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

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

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.

Study Overview

• Status: Terminated
• Conditions: Leishmaniasis
• Intervention / Treatment: Drug: GSK3186899; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 2GG
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.
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.	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.
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.	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.
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.	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.
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A- Cohorts 1 and 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and SAEs	An adverse event (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. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. Safety Population consisted of all randomized participants who received at least one dose of study treatment.	Up to Week 12
Part A- Cohort 3: Number of Participants With Non-SAEs and SAEs	An adverse event (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. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.	Up to Week 9
Part B: Number of Participants With Non-SAEs and SAEs	An adverse event (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. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline	PCI ranges were <0.0 or >0.1*10^9 cells per(/)liter(L)(basophils), <37 or >50 proportion of red blood cells(RBC) in blood(hematocrit),<130 or >170 grams/L(hemoglobin[Hb]), <1.2 or >3.65*10^9cells(c)/L (lymphocytes),<0.2 or >1*10^9c/L(monocytes), <2 or >7.5*10^9c/L(neutrophils), <150 or >400*10^9 c/L(platelets), <3.0 or >10*10^9c/L(white blood cell[WBC]count), <4.4 or >5.8*10^12 c/L(RBC count), <80 or >99 femtoliter(mean corpuscular[MC] volume), <26.0 or >33.5 picogram(MC Hb), <0.0 or >0.4*10^9 c/L(eosinophils). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became within range, were recorded in To within Range or No Change category.Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100 percentage(%).	Up to Week 12
Part A- Cohort 3: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline	Blood samples were planned to be collected to analyze hematology parameters.	Up to Week 9
Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline	Blood samples were planned to be collected to analyze hematology parameters.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	PCI ranges were <34 or >50 grams/L(albumin),<40 or >129 international units/L[IU/L](alkaline phosphatase),<10 or >50 IU/L(alanine aminotransferase),<0 or >37(aspartate aminotransferase), <0 or >20 micromoles(mcmol)/L (direct bilirubin),<0 or >20 mcmol/L(bilirubin), <2.2 or >2.6 millimoles/L(mmol/L)(calcium),<66 or >112 upper limit of normal mmol/L(creatinine), <3.5 or >5.1 mmol/L (potassium),<0.6 or >1 mmol/L (magnesium),<0.87 or >1.45mmol/L (phosphate),<63 or >83 g/L (protein),<135 or >145 mmol/L (sodium), <0.0 or >5.0 mg/L (C-reactive protein). Participants were counted in worst case category that their value changes to(low, within range [WR] or no change[NC] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became WR, were recorded in To WR or NC category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.	Up to Week 12
Part A- Cohort 3: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	Blood samples were planned to be collected to analyze chemistry parameters.	Up to Week 9
Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	Blood samples were planned to be collected to analyze chemistry parameters.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Urine samples were collected for analysis of occult blood, ketones and protein by a dipstick method. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine occult blood and protein can be read as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase means any increase to trace, 1+, 2+ or 3+ post-Baseline relative to Baseline. Number of participants with worst case any increase in urinalysis results post-Baseline relative to Baseline has been presented.	Up to Week 12
Part A- Cohort 3: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Urine samples were planned to be collected to analyze urine parameters.	Up to Week 9
Part B: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Urine samples were planned to be collected to analyze urine parameters.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings	Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.	Up to Week 12
Part A- Cohort 3: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings	Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.	Up to Week 9
Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings	Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury [mmHg]): <85 (low) or >160 (high), DBP (mmHg): <45 (low) or >100 (high), pulse rate (beats per minute): <40 (low) or >110 (high), respiration rate (breaths per minute): <10(low) or >25(high) and body temperature (degrees Celsius) <35 (low) or >38 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.	Up to Week 12
Part A- Cohort 3: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.	Up to Week 9
Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.	Up to Week 9
Part A- Cohorts 1 and 2: Number of Participants With Abnormal Cardiac Telemetry Findings	Continuous cardiac telemetry was performed in a supine position after at least 5 minutes of rest. Abnormal findings were categorized as CS and not NCS. Clinically significant abnormal findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.	Up to 24 hours post-dose
Part A- Cohort 3: Number of Participants Abnormal Cardiac Telemetry Findings	Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.	Up to 24 hours post-dose
