A Study To Assess The Safety And Tolerability Of GW642444 In Subjects With Chronic Obstructive Pulmonary Disease (COPD)

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

HR was measured using 28.5h ABPM on Day 1, Day 7 and Day 14. Baseline was defined as the pre-dose weighted mean of Day 1. Weighted mean was calculated by calculating the area under curve (AUC) of measurements made pre-dose on each day, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean change from Baseline was the average AUC minus Baseline (AAUCMB).

HR was measured using 28.5 h ABPM on Day 1 (continued till Day 2), Day 7 (continued till Day 8) and Day 14 (continued till Day 15). Baseline was defined as the pre-dose weighted mean of Day 1. Weighted mean was calculated by calculating the AUC of measurements made 0-4 h post-dose on Day 1, 2, 7, 8, 14 and 15 and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean change from Baseline was the AAUCMB.

HR was measured using 28.5 h ABPM on Day 1, Day 7 and Day 14. Baseline was defined as the pre-dose weighted mean of Day 1. Weighted mean was calculated by calculating the AUC of measurements made 0-24 h post-dose on Day 7 and 14, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean change from Baseline was the AAUCMB.

HR was measured using 28.5 h ABPM on Day 1 (continued till Day 2), Day 7 (continued till Day 8) and Day 14 (continued till Day 15). For the calculation of 0-4 h maximum change from Baseline, measurements post-dose up to 6 h (actual time) was included. Baseline was defined as the pre-dose weighted mean of Day 1. Maximum change from Baseline was calculated by subtracting the Baseline value (weighted mean pre-dose Day 1) from the maximum assessment value (during 0-4 h) of the individual post-Baseline time points.

HR was measured using 28.5 h ABPM. Weighted mean HR at 0-4 h was obtained from measurements made over 0-4 h post-dose on Day 1, 2, 7, 8, 14 and 15. Weighted mean HR at 0-24 h was obtained from measurements made 0-24 h post-dose on Day 1, 7 and 14. Maximum HR at 0-4 h was obtained from measurements made over 0-4 h post-dose on Day 1, 2, 7, 8, 14 and 15. Baseline was defined as the pre-dose weighted mean of Day 1.

HR was measured using 28.5 h ABPM. The assessments were analyzed hourly as 0-1 h, 1-2 h, 2-3 h, 3-4 h, 4-5 h, 5-6 h, 6-7 h, 7-8 h, 8-9 h, 9-10 h, 10-11 h, 11-12 h, 12-13 h, 13-14 h, 14-15 h, 15-16 h, 16-17 h, 17-18 h, 18-19 h, 19-20 h, 20-21 h, 21-22 h, 22-23 h and 23-24 h at Day 1, Day 7 and Day 14.

HR was measured using 28.5 h ABPM. The assessments for maximum HR were analyzed hourly as 0-1 h, 1-2 h, 2-3 h, 3-4 h, 4-5 h, 5-6 h, 6-7 h, 7-8 h, 8-9 h, 9-10 h, 10-11 h, 11-12 h, 12-13 h, 13-14 h, 14-15 h, 15-16 h, 16-17 h, 17-18 h, 18-19 h, 19-20 h, 20-21 h, 21-22 h, 22-23 h and 23-24 h at Day 1, Day 7 and Day 14.

BP was measured using 28.5 h ABPM. Weighted mean SBP and DBP at 0-4 h post-dose was obtained on Day 1, 2, 7, 8, 14 and 15. Weighted mean SBP and DBP at 0-24 h post-dose was obtained on Day 1, 7 and 14. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. Baseline was defined as the weighted mean SBP and DBP on pre-dose Day 1. The weighted mean change from Baseline was the AAUCMB. Data is reported for change from Baseline in weighted mean pre-dose values at Day 7 and Day 14; change from Baseline in weighted mean over 0-4 h at Day 1, 2, 7, 8, 14 and 15; and change from Baseline in weighted mean over 0-24 h at Day 1, 7 and 14.

BP was measured using 28.5 h ABPM. Maximum SBP and minimum DBP at 0-4 h post-dose was obtained on Day 1, 2, 7, 8, 14 and 15. For the calculation of 0-4 h maximum/minimum change from Baseline, measurements post-dose up to 6 h (actual time) was included. Baseline was defined as the pre-dose weighted mean of Day 1 for SBP and DBP. Maximum/minimum change from Baseline was calculated by subtracting the Baseline value (weighted mean pre-dose Day 1 for SBP and DBP) from the maximum/minimum assessment value (during 0-4 h) of the individual post-Baseline time points.

BP was measured using 28.5 h ABPM. Weighted mean SBP and DBP at 0-4 h post-dose was obtained on Day 1, 2, 7, 8, 14 and 15. Weighted mean SBP and DBP at 0-24 h post-dose was obtained on Day 1, 7 and 14. Maximum SBP and minimum DBP at 0-4 h post-dose was obtained on Day 1, 2, 7, 8, 14 and 15. Baseline was defined as the pre-dose weighted mean of Day 1.

