, 6	64.1 Beats per minute Standard Deviation 7.61	62.7 Beats per minute Standard Deviation 7.74	62.6 Beats per minute Standard Deviation 9.79	67.5 Beats per minute Standard Deviation 7.50
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 8 hr PD, n=9, 7, 9, 6	74.8 Beats per minute Standard Deviation 6.83	71.0 Beats per minute Standard Deviation 8.60	74.8 Beats per minute Standard Deviation 8.91	73.8 Beats per minute Standard Deviation 7.41
Mean Heart Rate (HR) on Days 1 and 7 Day 7, 24 hr PD, n=9, 7, 9, 6	73.8 Beats per minute Standard Deviation 7.00	75.6 Beats per minute Standard Deviation 11.50	72.6 Beats per minute Standard Deviation 8.97	70.8 Beats per minute Standard Deviation 9.89

PRIMARY outcome

Timeframe: Day 1 and Day 7

Population: All Subjects Population (ASP). The number of participants presented represent those with data available at the time point being presented; however, all participants in the ASP without missing covariate information are included in the analysis.

Maximum heart rate (Max HR) and weighted mean (WM) from 0-4 hour on Days 1 and 7 were derived. Max HR (0-4 h) is defined as the maximum heart rate attained within 0-4 h. The weighted mean HR (0-4 h) was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. Each of the maximum and weighted mean (0-4h) endpoints for heart rate, was statistically analyzed using a mixed effects model. The terms treatment, baseline, day and any relevant interactions were considered in the model. Least squares means are adjusted for treatment, Baseline, day, treatment by Baseline and Baseline by day interaction, where Baseline is defined as the mean of the three pre-dose assessments.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Maximum and Weighted Mean (0-4 Hour) Heart Rate at Days 1 and 7 Day 1, Max HR, n=9, 10, 10, 9	68.30 Beats per minute Standard Error 2.009	70.56 Beats per minute Standard Error 1.910	71.57 Beats per minute Standard Error 1.924	75.79 Beats per minute Standard Error 2.066
Maximum and Weighted Mean (0-4 Hour) Heart Rate at Days 1 and 7 Day 7, Max HR, n=9, 7, 9, 6	68.99 Beats per minute Standard Error 1.917	70.24 Beats per minute Standard Error 2.203	66.74 Beats per minute Standard Error 1.964	77.69 Beats per minute Standard Error 2.398
Maximum and Weighted Mean (0-4 Hour) Heart Rate at Days 1 and 7 Day 1, WM, n=9, 9, 10, 9	63.84 Beats per minute Standard Error 1.582	63.62 Beats per minute Standard Error 1.584	66.17 Beats per minute Standard Error 1.514	70.00 Beats per minute Standard Error 1.627
Maximum and Weighted Mean (0-4 Hour) Heart Rate at Days 1 and 7 Day 7, WM, n=9, 7, 9, 6	64.83 Beats per minute Standard Error 1.682	64.98 Beats per minute Standard Error 1.874	62.32 Beats per minute Standard Error 1.698	71.89 Beats per minute Standard Error 2.026

PRIMARY outcome

Timeframe: Day 1 (pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, and 8 hr post-dose) and Day 7 (pre-dose and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr)

Population: All Subjects Population. Only participants with data available at the indicated time points were summarized.

The number of participants with normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) ECG findings, as well as those with unavailable results (NA) at pre-dose (PD1, PD2, PD3), and 15 min, 45 min, 1.5 hr, 4 hr, and 8 hr post-dose (PD) on Day 1 and at pre-dose (PD1, PD2, PD3), and 15 min, 45 min, 1.5 hr, 4 hr, 8 hr, and 24 hr post-dose on Day 7 are reported. The following are of potential clinical importance: absolute QTc interval \>450 milliseconds (msec); increase from Baseline QTc \>60 msec; PR interval \<110 and \>220 msec; QRS interval \<75 and \>110 msec. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD1, NL, n=9, 10, 10, 9	5 Participants	3 Participants	6 Participants	6 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD1, Abn NCS, n=9, 10, 10, 9	4 Participants	7 Participants	4 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD1, Abn CS, n=9, 10, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD1, NA, n=9, 10, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD2, NL, n=9, 10, 10, 9	5 Participants	3 Participants	5 Participants	5 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD2, Abn NCS, n=9, 10, 10, 9	4 Participants	7 Participants	5 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD2, Abn CS, n=9, 10, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD2, NA, n=9, 10, 10, 9	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD3, NL, n=9, 10, 10, 9	4 Participants	4 Participants	5 Participants	5 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD3, Abn NCS, n=9, 10, 10, 9	5 Participants	6 Participants	5 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD3, Abn CS, 9, 10, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, PD3, NA, n=9, 10, 10, 9	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 15 min PD, NL, n=9, 9, 10, 9	4 Participants	3 Participants	7 Participants	6 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 45 min PD, Abn CS, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 15 min PD, Abn NCS, n=9, 9, 10, 9	5 Participants	6 Participants	3 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 15 min PD, Abn CS, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 15 min PD, NA, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 45 min PD, NL, n=9, 9, 10, 9	5 Participants	3 Participants	7 Participants	6 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 45 min PD, Abn NCS, n=9, 9, 10, 9	4 Participants	6 Participants	3 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 1.5 hr PD, Abn CS, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 1.5 hr PD, NL, n=9, 9, 10, 9	5 Participants	6 Participants	6 Participants	5 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 1.5 hr PD, Abn NCS, n=9, 9, 10, 9	4 Participants	3 Participants	4 Participants	4 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 1.5 hr PD, NA, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 4 hr PD, NL, n=9, 9, 10, 9	4 Participants	4 Participants	6 Participants	5 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 4 hr PD, Abn NCS, n=9, 9, 10, 9	5 Participants	5 Participants	4 Participants	4 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 4 hr PD, Abn CS, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 4 hr PD, NA, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 8 hr PD, NL, n=9, 9, 10, 9	5 Participants	6 Participants	7 Participants	6 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 8 hr PD, Abn NCS, n=9, 9, 10, 9	4 Participants	3 Participants	3 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD3, Abn CS, 9, 7, 8, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD3, NA, n=9, 7, 8, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 8 hr PD, Abn CS, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 8 hr PD, NA, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD1, NL, n=9, 7, 9, 6	4 Participants	4 Participants	7 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD1, Abn NCS, n=9, 7, 9, 6	5 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD1, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD1, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD2, NL, n=9, 7, 8, 6	4 Participants	4 Participants	6 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD2, Abn NCS, n=9, 7, 8, 6	5 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD2, Abn CS, n=9, 7, 8, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD2, NA, n=9, 7, 8, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD3, NL, n=9, 7, 8, 6	4 Participants	3 Participants	6 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, PD3, Abn NCS, n=9, 7, 8, 6	5 Participants	4 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 15 min PD, NL, n=9, 7, 9, 6	4 Participants	4 Participants	7 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 15 min PD, Abn NCS, n=9, 7, 9, 6	5 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 15 min PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 15 min PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 45 min PD, NL, n=9, 7, 9, 6	4 Participants	4 Participants	6 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 45 min PD, Abn NCS, n=9, 7, 9, 6	5 Participants	3 Participants	3 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 45 min PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 45 min PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 1.5 hr PD, NL, n=9, 7, 9, 6	4 Participants	4 Participants	7 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 1.5 hr PD, Abn NCS, n=9, 7, 9, 6	5 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 1.5 hr PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 1.5 hr PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 4 hr PD, NL, n=9, 7, 9, 6	5 Participants	5 Participants	7 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 4 hr PD, Abn NCS, n=9, 7, 9, 6	4 Participants	2 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 4 hr PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 4 hr PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 8 hr PD, NL, n=9, 7, 9, 6	4 Participants	4 Participants	7 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 8 hr PD, Abn NCS, n=9, 7, 9, 6	5 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 8 hr PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 8 hr PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 24 hr PD, NL, n=9, 7, 9, 6	4 Participants	2 Participants	6 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 24 hr PD, Abn NCS, n=9, 7, 9, 6	5 Participants	5 Participants	3 Participants	3 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 24 hr PD, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 7, 24 hr PD, NA, n=9, 7, 9, 6	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Values on Days 1 and 7 Day 1, 45 min PD, NA, n=9, 9, 10, 9	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Screening and Day 7

