Safety Study Using GSK573719 And Tiotropium In Patients With Chronic Obstructive Pulmonary Disease

A Randomised, Double Blind, Placebo-controlled, Double Dummy, 4-way Cross-over, Dose Ascending Study to Assess the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK573719 (250, 500 and 1000 μg) and Tiotropium Bromide (18 μg) Via DPI in COPD Patients.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00515502

Enrollment

Registered

2007-08-13

Start date

2007-06-21

Completion date

2007-11-06

Last updated

2017-08-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

chronic obstructive pulmonary disease,, GSK573719,, muscarinic receptor antagonist

Brief summary

GSK573719 is a high-affinity specific muscarinic receptor (mAChR) antagonist which is being developed for once daily treatment of chronic obstructive pulmonary disease (COPD). The long duration of action of GSK573719 when administered via inhalation in animal models supports the potential for use as a once-daily bronchodilator for COPD.

Detailed description

A randomised, double blind, placebo-controlled, double dummy, 4-way cross-over, dose ascending study to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of single inhaled doses of GSK573719 (3 escalating mcg doses will be used) and tiotropium bromide (18µg) via DPI in COPD patients

Interventions

DRUGGSK573719

250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg

DRUGTiotropium

strips of five capsules, each containing 18 μg administered via dry powder inhaler

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Caucasian male or female subjects aged 40-75 years inclusive. The need to recruit only Caucasian subjects is related to the need to rigorously exclude 2D6 poor metabolisers based on genotype. * Female subjects must be of non-childbearing potential. * An established clinical history of COPD (ATS/ERS definition). * 'Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.' * Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). * Subject has FEV1/FVC \< 0.7 post-bronchodilator (salbutamol) dose. * Subject has 40 ≥ FEV1 ≤ 80% of predicted normal for height, age and gender after inhalation of salbutamol dose. * Response to ipratropium bromide. * Subject is able and has given written informed consent to take part in the study. * Subject is available to complete all study measurements and procedures. * Subject's BMI is 18.0 - 32.0 kg/m2. * Subjects have a 24hr Holter recording that is within normal limits and does not demonstrate any clinically important abnormality that, in the opinion of the investigator, would make the subject unsuitable for participation in the study

Exclusion criteria

* Subjects who have a past or present disease of any organ system, which as judged by the Investigator, may affect the outcome of this study. * The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cannabis, Cocaine and Opiates. The detection of drugs with a legitimate medical use would not be an exclusion to study participation. * The subject has a positive pre-study alcohol screen. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study. * A suspected history of alcohol abuse within the six months previous to the screening visit. * The subject has tested positive for hepatitis C antibody, hepatitis B surface antigen or HIV (if determined by local SOP's). * Subject has received an investigational drug within 30 days of screening. * The subject is currently taking medication which is known to be a CYP 2D6 inhibitor/substrate. * The subject has donated a unit (400ml) of blood within 60 days of screening, or, intends to donate during the study. * The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium bromide, atropine and any of its derivatives or lactose/milk protein. * Subject is unable to use the DISKUS™/HandiHaler devices correctly. * Subject has prostatic hypertrophy, bladder outlet obstruction, or narrow angle glaucoma. * Subjects with a 2D6 poor metaboliser genotype (Caucasian). * The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet (American Association of Respiratory Care 2001 guidelines for body plethysmography) * Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Screening. Respiratory criteria * Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, allergic rhinitis, or asthma. * Subject has poorly controlled COPD, defined as either: acute worsening of COPD that is managed by the subject at home by treatment with corticosteroids in the 6 weeks prior to screening visit Or more than two exacerbations in the previous 6 months prior to screening that required a course of oral corticosteroids or antibiotics, or, for which the subject was hospitalised. * Subject has participated in a Pulmonary Rehabilitation Program within 4 weeks prior to screening visit or will enter a program during the study. * Subject has had a respiratory tract infection in the 4 weeks prior to the screening visit. Cardiovascular criteria * Current congestive heart failure (greater than NYHA I), myocardial infarction (within 3-years of the screening date) or ischaemic heart disease requiring regular therapy (such as β blockers, long-acting nitrates, calcium antagonists or nicorandil). Aspirin, Clopidogrel and statins are allowed. * A history of clinically significant arrhythmia or clinically important 24hr Holter findings that, in the opinion of the investigator, would cause a safety concern for entry into the study. * A mean QTc(B) value at screening \>450msec, the QTc(B) of all 3 screening ECGs are not within 10% of the mean, or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave) * Mobitz type II or third degree heart block. * Risk factors for torsades de pointes (heart failure NYHA II-IV, chronic hypokalaemia, familial long QT syndrome). * Elevated resting blood pressure or a mean blood pressure equal to or higher than 150/95 mmHg at screening. A history of hypertension is acceptable provided control has been achieved for \> 3 months prior to screening with diuretic only. * A mean heart rate outside the range 50-100 bpm at screening (from vital signs measurement). Concurrent medication criteria * Subject requires treatment with inhaled cromolyn sodium or nedocromil, oral β2-agonists, nebulised β2-agonists, nebulised anticholinergics or leukotriene modifiers. * Subject is unable to abstain from xanthines (other than caffeine) 13-15 days prior to the first dose of study medication until completion of the study (last study-related procedure at the follow-up visit). * Subject is unable to abstain from short-acting inhaled bronchodilators from 6hrs prior to screening until after completion of screening, or, from 6hrs prior to the administration of study medication until after completion of any given treatment period (i.e. the last assessment in a dosing period). * Subject is unable to abstain from long-acting inhaled bronchodilators from 72hrs prior to the screening until after completion of all treatment periods (i.e. the last assessment in the final dosing period). * Subject has changed dose of inhaled corticosteroids within the last 4 weeks, or, will be unable to maintain a constant dose of inhaled corticosteroids during the study. * Subject is receiving treatment with long term or short-term oxygen therapy or requires nocturnal positive pressure ventilation (CPAP or NIPPV). * Subject is receiving treatment with beta-blockers, except eye drops, Diltiazem or Verapamil. * Subject is receiving co-medication with drugs which are commonly recognised to prolong the QTc interval (e.g. quinolones, amiodarone, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol, ketoconazole, terfenadine, cisapride and terodiline).

Design outcomes

Primary

Measure	Time frame	Description
Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of the calcium, bicarbonate, chloride, glucose, IP, potassium, sodium, and urea at pre-dose and 24 hour (h) post-dose of each treatment period.
Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at pre-dose and 24 hour (h) post-dose of each treatment period.
Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of hemoglobin, MCHC, albumin and total protein at pre-dose and 24 hour (h) post-dose of each treatment period.
Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of hematocrit at pre-dose and 24 hour (h) post-dose of each treatment period.
Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of the mean corpuscle hemoglobin at pre-dose and 24 hour (h) post-dose of each treatment period.
Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of the mean corpuscle volume at pre-dose and 24 hour (h) post-dose of each treatment period.
Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of the red blood cells count at pre-dose and 24 hour (h) post-dose of each treatment period.
Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of platelets count and WBC count at pre-dose and 24 hour (h) post-dose of each treatment period.
Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of ALP, ALT, AST, CPK, and GGT at pre-dose and 24 hour (h) post-dose of each treatment period.
Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected for the measurement of total bilirubin, creatinine, and uric acid at pre-dose and 24 hour (h) post-dose of each treatment period.
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)	An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs.
Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. FEV1 and FVC measurements were taken at pre-dose and 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose of each treatment period.
Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting heart rate was measured at pre-dose and 15 minutes (min), 45min, 1.5 hour (h) 4 h, 8 h, and 24 h post-dose of each treatment period and the maximum value for heart rate (0-4hours) was derived at rest. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting heart rate was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for heart rate (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twelve-lead ECGs (electrocardiograms) were performed to measure QT interval corrected according to Bazzet's formula (QTcB) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twelve-lead ECGs were performed to measure QTcB at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twelve-lead ECGs were performed to measure QT interval corrected according to Fredericia's formula (QTcF) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twelve-lead ECGs were performed to measure QTcF at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.
Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twenty-four hour Holter monitoring was conducted to measure heart rate for the 24-hour period following dosing at each treatment period and the maximum value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect.
Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Twenty-four-hour Holter monitoring was conducted to measure heart rate for the 24-h period following dosing of each treatment period and the mean value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect.

Secondary

Measure	Time frame	Description
Maximum Observed Plasma Concentration (Cmax) of UMEC	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the Cmax. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.
Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive tmax, tlast and t1/2. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.
Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Day 1 of each treatment period (up to Study Day 46)	Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Ae(0-2), Ae(0-8), Ae(0-12), Ae(0-24), Ae(0-48), AUER(0-18) and AUER(0-36). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.
Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1	Day 1 of each treatment period (up to Study Day 46)	The CLr is defined as the apparent total clearance of the drug from plasma after oral administration. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.
Half-life for Renal Excretion of UMEC on Day 1	Day 1 of each treatment period (up to Study Day 46)	The terminal half-life (t1/2) of UMEC is defined as the time required for the urine concentration of UMEC to reach half of its original concentration. Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.
Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Day 1 of each treatment period (up to Study Day 46)	Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Fe(0-24) and Fe(0-48). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.
Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	Serial spirometry assessments were conducted on Day 1 of each treatment period over the course of 24 hours and were taken at 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose. The maximum of the 3 FEV1 measurements for each participant, treatment period and timepoint were used in the calculation of the mean for each treatment group at each timepoint.
Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	Day 1 of each treatment period (up to Study Day 46)	sGaw is the specific airways resistance (mid) which was assessed by whole body plethysmography. Values used were the mean of the 3 readings recorded at each timepoint. sGaw measurements were taken at 2 hour (h), 6 h, 12 h and 24 h post-dose of each treatment period. 1/kPa.s=1(the inverses)/kPa (kilopascal).s (second)
Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	Day 1 of each treatment period (up to Study Day 46)	Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the AUC(0-2) and AUC(0-t). Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Countries

Germany

Participant flow

Pre-assignment details

Participants were randomized to receive a sequence of 4 of 5 possible treatments over 4 treatment periods each separated by a washout period of at least 14 days. Participants were randomized to receive treatments in 12 possible sequences.

