A Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety and Tolerability of Inhaled GSK256066 in Mild to Moderate COPD Patients
Overview
- Phase
- Phase 2
- Intervention
- GSK256066
- Conditions
- Pulmonary Disease, Chronic Obstructive
- Sponsor
- GlaxoSmithKline
- Enrollment
- 104
- Locations
- 1
- Primary Endpoint
- Number of participants with adverse events (AEs) and serious adverse events (SAEs)
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This study will evaluate the safety and tolerability of the cfor the first time in mild to moderate COPD patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male adults or female adults of non-childbearing potential who are between 40 and 75 years of age (inclusive).
- •Subjects with a clinical diagnosis of COPD in accordance with the European Respiratory Society Consensus Statement and subjects categorised with moderate COPD as defined by the GOLD guidelines of 2006 \[GOLD, 2006\]
- •Subjects with a cigarette smoking history of ≥ 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or the equivalent). Both current and former smokers are eligible to be enrolled. A former smoker is defined as a subject who has not smoked for ≥6 months at Visit
- •Subjects with a post-bronchodilator FEV1 to FVC ratio (FEV1/FVC) \< 0.7 at Visit
- •Subjects will be assessed 30 (± 5) minutes after receiving salbutamol 400 μg.
- •Subjects with a post-bronchodilator FEV1 ≥ 50% and \< 80% of predicted normal for height, age and sex at Visit
- •Subjects will be assessed 30 (± 5) minutes after receiving salbutamol 400 μg.
- •Subjects with a normal echocardiogram at screening, as defined by the absence of clinically significant wall motion, chamber size or valvular abnormalities
- •The subject must be capable of giving informed consent and can comply with the study requirements and timetable.
Exclusion Criteria
- •Women who are pre-menopausal and of child-bearing potential.
- •Subjects weighing less than 50 kilograms (kg).
- •Subjects who are obese defined as having a body mass index (BMI) \>
- •Subjects with a current diagnosis of asthma.
- •Subjects who have required hospitalisation or treatment with oral corticosteroids and/or antibiotic therapy for acute worsening of COPD or lower respiratory tract infection in the 6 weeks prior to Screening.
- •Subjects who have received treatment with oral, intravenous, topical or intra-articular corticosteroids within 6 weeks of Screening or thereafter
- •Subjects with active tuberculosis, sarcoidosis or clinically overt bronchiectasis.
- •Subjects with a history of any type of malignancy with the exception of successfully treated squamous cell cancer of the skin.
- •Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with chronic inflammation (e.g. Inflammatory Bowel Disease).
- •Subjects with chronic infections (lasting longer than 6 months) such as gingivitis, periodontitis, prostatitis, gastritis, and urinary tract infections.
Arms & Interventions
25 mcg
25 microgram inhaled once daily
Intervention: GSK256066
87.5 mcg
87.5 microgram inhaled once daily
Intervention: GSK256066
Placebo
Placebo inhaled once daily
Intervention: Placebo
Outcomes
Primary Outcomes
Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Time Frame: Up to follow up (approximately 56 days)
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.
Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings
Time Frame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
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.
Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings-ventricular rate
Time Frame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
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.
Number of participants with abnormal (potential clinical importance [PCI]) systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)
Time Frame: Up to Day 27 (Visit 6a)
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.
Number of participants with abnormal (PCI) clinical chemistry
Time Frame: Up to Day 42 (follow up visit)
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.
Number of participants with abnormal (PCI) hematology
Time Frame: Up to Day 42 (follow up visit)
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.
Number of participants with abnormal urinalysis
Time Frame: Up to Day 56 (Visit follow up)
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.
Change from Baseline (Day 0) in lung function parameters: forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
Time Frame: Baseline (Day 0) and up to Day 27 (Visit 6a)
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.
Number of participants with abnormal Holter interpretations
Time Frame: Up to Day 27 (Visit 6a)
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.
Number of participants who withdrawn for exacerbations of chronic obstructive pulmonary disease (COPD)
Time Frame: Up to Day 27 (Visit 6a)
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.
Secondary Outcomes
- Plasma concentrations of GSK256066 and active metabolite GSK614917 and derived pharmacokinetic parameters: area under the plasma drug concentration versus time curve (AUC0-last)(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)(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)(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))
- Absolute numbers of bronchial epithelial cells, lymphocytes and eosinophils in induced sputum(Up to Day 28 (Visit 6b))
- Summary of concentration of total protein in induced sputum supernatant(Up to Day 28 (Visit 6b))
- The concentration of inflammatory biomarkers in induced sputum supernatant: interleukin (IL) 8(Up to Day 28 (Visit 6b))
- The concentration of inflammatory biomarkers in induced sputum supernatant: myeloperoxidase (MPO)(Up to Day 28 (Visit 6b))
- Change from Baseline (Day -3) total cell number (cells/mL) in induced sputum(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(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(Up to Day 28 (Visit 6b))
- Absolute numbers of leukocytes, neutrophils and macrophages in induced sputum(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(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)(Up to Day 28 (Visit 6b))
- Summary of lung function parameters (pre and post-bronchodilator): mean spirometry measures FEV1 and FVC(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)(Up to Day 27 (Visit 6a))
- Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: plus airway resistance (Raw)(Up to Day 27 (Visit 6a))
- Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: specific airway conductance (sGaw)(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)(Up to Day 27 (Visit 6a))
- Summary of lung function parameters (pre and post-bronchodilator): IOS-resonant frequency (RF)(Up to Day 27 (Visit 6a))
- Summary of lung function parameters (pre and post-bronchodilator): impulse oscillometry (IOS): peripheral resistance (R5-R15) and R15(Up to Day 27 (Visit 6a))
- Summary of lung function parameters (pre and post-bronchodilator): IOS-low frequence reactance area (AX)(Up to Day 27 (Visit 6a))
- The concentration of serum inflammatory biomarkers: fibrinogen(Up to Day 28 (Visit 6b))
- The concentration of serum inflammatory biomarkers: surfactant protein-D (SP-D)(Up to Day 28 (Visit 6b))