Population: All Subjects Population. Only participants with data available at the indicated time points were summarized.

Twenty-four hour Holter ECG values were obtained at Screening and on Day 7. During the Screening procedure and study, standard Holter monitors were used (in order to exclude participants with underlying cardiac arrhythmogenicity). During the treatment periods, Holter monitors were only switched on immediately prior to dosing (up to 15 minutes pre-dose) so as to capture Holter ECG data from the 24 hour period following dosing. The following summary data were transcribed into the Case Report Form: Maximum and mean (0 to24 hour) heart rate; normal and aberrant beats and arrhythmias. Analysis of the Holter tapes was arranged by GlaxoSmithKline.The number of participants with normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) ECG findings, as well as those with unavailable results (NA) at Screening and Day 7, are reported. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Screening, NL, n=9 ,10, 10, 9	2 Participants	6 Participants	5 Participants	3 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Screening, Abn NCS, n=9 ,10, 10, 9	7 Participants	4 Participants	4 Participants	5 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Screening, Abn CS, n=9 ,10, 10, 9	0 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Day7, NL, n=9, 7, 9, 6	3 Participants	3 Participants	2 Participants	1 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Day7, Abn NCS, n=9, 7, 9, 6	6 Participants	3 Participants	6 Participants	5 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Day7, Abn CS, n=9, 7, 9, 6	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal 24-hour Holter Findings at Screening and Day 7 Day7, NA, n=9, 7, 9, 6	0 Participants	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Day 7

Population: All Subjects Population. The number of participants presented represent those with data available at the time point being presented; however, all participants in the ASP without missing covariate information are included in the analysis.

Maximum heart rate (Max HR) and mean HR from 0-24 hour Holter monitoring on treatment Day 7 were derived. The analysis was adjusted for treatment and Baseline, where Baseline is defined as the corresponding summary measure (i.e., mean heart rate \[0-24 hours\] or maximum heart rate \[0-24 hours\]) from screening records.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=6 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=6 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Maximum and Mean (0-24 Hour) Heart Rate From Holter Monitoring on Day 7 Max HR	125.19 Beats per minute Standard Error 4.744	134.08 Beats per minute Standard Error 5.810	127.48 Beats per minute Standard Error 4.724	126.91 Beats per minute Standard Error 5.785
Maximum and Mean (0-24 Hour) Heart Rate From Holter Monitoring on Day 7 Mean HR	77.47 Beats per minute Standard Error 1.896	75.94 Beats per minute Standard Error 2.306	75.96 Beats per minute Standard Error 1.888	76.75 Beats per minute Standard Error 2.312

PRIMARY outcome

Timeframe: Screening, Day 1, and Day 7

Population: All Subjects Population. Only participants with data available at the indicated time points were summarized.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured at Screening, pre-dose, and 4 hours (hr) post-dose on Day 1 and Day 7. FEV1 tests were repeated until three technically acceptable measurements were made.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean Forced Expiratory Volume in One Second (FEV1) at Screening and on Days 1 and 7 Screening, n=9, 10, 10, 9	1.556 Liters Standard Deviation 0.6315	1.253 Liters Standard Deviation 0.4338	1.562 Liters Standard Deviation 0.5066	1.364 Liters Standard Deviation 0.3504
Mean Forced Expiratory Volume in One Second (FEV1) at Screening and on Days 1 and 7 Day 1, pre-dose, n=9, 10, 10, 9	1.294 Liters Standard Deviation 0.4642	1.059 Liters Standard Deviation 0.3509	1.443 Liters Standard Deviation 0.4840	1.289 Liters Standard Deviation 0.2968
Mean Forced Expiratory Volume in One Second (FEV1) at Screening and on Days 1 and 7 Day 1, 4 hr post-dose, n=9, 9, 10, 9	1.309 Liters Standard Deviation 0.4333	1.250 Liters Standard Deviation 0.3934	1.565 Liters Standard Deviation 0.5858	1.534 Liters Standard Deviation 0.3389
Mean Forced Expiratory Volume in One Second (FEV1) at Screening and on Days 1 and 7 Day 7, pre-dose, n=9, 7, 9, 6	1.263 Liters Standard Deviation 0.4695	1.153 Liters Standard Deviation 0.4066	1.593 Liters Standard Deviation 0.5425	1.483 Liters Standard Deviation 0.3055
Mean Forced Expiratory Volume in One Second (FEV1) at Screening and on Days 1 and 7 Day 7, 4 hr post-dose, n=9, 7, 9, 6	1.250 Liters Standard Deviation 0.5143	1.181 Liters Standard Deviation 0.3875	1.564 Liters Standard Deviation 0.5476	1.517 Liters Standard Deviation 0.2685

PRIMARY outcome

Timeframe: Day 1 to Day 7

Population: All Subjects Population. Only those participants who took at least one dose of salbutamol were summarized.

The total number of salbutamol doses taken per day was recorded by the participants in their dairy card over the entire 7-day treatment period. Diaries were reviewed by the Investigator when participants were admitted to the unit on Day 1, Day 7, and Day 8. Salbutamol was given as rescue medication, defined as a quick-relief or fast-acting medication that is given in addition to the investigational drug or placebo that can alleviate symptoms due to disease or lack of efficacy of the study treatment.