A 12-lead ECG was recorded on Day 1, 2, 7, 8, 14 and 15 with the participant in a supine position having rested in that position for at least 5 min before each reading. A total of 3 measurements separated by at least 1 min was taken at each visit and the mean recorded. The Baseline for pre-dose QTcF and QTcB measurements was the pre-dose assessment on Day 1. Weighted mean at 0-4 h for QTcF and QTcB was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean change from Baseline was the AAUCMB. The change from Baseline in maximum QTcF and QTcB at 0-4 h was calculated by subtracting the Baseline (pre-dose Day 1) value from the individual post-Baseline values.

A 12-lead ECG was recorded on Day 1, 2, 7, 8, 14 and 15 with the participant in a supine position having rested in that position for at least 5 min before each reading. A total of 3 measurements separated by at least 1 min was taken at each visit and the mean recorded. The pre-dose QTcF and QTcB assessment was done at Day 1, 7 and 14. Weighted mean at 0-4 h for QTcF and QTcB at Day 1, 2, 7, 8, 14 and 15 was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The maximum QTcF and QTcB at 0-4 h was obtained at Day 1, 2, 7, 8, 14 and 15.

A holter monitor is a machine that continuously records the heart's electrical activity. A 3-lead holter ECG monitoring device was used. The monitor was worn for 24 h during normal activity to record the ECG intervals. The assesmment for hourly maximums QTcF and QTcB was done on Day 1, Day 7 and Day 14. For each h of holter monitoring the maximum QTcF for that h was calculated using the maximum QT and mean HR of that given h as Maximum QT divided by (60/Mean HR)^1/3. For each h of holter monitoring the maximum QTcB for that h was calculated using the maximum QT and mean HR of that given h as Maximum QT divided by (60/Mean HR)^1/2.

A holter monitor is a machine that continuously records the heart's electrical activity. A 3-lead holter ECG monitoring device was used. The monitor was worn for 24 h during normal activity to record the heart's rhythm. The assessment for the events of supra ventricular ectopics, ventricular ectopics and ventricular runs per 24 h was done on Day 1, Day 7 and Day 14.

The parameters of biochemistry with their normal range included: alanine amino transferase ([ALT] 0-48 international units per liter [IU/L]), albumin (32-50 gram [g]/L), alkaline phosphatase ([ALP] 20-125 IU/L), aspartate amino transferase ([AST] 0-42 IU/L), calcium (2.12-2.56 millimole [mmol]/L, chloride (95-108 mmol/L), creatine kinase ([CK] 0-235 IU/L), creatinine (44-124 micromole [µmol]/L), direct bilirubin (0-6 µmol/L), gamma glutamyl transferase ([GGT] 0-65 IU/L), glucose (3.9-6.9 mmol/L), lactate dehydrogenase ([LDH] 0-250 IU/L), potassium (3.5-5.3 mmol/L), sodium (135-146 mmol/L), total bilirubin (0-22 µmol/L), total protein (60-85 g/L), urea (2.5-9 mmol/L) and uric acid (250-510 µmol/L). The assessments were performed on Day 1, Day 7 and Day 14. Baseline was defined as the assessment done on Day 1. Only those parameters for which at least one value of abnormality (to low or to high) change from Baseline, relative to normal ranges were reported are summarized.

The parameters of biochemistry with their normal range included: basophils (0-0.2 giga cells [GI]/L), eosinophils (0.05-0.55 GI/L), haematocrit (0.41-0.5 ratio), hemoglobin (138-172 g/L), lymphocytes (0.85-4.1 GI/L), mean corpuscle hemoglobin ([MCH] 27-33 picogram [pg]), mean corpuscle hemoglobin concentration ([MCHC] 320-360 g/L), mean corpuscle volume ([MCV] 80-100 femtoliter [fl]), monocytes (0.2-1.1 GI/L), segmented neutrophils (1.8-8 GI/L), total neutrophils (1.8-8 GI/L), platelet count (130-400 GI/L), red blood cell ([RBC] 4.4-5.8 trillion cells [TI]/L) count and white blood cell ([WBC] 3.8-10.8 GI/L) count. The assessments were performed on Day 1, Day 7 and Day 14. Baseline was defined as the assessment done on Day 1. Only those parameters for which at least one value of abnormality (to low or to high) change from Baseline, relative to normal ranges were reported are summarized.

