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Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT03874234
Recruitment Status : Suspended (This study is on hold due to toxicity findings in a pre-clinical asset with the same mode of action as GSK'899. We are assessing the impact of these findings.)
First Posted : March 14, 2019
Last Update Posted : December 8, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE March 12, 2019
First Posted Date  ICMJE March 14, 2019
Last Update Posted Date December 8, 2020
Actual Study Start Date  ICMJE April 30, 2019
Estimated Primary Completion Date March 18, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • Part A- Cohort 1: Number of subjects with adverse event(s) (AE) and serious adverse event(s) (SAE) [ Time Frame: Up to Week 12 ]
    AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
  • Part A- Cohort 2: Number of subjects with AEs and SAEs [ Time Frame: Up to Week 12 ]
    AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
  • Part A- Cohort 3: Number of subjects with AEs and SAEs [ Time Frame: Up to Week 9 ]
    AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
  • Part B: Number of subjects with AEs and SAEs [ Time Frame: Up to Week 9 ]
    AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
  • Part A- Cohort 1: Number of subjects with abnormal hematology parameters [ Time Frame: Up to Week 12 ]
    Hematology parameters will be analyzed including platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), percent reticulocytes, white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Part A- Cohort 2: Number of subjects with abnormal hematology parameters [ Time Frame: Up to Week 12 ]
    Hematology parameters will be analyzed including platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, percent reticulocytes, WBC count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Part A- Cohort 3: Number of subjects with abnormal hematology parameters [ Time Frame: Up to Week 9 ]
    Hematology parameters will be analyzed including platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, percent reticulocytes, WBC count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Part B: Number of subjects with abnormal hematology parameters [ Time Frame: Up to Week 9 ]
    Hematology parameters will be analyzed including platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, percent reticulocytes, WBC count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Part A- Cohort 1: Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Week 12 ]
    Clinical chemistry parameters will be analyzed including blood urea nitrogen (BUN), creatinine, glucose (fasting), magnesium, potassium, sodium, calcium, phosphate, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatine phosphokinase (CPK), total bilirubin, direct bilirubin, total protein, albumin and C-reactive protein (CRP).
  • Part A- Cohort 2: Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Week 12 ]
    Clinical chemistry parameters will be analyzed including BUN, creatinine, glucose (fasting), magnesium, potassium, sodium, calcium, phosphate, AST, ALT, GGT, alkaline phosphatase, CPK, total bilirubin, direct bilirubin, total protein, albumin and CRP.
  • Part A- Cohort 3: Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Week 9 ]
    Clinical chemistry parameters will be analyzed including BUN, creatinine, glucose (fasting), magnesium, potassium, sodium, calcium, phosphate, AST, ALT, GGT, alkaline phosphatase, CPK, total bilirubin, direct bilirubin, total protein, albumin and CRP.
  • Part B: Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Week 9 ]
    Clinical chemistry parameters will be analyzed including BUN, creatinine, glucose (fasting), magnesium, potassium, sodium, calcium, phosphate, AST, ALT, GGT, alkaline phosphatase, CPK, total bilirubin, direct bilirubin, total protein, albumin and CRP.
  • Part A- Cohort 1: Number of subjects with abnormal urinalysis parameters [ Time Frame: Up to Week 12 ]
    Urinalysis parameters will be analyzed including specific gravity, urine creatinine and phosphate. Dipstick test will be used to analyze potential of hydrogen (pH), glucose, protein, blood, ketones. Microscopic examination will be performed if blood or protein is abnormal.
  • Part A- Cohort 2: Number of subjects with abnormal urinalysis parameters [ Time Frame: Up to Week 12 ]
    Urinalysis parameters will be analyzed including specific gravity, urine creatinine and phosphate. Dipstick test will be used to analyze pH, glucose, protein, blood, ketones. Microscopic examination will be performed if blood or protein is abnormal.
  • Part A- Cohort 3: Number of subjects with abnormal urinalysis parameters [ Time Frame: Up to Week 9 ]
    Urinalysis parameters will be analyzed including specific gravity, urine creatinine and phosphate. Dipstick test will be used to analyze pH, glucose, protein, blood, ketones. Microscopic examination will be performed if blood or protein is abnormal.
