GSK3008348 is an investigational drug, being developed by GlaxoSmithKline Research and Development Limited (the Sponsor, a pharmaceutical company based in the UK) for the treatment of Idiopathic Pulmonary Fibrosis (IPF). IPF is a rare and poorly understood disease that causes scarring of the lungs. The main symptoms are shortness of breath and a dry cough. Symptoms generally worsen over time and in some subjects may prove fatal. The cause of IPF is unknown. This is a First Time in Human, Phase 1, 3-part study which is being carried out on behalf of the Sponsor by Quintiles. The primary purpose of Part A is to examine the safety and tolerability of single nebulised (a medicated spray) doses of GSK3008348 following inhalation in healthy volunteers. The secondary objective is to determine how and at what rate the body absorbs, distributes, breaksdown and eliminates the drug. Parts B and C of this study will be in-patients with Idiopathic Pulmonary Fibrosis (IPF). The purpose of Part B and C is to examine the safety and tolerability, and how much of the drug binds to its target, following single nebulised (a medicated spray) doses of GSK3008348 following inhalation in patients with Idiopathic Pulmonary Fibrosis (IPF). The secondary objective is to determine how and at what rate the bodies of these patients absorbs, distributes, breaksdown and eliminates the drug. The total duration of Part A will be 65 - 87 days, Part B 62 days and Part C 43 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
40
Nebuliser solution formulated at 5000 mcg/mL with 5% mannitol, citric acid, sodium citrate and water for injection, pH adjusted using Hydrochloric acid or Sodium hydroxide to the target pH 5.4 +/- 0.4. 4 ml of diluted dose of appropriate concentration will be administered by nebulisation.
5% mannitol nebuliser solution. 4 ml of solution will be administered by nebulisation
Formulated in 0.9% saline. The maximum amount of radioactivity injected during each PET scan will be 150 Megabecquerel (MBq) and maximum mass of \[18F\]-FBA-A20FMDV2 administered across all three administrations will be 100 mcg. Intravenous bolus infusion of 20 ml will be administered over about 30 seconds.
GSK Investigational Site
London, United Kingdom
Part A: Number of participants with adverse events (AE) as a measure of safety and tolerability
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.
Time frame: Up to Day 33
Part A: Temperature as a measure of safety and tolerability
Time frame: Up to Day 33
Part A: Systolic and diastolic blood pressure as a measure of safety and tolerability
Time frame: Up to Day 33
Part A: Pulse rate and respiratory rate as a measure of safety and tolerability
Time frame: Up to Day 33
Part A: Peripheral capillary oxygen saturation (SpO2) levels as a measure of safety and tolerability
SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry.
Time frame: Up to Day 33
Part A: ECG and Telemetry as a measure of safety and tolerability
12-lead ECG and cardiac telemetry will be performed.
Time frame: Up to Day 21
Part A: FEV1 and FVC as a measure of safety and tolerability
Forced expiratory volume in 1 second (FEV1) is the volume of air that can forcibly be blown out in one second, after full inspiration. Forced vital capacity (FVC) is the volume of air that can forcibly be blown out after full inspiration. Lung function test will be performed to obtain FEV1 and FVC .
Time frame: Up to Day 33
Part A: DLCO as a measure of safety and tolerability
Diffusing capacity (DLCO) is the carbon monoxide uptake from a single inspiration in a standard time (usually 10 seconds). Lung function test will be performed to obtain DLCO.
Time frame: Up to Day 20
Part A: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability
Subjects will be required to complete a taste questionnaire following dosing.
Time frame: Up to Day 19
Part A: Composite of hematology laboratory tests as a measure of safety and tolerability
Hematology laboratory tests will include platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Time frame: Up to Day 33
Part A: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability
Clinical chemistry laboratory tests will include urea, creatinine, glucose non-fasted, creatinine phosphokinase, potassium, sodium, calcium, aspartate aminotransferase alanine transaminase,total and direct bilirubin, total protein, alkaline phosphatise and albumin.
Time frame: Up to Day 33
Part A: Composite of urinalysis laboratory tests as a measure of safety and tolerability
Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal).
Time frame: Up to Day 33
Part B: AE as a measure of safety and tolerability
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.
Time frame: Up to Day 43
Part B: Temperature as a measure of safety and tolerability
Time frame: Up to Day 43
Part B: Systolic and diastolic blood pressure as a measure of safety and tolerability
Time frame: Up to Day 43
Part B: Pulse rate and respiratory rate as a measure of safety and tolerability
Time frame: Up to Day 43
Part B: SpO2 levels as a measure of safety and tolerability
SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry.
Time frame: Up to Day 43
Part B: ECG and Telemetry as a measure of safety and tolerability
12-lead ECG and cardiac telemetry will be performed.
Time frame: Up to Day 31
Part B: FEV1 and FVC as a measure of safety and tolerability
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FVC is the volume of air that can forcibly be blown out after full inspiration. Lung function test will be performed to obtain FEV1 and FVC .
Time frame: Up to Day 43
Part B: DLCO as a measure of safety and tolerability
DLCO is the carbon monoxide uptake from a single inspiration in a standard time (usually 10 seconds). Lung function test will be performed to obtain DLCO.