Participants by arm

Arm	Count
All Study Treatments Participants received a sequence containing 4 of the following 5 possible treatments: placebo, UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and Tiotropium 18 µg. Participants received each of the treatments in 1 of 4 single dose treatment periods, each of which was followed by a washout period. Treatment periods 1, 2, and 3 were followed by at least a 14-day washout period; Treatment period 4 was followed by a Follow-up visit within 10 days.	24
Total	24

Arm

Count

All Study Treatments

Participants received a sequence containing 4 of the following 5 possible treatments: placebo, UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and Tiotropium 18 µg. Participants received each of the treatments in 1 of 4 single dose treatment periods, each of which was followed by a washout period. Treatment periods 1, 2, and 3 were followed by at least a 14-day washout period; Treatment period 4 was followed by a Follow-up visit within 10 days.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008	FG009	FG010	FG011
Treatment Period 1	Adverse Event	0	0	0	0	0	0	1	0	1	0	0	1
Treatment Period 2	Adverse Event	0	1	0	0	0	0	0	0	0	0	0	0

Baseline characteristics

Characteristic	All Study Treatments
Age, Continuous	56.0 Years STANDARD_DEVIATION 5.32
Race/Ethnicity, Customized White - White/Caucasian/European	24 Participants
Sex: Female, Male Female	5 Participants
Sex: Female, Male Male	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 21	9 / 22	8 / 21	4 / 13	3 / 8
serious Total, serious adverse events	0 / 21	0 / 22	0 / 21	0 / 13	0 / 8

Outcome results

Primary

Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of ALP, ALT, AST, CPK, and GGT at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, Pre-dose,n=21, 22, 21, 13, 8	23.6 International units per liter (IU/L)	Standard Deviation 11.67
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, 24 h Post-dose, n=21, 22, 21, 13, 8	27.14 International units per liter (IU/L)	Standard Deviation 16.806
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, 24 h Post-dose,n=21, 22, 21, 13, 8	23.3 International units per liter (IU/L)	Standard Deviation 12.29
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, Pre-dose, n=21, 22, 21, 13, 8	27.81 International units per liter (IU/L)	Standard Deviation 18.287
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, 24 h Post-dose, n=21, 22, 21, 13, 8	99.97 International units per liter (IU/L)	Standard Deviation 61.307
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, 24 h Post-dose, n=21, 22, 21, 13, 8	67.20 International units per liter (IU/L)	Standard Deviation 18.388
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, Pre-dose, n=21, 22, 21, 13, 8	67.04 International units per liter (IU/L)	Standard Deviation 17.26
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, Pre-dose, n=21, 22, 21, 13, 8	124.33 International units per liter (IU/L)	Standard Deviation 89.568
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, 24 h Post-dose, n=21, 22, 21, 13, 8	21.68 International units per liter (IU/L)	Standard Deviation 8.625
Placebo	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, Pre-dose, n=21, 22, 20, 13, 8	21.98 International units per liter (IU/L)	Standard Deviation 7.525
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, 24 h Post-dose, n=21, 22, 21, 13, 8	65.04 International units per liter (IU/L)	Standard Deviation 15.289
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, Pre-dose, n=21, 22, 21, 13, 8	65.32 International units per liter (IU/L)	Standard Deviation 12.687
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, Pre-dose,n=21, 22, 21, 13, 8	24.1 International units per liter (IU/L)	Standard Deviation 9.8
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, 24 h Post-dose,n=21, 22, 21, 13, 8	23.0 International units per liter (IU/L)	Standard Deviation 9.36
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, Pre-dose, n=21, 22, 20, 13, 8	24.55 International units per liter (IU/L)	Standard Deviation 6.689
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, 24 h Post-dose, n=21, 22, 21, 13, 8	22.01 International units per liter (IU/L)	Standard Deviation 7.048
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, Pre-dose, n=21, 22, 21, 13, 8	101.88 International units per liter (IU/L)	Standard Deviation 49.41
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, 24 h Post-dose, n=21, 22, 21, 13, 8	82.81 International units per liter (IU/L)	Standard Deviation 30.913
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, Pre-dose, n=21, 22, 21, 13, 8	26.41 International units per liter (IU/L)	Standard Deviation 14.704
UMEC 250 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, 24 h Post-dose, n=21, 22, 21, 13, 8	25.33 International units per liter (IU/L)	Standard Deviation 13.962
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, 24 h Post-dose, n=21, 22, 21, 13, 8	20.58 International units per liter (IU/L)	Standard Deviation 5.761
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, Pre-dose, n=21, 22, 21, 13, 8	26.41 International units per liter (IU/L)	Standard Deviation 17.573
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, Pre-dose,n=21, 22, 21, 13, 8	21.3 International units per liter (IU/L)	Standard Deviation 8.37
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, 24 h Post-dose,n=21, 22, 21, 13, 8	20.5 International units per liter (IU/L)	Standard Deviation 7.56
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, 24 h Post-dose, n=21, 22, 21, 13, 8	64.96 International units per liter (IU/L)	Standard Deviation 14.933
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, Pre-dose, n=21, 22, 20, 13, 8	22.13 International units per liter (IU/L)	Standard Deviation 5.358
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, Pre-dose, n=21, 22, 21, 13, 8	104.39 International units per liter (IU/L)	Standard Deviation 42.381
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, Pre-dose, n=21, 22, 21, 13, 8	66.60 International units per liter (IU/L)	Standard Deviation 13.127
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, 24 h Post-dose, n=21, 22, 21, 13, 8	25.89 International units per liter (IU/L)	Standard Deviation 18.218
UMEC 500 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, 24 h Post-dose, n=21, 22, 21, 13, 8	83.77 International units per liter (IU/L)	Standard Deviation 29.233
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, 24 h Post-dose, n=21, 22, 21, 13, 8	61.76 International units per liter (IU/L)	Standard Deviation 12.253
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, 24 h Post-dose, n=21, 22, 21, 13, 8	29.38 International units per liter (IU/L)	Standard Deviation 19.277
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, Pre-dose, n=21, 22, 21, 13, 8	63.37 International units per liter (IU/L)	Standard Deviation 13.469
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, Pre-dose,n=21, 22, 21, 13, 8	26.2 International units per liter (IU/L)	Standard Deviation 10.53
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, 24 h Post-dose, n=21, 22, 21, 13, 8	20.75 International units per liter (IU/L)	Standard Deviation 6.947
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, 24 h Post-dose, n=21, 22, 21, 13, 8	87.78 International units per liter (IU/L)	Standard Deviation 37.566
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, Pre-dose, n=21, 22, 21, 13, 8	29.86 International units per liter (IU/L)	Standard Deviation 21.391
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, Pre-dose, n=21, 22, 21, 13, 8	100.16 International units per liter (IU/L)	Standard Deviation 44.497
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, 24 h Post-dose,n=21, 22, 21, 13, 8	25.6 International units per liter (IU/L)	Standard Deviation 9.69
UMEC 1000 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, Pre-dose, n=21, 22, 20, 13, 8	23.03 International units per liter (IU/L)	Standard Deviation 6.923
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, 24 h Post-dose,n=21, 22, 21, 13, 8	17.8 International units per liter (IU/L)	Standard Deviation 5.39
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, Pre-dose, n=21, 22, 21, 13, 8	19.94 International units per liter (IU/L)	Standard Deviation 6.369
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, Pre-dose, n=21, 22, 20, 13, 8	22.09 International units per liter (IU/L)	Standard Deviation 4.995
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	AST, 24 h Post-dose, n=21, 22, 21, 13, 8	19.23 International units per liter (IU/L)	Standard Deviation 5.473
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	GGT, 24 h Post-dose, n=21, 22, 21, 13, 8	19.59 International units per liter (IU/L)	Standard Deviation 6.431
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, Pre-dose, n=21, 22, 21, 13, 8	117.08 International units per liter (IU/L)	Standard Deviation 61.189
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, Pre-dose, n=21, 22, 21, 13, 8	71.06 International units per liter (IU/L)	Standard Deviation 19.304
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	CPK, 24 h Post-dose, n=21, 22, 21, 13, 8	109.36 International units per liter (IU/L)	Standard Deviation 90.411
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALT, Pre-dose,n=21, 22, 21, 13, 8	19.1 International units per liter (IU/L)	Standard Deviation 5.36
Tiotropium 18 µg	Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period	ALP, 24 h Post-dose, n=21, 22, 21, 13, 8	71.84 International units per liter (IU/L)	Standard Deviation 21.099