Outcome measures

Outcome measures
Measure	Placebo n=6 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=3 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=5 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=5 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Total Number of Salbutamol Doses Taken Over the 7 -Day Study Period	18 salbutamol doses	33 salbutamol doses	33 salbutamol doses	29 salbutamol doses

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of albumin, total protein, hemoglobin, and MCHC values pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Albumin, Day 1, n=9, 9, 10, 9	42.3 Grams per liter (G/L) Standard Deviation 3.43	43.9 Grams per liter (G/L) Standard Deviation 2.09	43.7 Grams per liter (G/L) Standard Deviation 2.16	44.1 Grams per liter (G/L) Standard Deviation 3.10
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Albumin, Day 7, n=8, 7, 9, 6	43.1 Grams per liter (G/L) Standard Deviation 1.81	44.0 Grams per liter (G/L) Standard Deviation 1.15	43.8 Grams per liter (G/L) Standard Deviation 2.64	44.0 Grams per liter (G/L) Standard Deviation 2.61
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Total protein, Day 1, n=9, 9, 10, 9	69.4 Grams per liter (G/L) Standard Deviation 5.48	70.0 Grams per liter (G/L) Standard Deviation 3.24	69.9 Grams per liter (G/L) Standard Deviation 3.70	69.8 Grams per liter (G/L) Standard Deviation 3.46
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Total protein, Day 7, n=8, 7, 9, 6	68.6 Grams per liter (G/L) Standard Deviation 3.16	70.0 Grams per liter (G/L) Standard Deviation 2.16	71.0 Grams per liter (G/L) Standard Deviation 4.53	69.7 Grams per liter (G/L) Standard Deviation 3.83
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Hemoglobin, Day 1, n=9, 9, 10, 9	152.2 Grams per liter (G/L) Standard Deviation 8.60	148.0 Grams per liter (G/L) Standard Deviation 14.19	147.4 Grams per liter (G/L) Standard Deviation 11.84	145.4 Grams per liter (G/L) Standard Deviation 16.18
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 Hemoglobin, Day 7, n=9, 6, 9, 6	151.4 Grams per liter (G/L) Standard Deviation 7.80	145.8 Grams per liter (G/L) Standard Deviation 14.77	147.4 Grams per liter (G/L) Standard Deviation 13.71	143.5 Grams per liter (G/L) Standard Deviation 16.61
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 MCHC, Day 1, n=9, 9, 10, 9	340.0 Grams per liter (G/L) Standard Deviation 6.10	338.7 Grams per liter (G/L) Standard Deviation 5.39	339.9 Grams per liter (G/L) Standard Deviation 5.49	337.2 Grams per liter (G/L) Standard Deviation 3.63
Albumin, Total Protein, Hemoglobin, and Mean Corpuscle Hemoglobin Concentration (MCHC) Values on Day 1 and Day 7 MCHC, Day 7, n=9, 6, 9, 6	337.6 Grams per liter (G/L) Standard Deviation 7.84	340.7 Grams per liter (G/L) Standard Deviation 5.20	337.4 Grams per liter (G/L) Standard Deviation 5.59	337.3 Grams per liter (G/L) Standard Deviation 5.20

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of ALP, ALT, AST, and GGT Pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 ALP, Day 1, n=9, 9, 10, 9	74.0 International units per liter (IU/L) Standard Deviation 20.20	76.8 International units per liter (IU/L) Standard Deviation 15.11	69.0 International units per liter (IU/L) Standard Deviation 18.43	63.8 International units per liter (IU/L) Standard Deviation 20.00
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 ALP, Day 7, n=8, 7, 9, 6	71.6 International units per liter (IU/L) Standard Deviation 20.18	73.1 International units per liter (IU/L) Standard Deviation 16.16	71.1 International units per liter (IU/L) Standard Deviation 16.47	67.7 International units per liter (IU/L) Standard Deviation 18.15
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 ALT, Day 1, n=9, 9, 10, 9	15.6 International units per liter (IU/L) Standard Deviation 10.36	15.6 International units per liter (IU/L) Standard Deviation 6.06	24.2 International units per liter (IU/L) Standard Deviation 9.66	18.6 International units per liter (IU/L) Standard Deviation 9.49
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 ALT, Day 7, n=8, 7, 9, 6	15.9 International units per liter (IU/L) Standard Deviation 6.85	15.6 International units per liter (IU/L) Standard Deviation 7.11	29.8 International units per liter (IU/L) Standard Deviation 12.81	20.7 International units per liter (IU/L) Standard Deviation 9.85
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 AST, Day 1, n=9, 9, 10, 9	20.9 International units per liter (IU/L) Standard Deviation 5.90	18.9 International units per liter (IU/L) Standard Deviation 3.48	26.5 International units per liter (IU/L) Standard Deviation 10.28	22.6 International units per liter (IU/L) Standard Deviation 8.65
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 AST, Day 7, n=8, 7, 9, 6	19.3 International units per liter (IU/L) Standard Deviation 6.16	19.4 International units per liter (IU/L) Standard Deviation 4.31	30.7 International units per liter (IU/L) Standard Deviation 12.16	25.2 International units per liter (IU/L) Standard Deviation 8.18
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 GGT, Day 1, n=9, 9, 10, 9	31.3 International units per liter (IU/L) Standard Deviation 20.62	28.0 International units per liter (IU/L) Standard Deviation 13.19	61.0 International units per liter (IU/L) Standard Deviation 56.20	37.7 International units per liter (IU/L) Standard Deviation 31.25
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) Values on Day1 and Day 7 GGT, Day 7, n=8, 7, 9, 6	29.9 International units per liter (IU/L) Standard Deviation 18.88	24.7 International units per liter (IU/L) Standard Deviation 6.78	66.0 International units per liter (IU/L) Standard Deviation 68.81	39.8 International units per liter (IU/L) Standard Deviation 32.73

