This is a dose escalation/dose finding, double-blind, placebo-controlled, parallel study of GSK2126458 in subjects with IPF. The study is designed to explore a number of doses of GSK2126458 for engagement of pharmacology after short term dosing. It is anticipated that approximately 24 subjects will be enrolled in this study. Actual number of cohorts in this study could vary up to a maximum of 6 cohorts (n=4/cohort; 3 on active and 1 on placebo). Each cohort will consist of four subjects who will be randomised to receive GSK2126458 (three subjects) or placebo (one subject) for approximately 8 days (7 to 10 days). On Day 1 they will receive their first dose of GSK2126458 (or placebo) and safety, tolerability and PK/PD in the blood will be measured for up to 8 hours post-dose. Subjects will then be discharged from the site with study drug until the last day of dosing. They will also receive hand held spirometers and instructions on action to be taken in case of deterioration in pulmonary function or any other adverse events (AEs). On the last day of dosing they will return to the site for a repeat of the Day 1 procedures. A bronchoalveolar lavage (BAL) and \[18F\]-fluoro-deoxyglucose (FDG)- positron emission tomography / computed tomography (PET/CT) scan will be conducted twice during the study; once, at least 2 days before dosing commences and again during the course of the dosing period. After the final subject in each cohort has completed dosing, a dose escalation meeting will take place. Safety and tolerability and PK data will be reviewed during this meeting and decisions made may include but are not limited to: escalate the dose, decrease the dose or repeat the same dose in the next cohort; stop the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
17
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Matching placebo will be available
GSK Investigational Site
London, United Kingdom
Pharmacodynamic (PD) endpoints pAKT/AKT in platelet-rich plasma and BAL cells, [18F]-FDG-PET/CT
Pharmacodynamic will be measured by inhibition of pAKT/AKT in platelet-rich plasma and BAL cells, as well as inhibition of glucose uptake as measured by thoracic\[18F\]-FDG-PET/CT
Time frame: Baseline, Day 1, mid-study BAL visit (Day 5-9) and final dosing day (Day 7, 8, 9 or 10) for each cohort
Area under the curve (AUC) in blood for GSK2126458
GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
Time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
Maximum observed concentration (Cmax) in blood for GSK2126458
GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
Time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
Pre-dose (trough) concentration at the end of the dosing interval (Ctrough) in blood for GSK2126458
GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
Time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
Concentration of GSK2126458 in bronchoalveolar lavage fluid (BALF)
GSK2126458 concentration in BALF in order to define the pulmonary PK/PD relationship for GSK2126458 in IPF subjects
Time frame: Baseline BAL visit and mid-study BAL visit (Day 5-9).
Safety and tolerability of GSK2126458 as assessed by number of subjects with adverse events (AE)s
Safety and tolerability parameters will include recording of AEs, throughout the study in subjects with IPF
Time frame: Baseline up to final dosing day (Day 7, 8, 9 or 10) for each cohort
Safety and tolerability of GSK2126458 as assessed by change from baseline in vital signs
Vital sign measurement will be done in a semi-supine position and will include systolic and diastolic blood pressure, pulse rate and tympanic temperature
Time frame: Day 1, final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose), for each cohort
Safety and tolerability of GSK2126458 as assessed by change from baseline in clinical laboratory parameters
Clinical laboratory assessments will include haematology, clinical chemistry, urinalysis and additional parameters
Time frame: Day 1, mid-study BAL visit (Day 5-9), final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose) for each cohort
Safety and tolerability of GSK2126458 as assessed by change from baseline in pulmonary function
Pulmonary function will be assessed by spirometry to test the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
Time frame: Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort
Safety and tolerability of GSK2126458 as assessed by change from baseline in electrocardiogram (ECG)
Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals
Time frame: Screening, Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort
Assessment of subject's breathlessness using MRC dyspnoea scale
The Medical Research Council (MRC) dyspnoea scale is a 5-point scale used for grading the degree of a patient's breathlessness.
Time frame: Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort
Assessment of FEV1 and FVC using daily hand-held spirometry
Subjects will be required to record their daily spirometry scores (FEV1 and FVC) using hand-held spirometers, at approximately the same time each morning between Screening and the Final Dosing Day
Time frame: Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort
Investigate the effect of GSK2126458 on the frequency and or severity of chronic cough using Leicester Cough Questionnaire (LCQ) in IPF subjects
Subjects will be required to complete the 19 questions - LCQ, which is a symptom specific questionnaire designed to assess the impact of cough severity, a major symptom of IPF. Subjects will be required to complete the 19 questions of the LCQ on Day 1 and the Final Dosing Day
Time frame: Day 1 and final dosing day (Day 7, 8, 9 or 10) for each cohort
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