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

Study Overview
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Brief Summary
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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
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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

Official Title
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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.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: GSK573719
* Drug: Tiotropium


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Seq 1: UMEC 250 µg, UMEC 500 µg, Tiotropium 18 µg, placebo<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: umeclidinium bromide (UMEC) 250 micrograms (µg), UMEC 500 µg, Tiotropium 18 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 2: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg, placebo<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>|
| Active Comparator: Seq 3: UMEC 250 µg, placebo, UMEC 500 µg, UMEC 1000 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, UMEC 500 µg and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>|
| Active Comparator: Seq 4: UMEC 250 µg, UMEC 500 µg, placebo, UMEC 1000 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, placebo and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>|
| Active Comparator: Seq 5: Placebo, UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, UMEC 250 µg, UMEC 500 µg and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>|
| Active Comparator: Seq 6: UMEC 250 µg, placebo, Tiotropium 18 µg, UMEC 500 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, Tiotropium 18 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 7: Placebo, Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, Tiotropium 18 µg, UMEC 250 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 8: Tiotropium 18 µg, placebo, UMEC 250 µg, UMEC 500 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, placebo, UMEC 250 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 9: Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg, placebo<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 10: Tiotropium 18 µg, UMEC 250 µg, placebo, UMEC 500 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, UMEC 250 µg, placebo and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 11: Placebo, UMEC 250 µg, Tiotropium 18 µg, UMEC 500 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, UMEC 250 µg, Tiotropium 18 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|
| Active Comparator: Seq 12: UMEC 250 µg, placebo, UMEC 500 µg, Tiotropium 18 µg<br>Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, UMEC 500 µg and Tiotropium 18 µg. Treatment periods were seperated by a washout period of at least 14 days. | Drug: GSK573719<br>* 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg<br>Drug: Tiotropium<br>* strips of five capsules, each containing 18 μg administered via dry powder inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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. | Day 1 of each treatment period (up to Study Day 46) | 
| 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) | Day 1 of each treatment period (up to Study Day 46) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic obstructive pulmonary disease,, GSK573719,, muscarinic receptor antagonist