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of direct bilirubin, total bilirubin, and creatinine at pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Direct bilirubin, Day 1, n=6, 9, 10	2.3 Micromoles per liter (µmol/L) Standard Deviation 1.97	1.7 Micromoles per liter (µmol/L) Standard Deviation 0.50	2.0 Micromoles per liter (µmol/L) Standard Deviation 1.15	NA Micromoles per liter (µmol/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, Cohort 3 data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Direct bilirubin, Day 7, n=5, 7, 9	2.0 Micromoles per liter (µmol/L) Standard Deviation 1.41	2.0 Micromoles per liter (µmol/L) Standard Deviation 0.58	2.2 Micromoles per liter (µmol/L) Standard Deviation 0.67	NA Micromoles per liter (µmol/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, Cohort 3 data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Total bilirubin, Day 1, n=9, 9, 10, 9	10.8 Micromoles per liter (µmol/L) Standard Deviation 4.44	8.2 Micromoles per liter (µmol/L) Standard Deviation 1.20	10.9 Micromoles per liter (µmol/L) Standard Deviation 4.01	10.2 Micromoles per liter (µmol/L) Standard Deviation 3.03
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Total bilirubin, Day 7, n=8, 7, 9, 6	9.3 Micromoles per liter (µmol/L) Standard Deviation 4.03	9.9 Micromoles per liter (µmol/L) Standard Deviation 2.27	10.8 Micromoles per liter (µmol/L) Standard Deviation 3.11	11.0 Micromoles per liter (µmol/L) Standard Deviation 3.16
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Creatinine, Day 1, n=9, 9, 10, 9	76.2 Micromoles per liter (µmol/L) Standard Deviation 12.15	84.3 Micromoles per liter (µmol/L) Standard Deviation 15.64	80.1 Micromoles per liter (µmol/L) Standard Deviation 14.26	87.0 Micromoles per liter (µmol/L) Standard Deviation 33.59
Direct Bilirubin, Total Bilirubin, and Creatinine Values on Day 1 and Day 7 Creatinine, Day 7, n=8, 7, 9, 6	78.8 Micromoles per liter (µmol/L) Standard Deviation 10.53	80.1 Micromoles per liter (µmol/L) Standard Deviation 14.37	82.6 Micromoles per liter (µmol/L) Standard Deviation 12.83	93.0 Micromoles per liter (µmol/L) Standard Deviation 39.80

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of calcium, glucose, potassium, sodium, and urea/BUN pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Sodium, Day 7, n=8, 7, 9, 6	140.4 Millimoles per liter (mmol/L) Standard Deviation 2.88	140.0 Millimoles per liter (mmol/L) Standard Deviation 1.15	140.2 Millimoles per liter (mmol/L) Standard Deviation 2.44	139.2 Millimoles per liter (mmol/L) Standard Deviation 2.40
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Potassium, Day 1, n=9, 9, 10, 9	4.67 Millimoles per liter (mmol/L) Standard Deviation 0.472	4.70 Millimoles per liter (mmol/L) Standard Deviation 0.485	4.50 Millimoles per liter (mmol/L) Standard Deviation 0.579	4.36 Millimoles per liter (mmol/L) Standard Deviation 0.364
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Glucose, Day 7, n=8, 7, 9, 6	5.25 Millimoles per liter (mmol/L) Standard Deviation 0.746	5.10 Millimoles per liter (mmol/L) Standard Deviation 0.792	5.84 Millimoles per liter (mmol/L) Standard Deviation 0.948	5.42 Millimoles per liter (mmol/L) Standard Deviation 0.717
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Potassium, Day 7, n=8, 7, 9, 6	4.58 Millimoles per liter (mmol/L) Standard Deviation 0.276	4.74 Millimoles per liter (mmol/L) Standard Deviation 0.431	4.48 Millimoles per liter (mmol/L) Standard Deviation 0.519	4.45 Millimoles per liter (mmol/L) Standard Deviation 0.428
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Calcium, Day 1, n=9, 9, 10, 9	2.317 Millimoles per liter (mmol/L) Standard Deviation 0.0622	2.329 Millimoles per liter (mmol/L) Standard Deviation 0.0697	2.342 Millimoles per liter (mmol/L) Standard Deviation 0.1215	2.311 Millimoles per liter (mmol/L) Standard Deviation 0.0807
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Calcium, Day 7, n=8, 7, 9, 6	2.320 Millimoles per liter (mmol/L) Standard Deviation 0.0454	2.321 Millimoles per liter (mmol/L) Standard Deviation 0.0308	2.370 Millimoles per liter (mmol/L) Standard Deviation 0.1411	2.343 Millimoles per liter (mmol/L) Standard Deviation 0.0631
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Glucose, Day 1, n=9, 9, 10, 9	5.16 Millimoles per liter (mmol/L) Standard Deviation 0.937	5.13 Millimoles per liter (mmol/L) Standard Deviation 0.524	5.38 Millimoles per liter (mmol/L) Standard Deviation 0.751	5.26 Millimoles per liter (mmol/L) Standard Deviation 0.921
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Sodium, Day 1, n=9, 9, 10, 9	138.8 Millimoles per liter (mmol/L) Standard Deviation 2.59	140.6 Millimoles per liter (mmol/L) Standard Deviation 1.51	140.6 Millimoles per liter (mmol/L) Standard Deviation 2.27	139.6 Millimoles per liter (mmol/L) Standard Deviation 1.59
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Urea/BUN, Day 1, n=9, 9, 10, 9	4.92 Millimoles per liter (mmol/L) Standard Deviation 1.730	5.29 Millimoles per liter (mmol/L) Standard Deviation 0.842	5.77 Millimoles per liter (mmol/L) Standard Deviation 1.854	5.72 Millimoles per liter (mmol/L) Standard Deviation 2.440
Calcium, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values on Day 1 and Day 7 Urea/BUN, Day 7, n=8, 7, 9, 6	5.15 Millimoles per liter (mmol/L) Standard Deviation 1.032	5.51 Millimoles per liter (mmol/L) Standard Deviation 0.691	5.70 Millimoles per liter (mmol/L) Standard Deviation 1.562	5.88 Millimoles per liter (mmol/L) Standard Deviation 3.020

