A Phase 2 interventional study of GSK256066 and Placebo in Pulmonary Disease, Chronic Obstructive, sponsored by GlaxoSmithKline. Completed at 15 sites in 6 countries. Open to participants aged 40 Years to 75 Years. Per ClinicalTrials.gov, last updated 2017-07-28.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
This study will evaluate the safety and tolerability of the cfor the first time in mild to moderate COPD patients.
3,303 studies on the registry are indexed under Lung Diseases; 355 are open to participants now.
This study's enrollment of 104 is above the median of 72 across 2,118 interventional studies indexed under Lung Diseases.
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Exclusion Criteria:
25 microgram inhaled once daily
Drug: GSK256066
87.5 microgram inhaled once daily
Drug: GSK256066
Placebo inhaled once daily
Drug: Placebo
PDE4 inhibitor
Placebo
Number of participants with adverse events (AEs) and serious adverse events (SAEs)
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention.
Time frame: Up to follow up (approximately 56 days)
Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings
ECG parameters consist of QT interval corrected by Bazett's (QTcB) and Fridericia's (QTcF) formulas, QT interval, QRS duration and PR interval. Baseline was defined as value at Day 0 (pre-bronchodilator). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was the mean of the 3 pre-salbutamol measurements at Day 0. It was assessed on Baseline, Day 1, 7, 14, 15, 21, 27 and 28. Post Baseline, ECG was performed 1-2 hours post dose.
Time frame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings-ventricular rate
ECG parameters consist of ventricular rate. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was the mean of the 3 pre-salbutamol measurements at Day 0. It was as/sessed on Baseline, Day 1, 7, 14, 15, 21, 27 and 28. Post Baseline, ECG was performed 1-2 hours post dose.
Time frame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
Number of participants with abnormal (potential clinical importance [PCI]) systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)
The PCI range for SBP was \< 85 and \> 160 millimeters of mercury (mmHg), DBP was \< 45 and \> 100 mmHg and for HR \< 40 and \> 110 beats per minute. It was assessed on Baseline (pre-bronchodilator), Day 14 and 27. Data for SBP high, SBP low, DBP high, DBP low, HR high and HR low is presented.
Time frame: Up to Day 27 (Visit 6a)
Number of participants with abnormal (PCI) clinical chemistry
Clinical chemistry included: albumin, bicarbonate, alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), blood urea, creatinine, magnesium, sodium, potassium, chloride, glucose, total bilirubin, direct bilirubin, indirect bilirubin, total protein, gamma glutamyltransferase (GGT), calcium, creatinine kinase, creatine kinase-MB, creatinine clearance (estimated; male and female), lactate dehydragenase, and troponin, triglycerides. Data for abnormal parameters (above and below range) is provided. It was assessed on Baseline (Day -3), Day 14, 28 and on follow up visit (Day 42). Data for only abnormal observations is presented.
Time frame: Up to Day 42 (follow up visit)
Number of participants with abnormal (PCI) hematology
Hematology included: haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell (RBC) indices, white blood cell (WBC), basophils, eosinophils, lymphocytes, monocytes, neutrophils and platelet count. Data for abnormal parameters (above and below range) is provided. It was assessed on Baseline (Day -3), Day 14, 28 and on follow up visit (Day 42). Data for only abnormal observations is presented.
Time frame: Up to Day 42 (follow up visit)
Number of participants with abnormal urinalysis
Abnormal urinalysis data for RBC in urine and haematuria presented. Data for abnormal parameters (above and below range) is provided. It was assessed on Baseline (Day -3), Day 7, 14, 21, 28 and on follow up visit (Day 42). Data for only abnormal observations is presented.
Time frame: Up to Day 56 (Visit follow up)
Change from Baseline (Day 0) in lung function parameters: forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value defined as the value on Day 0. It was assessed on Baseline (Day 0), Day 14 and 27. Spirometry tests was performed before and 30 minutes after dosing with salbutamol (bronchodilator) on Day 0 and before dosing with GSK256066. As they were analyzed separately, there were two Baselines for these tests, 'pre bronchodilator Baseline' and 'post bronchodilator Baseline'. Smoking and short acting bronchodilators were avoided 6 hour prior to administration of the salbutamol. Observations with best test review (BTR) grading of 'not acceptable' were excluded.