Primary

Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, Pre-dose	3.30 Percentage	Standard Deviation 2.336
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, 24 h Post-dose	56.26 Percentage	Standard Deviation 7.166
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, 24 h Post-dose	3.34 Percentage	Standard Deviation 1.914
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, Pre-dose	58.30 Percentage	Standard Deviation 8.159
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, 24 h Post-dose	8.10 Percentage	Standard Deviation 1.975
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, 24 h Post-dose	0.70 Percentage	Standard Deviation 0.434
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, Pre-dose	0.65 Percentage	Standard Deviation 0.284
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, Pre-dose	8.53 Percentage	Standard Deviation 1.842
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, 24 h Post-dose	31.60 Percentage	Standard Deviation 6.387
Placebo	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, Pre-dose	29.23 Percentage	Standard Deviation 6.82
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, 24 h Post-dose	0.65 Percentage	Standard Deviation 0.313
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, Pre-dose	0.73 Percentage	Standard Deviation 0.366
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, Pre-dose	3.46 Percentage	Standard Deviation 2.249
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, 24 h Post-dose	3.25 Percentage	Standard Deviation 1.839
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, Pre-dose	30.66 Percentage	Standard Deviation 7.355
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, 24 h Post-dose	30.86 Percentage	Standard Deviation 6.749
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, Pre-dose	8.50 Percentage	Standard Deviation 2.467
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, 24 h Post-dose	7.62 Percentage	Standard Deviation 1.934
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, Pre-dose	56.64 Percentage	Standard Deviation 9.081
UMEC 250 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, 24 h Post-dose	57.62 Percentage	Standard Deviation 7.74
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, 24 h Post-dose	30.99 Percentage	Standard Deviation 6.558
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, Pre-dose	58.10 Percentage	Standard Deviation 10.941
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, Pre-dose	3.67 Percentage	Standard Deviation 2.813
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, 24 h Post-dose	3.30 Percentage	Standard Deviation 2.164
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, 24 h Post-dose	0.56 Percentage	Standard Deviation 0.292
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, Pre-dose	28.91 Percentage	Standard Deviation 9.279
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, Pre-dose	8.60 Percentage	Standard Deviation 2.179
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, Pre-dose	0.74 Percentage	Standard Deviation 0.396
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, 24 h Post-dose	56.94 Percentage	Standard Deviation 7.164
UMEC 500 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, 24 h Post-dose	8.23 Percentage	Standard Deviation 1.985
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, 24 h Post-dose	0.58 Percentage	Standard Deviation 0.344
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, 24 h Post-dose	56.78 Percentage	Standard Deviation 6.204
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, Pre-dose	0.87 Percentage	Standard Deviation 0.275
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, Pre-dose	4.03 Percentage	Standard Deviation 2.679
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, 24 h Post-dose	31.72 Percentage	Standard Deviation 4.92
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, 24 h Post-dose	7.45 Percentage	Standard Deviation 1.406
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, Pre-dose	53.32 Percentage	Standard Deviation 7.825
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, Pre-dose	8.10 Percentage	Standard Deviation 1.626
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, 24 h Post-dose	3.49 Percentage	Standard Deviation 2.437
UMEC 1000 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, Pre-dose	33.70 Percentage	Standard Deviation 7.161
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, 24 h Post-dose	3.38 Percentage	Standard Deviation 1.552
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, Pre-dose	58.88 Percentage	Standard Deviation 9.403
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, Pre-dose	27.99 Percentage	Standard Deviation 7.637
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Lymphocytes, 24 h Post-dose	30.86 Percentage	Standard Deviation 6.298
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total neutrophils, 24 h Post-dose	55.63 Percentage	Standard Deviation 7.699
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, Pre-dose	9.33 Percentage	Standard Deviation 2.582
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, Pre-dose	0.71 Percentage	Standard Deviation 0.314
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Monocytes, 24 h Post-dose	9.40 Percentage	Standard Deviation 2.084
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Eosinophils, Pre-dose	3.05 Percentage	Standard Deviation 1.562
Tiotropium 18 µg	Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period	Basophils, 24 h Post-dose	0.76 Percentage	Standard Deviation 0.558

Primary

Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of the calcium, bicarbonate, chloride, glucose, IP, potassium, sodium, and urea at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, Pre-dose, n=21, 22, 21, 13, 8	5.225 Millimoles per liter (mmol/L)	Standard Deviation 0.5294
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8	2.270 Millimoles per liter (mmol/L)	Standard Deviation 0.0891
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, Pre-dose, n=21, 22, 21, 13, 8	106.88 Millimoles per liter (mmol/L)	Standard Deviation 2.727
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8	107.18 Millimoles per liter (mmol/L)	Standard Deviation 1.875
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, Pre-dose, n=21, 22, 21, 13, 8	2.283 Millimoles per liter (mmol/L)	Standard Deviation 0.0729
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8	5.278 Millimoles per liter (mmol/L)	Standard Deviation 0.58
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8	22.41 Millimoles per liter (mmol/L)	Standard Deviation 2.609
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7	22.98 Millimoles per liter (mmol/L)	Standard Deviation 2.414
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, Pre-dose, n=21, 22, 21, 13, 8	4.283 Millimoles per liter (mmol/L)	Standard Deviation 0.3178
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8	4.270 Millimoles per liter (mmol/L)	Standard Deviation 0.234
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, Pre-dose,n=21, 22, 21, 13, 8	140.45 Millimoles per liter (mmol/L)	Standard Deviation 2.253
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8	140.90 Millimoles per liter (mmol/L)	Standard Deviation 1.674
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, Pre-dose, n=21, 22, 21, 13, 8	1.153 Millimoles per liter (mmol/L)	Standard Deviation 0.1271
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, 24 h Post-dose, n=21, 22, 21, 13, 8	1.131 Millimoles per liter (mmol/L)	Standard Deviation 0.1455
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, Pre-dose, n=21, 22, 21, 13, 8	4.905 Millimoles per liter (mmol/L)	Standard Deviation 1.2041
Placebo	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, 24 h Post-dose, n=21, 22, 21, 13, 8	4.700 Millimoles per liter (mmol/L)	Standard Deviation 0.8093
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, 24 h Post-dose, n=21, 22, 21, 13, 8	1.118 Millimoles per liter (mmol/L)	Standard Deviation 0.1391
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8	4.274 Millimoles per liter (mmol/L)	Standard Deviation 0.3311
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, Pre-dose, n=21, 22, 21, 13, 8	4.177 Millimoles per liter (mmol/L)	Standard Deviation 0.2537
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, Pre-dose, n=21, 22, 21, 13, 8	4.629 Millimoles per liter (mmol/L)	Standard Deviation 0.9289
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7	22.62 Millimoles per liter (mmol/L)	Standard Deviation 2.995
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, Pre-dose, n=21, 22, 21, 13, 8	5.046 Millimoles per liter (mmol/L)	Standard Deviation 0.5583
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8	107.10 Millimoles per liter (mmol/L)	Standard Deviation 2.457
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8	2.290 Millimoles per liter (mmol/L)	Standard Deviation 0.0713
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, Pre-dose, n=21, 22, 21, 13, 8	2.277 Millimoles per liter (mmol/L)	Standard Deviation 0.0861
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, Pre-dose, n=21, 22, 21, 13, 8	1.095 Millimoles per liter (mmol/L)	Standard Deviation 0.1026
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8	5.203 Millimoles per liter (mmol/L)	Standard Deviation 0.6391
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, Pre-dose, n=21, 22, 21, 13, 8	107.11 Millimoles per liter (mmol/L)	Standard Deviation 1.972
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, 24 h Post-dose, n=21, 22, 21, 13, 8	4.721 Millimoles per liter (mmol/L)	Standard Deviation 0.9688
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8	140.68 Millimoles per liter (mmol/L)	Standard Deviation 1.864
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, Pre-dose,n=21, 22, 21, 13, 8	140.95 Millimoles per liter (mmol/L)	Standard Deviation 1.932
UMEC 250 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8	22.95 Millimoles per liter (mmol/L)	Standard Deviation 2.295
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, 24 h Post-dose, n=21, 22, 21, 13, 8	1.143 Millimoles per liter (mmol/L)	Standard Deviation 0.1486
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8	106.94 Millimoles per liter (mmol/L)	Standard Deviation 2.002
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, Pre-dose, n=21, 22, 21, 13, 8	5.082 Millimoles per liter (mmol/L)	Standard Deviation 0.5882
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8	5.224 Millimoles per liter (mmol/L)	Standard Deviation 0.55
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8	23.28 Millimoles per liter (mmol/L)	Standard Deviation 2.698
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7	23.30 Millimoles per liter (mmol/L)	Standard Deviation 2.6
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, Pre-dose, n=21, 22, 21, 13, 8	5.002 Millimoles per liter (mmol/L)	Standard Deviation 1.1933
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, Pre-dose, n=21, 22, 21, 13, 8	4.209 Millimoles per liter (mmol/L)	Standard Deviation 0.2255
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8	4.266 Millimoles per liter (mmol/L)	Standard Deviation 0.3065
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, Pre-dose,n=21, 22, 21, 13, 8	140.84 Millimoles per liter (mmol/L)	Standard Deviation 1.551
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8	140.93 Millimoles per liter (mmol/L)	Standard Deviation 1.61
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, Pre-dose, n=21, 22, 21, 13, 8	1.135 Millimoles per liter (mmol/L)	Standard Deviation 0.1406
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, Pre-dose, n=21, 22, 21, 13, 8	2.267 Millimoles per liter (mmol/L)	Standard Deviation 0.0809
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, 24 h Post-dose, n=21, 22, 21, 13, 8	4.710 Millimoles per liter (mmol/L)	Standard Deviation 0.9958
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8	2.265 Millimoles per liter (mmol/L)	Standard Deviation 0.0704
UMEC 500 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, Pre-dose, n=21, 22, 21, 13, 8	106.42 Millimoles per liter (mmol/L)	Standard Deviation 1.857
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8	4.279 Millimoles per liter (mmol/L)	Standard Deviation 0.3587
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, 24 h Post-dose, n=21, 22, 21, 13, 8	4.579 Millimoles per liter (mmol/L)	Standard Deviation 0.8701
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, Pre-dose,n=21, 22, 21, 13, 8	141.07 Millimoles per liter (mmol/L)	Standard Deviation 0.825
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, 24 h Post-dose, n=21, 22, 21, 13, 8	1.121 Millimoles per liter (mmol/L)	Standard Deviation 0.1735
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8	141.13 Millimoles per liter (mmol/L)	Standard Deviation 1.165
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8	5.031 Millimoles per liter (mmol/L)	Standard Deviation 0.3691
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, Pre-dose, n=21, 22, 21, 13, 8	1.105 Millimoles per liter (mmol/L)	Standard Deviation 0.149
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8	107.17 Millimoles per liter (mmol/L)	Standard Deviation 2.83
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, Pre-dose, n=21, 22, 21, 13, 8	2.242 Millimoles per liter (mmol/L)	Standard Deviation 0.0625
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, Pre-dose, n=21, 22, 21, 13, 8	107.26 Millimoles per liter (mmol/L)	Standard Deviation 2.738
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7	23.80 Millimoles per liter (mmol/L)	Standard Deviation 2.822
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, Pre-dose, n=21, 22, 21, 13, 8	5.098 Millimoles per liter (mmol/L)	Standard Deviation 0.4362
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, Pre-dose, n=21, 22, 21, 13, 8	4.248 Millimoles per liter (mmol/L)	Standard Deviation 0.2717
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, Pre-dose, n=21, 22, 21, 13, 8	4.904 Millimoles per liter (mmol/L)	Standard Deviation 0.9358
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8	23.08 Millimoles per liter (mmol/L)	Standard Deviation 2.401
UMEC 1000 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8	2.244 Millimoles per liter (mmol/L)	Standard Deviation 0.0864
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, Pre-dose, n=21, 22, 21, 13, 8	1.161 Millimoles per liter (mmol/L)	Standard Deviation 0.1763
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, 24 h Post-dose, n=21, 22, 21, 13, 8	4.359 Millimoles per liter (mmol/L)	Standard Deviation 0.3642
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, Pre-dose, n=21, 22, 21, 13, 8	4.820 Millimoles per liter (mmol/L)	Standard Deviation 1.2474
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, Pre-dose, n=21, 22, 21, 13, 8	5.326 Millimoles per liter (mmol/L)	Standard Deviation 0.6739
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, 24 h Post-dose, n=21, 22, 21, 13, 8	2.280 Millimoles per liter (mmol/L)	Standard Deviation 0.0428
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, 24 h Post-dose, n=21, 22, 21, 13, 7	25.14 Millimoles per liter (mmol/L)	Standard Deviation 2.738
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, Pre-dose,n=21, 22, 21, 13, 8	140.86 Millimoles per liter (mmol/L)	Standard Deviation 2.458
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Urea, 24 h Post-dose, n=21, 22, 21, 13, 8	4.764 Millimoles per liter (mmol/L)	Standard Deviation 1.6021
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Glucose, 24 h Post-dose, n=21, 22, 21, 13, 8	5.291 Millimoles per liter (mmol/L)	Standard Deviation 0.535
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Potassium, Pre-dose, n=21, 22, 21, 13, 8	4.193 Millimoles per liter (mmol/L)	Standard Deviation 0.1896
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Calcium, Pre-dose, n=21, 22, 21, 13, 8	2.278 Millimoles per liter (mmol/L)	Standard Deviation 0.0547
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Sodium, 24 h Post-dose, n=21, 22, 21, 13, 8	140.56 Millimoles per liter (mmol/L)	Standard Deviation 1.749
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Bicarbonate, Pre-dose, n=21, 22, 21, 13, 8	22.98 Millimoles per liter (mmol/L)	Standard Deviation 4.179
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	IP, 24 h Post-dose, n=21, 22, 21, 13, 8	1.158 Millimoles per liter (mmol/L)	Standard Deviation 0.1179
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, 24 h Post-dose, n=21, 22, 21, 13, 8	106.59 Millimoles per liter (mmol/L)	Standard Deviation 1.46
Tiotropium 18 µg	Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period	Chloride, Pre-dose, n=21, 22, 21, 13, 8	106.49 Millimoles per liter (mmol/L)	Standard Deviation 2.255