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC), platelets, and white blood cell (WBC) count pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Basophils, Day 1, n=9, 9, 10, 9	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Basophils, Day 7, n=9, 6, 9, 6	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Eosinophils, Day 1, n=9, 9, 10, 9	0.248 10^9 cells per liter (GI/L) Standard Deviation 0.1052	0.319 10^9 cells per liter (GI/L) Standard Deviation 0.1968	0.352 10^9 cells per liter (GI/L) Standard Deviation 0.2951	0.144 10^9 cells per liter (GI/L) Standard Deviation 0.0910
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Eosinophils, Day 7, n=9, 6, 9, 6	0.232 10^9 cells per liter (GI/L) Standard Deviation 0.0793	0.280 10^9 cells per liter (GI/L) Standard Deviation 0.1754	0.312 10^9 cells per liter (GI/L) Standard Deviation 0.2672	0.153 10^9 cells per liter (GI/L) Standard Deviation 0.0911
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Lymphocytes, Day 1, n=9, 9, 10, 9	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Lymphocytes, Day 7, n=9, 6, 9, 6	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.	NA 10^9 cells per liter (GI/L) Standard Deviation NA Per protocol, data were collected for participants in all 3 cohorts; however, data were not fully reported to GSK by the vendor. This oversight was recently detected, and this summary will be amended once remedial work has been completed.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Monocytes, Day 1, n=9, 9, 10, 9	0.510 10^9 cells per liter (GI/L) Standard Deviation 0.1348	0.614 10^9 cells per liter (GI/L) Standard Deviation 0.3648	0.607 10^9 cells per liter (GI/L) Standard Deviation 0.1594	0.506 10^9 cells per liter (GI/L) Standard Deviation 0.2010
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Monocytes, Day 7, n=9, 6, 9, 6	0.448 10^9 cells per liter (GI/L) Standard Deviation 0.1313	0.562 10^9 cells per liter (GI/L) Standard Deviation 0.2791	0.657 10^9 cells per liter (GI/L) Standard Deviation 0.1993	0.503 10^9 cells per liter (GI/L) Standard Deviation 0.2430
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 ANC, Day 1, n=9, 9, 10, 9	5.233 10^9 cells per liter (GI/L) Standard Deviation 2.0968	5.306 10^9 cells per liter (GI/L) Standard Deviation 1.3061	4.244 10^9 cells per liter (GI/L) Standard Deviation 1.3332	4.946 10^9 cells per liter (GI/L) Standard Deviation 2.3879
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 ANC, Day 7, n=9, 6, 9, 6	4.706 10^9 cells per liter (GI/L) Standard Deviation 1.8634	5.023 10^9 cells per liter (GI/L) Standard Deviation 1.4969	4.067 10^9 cells per liter (GI/L) Standard Deviation 1.0184	5.323 10^9 cells per liter (GI/L) Standard Deviation 1.8539
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Platelets, Day 1, n=9, 9, 10, 9	278.1 10^9 cells per liter (GI/L) Standard Deviation 66.25	238.2 10^9 cells per liter (GI/L) Standard Deviation 39.71	254.7 10^9 cells per liter (GI/L) Standard Deviation 51.04	222.4 10^9 cells per liter (GI/L) Standard Deviation 43.16
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 Platelets, Day 7, n=9, 6, 9, 6	271.8 10^9 cells per liter (GI/L) Standard Deviation 53.73	256.8 10^9 cells per liter (GI/L) Standard Deviation 36.71	255.1 10^9 cells per liter (GI/L) Standard Deviation 61.42	250.3 10^9 cells per liter (GI/L) Standard Deviation 59.37
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 WBC count, Day 1, n=9, 9, 10, 9	8.06 10^9 cells per liter (GI/L) Standard Deviation 2.220	8.52 10^9 cells per liter (GI/L) Standard Deviation 2.153	7.11 10^9 cells per liter (GI/L) Standard Deviation 1.692	7.56 10^9 cells per liter (GI/L) Standard Deviation 2.572
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil (ANC: Absolute Neutrophil Count), Platelet, and White Blood Cell (WBC) Count Values on Day 1 and Day 7 WBC count, Day 7, n=9, 6, 9, 6	7.49 10^9 cells per liter (GI/L) Standard Deviation 2.211	8.15 10^9 cells per liter (GI/L) Standard Deviation 2.519	7.13 10^9 cells per liter (GI/L) Standard Deviation 1.564	7.87 10^9 cells per liter (GI/L) Standard Deviation 2.067

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of MCH pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean Corpuscle Hemoglobin (MCH) Values on Day 1 and Day 7 Day 1, n=9, 9, 10, 9	31.92 picograms/cell (pg) Standard Deviation 1.711	32.44 picograms/cell (pg) Standard Deviation 2.371	31.25 picograms/cell (pg) Standard Deviation 1.978	31.70 picograms/cell (pg) Standard Deviation 1.859
Mean Corpuscle Hemoglobin (MCH) Values on Day 1 and Day 7 Day 7, n=9, 6, 9, 6	31.71 picograms/cell (pg) Standard Deviation 1.661	32.20 picograms/cell (pg) Standard Deviation 2.871	31.22 picograms/cell (pg) Standard Deviation 1.999	31.95 picograms/cell (pg) Standard Deviation 2.146

PRIMARY outcome

Timeframe: Day 1 and Day 7

Blood samples were collected for the measurement of MCV pre-dose on Day 1 and Day 7.

Outcome measures

Outcome measures
Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean Corpuscle Volume (MCV) Values on Day 1 and Day 7 Day 7, n=9, 6, 9, 6	94.0 10^-15 liters (femtoliters) Standard Deviation 3.50	94.5 10^-15 liters (femtoliters) Standard Deviation 7.12	92.6 10^-15 liters (femtoliters) Standard Deviation 5.34	94.8 10^-15 liters (femtoliters) Standard Deviation 5.49
Mean Corpuscle Volume (MCV) Values on Day 1 and Day 7 Day 1, n=9, 9, 10, 9	93.9 10^-15 liters (femtoliters) Standard Deviation 3.66	95.9 10^-15 liters (femtoliters) Standard Deviation 7.06	91.9 10^-15 liters (femtoliters) Standard Deviation 4.93	94.0 10^-15 liters (femtoliters) Standard Deviation 5.32

SECONDARY outcome

Timeframe: Day 1 and Day 7: pre-dose, and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose; 24 hr post-dose on Day 7

Population: Pharmacokinetic (PK) Population: participants (par.) in the ASP for whom a PK sample was obtained and analyzed. Different par. may have been summarized for different parameters/at different time points (reflected by n=X, X, X, X in the category titles), so the overall number of par. summarized reflects everyone in the PK Population.

Area under the concentration-time (AUC) curve from time zero (pre-dose) to 2 hours (AUC\[0-2\]), from time zero to 8 hours (AUC\[0-8\]), from time zero to the last time of a quantifiable concentration of UMEC (AUC\[0-t\]) on Day 1 and Day 7 were measured. AUC is a measure of systemic exposure. Blood samples were collected pre-dose and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose on Day 1 and Day 7. Also, a 24 hr blood sample was collected on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-2), Day 1, n=0, 8, 9, 9	—	0.19675 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 19.7	0.08134 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 108.0	0.95719 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 233.2
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-2), Day 7, n=0, 6, 8, 6	—	0.31951 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 51.6	0.15527 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 66.5	1.92508 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 31.1
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-8), Day 1, n=0, 0, 0, 9	—	NA hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Due to non-quantifiable data at the lower dose (250 µg) at later time points, data for this parameter could not be calculated.	NA hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Due to non-quantifiable data at the lower dose (250 µg) at later time points, data for this parameter could not be calculated.	2.029 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 69.8
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-8), Day 7, n=0, 0, 0, 6	—	NA hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Due to non-quantifiable data at the lower dose (250 µg) at later time points, data for this parameter could not be calculated.	NA hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation NA Due to non-quantifiable data at the lower dose (250 µg) at later time points, data for this parameter could not be calculated.	3.320 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 33.3
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-t), Day 1, n=0, 8, 9, 9	—	0.26071 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 39.1	0.03614 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 1707.8	0.93299 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 5820.5
Mean AUC(0-2), AUC(0-8), and AUC(0-t) of UMEC on Day 1 and Day 7 AUC(0-t), Day 7, n=0, 6, 8, 6	—	0.55514 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 113.2	0.30526 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 134.3	4.86204 hr * nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 42.8

SECONDARY outcome

Timeframe: Day 1 and Day 7: pre-dose, and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose; 24 hr post-dose on Day 7

Population: PK Population. Only participants with data available at the indicated time points were summarized.