  • Part B: Number of subjects with abnormal urinalysis parameters [ Time Frame: Up to Week 9 ]
    Urinalysis parameters will be analyzed including specific gravity, urine creatinine and phosphate. Dipstick test will be used to analyze pH, glucose, protein, blood, ketones. Microscopic examination will be performed if blood or protein is abnormal.
  • Part A- Cohort 1: Number of subjects with abnormal 12-lead electrocardiogram (ECG) [ Time Frame: Up to Week 12 ]
    12-lead ECGs will be obtained by using an automated ECG machine to measure PR, QRS, QT, and QTc intervals and calculates heart rate.
  • Part A- Cohort 2: Number of subjects with abnormal 12-lead ECG [ Time Frame: Up to Week 12 ]
    12-lead ECGs will be obtained by using an automated ECG machine to measure PR, QRS, QT, and QTc intervals and calculates heart rate.
  • Part A- Cohort 3: Number of subjects with abnormal 12-lead ECG [ Time Frame: Up to Week 9 ]
    12-lead ECGs will be obtained by using an automated ECG machine to measure PR, QRS, QT, and QTc intervals and calculates heart rate.
  • Part B: Number of subjects with abnormal 12-lead ECG [ Time Frame: Up to Week 9 ]
    12-lead ECGs will be obtained by using an automated ECG machine to measure PR, QRS, QT, and QTc intervals and calculates heart rate.
  • Part A- Cohort 1: Number of subjects with abnormal vital signs [ Time Frame: Up to Week 12 ]
    Vital sign parameters will be analyzed including tympanic temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate will be measured in a supine position and at least 5 minutes of rest in a quiet setting without distractions.
  • Part A- Cohort 2: Number of subjects with abnormal vital signs [ Time Frame: Up to Week 12 ]
    Vital sign parameters will be analyzed including tympanic temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate will be measured in a supine position and at least 5 minutes of rest in a quiet setting without distractions.
  • Part A- Cohort 3: Number of subjects with abnormal vital signs [ Time Frame: Up to Week 9 ]
    Vital sign parameters will be analyzed including tympanic temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate will be measured in a supine position and at least 5 minutes of rest in a quiet setting without distractions.
  • Part B: Number of subjects with abnormal vital signs [ Time Frame: Up to Week 9 ]
    Vital sign parameters will be analyzed including tympanic temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate will be measured in a supine position and at least 5 minutes of rest in a quiet setting without distractions.
  • Part A- Cohort 1: Number of subjects with abnormal cardiac telemetry [ Time Frame: Up to 24 hours post-dose ]
    Continuous cardiac telemetry will be performed in a supine position after at least 5 minutes of rest.
  • Part A- Cohort 2: Number of subjects with abnormal cardiac telemetry [ Time Frame: Up to 24 hours post-dose ]
    Continuous cardiac telemetry will be performed in a supine position after at least 5 minutes of rest.
  • Part A- Cohort 3: Number of subjects with abnormal cardiac telemetry [ Time Frame: Up to 24 hours post-dose ]
    Continuous cardiac telemetry will be performed in a supine position after at least 5 minutes of rest.
  • Part B: Number of subjects with abnormal cardiac telemetry [ Time Frame: Up to 24 hours post-dose ]
    Continuous cardiac telemetry will be performed in a supine position after at least 5 minutes of rest.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • Part A- Cohort 1: Plasma concentration after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: Plasma concentration after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: Plasma concentration after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC[0-t]) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: AUC(0-t) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: AUC(0-t) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Area under the plasma concentration-time curve from time 0 to extrapolated to infinity (AUC[0-infinity]) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: AUC(0-infinity) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: AUC(0-infinity) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Maximum observed plasma drug concentration (Cmax) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: Cmax after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: Cmax after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Time to maximum observed plasma drug concentration (Tmax) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: Tmax after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: Tmax after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Trough plasma concentration (Ctau) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: Ctau after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: Ctau after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Apparent terminal half-life (T1/2) after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: T1/2 after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: T1/2 after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Predicted accumulation ratio after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 2: Predicted accumulation ratio after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 3: Predicted accumulation ratio after single dose administration of GSK3186899 [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: Plasma concentration after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: AUC(0-t) after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: AUC(0-infinity) after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: Area under the plasma concentration-time curve from time 0 to time tau over the dosing interval (AUC[0-tau]) after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: Cmax after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: Tmax after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part B: T1/2 after repeat dose administration of GSK3186899 [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Blood samples will be collected at specified time points for PK analysis of GSK3186899.