Primary

Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period

FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. FEV1 and FVC measurements were taken at pre-dose and 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, Pre-dose, n= 21, 22, 21, 13, 8	1.637 Liters	Standard Deviation 0.3991
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 1h, n=21, 20, 21, 13, 8	3.490 Liters	Standard Deviation 0.8721
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 24h, =21, 22, 21, 13, 8	1.612 Liters	Standard Deviation 0.3189
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, Pre-dose, n=21, 22, 21, 13, 8	3.438 Liters	Standard Deviation 0.8138
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 12h, n=21, 22, 21, 13, 8	3.595 Liters	Standard Deviation 0.8178
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.689 Liters	Standard Deviation 0.4172
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 9h, n=21, 19, 21, 13, 7	3.662 Liters	Standard Deviation 0.8436
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	1.700 Liters	Standard Deviation 0.4055
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 24h, n=21, 22, 21, 13, 8	3.389 Liters	Standard Deviation 0.7272
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 6h, n=21, 22, 21, 13, 8	3.572 Liters	Standard Deviation 0.8555
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.754 Liters	Standard Deviation 0.3664
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 1h, n=21, 20, 21, 13, 8	1.670 Liters	Standard Deviation 0.413
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 2h, n=21, 20, 21, 13, 8	3.545 Liters	Standard Deviation 0.8796
Placebo	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13,8	1.688 Liters	Standard Deviation 0.3797
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13,8	1.933 Liters	Standard Deviation 0.3756
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.984 Liters	Standard Deviation 0.3554
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.000 Liters	Standard Deviation 0.4251
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 24h, =21, 22, 21, 13, 8	1.830 Liters	Standard Deviation 0.4033
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 1h, n=21, 20, 21, 13, 8	1.874 Liters	Standard Deviation 0.3414
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, Pre-dose, n=21, 22, 21, 13, 8	3.247 Liters	Standard Deviation 0.7574
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 1h, n=21, 20, 21, 13, 8	3.751 Liters	Standard Deviation 0.8688
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, Pre-dose, n= 21, 22, 21, 13, 8	1.559 Liters	Standard Deviation 0.2867
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 12h, n=21, 22, 21, 13, 8	3.841 Liters	Standard Deviation 0.919
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 6h, n=21, 22, 21, 13, 8	3.940 Liters	Standard Deviation 0.9583
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 2h, n=21, 20, 21, 13, 8	3.877 Liters	Standard Deviation 0.9571
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.969 Liters	Standard Deviation 0.376
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 24h, n=21, 22, 21, 13, 8	3.712 Liters	Standard Deviation 0.9878
UMEC 250 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 9h, n=21, 19, 21, 13, 7	4.015 Liters	Standard Deviation 0.8461
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13,8	1.988 Liters	Standard Deviation 0.3463
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, Pre-dose, n= 21, 22, 21, 13, 8	1.589 Liters	Standard Deviation 0.2871
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 1h, n=21, 20, 21, 13, 8	1.905 Liters	Standard Deviation 0.3574
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	2.015 Liters	Standard Deviation 0.3512
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.073 Liters	Standard Deviation 0.3343
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	2.010 Liters	Standard Deviation 0.3113
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 24h, =21, 22, 21, 13, 8	1.817 Liters	Standard Deviation 0.3569
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, Pre-dose, n=21, 22, 21, 13, 8	3.337 Liters	Standard Deviation 0.7139
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 1h, n=21, 20, 21, 13, 8	3.845 Liters	Standard Deviation 0.7974
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 2h, n=21, 20, 21, 13, 8	3.976 Liters	Standard Deviation 0.8479
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 6h, n=21, 22, 21, 13, 8	4.064 Liters	Standard Deviation 0.8822
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 9h, n=21, 19, 21, 13, 7	3.969 Liters	Standard Deviation 0.8783
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 12h, n=21, 22, 21, 13, 8	3.923 Liters	Standard Deviation 0.8966
UMEC 500 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 24h, n=21, 22, 21, 13, 8	3.705 Liters	Standard Deviation 0.8597
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13,8	2.103 Liters	Standard Deviation 0.3633
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 1h, n=21, 20, 21, 13, 8	4.006 Liters	Standard Deviation 0.943
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	2.135 Liters	Standard Deviation 0.285
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 2h, n=21, 20, 21, 13, 8	4.205 Liters	Standard Deviation 0.9935
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.198 Liters	Standard Deviation 0.3329
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, Pre-dose, n= 21, 22, 21, 13, 8	1.732 Liters	Standard Deviation 0.208
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 6h, n=21, 22, 21, 13, 8	4.257 Liters	Standard Deviation 1.039
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	2.123 Liters	Standard Deviation 0.3757
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 9h, n=21, 19, 21, 13, 7	4.184 Liters	Standard Deviation 0.9694
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 1h, n=21, 20, 21, 13, 8	1.966 Liters	Standard Deviation 0.3781
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 24h, n=21, 22, 21, 13, 8	3.993 Liters	Standard Deviation 0.9759
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 24h, =21, 22, 21, 13, 8	1.978 Liters	Standard Deviation 0.3416
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 12h, n=21, 22, 21, 13, 8	4.130 Liters	Standard Deviation 1.0544
UMEC 1000 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, Pre-dose, n=21, 22, 21, 13, 8	3.640 Liters	Standard Deviation 0.7869
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 24h, =21, 22, 21, 13, 8	1.454 Liters	Standard Deviation 0.3135
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 24h, n=21, 22, 21, 13, 8	3.280 Liters	Standard Deviation 0.6741
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 1h, n=21, 20, 21, 13, 8	3.631 Liters	Standard Deviation 0.7223
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.767 Liters	Standard Deviation 0.4555
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, Pre-dose, n=21, 22, 21, 13, 8	3.080 Liters	Standard Deviation 0.6682
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, Pre-dose, n= 21, 22, 21, 13, 8	1.400 Liters	Standard Deviation 0.2545
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 9h, n=21, 19, 21, 13, 7	3.544 Liters	Standard Deviation 0.7176
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 2h, n=21, 20, 21, 13, 8	3.674 Liters	Standard Deviation 0.7766
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	1.841 Liters	Standard Deviation 0.4372
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 1h, n=21, 20, 21, 13, 8	1.663 Liters	Standard Deviation 0.325
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13,8	1.619 Liters	Standard Deviation 0.4182
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 12h, n=21, 22, 21, 13, 8	3.563 Liters	Standard Deviation 0.7816
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FVC, 6h, n=21, 22, 21, 13, 8	3.780 Liters	Standard Deviation 0.8023
Tiotropium 18 µg	Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.696 Liters	Standard Deviation 0.3311