Cmax is defined as the maximum observed concentration of UMEC and was measured on Day 1 and Day 7. Blood samples were collected pre-dose and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose on Day 1 and Day 7. Also, a 24 hr blood sample was collected on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Cmax of UMEC on Day 1 and Day 7 Day 1, n=0, 8, 9, 9	—	0.21654 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 32.0	0.07915 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 147.6	1.52835 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 53.6
Cmax of UMEC on Day 1 and Day 7 Day 7, n=0, 6, 8, 6	—	0.33206 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 58.3	0.16448 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 74.2	2.75864 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 60.5

SECONDARY outcome

Timeframe: Day 1 and Day 7: pre-dose, and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose; 24 hr post-dose on Day 7

Population: PK Population. Only participants with data available at the indicated time points were summarized. Different participants may have been summarized for different parameters/at different time points (reflected by n=X, X, X, X in the category titles), so the overall number of participants summarized reflects everyone in the PK Population.

Tmax is defined as the time to reach the observed maximum concentration, and tlast is defined as the time of the last quantifiable concentration of UMEC; both were measured on Day 1 and Day 7. Blood samples were collected pre-dose, and 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, and 8 hr post-dose on Day 1 and Day 7. Also, a 24 hr blood sample was collected on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Tmax and Tlastof UMEC on Day 1 and Day 7 tmax, Day 1, n=0, 8, 8, 9	—	0.080 hours Interval 0.08 to 0.5	0.250 hours Interval 0.08 to 0.28	0.250 hours Interval 0.08 to 0.28
Tmax and Tlastof UMEC on Day 1 and Day 7 tmax, Day 7, n=0, 6, 8, 6	—	0.080 hours Interval 0.02 to 0.25	0.165 hours Interval 0.08 to 0.32	0.240 hours Interval 0.07 to 0.25
Tmax and Tlastof UMEC on Day 1 and Day 7 tlast, Day 1, n=0, 8, 8, 9	—	4.000 hours Interval 2.0 to 8.12	2.000 hours Interval 0.08 to 4.0	8.000 hours Interval 0.08 to 8.0
Tmax and Tlastof UMEC on Day 1 and Day 7 tlast, Day 7, n=0, 6, 8, 6	—	6.000 hours Interval 2.0 to 27.05	6.015 hours Interval 2.0 to 24.0	24.010 hours Interval 24.0 to 24.48

SECONDARY outcome

Timeframe: From 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1; from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7

Urinary recovery of unchanged drug (UMEC) within the first 8, 12, and 24 hours (Ae\[0-8\], Ae\[0-12\], and Ae\[0-24\], respectively) on Day 1 and within the first 4, 8, 12, and 24 hours (Ae\[0-4\], Ae\[0-8\], Ae\[0-12\], and Ae\[0-24\], respectively) on Day 7 was estimated. Urine samples were collected from 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1 and from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-12), Day 1, n=0, 6, 7, 8	—	2022.3 nanograms (ng) Geometric Coefficient of Variation 41.2	921.7 nanograms (ng) Geometric Coefficient of Variation 97.6	16069.2 nanograms (ng) Geometric Coefficient of Variation 56.0
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-12), Day 7, n=0, 5, 8, 6	—	4165.6 nanograms (ng) Geometric Coefficient of Variation 15.3	1960.5 nanograms (ng) Geometric Coefficient of Variation 53.6	23496.1 nanograms (ng) Geometric Coefficient of Variation 44.7
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-24), Day 1, n=0, 6, 7, 8	—	2503.5 nanograms (ng) Geometric Coefficient of Variation 38.0	1420.3 nanograms (ng) Geometric Coefficient of Variation 130.9	19552.7 nanograms (ng) Geometric Coefficient of Variation 47.4
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-24), Day 7, n=0, 5, 8, 6	—	5606.2 nanograms (ng) Geometric Coefficient of Variation 15.3	2984.5 nanograms (ng) Geometric Coefficient of Variation 52.9	32140.0 nanograms (ng) Geometric Coefficient of Variation 36.2
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-4), Day 7, n=0, 5, 8, 6	—	1223.6 nanograms (ng) Geometric Coefficient of Variation 77.8	669.5 nanograms (ng) Geometric Coefficient of Variation 129.8	11854.5 nanograms (ng) Geometric Coefficient of Variation 65.8
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-8), Day 1, n=0, 6, 7, 8	—	1756.0 nanograms (ng) Geometric Coefficient of Variation 46.6	755.9 nanograms (ng) Geometric Coefficient of Variation 101.5	13435.9 nanograms (ng) Geometric Coefficient of Variation 53.8
Ae(0-4), Ae(0-8), Ae(0-12), and Ae(0-24) of UMEC on Day 1 and Day 7 Ae(0-8), Day 7, n=0, 5, 8, 6	—	3115.8 nanograms (ng) Geometric Coefficient of Variation 27.2	1430.8 nanograms (ng) Geometric Coefficient of Variation 49.6	19319.3 nanograms (ng) Geometric Coefficient of Variation 50.5

SECONDARY outcome

Timeframe: From 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1; from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7

Population: PK Population: Only participants with data available at the indicated time points were summarized. Different participants may have been summarized for different parameters/at different time points (reflected by n=X, X, X, X in the category titles), so the overall number of participants summarized reflects everyone in the PK Population.

The fraction of the total dose excreted (Fe) in each interval was estimated as the urinary recovery of unchanged drug (Ae) per dose. Urine samples were collected from 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1 and from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-4), Day 7, n=0, 5, 8, 6	—	0.58 Percentage of dose administered Standard Deviation 0.35	0.37 Percentage of dose administered Standard Deviation 0.30	1.35 Percentage of dose administered Standard Deviation 0.70
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-8), Day 1, n=0, 6, 8, 8	—	0.76 Percentage of dose administered Standard Deviation 0.35	0.34 Percentage of dose administered Standard Deviation 0.28	1.49 Percentage of dose administered Standard Deviation 0.68
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-8), Day 7, n=0, 5, 8, 6	—	1.28 Percentage of dose administered Standard Deviation 0.30	0.62 Percentage of dose administered Standard Deviation 0.26	2.10 Percentage of dose administered Standard Deviation 0.84
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-12), Day 1, n=0, 6, 8, 8	—	0.87 Percentage of dose administered Standard Deviation 0.38	0.41 Percentage of dose administered Standard Deviation 0.32	1.78 Percentage of dose administered Standard Deviation 0.77
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-12), Day 7, n=0, 5, 8, 6	—	1.68 Percentage of dose administered Standard Deviation 0.25	0.86 Percentage of dose administered Standard Deviation 0.36	2.52 Percentage of dose administered Standard Deviation 0.99
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-24), Day 1, n=0, 6, 8, 8	—	1.06 Percentage of dose administered Standard Deviation 0.41	0.70 Percentage of dose administered Standard Deviation 0.61	2.12 Percentage of dose administered Standard Deviation 0.82
Fe(0-4), Fe(0-8), Fe(0-12), and Fe(0-24) of UMEC on Day 1 and Day 7 Fe(0-24), Day 7, n=0, 5, 8, 6	—	2.26 Percentage of dose administered Standard Deviation 0.33	1.31 Percentage of dose administered Standard Deviation 0.54	3.38 Percentage of dose administered Standard Deviation 1.15