Time frame: Baseline (Day 0) and up to Day 27 (Visit 6a)
Number of participants with abnormal Holter interpretations
Holter parameters were derived by visit over the 24 hour period as: maximum HR over 24 hours was the maximum HR of all time slices and mean HR over 24 hours was the mean HR of all time slices, weighted by the time length of each slice. The total number of ventricular runs and the number of supraventricular runs over 24 hours were derived by summing each count across all time slices. Data for normal, abnormal: not clinically significant and abnormal: clinically significant is presented. It was assessed on Baseline (Day 0), Day 14and 27. Data for normal, abnormal: clinically significant and abnormal: clinically not significant presented.
Time frame: Up to Day 27 (Visit 6a)
Number of participants who withdrawn for exacerbations of chronic obstructive pulmonary disease (COPD)
An exacerbation of COPD was defined as worsening of COPD symptoms requiring changes to normal treatment including antimicrobial therapy, short courses of oral steroids and other bronchodilator therapy. If clinically indicated, short-term treatment with antibiotics could be prescribed for the exacerbation. Any participants requiring treatment with inhaled or oral corticosteroids or admission to hospital were withdrawn from the study.
Time frame: Up to Day 27 (Visit 6a)
Plasma concentrations of GSK256066 and active metabolite GSK614917 and derived pharmacokinetic parameters: area under the plasma drug concentration versus time curve (AUC0-last)
AUC0-last determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. AUC0-last for GSK256066 is presented. As GSK614917 concentrations were generally non-quantifiable, no summary statistics were derived for GSK614917 pharmacokinetic parameters due to the large number of missing values resulting from non-quantifiable concentration-time data. AUC(0-t) imputed with half lowest observed AUC(0-t) (half of 1.28 hour×picogram/ milliliters \[mL\]).
Time frame: Pre-dose and at 15, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hour post dosing at Baseline (Visit 2a) and Days 14 and 27 (Visits 4a and 6a)
Plasma concentrations of GSK256066 and active metabolite GSK614917 and derived pharmacokinetic parameters: maximum observed plasma drug concentration (Cmax)
The first occurrence of the maximum observed concentration determined directly from the raw concentration-time data. Cmax for GSK256066 is presented. As GSK614917 concentrations were generally non-quantifiable, no summary statistics were derived for GSK614917 pharmacokinetic parameters due to the large number of missing values resulting from non-quantifiable concentration-time data. One pre-dose GSK614917 concentration at the Baseline visit which was \>5% of the corresponding Cmax was excluded from the pharmacokinetic analysis. Cmax imputed with half lower limit of quantification (LLQ; half of 5 picogram/mL).
Time frame: Pre-dose and at 15, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hour post dosing at Baseline (Visit 2a) and Days 14 and 27 (Visits 4a and 6a)
Plasma concentrations of GSK256066 and GSK614917 and derived pharmacokinetic parameters: time to maximum observed plasma drug concentration (tmax)
The tmax was the time at which Cmax was observed. Tmax was determined directly from the raw concentration-time data. Pharmacokinetic data of GSK256066 is presented. As GSK614917 concentrations were generally non-quantifiable, no summary statistics were derived for GSK614917 pharmacokinetic parameters due to the large number of missing values resulting from non-quantifiable concentration-time data.
Time frame: Pre-dose and at 15, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hour post dosing at Baseline (Visit 2a) and Days 14 and 27 (Visits 4a and 6a)
Change from Baseline (Day -3) total cell number (cells/mL) in induced sputum
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. One participant had a total number of neutrophil cell/ mLs count of 0 which was imputed to 1. Data for adjusted geometric means of macrophages, neutrophils cells per mLs and total leukocyte count is presented as geometric mean. The change from Baseline was calculated by subtracting the Baseline values from the Day 28 values. Baseline was defined as the value at Day -3. Total number of cells per mL was calculated by percentage of cells divided by 100 multiplied by total leukocyte count. It was assessed on Baseline and Day 28.