Primary

Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of hematocrit at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	0.427 Proportion of red blood cells in blood	Standard Deviation 0.0352
Placebo	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	0.421 Proportion of red blood cells in blood	Standard Deviation 0.0335
UMEC 250 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	0.428 Proportion of red blood cells in blood	Standard Deviation 0.0321
UMEC 250 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	0.424 Proportion of red blood cells in blood	Standard Deviation 0.0361
UMEC 500 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	0.418 Proportion of red blood cells in blood	Standard Deviation 0.0322
UMEC 500 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	0.423 Proportion of red blood cells in blood	Standard Deviation 0.0326
UMEC 1000 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	0.416 Proportion of red blood cells in blood	Standard Deviation 0.0345
UMEC 1000 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	0.417 Proportion of red blood cells in blood	Standard Deviation 0.0419
Tiotropium 18 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	0.445 Proportion of red blood cells in blood	Standard Deviation 0.0193
Tiotropium 18 µg	Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	0.434 Proportion of red blood cells in blood	Standard Deviation 0.0192

Primary

Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of hemoglobin, MCHC, albumin and total protein at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, Pre-dose	146.1 Grams per liter (G/L)	Standard Deviation 11.8
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, 24 h Post-dose	147.0 Grams per liter (G/L)	Standard Deviation 12.53
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, Pre-dose	347.2 Grams per liter (G/L)	Standard Deviation 7.03
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, 24 h Post-dose	344.9 Grams per liter (G/L)	Standard Deviation 6.35
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, Pre-dose	39.16 Grams per liter (G/L)	Standard Deviation 2.02
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, 24 h Post-dose	39.36 Grams per liter (G/L)	Standard Deviation 1.682
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, Pre-dose	66.05 Grams per liter (G/L)	Standard Deviation 4.12
Placebo	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, 24 h Post-dose	66.37 Grams per liter (G/L)	Standard Deviation 3.584
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, Pre-dose	343.3 Grams per liter (G/L)	Standard Deviation 5.78
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, 24 h Post-dose	38.75 Grams per liter (G/L)	Standard Deviation 1.742
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, Pre-dose	146.6 Grams per liter (G/L)	Standard Deviation 10.31
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, 24 h Post-dose	344.0 Grams per liter (G/L)	Standard Deviation 7.02
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, 24 h Post-dose	145.5 Grams per liter (G/L)	Standard Deviation 11.01
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, 24 h Post-dose	65.40 Grams per liter (G/L)	Standard Deviation 3.933
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, Pre-dose	39.24 Grams per liter (G/L)	Standard Deviation 2.109
UMEC 250 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, Pre-dose	66.04 Grams per liter (G/L)	Standard Deviation 4.245
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, Pre-dose	66.19 Grams per liter (G/L)	Standard Deviation 3.987
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, 24 h Post-dose	65.62 Grams per liter (G/L)	Standard Deviation 2.945
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, 24 h Post-dose	344.9 Grams per liter (G/L)	Standard Deviation 8.5
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, 24 h Post-dose	38.76 Grams per liter (G/L)	Standard Deviation 1.744
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, Pre-dose	344.1 Grams per liter (G/L)	Standard Deviation 7.87
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, 24 h Post-dose	144.1 Grams per liter (G/L)	Standard Deviation 10.97
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, Pre-dose	145.4 Grams per liter (G/L)	Standard Deviation 11.27
UMEC 500 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, Pre-dose	39.33 Grams per liter (G/L)	Standard Deviation 1.955
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, 24 h Post-dose	143.5 Grams per liter (G/L)	Standard Deviation 14.77
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, Pre-dose	346.8 Grams per liter (G/L)	Standard Deviation 4.62
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, 24 h Post-dose	345.2 Grams per liter (G/L)	Standard Deviation 6.57
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, Pre-dose	39.10 Grams per liter (G/L)	Standard Deviation 1.545
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, 24 h Post-dose	39.30 Grams per liter (G/L)	Standard Deviation 1.75
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, 24 h Post-dose	66.44 Grams per liter (G/L)	Standard Deviation 3.448
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, Pre-dose	143.8 Grams per liter (G/L)	Standard Deviation 12.34
UMEC 1000 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, Pre-dose	66.15 Grams per liter (G/L)	Standard Deviation 3.576
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, 24 h Post-dose	342.9 Grams per liter (G/L)	Standard Deviation 3.91
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, 24 h Post-dose	64.14 Grams per liter (G/L)	Standard Deviation 3.349
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	MCHC, Pre-dose	343.0 Grams per liter (G/L)	Standard Deviation 5.04
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total protein, Pre-dose	65.35 Grams per liter (G/L)	Standard Deviation 2.931
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, Pre-dose	152.0 Grams per liter (G/L)	Standard Deviation 7.23
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, 24 h Post-dose	38.38 Grams per liter (G/L)	Standard Deviation 2.93
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Hemoglobin, 24 h Post-dose	148.9 Grams per liter (G/L)	Standard Deviation 5.59
Tiotropium 18 µg	Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period	Albumin, Pre-dose	39.49 Grams per liter (G/L)	Standard Deviation 2.775

Primary

Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period

Twenty-four hour Holter monitoring was conducted to measure heart rate for the 24-hour period following dosing at each treatment period and the maximum value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	116.7 Beats per minute (bpm)	Standard Error 2.92
UMEC 250 µg	Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	111.5 Beats per minute (bpm)	Standard Error 3.06
UMEC 500 µg	Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	112.1 Beats per minute (bpm)	Standard Error 2.96
UMEC 1000 µg	Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	109.0 Beats per minute (bpm)	Standard Error 3.53
Tiotropium 18 µg	Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	111.4 Beats per minute (bpm)	Standard Error 3.79

95% CI: [-9.7, -0.7]Mixed Models Analysis

95% CI: [-8.9, -0.3]Mixed Models Analysis

95% CI: [-13.5, -1.8]Mixed Models Analysis

95% CI: [-11.8, 1.1]Mixed Models Analysis

95% CI: [-6.1, 6.4]Mixed Models Analysis

95% CI: [-6.1, 7.5]Mixed Models Analysis

95% CI: [-10.9, 6.2]Mixed Models Analysis

Primary

Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period

Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	82.7 Millimeters of mercury (mmHg)	Standard Error 0.96
UMEC 250 µg	Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	80.2 Millimeters of mercury (mmHg)	Standard Error 1.14
UMEC 500 µg	Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	80.6 Millimeters of mercury (mmHg)	Standard Error 1.01
UMEC 1000 µg	Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	86.0 Millimeters of mercury (mmHg)	Standard Error 1.46
Tiotropium 18 µg	Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	80.3 Millimeters of mercury (mmHg)	Standard Error 1.63

95% CI: [-5.1, 0.2]Mixed Models Analysis

95% CI: [-4.6, 0.4]Mixed Models Analysis

95% CI: [0, 6.6]Mixed Models Analysis

95% CI: [-5.9, 1.2]Mixed Models Analysis

95% CI: [-3.5, 3.3]Mixed Models Analysis

95% CI: [-3.5, 4.1]Mixed Models Analysis

95% CI: [1, 10.4]Mixed Models Analysis

Primary

Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period

Resting heart rate was measured at pre-dose and 15 minutes (min), 45min, 1.5 hour (h) 4 h, 8 h, and 24 h post-dose of each treatment period and the maximum value for heart rate (0-4hours) was derived at rest. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	69.1 Beats per minute (bpm)	Standard Error 1.01
UMEC 250 µg	Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	68.7 Beats per minute (bpm)	Standard Error 1.14
UMEC 500 µg	Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	69.5 Beats per minute (bpm)	Standard Error 1.04
UMEC 1000 µg	Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	71.2 Beats per minute (bpm)	Standard Error 1.54
Tiotropium 18 µg	Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	66.4 Beats per minute (bpm)	Standard Error 1.69

95% CI: [-3, 2.2]Mixed Models Analysis

95% CI: [-2.1, 2.9]Mixed Models Analysis

95% CI: [-1.4, 5.7]Mixed Models Analysis

95% CI: [-6.2, 0.9]Mixed Models Analysis

95% CI: [-1.3, 5.8]Mixed Models Analysis

95% CI: [-0.7, 6.9]Mixed Models Analysis

95% CI: [-0.1, 9.7]Mixed Models Analysis

Primary

Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period

Twelve-lead ECGs (electrocardiograms) were performed to measure QT interval corrected according to Bazzet's formula (QTcB) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	402.79 Milliseconds (msec)	Standard Error 2.263
UMEC 250 µg	Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	399.48 Milliseconds (msec)	Standard Error 2.621
UMEC 500 µg	Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	404.48 Milliseconds (msec)	Standard Error 2.396
UMEC 1000 µg	Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	401.25 Milliseconds (msec)	Standard Error 3.579
Tiotropium 18 µg	Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period	397.62 Milliseconds (msec)	Standard Error 3.867

95% CI: [-9.82, 3.21]Mixed Models Analysis

95% CI: [-4.7, 8.09]Mixed Models Analysis

95% CI: [-10.06, 6.98]Mixed Models Analysis

95% CI: [-13.84, 3.5]Mixed Models Analysis

95% CI: [-6.65, 10.37]Mixed Models Analysis

95% CI: [-2.35, 16.08]Mixed Models Analysis

95% CI: [-7.59, 14.85]Mixed Models Analysis

Primary

Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period

Twelve-lead ECGs were performed to measure QT interval corrected according to Fredericia's formula (QTcF) at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	394.25 Milliseconds (msec)	Standard Error 1.699
UMEC 250 µg	Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	394.34 Milliseconds (msec)	Standard Error 1.977
UMEC 500 µg	Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	395.60 Milliseconds (msec)	Standard Error 1.802
UMEC 1000 µg	Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	393.10 Milliseconds (msec)	Standard Error 2.604
Tiotropium 18 µg	Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period	393.93 Milliseconds (msec)	Standard Error 2.873