Time frame: Up to Day 30
Part B: Taste questionnaire for taste of nebulised GSK3008348 as a measure of safety and tolerability
Subjects will be required to complete a taste questionnaire following dosing.
Time frame: Up to Day 29
Part B: Changes in volume of distribution [VT]) at approximately 1 hour post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung
Positron Emission Tomography (PET) scan and a sample of blood will be taken simultaneously for measurement of \[18F\]-FBA-A20FMDV2 concentration. The blood volume in tissue will be determined by dividing the tissue tracer concentration by the blood value. Changes in the uptake of \[18F\]-FBA-A20FMDV2 in the lung will be calculated.
Time frame: Baseline (from Day 15), Up to Day 30
Part B: Composite of hematology laboratory tests as a measure of safety and tolerability
Hematology laboratory tests will include platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Time frame: Up to Day 30
Part B: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability
Clinical chemistry laboratory tests will include urea, creatinine, glucose fasted, creatinine phosphokinase, potassium, sodium, calcium, aspartate aminotransferase alanine transaminase, total and direct bilirubin, total protein, alkaline phosphatise and albumin.
Time frame: Up to Day 30
Part B: Composite of urinalysis laboratory tests as a measure of safety and tolerability
Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)
Time frame: Up to Day 30
Part C: Changes in VT at various time points post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung
PET scan and a sample of blood will be taken simultaneously for measurement of \[18F\]-FBA-A20FMDV2 concentration. The blood volume in tissue will be determined by dividing the tissue tracer concentration by the blood value. Changes in the uptake of \[18F\]-FBA-A20FMDV2 in the lung will be calculated.
Time frame: Baseline (from Day 1), Up to Day 29
Part A: Area under the curve (AUC) following single doses of GSK3008348
AUC from time zero to infinity (AUC\[0-inf\]), AUC from time zero to the time of last quantifiable concentration (AUC\[0-t\]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 minutes (mins), 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part A: Cmax following single doses of GSK3008348
Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part A: Tmax and t½ following single doses of GSK3008348
Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part B: Area under the curve (AUC) following single doses of GSK3008348
AUC from time zero to infinity (AUC\[0-inf\]), AUC from time zero to the time of last quantifiable concentration (AUC\[0-t\]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part B: Cmax following single doses of GSK3008348
Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.
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Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part B: Tmax and t½ following single doses of GSK3008348
Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part B: Changes in VT at 14-28 hours post-dose compared to pre-dose of [18F]-FBA-A20FMDV2 in the lung
PET scan and a sample of blood will be taken simultaneously for measurement of \[18F\]-FBA-A20FMDV2 concentration. The blood volume in tissue will be determined by dividing the tissue tracer concentration by the blood value. Changes in the uptake of \[18F\]-FBA-A20FMDV2 in the lung will be calculated.
Time frame: Baseline (from Day 15), Up to Day 30
Part C: Area under the curve (AUC) following single doses of GSK3008348
AUC from time zero to infinity (AUC\[0-inf\]), AUC from time zero to the time of last quantifiable concentration (AUC\[0-t\]) will be calculated from concentration-time curve using the linear trapezoidal rule based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and post-nebulisation at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part C: Cmax following single doses of GSK3008348
Maximum observed concentration (Cmax) will be calculated from concentration-time curve based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and post-nebulisation at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part C: Tmax and t½ following single doses of GSK3008348
Time of maximum concentration (tmax) will be calculated from concentration-time curve based on each individual subject's profile. Elimination half-life (t½) is time required for or drug in the body to reduced by one-half. t½ will be calculated from concentration-time curve based on each individual subject's profile.
Time frame: Blood samples will be collected at pre-dose and post-nebulisation at 5, 10, 15, 30 mins, 1, 2, 3, 4, 6, 8, 12 hours (Day 1) and 24 hours (Day 2) post-dose of each treatment period
Part C: AE as a measure of safety and tolerability
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE will be collected from the start of study treatment until the final follow-up visit.
Time frame: Up to Day 43
Part C: Temperature as a measure of safety and tolerability
Time frame: Up to Day 43
Part C: Systolic and diastolic blood pressure as a measure of safety and tolerability
Time frame: Up to Day 43
Part C: Pulse rate and respiratory rate as a measure of safety and tolerability
Time frame: Up to Day 43
Part C: Peripheral capillary oxygen saturation (SpO2) levels as a measure of safety and tolerability
SpO2 levels are estimates of the amount of oxygen in the blood. SpO2 will be measured by pulse oximetry.
Time frame: Up to Day 43
Part C: Composite of hematology laboratory tests as a measure of safety and tolerability
Hematology laboratory tests will include platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Time frame: Up to Day 43
Part C: Composite of clinical chemistry laboratory tests as a measure of safety and tolerability
Clinical chemistry laboratory tests will include urea, creatinine, glucose fasted, creatinine phosphokinase, potassium, sodium, calcium, aspartate aminotransferase alanine transaminase,, total and direct bilirubin, , total protein, alkaline phosphatise and albumin.
Time frame: Up to Day 43
Part C: Composite of urinalysis laboratory tests as a measure of safety and tolerability
Urinalysis laboratory tests will include specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)
Time frame: Up to Day 43