GSK2269557 is a potent and highly selective inhaled Phosphoinositide 3-Kinase (PI3K) delta inhibitor being developed as an anti-inflammatory and anti-infective agent for the treatment of inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD). The purpose of the study is to assess the safety, tolerability and pharmacokinetics (PK) of single and repeat doses of GSK2269557 administered via the ELLIPTA dry powder inhaler (DPI) to healthy Japanese subjects. This is the first time for Japanese subjects that GSK2269557 will be administered via the ELLIPTA DPI with the addition of magnesium stearate. In each group of this study, subjects will receive a single dose of either GSK2269557 or placebo in Session 1 and receive daily dose of GSK2269557 or placebo for 10 days in Session 2. Session 1 of the next dose strength may be run in parallel with the Session 2 of the previous dose. The doses planned for the study are 200 micrograms (mcg), 500 mcg and 700 mcg. There will be at least 10 days washout between the two dosing sessions. Follow up period will start 10 days (+-1 day) after the last dose of Session 2. A total number of 36 subjects will be enrolled for the study with 27 subjects receiving a dose strength of GSK2269557 and 9 subjects will receive each dose strength of GSK2269557. ELLIPTA is a trademark of the GSK group of companies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
36
GSK2269557 ELLIPTA DPI contains GSK2269557 blended with lactose and magnesium stearate. This will be supplied in two strength of 100 mcg per blister and 500 mcg per blister.
Placebo ELLIPTA DPI contains lactose
GSK Investigational Site
Fukuoka, Japan
Number of subjects with any adverse event(s) (AE) and serious adverse event(s) (SAE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in persisting disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
Time frame: Approximately up to 37 days
Session 1: Number of subjects having abnormal clinical laboratory parameters as a measure of safety
Blood samples will be collected to analyse blood urea nitrogen, creatinine, glucose (fasting), uric acid, high density lipoprotein-cholesterol, amylase, potassium, sodium, calcium, triglycerides, lactate dehydrogenase (LDH), chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, gamma-glutamyl transpeptidase (GGT), phosphorus, total bilirubin, direct bilirubin, total protein, albumin, low density lipoprotein-cholesterol, creatine phosphokinase (CPK)
Time frame: Approximately up to 4 days
Session 2: Number of subjects having abnormal clinical laboratory parameters as a measure of safety
Blood samples will be collected to analyse blood urea nitrogen, creatinine, glucose (fasting), uric acid, high density lipoprotein-cholesterol, amylase, potassium, sodium, calcium, triglycerides, LDH, chloride, AST, ALT, ALP, total cholesterol, GGT, phosphorus, total bilirubin, direct bilirubin, total protein, albumin, low density lipoprotein-cholesterol, CPK
Time frame: Approximately up to 22 days
Session 1:Number of subjects having abnormal hematology laboratory parameters as a measure of safety
Blood samples will be collected to analyse platelet count, Red Blood Cells (RBC) count, hemoglobin, hematocrit, RBC Indices, mean corpuscular volume ( MCV), mean corpuscular hemoglobin (MCH), percent reticulocytes, White Blood Cells (WBC), neutrophils, lymphocytes, monocytes, eosionophils, and basophils
Time frame: Approximately up to 4 days
Session 2: Number of subjects having abnormal hematology laboratory parameters as a measure of safety
Blood samples will be collected to analyse platelet count, RBC count, hemoglobin, hematocrit, RBC Indices, MCV, MCH, percent reticulocytes, WBC, neutrophils, lymphocytes, monocytes, eosionophils, and basophils
Time frame: Approximately up to 22 days
Session 1: Number of subjects having abnormal urinalysis as a measure of safety
Urine samples will be collected to analyse specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen for dipstick, and microscopic examination
Time frame: Approximately up to 4 days
Session 2: Number of subjects having abnormal urinalysis as a measure of safety
Urine samples will be collected to analyse specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen for dipstick, and microscopic examination
Time frame: Approximately up to 22 days
Session 1: Body temperature assessment as a safety measure
Temperature will be recorded in a supine position after 5 minutes rest
Time frame: Approximately up to 4 days
Session 2: Body temperature assessment as a safety measure
Temperature will be recorded in a supine position after 5 minutes rest
Time frame: Approximately up to 22 days
Session 1: Blood pressure assessment as a safety measure
Systolic and diastolic blood pressure will be measured in a supine positon after 5 minutes rest
Time frame: Approximately up to 4 days
Session 2: Blood pressure assessment as a safety measure
Systolic and diastolic blood pressure will be measured in a supine position after 5 minutes rest
Time frame: Approximately up to 22 days
Session 1: Measurement of pulse rate as a safety measure
Pulse rate will be measured in a supine position after 5 minutes rest
Time frame: Approximately up to 4 days
Session 2: Measurement of pulse rate as a safety measure
Pulse rate will be measured in a supine position after 5 minutes rest
Time frame: Approximately up to 22 days
Session 1: Electrocardiogram (ECG) assessment as a measure of safety.