SECONDARY outcome

Timeframe: From 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1; from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7

Renal clearance was calculated as the urinary recovery of unchanged drug from time zero to time x (Ae\[0-x\])/area under concentration from time zero to time x (AUC\[0-x\]) for the longest period of time after dosing when both could be accurately determined (where x is either 8, 12, or 24). Urine samples were collected from 0-8 hours (hr), 8-12 hr, and 12-24 hr on Day 1 and from 0-4 hr, 4-8 hr, 8-12 hr, and 12-24 hr on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=8 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=9 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Renal Clearance of UMEC on Day 1 and Day 7 Day 1, n=0, 1, 0, 8	—	6.5229 Liters/hour (L/hr) Geometric Coefficient of Variation NA A dispersion cannot be calculated for a single participant.	NA Liters/hour (L/hr) Geometric Coefficient of Variation NA Due to non-quantifiable data at the lower dose (250 µg) at later time points, data for this parameter could not be calculated.	5.6173 Liters/hour (L/hr) Geometric Coefficient of Variation 39.5
Renal Clearance of UMEC on Day 1 and Day 7 Day 7, n=0, 4, 6, 6	—	2.5923 Liters/hour (L/hr) Geometric Coefficient of Variation 103.6	4.0826 Liters/hour (L/hr) Geometric Coefficient of Variation 19.3	6.6104 Liters/hour (L/hr) Geometric Coefficient of Variation 33.1

SECONDARY outcome

Timeframe: From 0-4 hours (hr), 4-8 hr, 8-12 hr, and 12-24 hr on Day 7

Population: PK Population. Only participants with data available at the indicated time points were summarized.

Urine half life (t1/2) of UMEC on Day 7 was estimated. Urine samples were collected from 0-4 hours (hr), 4-8 hr, 8-12 hr, and 12-24 hr on Day 7.

Outcome measures

Outcome measures
Measure	Placebo Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=2 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=4 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=4 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Urine Half Life (t1/2) of UMEC on Day 7	—	5.785 hours Geometric Coefficient of Variation 39.4	8.299 hours Geometric Coefficient of Variation 37.3	7.643 hours Geometric Coefficient of Variation 33.4

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 1 UMEC 250 µg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Cohort 2 UMEC 250 µg in Error

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Cohort 3 UMEC 1000 µg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