95% CI: [-4.98, 5.15]Mixed Models Analysis

95% CI: [-3.65, 6.34]Mixed Models Analysis

95% CI: [-7.49, 5.19]Mixed Models Analysis

95% CI: [-6.89, 6.24]Mixed Models Analysis

95% CI: [-6.13, 6.94]Mixed Models Analysis

95% CI: [-5.34, 8.67]Mixed Models Analysis

95% CI: [-8.97, 7.32]Mixed Models Analysis

Primary

Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period

Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the maximum value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	129.7 Millimeters of mercury (mmHg)	Standard Error 1.59
UMEC 250 µg	Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	129.0 Millimeters of mercury (mmHg)	Standard Error 1.84
UMEC 500 µg	Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	126.2 Millimeters of mercury (mmHg)	Standard Error 1.65
UMEC 1000 µg	Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	133.0 Millimeters of mercury (mmHg)	Standard Error 2.41
Tiotropium 18 µg	Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	131.0 Millimeters of mercury (mmHg)	Standard Error 2.78

95% CI: [-7.6, 0.6]Mixed Models Analysis

95% CI: [-2.2, 8.7]Mixed Models Analysis

95% CI: [-4.7, 7.2]Mixed Models Analysis

95% CI: [-7.7, 3.6]Mixed Models Analysis

95% CI: [-5, 3.4]Mixed Models Analysis

95% CI: [-11.2, 1.6]Mixed Models Analysis

95% CI: [-5.9, 10]Mixed Models Analysis

Primary

Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period

Twenty-four-hour Holter monitoring was conducted to measure heart rate for the 24-h period following dosing of each treatment period and the mean value for heart rate (0-24 hours) was derived. Analysis was performed using a mixed model of period and treatment group fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	77.1 Beats per minute (bpm)	Standard Error 1.61
UMEC 250 µg	Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	75.3 Beats per minute (bpm)	Standard Error 1.66
UMEC 500 µg	Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	76.8 Beats per minute (bpm)	Standard Error 1.62
UMEC 1000 µg	Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	75.5 Beats per minute (bpm)	Standard Error 1.8
Tiotropium 18 µg	Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period	76.1 Beats per minute (bpm)	Standard Error 1.89

95% CI: [-3.6, 0]Mixed Models Analysis

95% CI: [-2, 1.4]Mixed Models Analysis

95% CI: [-3.9, 0.8]Mixed Models Analysis

95% CI: [-3.6, 1.6]Mixed Models Analysis

95% CI: [-3.3, 1.7]Mixed Models Analysis

95% CI: [-2, 3.4]Mixed Models Analysis

95% CI: [-4.1, 2.9]Mixed Models Analysis

Primary

Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of the mean corpuscle hemoglobin at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	32.56 picograms/cell (pg)	Standard Deviation 1.402
Placebo	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 Hour Post-dose	32.41 picograms/cell (pg)	Standard Deviation 1.354
UMEC 250 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	32.36 picograms/cell (pg)	Standard Deviation 1.365
UMEC 250 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 Hour Post-dose	32.36 picograms/cell (pg)	Standard Deviation 1.208
UMEC 500 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	32.36 picograms/cell (pg)	Standard Deviation 1.513
UMEC 500 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 Hour Post-dose	32.36 picograms/cell (pg)	Standard Deviation 1.359
UMEC 1000 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 Hour Post-dose	32.15 picograms/cell (pg)	Standard Deviation 1.309
UMEC 1000 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	32.29 picograms/cell (pg)	Standard Deviation 1.393
Tiotropium 18 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	32.86 picograms/cell (pg)	Standard Deviation 0.971
Tiotropium 18 µg	Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 Hour Post-dose	32.79 picograms/cell (pg)	Standard Deviation 1.018

Primary

Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of the mean corpuscle volume at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	93.78 Femtoliters (FL)	Standard Deviation 3.701
Placebo	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	93.99 Femtoliters (FL)	Standard Deviation 3.597
UMEC 250 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	94.23 Femtoliters (FL)	Standard Deviation 3.547
UMEC 250 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	94.09 Femtoliters (FL)	Standard Deviation 3.763
UMEC 500 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	94.04 Femtoliters (FL)	Standard Deviation 3.734
UMEC 500 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	93.85 Femtoliters (FL)	Standard Deviation 3.955
UMEC 1000 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	93.15 Femtoliters (FL)	Standard Deviation 3.652
UMEC 1000 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	93.11 Femtoliters (FL)	Standard Deviation 3.84
Tiotropium 18 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	95.83 Femtoliters (FL)	Standard Deviation 3.31
Tiotropium 18 µg	Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	95.65 Femtoliters (FL)	Standard Deviation 2.946

Primary

Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)

An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs.

Time frame: From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)

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

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any AE	6 Participants
Placebo	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any SAE	0 Participants
UMEC 250 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any AE	9 Participants
UMEC 250 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any SAE	0 Participants
UMEC 500 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any AE	8 Participants
UMEC 500 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any SAE	0 Participants
UMEC 1000 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any SAE	0 Participants
UMEC 1000 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any AE	4 Participants
Tiotropium 18 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any AE	3 Participants
Tiotropium 18 µg	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	Any SAE	0 Participants

Primary

Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of platelets count and WBC count at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, Pre-dose	7.623 10^9 cells per liter (GI/L)	Standard Deviation 1.7271
Placebo	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, 24 h Post-dose	248.8 10^9 cells per liter (GI/L)	Standard Deviation 69.53
Placebo	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, 24 h Post-dose	7.520 10^9 cells per liter (GI/L)	Standard Deviation 1.3103
Placebo	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, Pre-dose	247.2 10^9 cells per liter (GI/L)	Standard Deviation 70.84
UMEC 250 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, Pre-dose	7.130 10^9 cells per liter (GI/L)	Standard Deviation 1.6116
UMEC 250 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, Pre-dose	245.0 10^9 cells per liter (GI/L)	Standard Deviation 71.33
UMEC 250 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, 24 h Post-dose	245.4 10^9 cells per liter (GI/L)	Standard Deviation 76.18
UMEC 250 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, 24 h Post-dose	7.385 10^9 cells per liter (GI/L)	Standard Deviation 1.7548
UMEC 500 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, 24 h Post-dose	250.3 10^9 cells per liter (GI/L)	Standard Deviation 63.51
UMEC 500 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, Pre-dose	7.560 10^9 cells per liter (GI/L)	Standard Deviation 1.686
UMEC 500 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, Pre-dose	250.7 10^9 cells per liter (GI/L)	Standard Deviation 69.06
UMEC 500 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, 24 h Post-dose	7.218 10^9 cells per liter (GI/L)	Standard Deviation 1.4426
UMEC 1000 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, 24 h Post-dose	7.999 10^9 cells per liter (GI/L)	Standard Deviation 1.6531
UMEC 1000 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, 24 h Post-dose	237.9 10^9 cells per liter (GI/L)	Standard Deviation 46.3
UMEC 1000 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, Pre-dose	235.9 10^9 cells per liter (GI/L)	Standard Deviation 47.15
UMEC 1000 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, Pre-dose	7.121 10^9 cells per liter (GI/L)	Standard Deviation 1.2807
Tiotropium 18 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, Pre-dose	243.4 10^9 cells per liter (GI/L)	Standard Deviation 104.43
Tiotropium 18 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, Pre-dose	6.763 10^9 cells per liter (GI/L)	Standard Deviation 1.0249
Tiotropium 18 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	WBC count, 24 h Post-dose	6.623 10^9 cells per liter (GI/L)	Standard Deviation 1.2366
Tiotropium 18 µg	Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Platelets count, 24 h Post-dose	237.6 10^9 cells per liter (GI/L)	Standard Deviation 101.59

Primary

Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of the red blood cells count at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	4.493 10^12 cells per liter (TI/L)	Standard Deviation 0.3992
Placebo	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	4.539 10^12 cells per liter (TI/L)	Standard Deviation 0.396
UMEC 250 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	4.537 10^12 cells per liter (TI/L)	Standard Deviation 0.3487
UMEC 250 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	4.498 10^12 cells per liter (TI/L)	Standard Deviation 0.376
UMEC 500 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	4.498 10^12 cells per liter (TI/L)	Standard Deviation 0.3758
UMEC 500 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	4.457 10^12 cells per liter (TI/L)	Standard Deviation 0.3614
UMEC 1000 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	4.464 10^12 cells per liter (TI/L)	Standard Deviation 0.4511
UMEC 1000 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	4.456 10^12 cells per liter (TI/L)	Standard Deviation 0.3987
Tiotropium 18 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	Pre-dose	4.625 10^12 cells per liter (TI/L)	Standard Deviation 0.2469
Tiotropium 18 µg	Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period	24 h Post-dose	4.543 10^12 cells per liter (TI/L)	Standard Deviation 0.2232