Single 12-lead ECG will be obtained in a supine position after 5 minutes rest using an ECG machine that measures PR, QRS, QT, and Corrected QT interval by Fridericia's formula (QTcF) intervals. Single ECGs will be obtained at each time point.
Time frame: Approximately up to 4 days
Session 2: ECG assessment as a measure of safety.
Single 12-lead ECG will be obtained in a supine position after 5 minutes rest using an ECG machine that measures PR, QRS, QT, and QTcF intervals. Single ECGs will be obtained at each time point.
Time frame: Approximately up to 22 days
Session 1: Spirometry assessment as a safety measure
Spirometry assessments will be performed whilst the subject is in a standing position. Assessments will be repeated until 3 technically acceptable measurements have been made.
Time frame: Approximately up to 4 days
Session 2: Spirometry assessment as a safety measure
Spirometry assessments will be performed whilst the subject is in a standing position. Assessments will be repeated until 3 technically acceptable measurements have been made.
Time frame: Approximately up to 22 days
Session 1: Area under the plasma concentration curve (AUC) from time zero to the time of last quantifiable concentration [AUC(0-t)]
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC \[0-t\]
Time frame: Pre-dose, 5, 15, 30 minutes (min), 1, 2 , 4 , 6, 12, 24, 36, 48, and 72hours (h) post-dose
Session 1: AUC from time zero to 24 hours post dose [AUC(0-24)] of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC\[0-24\]
Time frame: Pre-dose, 5, 15, 30 min, 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 1: AUC from time zero to infinity [AUC(0-infinity)] of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC (0-infinity).
Time frame: Pre-dose, 5, 15, 30 min, 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 2: AUC from time zero to the time of last quantifiable concentration [AUC(0-t)] of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC \[0-t\]
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 2: AUC from time zero to 24 hours post dose [AUC(0-24)] of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC\[0-24\]
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 2: AUC from time zero to infinity [AUC(0-infinity)] of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating AUC (0-infinity)
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 1: Trough observed plasma drug concentration (Ctrough) of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Ctrough
Time frame: Pre-dose, 5, 15, 30 minutes (min), 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 1: Maximum observed plasma concentration (Cmax) of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Cmax
Time frame: Pre-dose, 5, 15, 30 minutes (min), 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 1: Maximum/trough observed plasma drug concentration (Cmax/Ctrough) of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Cmax/Ctrough
Time frame: Pre-dose, 5, 15, 30 minutes (min), 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 2: Trough observed plasma drug concentration (Ctrough) of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Ctrough
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 2: Maximum observed plasma concentration (Cmax) of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Cmax
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 2: Maximum/trough observed plasma drug concentration (Cmax/Ctrough) of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating Cmax/Ctrough
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 1: Time to maximum observed plasma drug concentration (Tmax) of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating tmax
Time frame: Pre-dose, 5, 15, 30 min, 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 1: Terminal half-life (t1/2) of GSK2269557 following a single dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating t1/2
Time frame: Pre-dose, 5, 15, 30 min, 1, 2 , 4 , 6, 12, 24, 36, 48, and 72h post-dose
Session 2: Time to maximum observed plasma drug concentration (Tmax) of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating tmax
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Session 2: Terminal half-life (t1/2) of GSK2269557 following repeat dose administration
Blood samples will be collected at pre-dose and at specific post dose time points for calculating tmax and t1/2
Time frame: Day 1: pre-dose, 5 min and 24 h post-dose; Day 2: 5 min post-dose; Days 3, 4, 5, 6, 7, 8, and 9: pre-dose and 5 min post-dose; Day 10: pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, 6 h post-dose; 24 h, 48 h, 72 h, 96 h and 120 h post-Day 10 dose
Ratio of accumulation factor (Ro) of GSK2269557 following single and repeat inhalations
Ro is defined as AUC(0-24) of Session 2 at day10 divided by AUC(0-24) of Session1
Time frame: Day 1 of session 2 and day 10 of session 2
Ratio of accumulation factor (Rs) of GSK2269557 following single and repeat inhalations
Rs is defined as AUC(0-24) of Session 2 at day10 divided by AUC(0-infinity) of Session 1
Time frame: Day 1 of session 2 and day 10 of session 2
Ratio of accumulation factor (R[Cmax]) of GSK2269557 following single and repeat inhalations
R\[Cmax\] is defined as Cmax of Session 2 at day10 divided by Cmax of Session 1
Time frame: Day 1 of session 2 and day 10 of session 2
Ratio of accumulation factor (R[Ctrough]) of GSK2269557 following single and repeat inhalations
R\[Ctrough\] is defined as Ctrough of Session 2 at day10 divided by C24 of Session 1
Time frame: Day 1 of session 2 and day 10 of session 2
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