  • Part A- Cohort 1: Dose-proportionality of GSK3186899 administered as single dose based on AUC(0-infinity) [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the AUC(0-infinity) following administration of GSK3186899 as single dose.
  • Part A- Cohort 2: Dose-proportionality of GSK3186899 administered as single dose based on AUC(0-infinity) [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the AUC(0-infinity) following administration of GSK3186899 as single dose.
  • Part A- Cohort 3: Dose-proportionality of GSK3186899 administered as single dose based on AUC(0-infinity) [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the AUC(0-infinity) following administration of GSK3186899 as single dose.
  • Part A- Cohort 1: Dose-proportionality of GSK3186899 administered as single dose based on Cmax [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the Cmax following administration of GSK3186899 as single dose.
  • Part A- Cohort 2: Dose-proportionality of GSK3186899 administered as single dose based on Cmax [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the Cmax following administration of GSK3186899 as single dose.
  • Part A- Cohort 3: Dose-proportionality of GSK3186899 administered as single dose based on Cmax [ Time Frame: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose ]
    Dose proportionality will be assessed from the Cmax following administration of GSK3186899 as single dose.
  • Part B: Dose-proportionality of GSK3186899 administered as repeat dose based on AUC(0-tau) [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Dose proportionality will be assessed from the AUC(0-tau) following administration of GSK3186899 as repeat dose.
  • Part B: Dose-proportionality of GSK3186899 administered as repeat dose based on Cmax [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Dose proportionality will be assessed from the Cmax following administration of GSK3186899 as repeat dose.
  • Part B: Dose-proportionality of GSK3186899 administered as repeat dose based on Ctau [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Dose proportionality will be assessed from the Ctau following administration of GSK3186899 as repeat dose.
  • Part B: Relative accumulation ratio of GSK3186899 after repeat dose administration by AUC (0-tau) [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Accumulation ratio will be estimated from the ratio of AUC (0-tau) on last dose / AUC (0-tau) on first dose following dosing of GSK3186899.
  • Part B: Relative accumulation ratio of GSK3186899 after repeat dose administration by Cmax [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Accumulation ratio will be estimated from the ratio of Cmax on last dose /Cmax on first dose following dosing of GSK3186899.
  • Part B: Relative accumulation ratio of GSK3186899 after repeat dose administration by Ctau [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose ]
    Accumulation ratio will be estimated from the ratio of Ctau on last dose /Ctau on first dose following dosing of GSK3186899.
  • Part B: Time invariance ratio of GSK3186899 after repeat dose administration by AUC [ Time Frame: Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose ]
    Time-invariance ratio will be calculation as: area under the concentration time-curve from time 0 to 12 hours (AUC [0-12]) on day 10/AUC(0-infinity) on day 1.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects
Official Title  ICMJE A Randomized, Double-blind (Sponsor Unblinded), Placebo-controlled, First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single (in Both Fed and Fasted States) and Repeat Doses of GSK3186899 in Healthy Participants
Brief Summary The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Subjects will receive escalating doses of GSK3186899 and placebo in Part A of the study. Subjects will receive repeat doses either of GSK3186899 or placebo in Part B of the study.
Masking: Double (Participant, Investigator)
Masking Description:
This will be a double-blind study. Subjects and Investigator will be blinded to the study treatment.
Primary Purpose: Treatment
Condition  ICMJE Leishmaniasis
Intervention  ICMJE
  • Drug: GSK3186899
    GSK3186899 will be available as white to slightly colored, spray dried powder in a bottle to be administered orally along with mixture of propylene glycol and water.