Primary

Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period

Blood samples were collected for the measurement of total bilirubin, creatinine, and uric acid at pre-dose and 24 hour (h) post-dose of each treatment period.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: All Subjects Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, Pre-dose	7.92 Micromoles per liter (µmol/L)	Standard Deviation 2.457
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, 24 h Post-dose	8.70 Micromoles per liter (µmol/L)	Standard Deviation 2.602
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, 24 h Post-dose	78.02 Micromoles per liter (µmol/L)	Standard Deviation 6.451
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, Pre-dose	295.86 Micromoles per liter (µmol/L)	Standard Deviation 64.155
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, 24 h Post-dose	285.55 Micromoles per liter (µmol/L)	Standard Deviation 63.35
Placebo	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, Pre-dose	78.55 Micromoles per liter (µmol/L)	Standard Deviation 7.589
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, 24 h Post-dose	79.08 Micromoles per liter (µmol/L)	Standard Deviation 8.324
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, Pre-dose	8.33 Micromoles per liter (µmol/L)	Standard Deviation 2.234
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, 24 h Post-dose	8.26 Micromoles per liter (µmol/L)	Standard Deviation 2.955
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, 24 h Post-dose	293.21 Micromoles per liter (µmol/L)	Standard Deviation 65.637
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, Pre-dose	80.50 Micromoles per liter (µmol/L)	Standard Deviation 8.012
UMEC 250 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, Pre-dose	301.24 Micromoles per liter (µmol/L)	Standard Deviation 77.192
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, Pre-dose	303.18 Micromoles per liter (µmol/L)	Standard Deviation 77.389
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, Pre-dose	8.66 Micromoles per liter (µmol/L)	Standard Deviation 3.387
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, Pre-dose	80.24 Micromoles per liter (µmol/L)	Standard Deviation 10.079
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, 24 h Post-dose	9.48 Micromoles per liter (µmol/L)	Standard Deviation 3.523
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, 24 h Post-dose	296.28 Micromoles per liter (µmol/L)	Standard Deviation 70.307
UMEC 500 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, 24 h Post-dose	78.14 Micromoles per liter (µmol/L)	Standard Deviation 9.684
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, Pre-dose	78.64 Micromoles per liter (µmol/L)	Standard Deviation 8.296
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, Pre-dose	8.68 Micromoles per liter (µmol/L)	Standard Deviation 2.238
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, 24 h Post-dose	10.27 Micromoles per liter (µmol/L)	Standard Deviation 3.086
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, 24 h Post-dose	76.44 Micromoles per liter (µmol/L)	Standard Deviation 7.241
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, Pre-dose	317.09 Micromoles per liter (µmol/L)	Standard Deviation 76.125
UMEC 1000 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, 24 h Post-dose	306.26 Micromoles per liter (µmol/L)	Standard Deviation 72.701
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, Pre-dose	281.19 Micromoles per liter (µmol/L)	Standard Deviation 67.657
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, Pre-dose	79.79 Micromoles per liter (µmol/L)	Standard Deviation 8.333
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, 24 h Post-dose	6.83 Micromoles per liter (µmol/L)	Standard Deviation 2.036
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Total bilirubin, Pre-dose	7.69 Micromoles per liter (µmol/L)	Standard Deviation 1.549
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Creatinine, 24 h Post-dose	76.29 Micromoles per liter (µmol/L)	Standard Deviation 8.999
Tiotropium 18 µg	Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period	Uric acid, 24 h Post-dose	268.64 Micromoles per liter (µmol/L)	Standard Deviation 61.525

Primary

Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period

Resting diastolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for diastolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	79.21 Millimeters of mercury (mmHg)	Standard Error 0.759
UMEC 250 µg	Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	76.23 Millimeters of mercury (mmHg)	Standard Error 0.902
UMEC 500 µg	Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	77.69 Millimeters of mercury (mmHg)	Standard Error 0.798
UMEC 1000 µg	Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	81.42 Millimeters of mercury (mmHg)	Standard Error 1.156
Tiotropium 18 µg	Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period	75.89 Millimeters of mercury (mmHg)	Standard Error 1.293

95% CI: [-5.08, -0.87]Mixed Models Analysis

95% CI: [-3.53, 0.5]Mixed Models Analysis

95% CI: [-0.46, 4.88]Mixed Models Analysis

95% CI: [-6.13, -0.5]Mixed Models Analysis

95% CI: [-2.38, 3.07]Mixed Models Analysis

95% CI: [-1.22, 4.82]Mixed Models Analysis

95% CI: [1.81, 9.25]Mixed Models Analysis

Primary

Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period

Resting heart rate was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for heart rate (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	64.66 Beats per minute (bpm)	Standard Error 0.882
UMEC 250 µg	Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	63.88 Beats per minute (bpm)	Standard Error 0.953
UMEC 500 µg	Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	65.69 Beats per minute (bpm)	Standard Error 0.894
UMEC 1000 µg	Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	66.61 Beats per minute (bpm)	Standard Error 1.177
Tiotropium 18 µg	Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	62.93 Beats per minute (bpm)	Standard Error 1.275

95% CI: [-2.47, 0.92]Mixed Models Analysis

95% CI: [-0.57, 2.64]Mixed Models Analysis

95% CI: [-0.35, 4.26]Mixed Models Analysis

95% CI: [-4.11, 0.67]Mixed Models Analysis

95% CI: [-1.44, 3.33]Mixed Models Analysis

95% CI: [0.24, 5.28]Mixed Models Analysis

95% CI: [0.34, 7.02]Mixed Models Analysis

Primary

Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period

Twelve-lead ECGs were performed to measure QTcB at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcB (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	391.266 Milliseconds (msec)	Standard Error 1.7582
UMEC 250 µg	Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	390.968 Milliseconds (msec)	Standard Error 2.0079
UMEC 500 µg	Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	392.332 Milliseconds (msec)	Standard Error 1.8401
UMEC 1000 µg	Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	389.204 Milliseconds (msec)	Standard Error 2.7044
Tiotropium 18 µg	Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period	391.628 Milliseconds (msec)	Standard Error 2.9378

95% CI: [-4.961, 4.365]Mixed Models Analysis

95% CI: [-3.495, 5.627]Mixed Models Analysis

95% CI: [-8.247, 4.122]Mixed Models Analysis

95% CI: [-6.003, 6.726]Mixed Models Analysis

95% CI: [-6.873, 5.554]Mixed Models Analysis

95% CI: [-6.064, 7.473]Mixed Models Analysis

95% CI: [-10.84, 5.993]Mixed Models Analysis

Primary

Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period

Twelve-lead ECGs were performed to measure QTcF at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for QTcF (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	386.501 Milliseconds (msec)	Standard Error 1.3698
UMEC 250 µg	Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	387.965 Milliseconds (msec)	Standard Error 1.5869
UMEC 500 µg	Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	386.750 Milliseconds (msec)	Standard Error 1.4414
UMEC 1000 µg	Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	383.856 Milliseconds (msec)	Standard Error 2.116
Tiotropium 18 µg	Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period	389.086 Milliseconds (msec)	Standard Error 2.3515

95% CI: [-2.492, 5.419]Mixed Models Analysis

95% CI: [-3.647, 4.144]Mixed Models Analysis

95% CI: [-7.687, 2.396]Mixed Models Analysis

95% CI: [-2.671, 7.84]Mixed Models Analysis

95% CI: [-6.308, 4.067]Mixed Models Analysis

95% CI: [-7.952, 3.28]Mixed Models Analysis

95% CI: [-11.96, 1.504]Mixed Models Analysis

Primary

Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period

Resting systolic blood pressure was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for systolic blood pressure (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	124.49 Millimeters of mercury (mmHg)	Standard Error 1.445
UMEC 250 µg	Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	122.07 Millimeters of mercury (mmHg)	Standard Error 1.67
UMEC 500 µg	Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	122.61 Millimeters of mercury (mmHg)	Standard Error 1.503
UMEC 1000 µg	Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	125.61 Millimeters of mercury (mmHg)	Standard Error 2.19
Tiotropium 18 µg	Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period	124.80 Millimeters of mercury (mmHg)	Standard Error 2.517

95% CI: [-6.23, 1.39]Mixed Models Analysis

95% CI: [-5.56, 1.79]Mixed Models Analysis

95% CI: [-3.82, 6.07]Mixed Models Analysis

95% CI: [-5.07, 5.69]Mixed Models Analysis

95% CI: [-7.84, 2.38]Mixed Models Analysis

95% CI: [-7.97, 3.59]Mixed Models Analysis

95% CI: [-6.39, 8.02]Mixed Models Analysis

Secondary

Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC

Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Ae(0-2), Ae(0-8), Ae(0-12), Ae(0-24), Ae(0-48), AUER(0-18) and AUER(0-36). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-8)	1676.101 ng	Geometric Coefficient of Variation 54.7
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-48)	2729.434 ng	Geometric Coefficient of Variation 45
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-24)	2352.662 ng	Geometric Coefficient of Variation 47.5
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-2)	734.525 ng	Geometric Coefficient of Variation 56
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-36)	2487.288 ng	Geometric Coefficient of Variation 48.8
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-18)	2119.916 ng	Geometric Coefficient of Variation 48.4
Placebo	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-12)	1987.910 ng	Geometric Coefficient of Variation 50
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-24)	5486.724 ng	Geometric Coefficient of Variation 48.3
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-2)	1793.951 ng	Geometric Coefficient of Variation 40.5
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-8)	4146.206 ng	Geometric Coefficient of Variation 50.6
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-12)	4712.376 ng	Geometric Coefficient of Variation 50.1
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-48)	6361.233 ng	Geometric Coefficient of Variation 47
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-18)	4830.401 ng	Geometric Coefficient of Variation 47.9
UMEC 250 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-36)	5752.880 ng	Geometric Coefficient of Variation 49.3
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-48)	13671.981 ng	Geometric Coefficient of Variation 34.7
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-8)	9935.792 ng	Geometric Coefficient of Variation 33.4
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-36)	12363.246 ng	Geometric Coefficient of Variation 35
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	AUER(0-18)	10919.838 ng	Geometric Coefficient of Variation 34.6
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-24)	12401.722 ng	Geometric Coefficient of Variation 33.7
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-12)	10983.771 ng	Geometric Coefficient of Variation 34.5
UMEC 500 µg	Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC	Ae(0-2)	4456.582 ng	Geometric Coefficient of Variation 43.5

Secondary

Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC

Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the AUC(0-2) and AUC(0-t). Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: Pharmacokinetic (PK) Population:all participants in the All Subjects Population for whom a PK sample was obtained and analyzed.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-2)	0.10264 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 58.9
Placebo	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-t)	0.10271 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 70
UMEC 250 µg	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-2)	0.27099 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 58.5
UMEC 250 µg	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-t)	0.35491 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 65.2
UMEC 500 µg	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-2)	0.71522 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 21.8
UMEC 500 µg	Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	AUC(0-t)	0.96100 hr * nanograms per milliliter (ng/mL)	Geometric Coefficient of Variation 27.7