Time frame: Baseline (Day -3) and Day 28 (Visit 6b)
Change from Baseline (Day -3) in neutrophils and macrophages as a percentage of total cells in induced sputum
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. One participant had a total number of neutrophil cell/ mLs count of 0 which was imputed to 1. Data for adjusted means of percentage of total cells macrophages and neutrophils is presented as least square mean. The change from Baseline was calculated by subtracting the Baseline values from the Day 28 values. Baseline was defined as the value at Day -3. Percentage cells was calculated by absolute cell count divided by total non squamous cell count multiplied by 100. It was assessed on Baseline and Day 28.
Time frame: Baseline (Day -3) and Day 28 (Visit 6b)
Summary of mean lymphocytes, bronchial epithelial cells and eosinophils as a percentage of total cells in induced sputum
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. Data for adjusted means of percentage of total cells macrophages and neutrophils is presented as geometric mean. The change from Baseline was calculated by subtracting the Baseline values from the Day 28 values. Baseline was defined as the value at Day -3. Percentage cells was calculated by absolute cell count divided by total non squamous cell count multiplied by 100. It was assessed on Baseline and Day 28.
Time frame: Up to Day 28 (Visit 6b)
Absolute numbers of leukocytes, neutrophils and macrophages in induced sputum
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. One participant had a total number of neutrophil cell/ mLs count of 0 which was imputed to 1. Total number of cells per mL was calculated by percentage of cells divided by 100 multiplied by total leukocyte count. It was assessed on Baseline and Day 28. One participant had a total number of neutrophil cell/ mLs count of 0 which was imputed to 1.
Time frame: Up to Day 28 (Visit 6b)
Absolute numbers of bronchial epithelial cells, lymphocytes and eosinophils in induced sputum
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. One participant had a total number of neutrophil cell/ mL count of 0 which was imputed to 1. Total number of cells per mL was calculated by percentage of cells divided by 100 multiplied by total leukocyte count. It was assessed on Baseline and Day 28.
Time frame: Up to Day 28 (Visit 6b)
Summary of concentration of total protein in induced sputum supernatant
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. It was assessed on Baseline and Day 28. Values below LLQ or above upper limit of quantification (ULQ) was imputed to half the LLQ or ULQ, LLQs: total protein: 62.5 µg/mL and ULQ: total protein: 400 µg/mL. Adjusted mean values for current smokers and former smokers is presented as least square mean.
Time frame: Up to Day 28 (Visit 6b)
The concentration of inflammatory biomarkers in induced sputum supernatant: interleukin (IL) 8
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. It was assessed on Baseline and Day 28. Values below LLQ or above ULQ was imputed to half the LLQ or ULQ, LLQs: IL8: 70000 picograms/mL and ULQ: IL8: 360000 picograms/mL.
Time frame: Up to Day 28 (Visit 6b)
The concentration of inflammatory biomarkers in induced sputum supernatant: myeloperoxidase (MPO)
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. It was assessed on Baseline and Day 28. Values below LLQ or above ULQ was imputed to half the LLQ or ULQ, LLQs: MPO: 90 nanograms/mL and ULQ: IL8: 5000 nanograms/mL.
Time frame: Up to Day 28 (Visit 6b)
Summary of messenger ribonucleic acid (mRNA) and/or protein in induced sputum of established and exploratory markers of inflammation: IL-6, IL-1 beta and IL-8
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. It was assessed on Baseline and Day 28. Data for adjusted mean is presented as least square mean.
Time frame: Day 28 (Visit 6b)
Summary of mRNA and/or protein in induced sputum of established and exploratory pharmacodynamic markers: Phosphodiesterase-4 B (PDE4B), SNF1 like kinase (SNF1LK)
Sputum was performed using ipratropium bromide. Participants must fast for 2 hour prior to the sputum induction (only water was allowed) and on Day 28 (Visit 6b), it was performed 2-4 hours after the final dose of study medication. It was assessed on Baseline and Day 28.