  • Drug: Placebo
    Placebo will be available as white to slightly colored, blend powder in a bottle to be administered orally along with mixture of propylene glycol and water.
Study Arms  ICMJE
  • Experimental: Part A: Subjects receiving GSK3186899 + placebo in Cohort 1
    Subjects will receive 3 single ascending oral doses (SAD) of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 1 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
    Interventions:
    • Drug: GSK3186899
    • Drug: Placebo
  • Experimental: Part A: Subjects receiving GSK3186899 + placebo in Cohort 2
    Subjects will receive 3 SAD of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 2 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
    Interventions:
    • Drug: GSK3186899
    • Drug: Placebo
  • Experimental: Part A: Subjects receiving GSK3186899 in Cohort 3
    Subjects will receive GSK3186899 orally, under fasted condition and fed conditions on Day 1 of cohort 3 in each of the two treatment periods. There will be a wash out period of at least 10 days between each treatment period. A dose level will be determined based on the effect of food on the safety, tolerability and PK of a single dose of GSK3186899, with dose level selected from Cohorts 1 and 2.
    Intervention: Drug: GSK3186899
  • Experimental: Part B: Subjects receiving GSK3186899
    Subjects will receive GSK3186899, orally, twice daily (BID) on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.
    Intervention: Drug: GSK3186899
  • Placebo Comparator: Part B: Subjects receiving placebo
    Subjects will receive placebo, orally, BID on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: March 12, 2019)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 18, 2022
Estimated Primary Completion Date March 18, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
  • Healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the normal reference range for the population being studied may be included only if the Investigator in consultation with the Medical Monitor (if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 18.5 to 28 kilogram per square meter (kg/m^2) (inclusive).
  • Male and/or female subjects: A male subject with a female partner of reproductive potential must agree to use contraception during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period. A female subject is eligible to participate if she is not a woman of childbearing potential (WONCBP).
  • Capable of giving signed informed consent.

Exclusion Criteria

  • History or presence of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
  • Previous history of leishmaniasis.
  • ALT >1.5* upper limit of normal (ULN).
  • Bilirubin >1.5*ULN (isolated bilirubin >1.5*ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Current or past history of clinically significant gastritis or gastroduodenal ulcers or regular use of non-steroidal anti-inflammatory drugs (NSAID).
  • ECG QT interval corrected for heart rate (QTc) >450 milliseconds (msec).
  • Past or intended use of over-the-counter or prescription medication, including herbal medications, NSAIDs, proton-pump inhibitors (PPIs) or anti-H2 antagonists within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longest) prior to dosing. Other concomitant medication may be considered on a case by case basis by the Investigator in consultation with the medical monitor.
  • Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within a 56-day period.
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates participation in the study.
  • Regular use of known drugs of abuse.
  • Subjects with renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) with an age appropriate glomerular filtration rate (GFR) <=80 (mL/minute/1.73m^2).
  • Presence of Hepatitis B surface antigen (HBsAg) or Positive Hepatitis C antibody test result at screening.
  • Positive human immunodeficiency virus (HIV) antibody test.
  • Positive pre-study drug/alcohol screen.
  • Presence of clinically significant hematuria and/or proteinuria.
  • Carbon monoxide levels indicative of smoking or history or regular use of tobacco or nicotine-containing products within 3 months prior to screening.
  • Part A (Food effect) Cohort 3 only: Subject must have no dietary restrictions (example, lactose intolerance) or inability to eat an adapted standard meal (includes 35-40 percent fat content).
  • Part A (Food effect) Cohort 3 only: History of gall bladder surgery or gall bladder removal, or history of an acute disease state (example, cholelithiasis) within 14 days prior to receiving the study treatment.
  • Part B only: Early morning cortisol <420 nanomoles per liter (nmol/L) and inadequate response (rise of <250 millimoles per liter (mmol/L) from Baseline) to adrenocorticotropic hormone (ACTH) stimulation test at Day -1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03874234
Other Study ID Numbers  ICMJE 208436
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP