A Study To Investigate The Effect Of Inhaling A Single Dose Of GW642444M In COPD Patients.

Study Overview
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Brief Summary
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This study will involve the use of a new compound, GW642444 that is being developed for the treatment of asthma and chronic obstructive pulmonary disease (COPD). It works by acting on cells in the lungs, causing some of the muscles around the lungs to relax and open up better (bronchodilation), making breathing easier. When a medicine is made into a form ready to be given to patients, the active ingredient is often prepared in the form of a salt, and inactive ingredients (excipients) are often added. Inactive ingredients might be used to help a medicine work better, to make it easier to produce the medicine, or to make it easier to get an accurate dose of medicine. In previous studies the study drug has been given as a dry powder in the form of either the 'H' salt (with the excipient lactose), or in the form of the 'M' salt (with the excipients lactose and cellobiose octaacetate). In this study the 'M' salt form of the study drug has been prepared with lactose and a new excipient called magnesium stearate (instead of cellobiose octaacetate). Participants in this study will receive both the 'H' salt (GW642444H) and the new 'M' salt (GW642444M) containing magnesium stearate. This study will be the first time the new 'M' salt form of the study drug will be given to COPD patients.

Official Title
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A Randomised, Single-dose, Dose Ascending, Double-blind, Placebo Controlled, Four-way, Incomplete Block Crossover Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Inhaled Doses of GW642444M With Magnesium Stearate in COPD Patients.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: GW642444M
* Drug: GW642444H
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female (of non-childbearing potential) > or = 40 years History of COPD Smoker or ex-smoker Body weight > or = 50 kg with BMI 18-32 kg/m2 Exclusion criteria: History of significant disease Subjects with a primary asthma diagnosis Alpha-1 antitrypsin deficiency as underlying cause of COPD Recent respiratory tract infection Poorly controlled COPD Blood potassium level < 3.5mmol/L Short-term or long tern oxygen therapy Recent participation in another trial History of drug or alcohol abuse Known allergies Recent blood donation ECG abnormalities