Part B: Number of Participants Abnormal Cardiac Telemetry Findings	Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.	Up to 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A- Cohorts 1 and 2: Plasma Concentration After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3186899. PK Population consisted of all participants in the Safety Population who received at least 1 non-missing PK assessment.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Plasma Concentration After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: 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	Blood samples were collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: AUC(0-t) After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Area Under the Plasma Concentration-time Curve From Time 0 to Extrapolated to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: AUC(0-infinity) After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Maximum Observed Plasma Drug Concentration (Cmax) After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Cmax After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Time to Maximum Observed Plasma Drug Concentration (Tmax) After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Tmax After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Trough Plasma Concentration (Ctau) After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Ctau After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Apparent Terminal Half-life (T1/2) After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: T1/2 After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Predicted Accumulation Ratio After Single Dose Administration of GSK3186899	Blood samples were collected at indicated time points for PK analysis of GSK3186899. Predicted accumulation ratio is calculated as 1/(1-e^[k*tau]) where k is elimination rate constant following the single dose and tau is the dosing interval for the intended repeat dosing.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Predicted Accumulation Ratio After Single Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part B: Plasma Concentration After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part B: AUC(0-t) After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part B: AUC(0-infinity) After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
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	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part B: Cmax After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part B: Tmax After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part B: T1/2 After Repeat Dose Administration of GSK3186899	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.	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
Part A- Cohorts 1 and 2: Dose-proportionality of GSK3186899 Administered as Single Dose Based on AUC(0-infinity)	Blood samples were collected at indicated time points for PK analysis. Dose proportionality was assessed using Power model with fixed effects of logarithm of treatment and participant as random effect. Slope and 90% confidence interval for the slope are presented.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Dose-proportionality of GSK3186899 Administered as Single Dose Based on AUC(0-infinity)	Blood samples were planned to be collected at indicated time points for PK analysis.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohorts 1 and 2: Dose-proportionality of GSK3186899 Administered as Single Dose Based on Cmax	Blood samples were collected at indicated time points for PK analysis. Dose proportionality was assessed using Power model with fixed effects of logarithm of treatment and participant as random effect. Slope and 90% confidence interval for the slope are presented.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part A- Cohort 3: Dose-proportionality of GSK3186899 Administered as Single Dose Based on Cmax	Blood samples were planned to be collected at indicated time points for PK analysis.	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on AUC(0-tau)	Blood samples were planned to be collected at indicated time points for PK analysis.	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
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on Cmax	Blood samples were planned to be collected at indicated time points for PK analysis.	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
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on Ctau	Blood samples were planned to be collected at indicated time points for PK analysis.	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
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by AUC(0-tau)	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of AUC(0-tau) at Day 10 to AUC(0-tau) at Day 1.	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
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by Cmax	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of Cmax at Day 10 to Cmax at Day 1.	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
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by Ctau	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of Ctau at Day 10 to Ctau at Day 1.	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
Part B: Time Invariance Ratio of GSK3186899 After Repeat Dose Administration Using AUC	Blood samples were planned to be collected at indicated time points for PK analysis. Time-invariance ratio was planned to be calculated as AUC(0-12) on Day 10 to AUC(0-infinity) on Day 1.	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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2019
• Primary Completion (Actual): October 17, 2019
• Study Completion (Actual): October 17, 2019

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: March 12, 2019
• First Posted (Actual): March 14, 2019

Study Record Updates

• Last Update Posted (Estimate): February 27, 2023
• Last Update Submitted That Met QC Criteria: May 24, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Multiple ascending dose; Single ascending dose; First time in human; Dose escalation phase; GSK3186899
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; GSK3186899
• Other Study ID Numbers: 208436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No