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

Restriction type: OTHER

Measure	Placebo n=9 Participants Participants received either a single inhaled dose or four inhaled doses of matching placebo once daily (QD) for 7 days via a dry powder inhaler (DPI).	Cohort 1 UMEC 250 µg n=10 Participants Participants received a single inhaled dose of umeclidinium (UMEC) 250 micrograms (µg) formulated with magnesium stearate (MgSt) QD for 7 days via a DPI.	Cohort 2 UMEC 250 µg in Error n=10 Participants Participants received a single inhaled dose of UMEC 250 μg formulated with MgSt QD for 7 days via a DPI. These participants were to have been randomized to receive UMEC 1000 µg; however, they received UMEC 250 µg in error.	Cohort 3 UMEC 1000 µg n=9 Participants Participants received four inhaled doses of UMEC 250 μg (equivalent to 1000 μg) formulated with MgSt QD for 7 days via a DPI.
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, 15 min PD, n=9, 9, 10, 8	79.6 Millimeters of mercury (mmHg) Standard Deviation 9.76	83.6 Millimeters of mercury (mmHg) Standard Deviation 7.47	81.4 Millimeters of mercury (mmHg) Standard Deviation 7.71	85.8 Millimeters of mercury (mmHg) Standard Deviation 10.46
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, 45 min PD, n=9, 9, 10, 9	78.9 Millimeters of mercury (mmHg) Standard Deviation 8.85	79.6 Millimeters of mercury (mmHg) Standard Deviation 9.58	82.8 Millimeters of mercury (mmHg) Standard Deviation 9.96	83.8 Millimeters of mercury (mmHg) Standard Deviation 7.90
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, 1.5 hr PD, n=9, 9, 10, 9	79.3 Millimeters of mercury (mmHg) Standard Deviation 8.54	82.3 Millimeters of mercury (mmHg) Standard Deviation 9.26	84.0 Millimeters of mercury (mmHg) Standard Deviation 6.55	85.4 Millimeters of mercury (mmHg) Standard Deviation 6.88
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, 4 hr PD, n=9, 9, 10, 9	83.4 Millimeters of mercury (mmHg) Standard Deviation 11.14	81.0 Millimeters of mercury (mmHg) Standard Deviation 10.91	83.1 Millimeters of mercury (mmHg) Standard Deviation 11.13	83.7 Millimeters of mercury (mmHg) Standard Deviation 6.06
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, 8 hr PD, n=9, 9, 10, 9	77.8 Millimeters of mercury (mmHg) Standard Deviation 8.67	79.9 Millimeters of mercury (mmHg) Standard Deviation 8.85	80.5 Millimeters of mercury (mmHg) Standard Deviation 7.84	85.3 Millimeters of mercury (mmHg) Standard Deviation 6.08
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, pre-dose, n=9, 7, 9, 6	78.7 Millimeters of mercury (mmHg) Standard Deviation 8.64	82.6 Millimeters of mercury (mmHg) Standard Deviation 8.85	85.8 Millimeters of mercury (mmHg) Standard Deviation 7.79	76.5 Millimeters of mercury (mmHg) Standard Deviation 4.35
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 15 min PD, n=9, 7, 9, 6	82.8 Millimeters of mercury (mmHg) Standard Deviation 11.78	82.7 Millimeters of mercury (mmHg) Standard Deviation 9.11	82.9 Millimeters of mercury (mmHg) Standard Deviation 9.29	81.8 Millimeters of mercury (mmHg) Standard Deviation 5.46
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, pre-dose, n=9, 10, 10, 9	138.9 Millimeters of mercury (mmHg) Standard Deviation 11.43	132.8 Millimeters of mercury (mmHg) Standard Deviation 11.97	137.4 Millimeters of mercury (mmHg) Standard Deviation 10.71	138.6 Millimeters of mercury (mmHg) Standard Deviation 19.13
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, 15 min PD, n=9, 9, 10, 8	135.1 Millimeters of mercury (mmHg) Standard Deviation 12.96	134.9 Millimeters of mercury (mmHg) Standard Deviation 15.05	137.7 Millimeters of mercury (mmHg) Standard Deviation 9.94	135.0 Millimeters of mercury (mmHg) Standard Deviation 14.72
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, 45 min PD, n=9, 9, 10, 9	133.3 Millimeters of mercury (mmHg) Standard Deviation 9.35	135.8 Millimeters of mercury (mmHg) Standard Deviation 14.63	133.9 Millimeters of mercury (mmHg) Standard Deviation 11.28	140.1 Millimeters of mercury (mmHg) Standard Deviation 17.64
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 45 min PD, n=9, 7, 9, 6	80.6 Millimeters of mercury (mmHg) Standard Deviation 10.36	81.4 Millimeters of mercury (mmHg) Standard Deviation 9.45	82.4 Millimeters of mercury (mmHg) Standard Deviation 7.04	81.8 Millimeters of mercury (mmHg) Standard Deviation 6.49
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 1.5 hr PD, n=9, 7, 9, 6	82.2 Millimeters of mercury (mmHg) Standard Deviation 9.91	82.6 Millimeters of mercury (mmHg) Standard Deviation 8.90	83.1 Millimeters of mercury (mmHg) Standard Deviation 9.97	81.7 Millimeters of mercury (mmHg) Standard Deviation 3.50
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, 1.5 hr PD, n=9, 9, 10, 9	140.0 Millimeters of mercury (mmHg) Standard Deviation 19.42	138.2 Millimeters of mercury (mmHg) Standard Deviation 15.79	142.1 Millimeters of mercury (mmHg) Standard Deviation 12.91	145.0 Millimeters of mercury (mmHg) Standard Deviation 21.27
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 4 hr PD, n=9, 7, 9, 6	79.0 Millimeters of mercury (mmHg) Standard Deviation 8.97	84.0 Millimeters of mercury (mmHg) Standard Deviation 7.68	83.0 Millimeters of mercury (mmHg) Standard Deviation 8.09	81.0 Millimeters of mercury (mmHg) Standard Deviation 4.00
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 8 hr PD, n=9, 7, 9, 6	76.2 Millimeters of mercury (mmHg) Standard Deviation 8.70	77.1 Millimeters of mercury (mmHg) Standard Deviation 11.51	80.7 Millimeters of mercury (mmHg) Standard Deviation 7.45	77.8 Millimeters of mercury (mmHg) Standard Deviation 3.54
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 7, 24 hr PD, n=9, 7, 9, 6	78.2 Millimeters of mercury (mmHg) Standard Deviation 8.87	81.6 Millimeters of mercury (mmHg) Standard Deviation 9.05	81.7 Millimeters of mercury (mmHg) Standard Deviation 9.70	79.8 Millimeters of mercury (mmHg) Standard Deviation 4.79
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, 4 hr PD, n=9, 9, 10, 9	141.0 Millimeters of mercury (mmHg) Standard Deviation 15.41	139.4 Millimeters of mercury (mmHg) Standard Deviation 21.43	141.6 Millimeters of mercury (mmHg) Standard Deviation 8.86	138.9 Millimeters of mercury (mmHg) Standard Deviation 11.79
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 1, 8 hr PD, n=9, 9, 10, 9	134.8 Millimeters of mercury (mmHg) Standard Deviation 12.22	135.7 Millimeters of mercury (mmHg) Standard Deviation 15.28	140.8 Millimeters of mercury (mmHg) Standard Deviation 13.14	146.2 Millimeters of mercury (mmHg) Standard Deviation 14.19
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, pre-dose, n=9, 7, 9, 6	134.3 Millimeters of mercury (mmHg) Standard Deviation 9.16	131.8 Millimeters of mercury (mmHg) Standard Deviation 14.47	139.3 Millimeters of mercury (mmHg) Standard Deviation 10.59	120.2 Millimeters of mercury (mmHg) Standard Deviation 10.97
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 15 min PD, n=9, 7, 9, 6	141.3 Millimeters of mercury (mmHg) Standard Deviation 13.95	134.4 Millimeters of mercury (mmHg) Standard Deviation 15.54	138.8 Millimeters of mercury (mmHg) Standard Deviation 12.67	127.5 Millimeters of mercury (mmHg) Standard Deviation 14.29
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 45 min PD, n=9, 7, 9, 6	139.7 Millimeters of mercury (mmHg) Standard Deviation 13.93	135.4 Millimeters of mercury (mmHg) Standard Deviation 19.08	135.8 Millimeters of mercury (mmHg) Standard Deviation 9.28	126.3 Millimeters of mercury (mmHg) Standard Deviation 14.28
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 1.5 hr PD, n=9, 7, 9, 6	137.8 Millimeters of mercury (mmHg) Standard Deviation 15.34	141.6 Millimeters of mercury (mmHg) Standard Deviation 18.35	141.3 Millimeters of mercury (mmHg) Standard Deviation 10.9	130.2 Millimeters of mercury (mmHg) Standard Deviation 10.76
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 4 hr PD, n=9, 7, 9, 6	139.4 Millimeters of mercury (mmHg) Standard Deviation 12.91	139.6 Millimeters of mercury (mmHg) Standard Deviation 15.18	141.6 Millimeters of mercury (mmHg) Standard Deviation 8.56	135.0 Millimeters of mercury (mmHg) Standard Deviation 14.6
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 8 hr PD, n=9, 7, 9, 6	136.1 Millimeters of mercury (mmHg) Standard Deviation 13.17	129.4 Millimeters of mercury (mmHg) Standard Deviation 14.32	136.1 Millimeters of mercury (mmHg) Standard Deviation 13.7	125.7 Millimeters of mercury (mmHg) Standard Deviation 8.29
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 SBP, Day 7, 24 hr PD, n=9, 7, 9, 6	132.1 Millimeters of mercury (mmHg) Standard Deviation 9.49	135.7 Millimeters of mercury (mmHg) Standard Deviation 9.39	136.0 Millimeters of mercury (mmHg) Standard Deviation 9.82	127.5 Millimeters of mercury (mmHg) Standard Deviation 7.71
Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) on Days 1 and 7 DBP, Day 1, pre-dose, n=9, 10, 10, 9	81.6 Millimeters of mercury (mmHg) Standard Deviation 8.52	79.0 Millimeters of mercury (mmHg) Standard Deviation 6.69	82.1 Millimeters of mercury (mmHg) Standard Deviation 7.63	82.4 Millimeters of mercury (mmHg) Standard Deviation 5.25