Secondary

Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC

Urine samples were collected to determine the urine concentrations of UMEC from 0 min up to 48 hours post-dose of each treatment period to derive Fe(0-24) and Fe(0-48). Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population

Arm	Measure	Group	Value (MEDIAN)
Placebo	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-24)	0.993 Percentage of total dose administered
Placebo	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-48)	1.142 Percentage of total dose administered
UMEC 250 µg	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-24)	1.253 Percentage of total dose administered
UMEC 250 µg	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-48)	1.413 Percentage of total dose administered
UMEC 500 µg	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-24)	1.360 Percentage of total dose administered
UMEC 500 µg	Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC	Fe(0-48)	1.512 Percentage of total dose administered

Secondary

Half-life for Renal Excretion of UMEC on Day 1

The terminal half-life (t1/2) of UMEC is defined as the time required for the urine concentration of UMEC to reach half of its original concentration. Urine samples for PK analysis of UMEC were obtained on Day 1; a single sample was collected at each of the following timepoints: 0-2 h, 2-8 h, 8-12 h, 12-24 h and 24-48 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Half-life for Renal Excretion of UMEC on Day 1	10.679 Hours	Geometric Coefficient of Variation 37.2
UMEC 250 µg	Half-life for Renal Excretion of UMEC on Day 1	12.023 Hours	Geometric Coefficient of Variation 44.9
UMEC 500 µg	Half-life for Renal Excretion of UMEC on Day 1	10.821 Hours	Geometric Coefficient of Variation 32.8

Secondary

Maximum Observed Plasma Concentration (Cmax) of UMEC

Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the Cmax. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Maximum Observed Plasma Concentration (Cmax) of UMEC	0.12615 ng/mL	Geometric Coefficient of Variation 43.4
UMEC 250 µg	Maximum Observed Plasma Concentration (Cmax) of UMEC	0.30389 ng/mL	Geometric Coefficient of Variation 40.7
UMEC 500 µg	Maximum Observed Plasma Concentration (Cmax) of UMEC	0.83228 ng/mL	Geometric Coefficient of Variation 22.9

Secondary

Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period

Serial spirometry assessments were conducted on Day 1 of each treatment period over the course of 24 hours and were taken at 1 hour (h), 2 h, 6 h, 9 h, 12 h and 24 h post-dose. The maximum of the 3 FEV1 measurements for each participant, treatment period and timepoint were used in the calculation of the mean for each treatment group at each timepoint.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	1.669 Liters	Standard Error 0.0497
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.654 Liters	Standard Error 0.0433
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 24h, n=21, 22, 21, 13, 8	1.583 Liters	Standard Error 0.0411
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13, 7	1.662 Liters	Standard Error 0.0501
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.721 Liters	Standard Error 0.0418
Placebo	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 1 h, n= 21, 20, 21, 13, 8	1.638 Liters	Standard Error 0.041
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13, 7	1.917 Liters	Standard Error 0.0514
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 24h, n=21, 22, 21, 13, 8	1.818 Liters	Standard Error 0.0431
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.951 Liters	Standard Error 0.0456
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	1.991 Liters	Standard Error 0.051
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.938 Liters	Standard Error 0.0446
UMEC 250 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 1 h, n= 21, 20, 21, 13, 8	1.861 Liters	Standard Error 0.0437
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.083 Liters	Standard Error 0.0492
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 24h, n=21, 22, 21, 13, 8	1.827 Liters	Standard Error 0.041
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13, 7	1.996 Liters	Standard Error 0.0497
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	2.021 Liters	Standard Error 0.0416
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	2.027 Liters	Standard Error 0.0431
UMEC 500 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 1 h, n= 21, 20, 21, 13, 8	1.915 Liters	Standard Error 0.0408
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.992 Liters	Standard Error 0.057
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 1 h, n= 21, 20, 21, 13, 8	1.834 Liters	Standard Error 0.0542
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	2.024 Liters	Standard Error 0.0553
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.070 Liters	Standard Error 0.0648
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 24h, n=21, 22, 21, 13, 8	1.856 Liters	Standard Error 0.0544
UMEC 1000 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13, 7	1.988 Liters	Standard Error 0.0654
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 24h, n=21, 22, 21, 13, 8	1.655 Liters	Standard Error 0.0646
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 1 h, n= 21, 20, 21, 13, 8	1.880 Liters	Standard Error 0.0644
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 2h, n= 21, 20, 21, 13, 8	1.910 Liters	Standard Error 0.0684
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 6h, n=21, 22, 21, 13, 8	2.050 Liters	Standard Error 0.0793
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 9h, n=21, 19, 21, 13, 7	1.927 Liters	Standard Error 0.0673
Tiotropium 18 µg	Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period	FEV1, 12h, n=21, 22, 21, 13, 7	1.812 Liters	Standard Error 0.0801

Secondary

Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period

sGaw is the specific airways resistance (mid) which was assessed by whole body plethysmography. Values used were the mean of the 3 readings recorded at each timepoint. sGaw measurements were taken at 2 hour (h), 6 h, 12 h and 24 h post-dose of each treatment period. 1/kPa.s=1(the inverses)/kPa (kilopascal).s (second)

Time frame: Day 1 of each treatment period (up to Study Day 46)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 2h, n= 21, 20, 21, 13, 8	0.400 1/kPa*s	Standard Error 0.0598
Placebo	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 6h, n=21, 21, 21, 13, 8	0.426 1/kPa*s	Standard Error 0.0574
Placebo	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 12h, n=21, 21, 21, 13, 8	0.403 1/kPa*s	Standard Error 0.0661
Placebo	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 24h, n=21, 21, 21, 13, 8	0.379 1/kPa*s	Standard Error 0.0627
UMEC 250 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 2h, n= 21, 20, 21, 13, 8	0.652 1/kPa*s	Standard Error 0.0631
UMEC 250 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 24h, n=21, 21, 21, 13, 8	0.514 1/kPa*s	Standard Error 0.0662
UMEC 250 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 6h, n=21, 21, 21, 13, 8	0.734 1/kPa*s	Standard Error 0.0603
UMEC 250 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 12h, n=21, 21, 21, 13, 8	0.637 1/kPa*s	Standard Error 0.0692
UMEC 500 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 24h, n=21, 21, 21, 13, 8	0.501 1/kPa*s	Standard Error 0.063
UMEC 500 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 6h, n=21, 21, 21, 13, 8	0.806 1/kPa*s	Standard Error 0.0578
UMEC 500 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 12h, n=21, 21, 21, 13, 8	0.735 1/kPa*s	Standard Error 0.0665
UMEC 500 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 2h, n= 21, 20, 21, 13, 8	0.699 1/kPa*s	Standard Error 0.0602
UMEC 1000 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 2h, n= 21, 20, 21, 13, 8	0.714 1/kPa*s	Standard Error 0.0753
UMEC 1000 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 6h, n=21, 21, 21, 13, 8	0.778 1/kPa*s	Standard Error 0.072
UMEC 1000 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 24h, n=21, 21, 21, 13, 8	0.514 1/kPa*s	Standard Error 0.079
UMEC 1000 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 12h, n=21, 21, 21, 13, 8	0.730 1/kPa*s	Standard Error 0.0836
Tiotropium 18 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 24h, n=21, 21, 21, 13, 8	0.440 1/kPa*s	Standard Error 0.0945
Tiotropium 18 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 12h, n=21, 21, 21, 13, 8	0.550 1/kPa*s	Standard Error 0.1008
Tiotropium 18 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 6h, n=21, 21, 21, 13, 8	0.711 1/kPa*s	Standard Error 0.0848
Tiotropium 18 µg	Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period	sGaw, 2h, n= 21, 20, 21, 13, 8	0.648 1/kPa*s	Standard Error 0.0893

Secondary

Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1

The CLr is defined as the apparent total clearance of the drug from plasma after oral administration. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1	5.317 Liters per hour (L/hr)	Geometric Coefficient of Variation 56.2
UMEC 250 µg	Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1	6.395 Liters per hour (L/hr)	Geometric Coefficient of Variation 36.9
UMEC 500 µg	Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1	6.831 Liters per hour (L/hr)	Geometric Coefficient of Variation 56.8

Secondary

Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC

Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive tmax, tlast and t1/2. Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Time frame: Day 1 of each treatment period (up to Study Day 46)

Population: PK Population. Only those participants with non-missing observations (including non-calculable values) were analyzed (represented by n=X, X, X in the category titles). Different participants may have been analyzed for different parameters/at different time points, so the overall number of participants analyzed reflects everyone in the PK Population

Arm	Measure	Group	Value (MEDIAN)
Placebo	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tlast, n=22, 21, 13	1.975 Hours
Placebo	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tmax, n=22, 21, 13	0.090 Hours
Placebo	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	t1/2, n=22, 21, 13	NA Hours
UMEC 250 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tlast, n=22, 21, 13	4.030 Hours
UMEC 250 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tmax, n=22, 21, 13	0.100 Hours
UMEC 250 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	t1/2, n=22, 21, 13	1.24490 Hours
UMEC 500 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tmax, n=22, 21, 13	0.250 Hours
UMEC 500 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	t1/2, n=22, 21, 13	1.19780 Hours
UMEC 500 µg	Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC	tlast, n=22, 21, 13	6.000 Hours

Source: ClinicalTrials.gov · Data processed: Mar 24, 2026

Safety Study Using GSK573719 And Tiotropium In Patients With Chronic Obstructive Pulmonary Disease

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Brief summary

Detailed description

Related papers

Interventions

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Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period

Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period

Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period

Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period

Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period

Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period

Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period

Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period

Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period

Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period

Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period

Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period

Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period

Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period

Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period

Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)

Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period

Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period

Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period

Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period

Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period

Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period

Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period

Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period

Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC

Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC

Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC

Half-life for Renal Excretion of UMEC on Day 1

Maximum Observed Plasma Concentration (Cmax) of UMEC

Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period

Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period

Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1

Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC