Clinical trial NCT00549679: Study To Evaluate Safety And Tolerability Of GSK256066 In Chronic Obstructive Pulmonary Disease (COPD) Patients
Official title: A Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety and Tolerability of Inhaled GSK256066 in Mild to Moderate COPD Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease (COPD)
COPD
Repeat Dose
GSK256066
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-10-26
Enrollment: 104
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety and tolerability of the cfor the first time in mild to moderate COPD patients.


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 1.
* Subjects with a post-bronchodilator FEV1 to FVC ratio (FEV1/FVC) \< 0.7 at Visit 1. 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 1. 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) \> 30.
* 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.
* Subjects with any acute infection, sinus symptoms, or significant trauma (burns, fractures).
* Subjects with clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension or any other clinically significant cardiovascular, neurological, endocrine, or haematological abnormalities that are uncontrolled on permitted therapy.
* Subjects who have participated in any GSK study/studies involving administration of COA.
* The subject has a screening ECG parameters outside of ranges specified in protocol.
* Subjects with hypoxaemia
* Risk factors for human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection at Screening (Visit 1).
* Subjects who have undergone surgery including lung volume reduction surgery in the last six months or have conditions that prevent them from performing spirometry.
* Subjects with a history (or suspected history) of alcohol misuse or any other recreational substance abuse.
* Subjects who require treatment with any of the following from the start of the run-in period (Day -14) until the end of the treatment phase:
* Inhaled corticosteroids
* Inhaled cromolyn sodium or nedocromil
* Xanthines (theophylline preparations).
* Leukotriene modifiers
* Tiotropium
* Long-acting inhaled beta2-agonists (salmeterol, formoterol)
* Oral beta2-agonists
* Subjects who are unable to abstain from other courses of medication during the run in phase including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-histamines, anti-rhinitis or hay fever medication, other than short acting inhaled beta-agonists, ipratropium bromide and paracetamol (up to 4 g per day) for the treatment of minor ailments (eg headache) from 48h before the first dose until the follow-up visit. Subjects requiring medication between dosing and follow up may be excluded at the principal investigators discretion.
* Subjects with any known hypersensitivity to salbutamol or ipratropium bromide.
* Subjects who are participating or plan to participate in the active phase of a pulmonary rehabilitation programme during the study.
* Subjects who have received an investigational drug within 30 days or within five drug half-lives of the investigational drug (whichever is longer).
* Subjects with any clinically relevant abnormality detected by the assessments at Screening.
* Subjects who have experienced an exacerbation during the run-in period requiring treatment with oral corticosteroids and/or macrolide antibiotics and/or hospitalisation.

Primary outcomes:
measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to follow up (approximately 56 days)
measure: Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings
timeFrame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
measure: Change from Baseline (Day 0 [pre-bronchodilator]) in 12-lead electrocardiogram (ECG) findings-ventricular rate
timeFrame: Baseline (Day 0 [pre-bronchodilator]) and up to Day 28 (Visit 6b)
measure: Number of participants with abnormal (potential clinical importance [PCI]) systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)
timeFrame: Up to Day 27 (Visit 6a)
measure: Number of participants with abnormal (PCI) clinical chemistry
timeFrame: Up to Day 42 (follow up visit)
measure: Number of participants with abnormal (PCI) hematology
timeFrame: Up to Day 42 (follow up visit)
measure: Number of participants with abnormal urinalysis
timeFrame: Up to Day 56 (Visit follow up)
measure: Change from Baseline (Day 0) in lung function parameters: forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
timeFrame: Baseline (Day 0) and up to Day 27 (Visit 6a)
measure: Number of participants with abnormal Holter interpretations
timeFrame: Up to Day 27 (Visit 6a)
measure: Number of participants who withdrawn for exacerbations of chronic obstructive pulmonary disease (COPD)
timeFrame: Up to Day 27 (Visit 6a)
Secondary outcomes:
measure: Plasma concentrations of GSK256066 and active metabolite GSK614917 and derived pharmacokinetic parameters: area under the plasma drug concentration versus time curve (AUC0-last)
timeFrame: 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)
measure: Plasma concentrations of GSK256066 and active metabolite GSK614917 and derived pharmacokinetic parameters: maximum observed plasma drug concentration (Cmax)
timeFrame: 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)
measure: Plasma concentrations of GSK256066 and GSK614917 and derived pharmacokinetic parameters: time to maximum observed plasma drug concentration (tmax)
timeFrame: 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)
measure: Change from Baseline (Day -3) total cell number (cells/mL) in induced sputum
timeFrame: Baseline (Day -3) and Day 28 (Visit 6b)
measure: Change from Baseline (Day -3) in neutrophils and macrophages as a percentage of total cells in induced sputum
timeFrame: Baseline (Day -3) and Day 28 (Visit 6b)
measure: Summary of mean lymphocytes, bronchial epithelial cells and eosinophils as a percentage of total cells in induced sputum
timeFrame: Up to Day 28 (Visit 6b)
measure: Absolute numbers of leukocytes, neutrophils and macrophages in induced sputum
timeFrame: Up to Day 28 (Visit 6b)
measure: Absolute numbers of bronchial epithelial cells, lymphocytes and eosinophils in induced sputum
timeFrame: Up to Day 28 (Visit 6b)
measure: Summary of concentration of total protein in induced sputum supernatant
timeFrame: Up to Day 28 (Visit 6b)
measure: The concentration of inflammatory biomarkers in induced sputum supernatant: interleukin (IL) 8
timeFrame: Up to Day 28 (Visit 6b)
measure: The concentration of inflammatory biomarkers in induced sputum supernatant: myeloperoxidase (MPO)
timeFrame: Up to Day 28 (Visit 6b)
measure: 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
timeFrame: Day 28 (Visit 6b)
measure: Summary of mRNA and/or protein in induced sputum of established and exploratory pharmacodynamic markers: Phosphodiesterase-4 B (PDE4B), SNF1 like kinase (SNF1LK)
timeFrame: Up to Day 28 (Visit 6b)
measure: Summary of lung function parameters (pre and post-bronchodilator): mean spirometry measures FEV1 and FVC
timeFrame: Up to Day 27 (Visit 6a)
measure: 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)
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: plus airway resistance (Raw)
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): plethysmography measures: specific airway conductance (sGaw)
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): impulse oscillometry (IOS): total resistance (R5) and large airway resistance (R25); low frequence reactance (X5)
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): IOS-resonant frequency (RF)
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): impulse oscillometry (IOS): peripheral resistance (R5-R15) and R15
timeFrame: Up to Day 27 (Visit 6a)
measure: Summary of lung function parameters (pre and post-bronchodilator): IOS-low frequence reactance area (AX)
timeFrame: Up to Day 27 (Visit 6a)
measure: The concentration of serum inflammatory biomarkers: fibrinogen
timeFrame: Up to Day 28 (Visit 6b)
measure: The concentration of serum inflammatory biomarkers: surfactant protein-D (SP-D)
timeFrame: Up to Day 28 (Visit 6b)
Other outcomes:
Locations:
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tampere
country: Finland
facility: GSK Investigational Site
city: Gauting
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hoorn
country: Netherlands
facility: GSK Investigational Site
city: Horn
country: Netherlands
facility: GSK Investigational Site
city: Veldhoven
country: Netherlands
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Kosice
country: Slovakia
facility: GSK Investigational Site
city: Martin
country: Slovakia
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Watz H, Mistry SJ, Lazaar AL; IPC101939 investigators. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm Pharmacol Ther. 2013 Oct;26(5):588-95. doi: 10.1016/j.pupt.2013.05.004. Epub 2013 May 21.