Time frame: Up to Day 28 (Visit 6b)
Summary of lung function parameters (pre and post-bronchodilator): mean spirometry measures FEV1 and FVC
Spirometry tests was performed before and 30 minutes after dosing with salbutamol (bronchodilator) on Day 0 and before dosing with GSK256066. As they were analyzed separately, there were two Baselines for these tests, 'pre bronchodilator Baseline' and 'post bronchodilator Baseline'. Smoking and short acting bronchodilators were avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0), Day 14 and 27. Observations with BTR grading of 'not acceptable' were excluded.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), slow vital capacity (SVC) and thoracic gas volume (TGV)
Plethysmography procedures was performed 30 minutes after dosing with salbutamol and prior to dosing with GSK256066. Participants were resting in the body box for at least 1 minute prior to any assessments. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: plus airway resistance (Raw)
Plethysmography procedures was performed 30 minutes after dosing with salbutamol and prior to dosing with GSK256066. Participants were resting in the body box for at least 1 minute prior to any assessments. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: specific airway conductance (sGaw)
Plethysmography procedures was performed 30 minutes after dosing with salbutamol and prior to dosing with GSK256066. Participants were resting in the body box for at least 1 minute prior to any assessments. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): impulse oscillometry (IOS): total resistance (R5) and large airway resistance (R25); low frequence reactance (X5)
IOS tests were performed prior to other measurements of pulmonary function to avoid any influence of forced expiratory manoeuvres on airway function during resting breathing. IOS test was performed before and 30 minutes after dosing with salbutamol and before dosing with GSK256066. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Observations with BTR grading of 'not acceptable' were excluded. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): IOS-resonant frequency (RF)
IOS tests were performed prior to other measurements of pulmonary function to avoid any influence of forced expiratory manoeuvres on airway function during resting breathing. IOS test was performed before and 30 minutes after dosing with salbutamol and before dosing with GSK256066. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Observations with BTR grading of 'not acceptable' were excluded. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): impulse oscillometry (IOS): peripheral resistance (R5-R15) and R15
IOS tests were performed prior to other measurements of pulmonary function to avoid any influence of forced expiratory manoeuvres on airway function during resting breathing. IOS test was performed before and 30 minutes after dosing with salbutamol and before dosing with GSK256066. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Observations with BTR grading of 'not acceptable' were excluded. The parameter 'R5-R15' was derived by subtracting R15 from R5 for each subject at each time point.
Time frame: Up to Day 27 (Visit 6a)
Summary of lung function parameters (pre and post-bronchodilator): IOS-low frequence reactance area (AX)
IOS tests were performed prior to other measurements of pulmonary function to avoid any influence of forced expiratory manoeuvres on airway function during resting breathing. IOS test was performed before and 30 minutes after dosing with salbutamol and before dosing with GSK256066. Smoking and short acting bronchodilators should be avoided 6 hour prior to administration of the salbutamol. It was assessed on Baseline (Day 0) and 27. Observations with BTR grading of 'not acceptable' were excluded.
Time frame: Up to Day 27 (Visit 6a)
The concentration of serum inflammatory biomarkers: fibrinogen
Blood samples were collected to determine serum concentrations of inflammation biomarkers such as fibrinogen, tumour necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-Rs), IL-8, IL-6, IL-1-beta using an appropriately validated assay including ELISA and multiplex analysis. TNFα, sTNF-Rs, IL-8, IL-6 and IL-1-beta data were not collected. Values below LLQ or above ULQ have been imputed to half the LLQ or ULQ. LLQ for fibrinogen-0.4 grams per liter and ULQs for fibrinogen-14 grams per liter. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 28 (Visit 6b)
The concentration of serum inflammatory biomarkers: surfactant protein-D (SP-D)
Blood samples were collected to determine serum concentrations of inflammation biomarkers such as fibrinogen, tumour necrosis factor-alpha (TNF-alpha), sTNF-Rs, IL-8, IL-6, IL-1-beta using an appropriately validated assay including ELISA and multiplex analysis. TNFα, sTNF-Rs, IL-8, IL-6 and IL-1-beta data were not collected. Surfactant protein D (SP-D) was collected. Values below LLQ or above ULQ have been imputed to half the LLQ or ULQ. LLQ for SP-D-7.8 nanograms per mL and ULQs for SP-D-2000 nanograms per mL. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 28 (Visit 6b)
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