FEV1 is defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was assessed pre-dose at Day 1, 2, 7, 8, 14 and 15. FEV1 was assessed post-dose at Day 1, 2, 7, 8 and 14. Lung function test of FEV1 was performed at the approximately same time at each visit in the morning and highest of the 3 measurements were recorded. Baseline was defined as the assessment done on pre-dose Day 1. The change from Baseline pre-dose was calculated by subtracting the Baseline value (pre-dose Day 1) from the individual post Baseline (Day 2, 7, 8, 14 and 15) values. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean FEV1 0-4 h change from Baseline was the AAUCMB obtained at Day 1, 2, 7, 8, 14 and 15. The maximum FEV1 0-4 h change from Baseline was obtained at Day 1, Day 2, Day 7, Day 8, Day 14 and Day 15.

FEV1 is defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 was assessed pre-dose and post-dose at Day 1, 2, 7, 8, 14 and 15. Lung function test of FEV1 was performed at the approximately same time at each visit in the morning and highest of the 3 measurements were recorded. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean FEV1 0-4 h and maximum FEV1 0-4 h was obtained at Day 1, 2, 7, 8, 14 and 15.

FEV1 is defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Lung function test of FEV1 was performed at the approximately same time at each visit in the morning and highest of the 3 measurements were recorded. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. The weighted mean FEV1 over 22-24 h was obtained at Day 1, Day 7 and Day 14 which was recorded up to Day 2, Day 8 and Day 15. Baseline was defined as the assessment on Day 1 pre-dose. Change from Baseline was calculated by subtracting the Baseline (Day 1, pre-dose) value from the individual post Baseline (Day 1, Day 7 and Day 14) values.

PEF is a measure of lung function and measures how fast a person can breathe out. It was measured using a peak flow meter by the participants and recorded on daily record cards each day in the morning and evening from Screening up to Follow-up. The morning measurements were performed prior to the participant taking the morning dose of study medication or rescue medication. The evening measurements were performed prior to the participant taking the evening dose of study medication or rescue medication. The highest of the 3 values of morning and evening PEF were recorded on the diary card. The mean of 7 days of each morning and evening measurements were reported for the Run-in Week, Week 1, Week 2 and Follow-up.

Ipratropium bromide was provided as the rescue medication. The use of rescue medication was recorded by the participants on daily record cards each day in the morning and evening from Screening up to Follow-up. The mean of 7 days (puffs per 24 h) were reported for the Run-in Week, Week 1, Week 2 and Follow-up.

Ipratropium bromide was provided as the rescue medication. The use of rescue medication was recorded by the participants on daily record cards each day in the morning and evening from Screening up to Follow-up. The percentage of rescue free days during the Run-in week, Week 1, Week 2 and Follow-up Week were assessed. Data is reported for number of participants with < 20%, >=20 to <40%, >=40 to <60%, >=60 to <80% and >=80% rescue free days.

Blood samples were collected at pre-dose on Day 1, Day 7 and Day 14. Baseline was defined as the assessment done on pre-dose, Day 1. Change from Baseline was calculated by subtracting the Baseline (Day 1, pre-dose) value from the individual post Baseline (Day 7 and Day 14) values.

Blood samples were collected at pre-dose and 4 h post-dose on Day 1, Day 2, Day 7, Day 8, Day 14 and Day 15. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule. Baseline was defined as the assessment on Day 1 pre-dose. The weighted mean change from Baseline was the AAUCMB. Change from Baseline in maximum glucose 0-4 h and minimum potassium 0-4 h was calculated by subtracting the Baseline (Day 1, pre-dose) value from the individual post Baseline (Day 1 to Day 15) values.

Blood samples were collected at pre-dose and 4 h post-dose on Day 1, Day 2, Day 7, Day 8, Day 14 and Day 15. Weighted mean was calculated by calculating the AUC, and then dividing by the relevant time interval. AUC was calculated using the trapezoidal rule.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The AUC over 4 h as AUC from zero (pre-dose) to 2 h post-dose (AUC [0-2]), AUC from zero (pre-dose) to 4 h post-dose (AUC [0-4]) and AUC from zero (pre-dose) to time of last quantifiable concentration (AUC [0-t]) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The first occurrence of the Cmax was determined directly from the raw concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The time at which Cmax was observed and tlast was determined directly from the raw concentration-time data.

CCI2189 is a counterion of GW642444H. Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The AUC (0-4) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

CCI2189 is a counterion of GW642444H. Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The first occurrence of the Cmax was determined directly from the raw concentration-time data.

GW630200 and GSK932009 are metabolites of GW642444H. Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The AUC (0-4) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

GW630200 and GSK932009 are metabolites of GW642444H. Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The first occurrence of the Cmax was determined directly from the raw concentration-time data.

GW630200 and GSK932009 are metabolites of GW642444H. CCI2189 is a counterion of GW642444H. Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The time at which Cmax was observed was determined directly from the raw concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The AUC (0-4) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The first occurrence of the Cmax was determined directly from the raw concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose), Day 7 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose) and Day 14 (pre-dose, 5 min, 1 h, 2 h and 4 h post-dose). The pre-dose sample was collected within 5 min prior to study medication administration. The time at which Cmax was observed was determined directly from the raw concentration-time data.