Ages Eligible for Study
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Minimum Age: 40 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 |
| --- | --- |
| Experimental: GW642444M 25mcg<br> | Drug: GW642444M<br>* drug<br>Drug: placebo<br> <br> |
| Experimental: GW642444M 50mcg<br> | Drug: GW642444M<br>* drug<br>|
| Experimental: GW642444M 100mcg<br> | Drug: GW642444M<br>* drug<br>Drug: placebo<br> <br> |
| Experimental: GW642444H 100mcg<br> | Drug: GW642444H<br>* drug<br>Drug: placebo<br> <br> |
| Experimental: placebo<br> | Drug: placebo<br> <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) During the Treatment Period | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (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. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of AEs and SAEs. | From the first dose of the study medication until the Follow-up Visit (up to Study Day 60) | 
| Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cell Count at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count, and white blood cell (WBC) count at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of hemoglobin and MCHC at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Reticulocyte and Red Blood Cell (RBC) Count at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of reticulocyte and RBCs at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Hematocrit at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of hematocrit at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Mean Corpuscle Volume (MCV) at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of MCV at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Values at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of MCH at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT) Values at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of ALT, ALP, AST, and GGT at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Albumin and Total Protein at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of albumin and total protein at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Cholesterol, Chloride, Potassium, Sodium, Triglycerides, and Urea at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of cholesterol, chloride, potassium, sodium, triglycerides, and urea at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Total Bilirubin and Creatinine at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of total bilirubin and creatinine at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in C-reactive Protein at 24 Hours Post-dose on Day 1 of Each Treatment Period | Blood samples were collected for the measurement of c-reactive protein at Baseline and 24 hours post-dose on Day 1of each treatment period. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Over the Post-dose 24 Hour (h) Period | SBP and DBP were measured at Baseline and over the post-dose 24 h period at the following scheduled time points: 20 minutes (M), 45 M, 1h, 2h, 3h, 4h, 6h, and 24 h. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Heart Rate Over the Post-dose 24 Hour (h) Period | Heart rate (HR) was measured at Baseline and over the post-dose 24 h period at the following scheduled time points: 20 minutes (M), 45 M, 1 h, 2 h, 3 h, 4 h, 6 h, and 24 h. Baseline is defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Change From Baseline in Electrocardiographic (ECG) Parameters Over the Post-dose 24 Hour (h) Period | ECG parameters [PR, QRS, RR, QT (uncorrected), QTcB (QT corrected by Bazett's formula) and QTcF (QT corrected by Fridericia's formula) intervals] were measured at Baseline and over the post-dose 24h period at the following scheduled time points: 20 minutes (min), 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, and 24 h. Baseline was defined as the measurement at Screening (Day -28 to Day -1). Change from Baseline was calculated as the value at the post-Baseline time point minus the value at Baseline. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean FEV1 Over 23 and 24 Hours After Dosing | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured electronically by spirometry. The data is presented as adjusted mean of the FEV1 values over 23 and 24 hours after dosing. Changed in trough FEV1 will be analysed using a model with baseline, treatment, period, as fixed effects . | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Weighted Mean and Maximum Value (0 - 4 Hours) QTc(B) and QTc(F) | QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the 12-lead ECG. QTcB is the QT interval corrected for heart rate using Bazett's formula; QTcF is the QT interval corrected for heart rate using Fridericia's formula. Weighted mean (WM) is derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. QTcB and QTcF recorded at 20 minutes, 45 minutes, 1, 2, 3, and 4 hours post-dose on Day 1 of each treatment period were used for analysis. The data is presented as the adjusted means of WM and maximum QTc(B) and QTc(F). | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Weighted Mean and Maximum Value (0 - 4 Hours) Supine Heart Rate | Weighted mean (WM) is derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. Heart rate was recorded at Screening, prior to dosing, and at 20 minutes, 45 minutes, 1, 2, 3, 4 and 6 hours post-dose on Day 1of each treatment period. Heart rate recorded at 20 minutes, 45 minutes and 1, 2, 3 and 4 hours post-dose on Day 1of the each treatment period were used for analysis. Heart rate measurement was taken in a supine position having rested in this position for at least 10 minutes before each reading. The data is presented as adjusted mean of WM and maximum heart rate. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Weighted Mean and Maximum Value (0 - 4 Hours) of Supine Systolic and Diastolic Blood Pressure | Blood pressure (BP) measurement included systolic blood pressure (SBP) and diastolic BP (DBP). Weighted mean (WM) is derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. SBP and DBP were recorded at Screening, prior to dosing, and at 20 minutes, 45 minutes, 1,2, 3, 4 and 6 hours post-dose on Day 1of the each treatment period. SBP and DBP recorded at 20 minutes, 45 minutes and 1, 2, 3 and 4 hours post-dose on Day 1of the each treatment period were used for analysis. Heart rate measurement was taken in a supine position having rested in this position for at least 10 minutes before each reading. The data is presented as adjusted mean of WM and maximum SBP and DBP. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Weighted Mean and Maximum/Minimum Value (0 - 4 Hours) for Glucose and Potassium | Blood samples were collected for the measurement of potassium and glucose at Screening, prior to dosing, and at 20 minutes, 45 minutes, 1,2, 3 and 4 hours post-dose on Day 1of the each treatment period. Whole blood samples (approximately 1.0 milliliter [mL]) was analysed for potassium and glucose using the i-STAT1 portable chemical analyser. The i-STAT1 system is an analyser designed for point of care testing and employs a hand-held chemistry analyzer and disposable cartridges, which in the configuration tested, are capable of measuring potassium, glucose, blood gases, electrolytes, metabolites and coagulation. Weighted mean (WM) is derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. The data is presented as adjusted mean of WM and maximum (max) glucose /minimum (min) potassium. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| AUC(0- t) and up to 1 Hour Post-dose (AUC[0-1]) of GW642444 and Its Metabolites GI179710, GW630200, and GSK932009, After a Single Dose of GW642444 | Blood samples were collected pre-dose and at 2, 5, 10, 20, and 30 minutes, 1, 2, 4, 6, 8, 10, and 24 hour post-dose. Blood samples were analyzed for GW642444 and its metabolites GI179710, GW630200 and GSK932009 using a high performance liquid chromatography/mass spectrometry/mass (HPLC/MS/MS) spectrometry. AUC defined as area under the plasma concentration curve from time zero to the last quantifiable concentration (AUC(0-t)), and up to 1 hour post-dose (AUC(0-1)) were determined by non-compartmental methods. Assay censoring refers to some of the values being below the limit of quantification such that this parameter could not be defined. | Baseline and Day 1 of each treatment period (up to Study Day 54) | 
| Cmax of GW642444 and Its Metabolites GI179710, GW630200, and GSK932009, After a Single Dose of GW642444 | Blood samples were collected pre-dose and at 2, 5, 10, 20, and 30 minutes, 1, 2, 4, 6, 8, 10, and 24 hour post-dose. Blood samples were analyzed for GW642444 and its metabolites GI179710, GW630200 and GSK932009, using a high performance liquid chromatography/mass spectrometry/mass (HPLC/MS/MS) spectrometry. The maximum observed plasma concentration (Cmax) was determined from the concentration time data by non-compartmental methods. Assay censoring refers to some of the values being below the limit of quantification such that this parameter could not be defined. | Day 1 of each treatment period (up to Study Day 54) | 
| Tmax of GW642444 and Its Metabolites GI179710, GW630200, and GSK932009, After a Single Dose of GW642444 | Blood samples were collected pre-dose and at 2, 5, 10, 20, and 30 minutes, 1, 2, 4, 6, 8, 10, and 24 hour post-dose. Blood samples were analyzed for GW642444 and its metabolites GI179710, GW630200 and GSK932009, using a high performance liquid chromatography/mass spectrometry/mass (HPLC/MS/MS) spectrometry. The Time to maximum plasma concentration (Tmax) was determined from the concentration time data by non-compartmental methods. Assay censoring refers to some of the values being below the limit of quantification such that this parameter could not be defined. | Day 1 of each treatment period (up to Study Day 54) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacodynamics,, Chronic Obstructive Pulmonary Disease (COPD), safety,, COPD patients, pharmacokinetics,, tolerability,, GW642444,