Clinical Trials/NCT04493684

NCT04493684

Completed

Phase 1

A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3739937 in Healthy Participants

ViiV Healthcare1 site in 1 country91 target enrollmentJuly 31, 2020

ConditionsHIV Infections

InterventionsPlacebo GSK3739937 (PIB)GSK3739937 (Tablet)

DrugsGSK3739937 (PIB)Placebo GSK3739937 (Tablet)

Overview

Phase: Phase 1
Intervention: Placebo
Conditions: HIV Infections
Sponsor: ViiV Healthcare
Enrollment: 91
Locations: 1
Primary Endpoint: Part 1 - Number of Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
Status: Completed
Last Updated: 9 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-controlled, single- and repeat-dose escalation study including a weekly oral dose (MAD) cohort and a relative bioavailability (RBA) and food effect (FE) cohort to investigate the safety, tolerability and PK of VH3739937 in healthy participants. This is a three part study. Part 1 and Part 2 is designed to gain information on the safety, tolerability, and pharmacokinetic (PK) properties of GSK3739937 when administered as powder-in-a-bottle (PiB). Part 3 will evaluate the RBA of the GSK3739937 PiB and GSK3739937 Tablet and the safety, tolerability and PK parameters of the tablet formulation when administered under fasting and fed conditions.

Registry

clinicaltrials.gov

Start Date

July 31, 2020

End Date

August 30, 2021

Last Updated

9 months ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

ViiV Healthcare

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
•Participants who are overtly 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 (history and ECG).
•Participants who are negative on two consecutive tests for severe acute respiratory syndrome coronavirus-2 (SARs-CoV-2), performed at Screening and on admission and (re-)admission to the Phase I unit, using an approved molecular test polymerase chain reaction (PCR).
•Participants who are able to understand and comply with protocol requirements and timetables, instructions, and protocol-stated restrictions.
•Body weight \>=50.0 kilograms (kg) (110 pound \[lbs\]) for men and \>=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 32.0 kilogram per square meter (kg/m\^2).
•Male participants are eligible to participate if they agree to use contraceptive methods
•A female participant is eligible to participate if she is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP). - Capable of giving signed informed consent

Exclusion Criteria

•Signs and symptoms which in the opinion of the investigator are suggestive of coronavirus disease 2019 (COVID-19) (i.e. fever, cough etc) within 14 days of inpatient admission.
•Contact with known COVID-19 positive persons in the 14 days prior to inpatient admission.
•History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, distribution, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
•Pre-existing clinically relevant, in the opinion of the principal investigator (PI), gastro-intestinal pathology or diagnosis - e.g. irritable bowel syndrome, inflammatory bowel disease, and/or significant baseline signs and symptoms.
•Medical history of cardiac arrhythmias or cardiac disease or a family and personal history of long QT syndrome.
•Any known or suspected pre-existing psychiatric condition
•Any positive (abnormal) response confirmed by the investigator or clinician (or qualified designee) administered Columbia Suicide Severity Rating Scale (CSSRS) at screening .
•Any other clinical condition (including but not limited to active substance use) or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits; or a condition that could affect the absorption, distribution, metabolism or excretion of the drug.
•Estimated glomerular filtration rate (eGFR) \<90 milliliters/minute (mL/min) or serum creatinine \>1.1 x upper limit of normal (ULN).
•Hemoglobin \<12.5 grams/deciliter (g/dL) for men and \<11 g/dL for women.

Arms & Interventions

Part 1: Cohort 2: Participants receiving Placebo

In this cohort, participants will be randomized to receive placebo.

Intervention: Placebo

Part 1: Cohort 1: Participants receiving GSK3739937

Part 1 cohort 1 may contain up to 4 escalating doses (Period 1- 10 milligram \[mg\], Period 2- 80 mg, and Period 3- 320 mg, Period 4- 800 mg) of GSK3739937.

Intervention: GSK3739937 (PIB)

Part 1: Cohort 1: Participants receiving Placebo

In this cohort, participants will be randomized to receive placebo.

Intervention: Placebo

Part 1: Cohort 2: Participants receiving GSK3739937

Part 1 cohort 2 may contain up to 3 escalating doses ( Period 1- 30 mg, Period 2- 160 mg, and Period 3- 640 mg) of GSK3739937.

Intervention: GSK3739937 (PIB)

Part 2: Cohort 3: Participants receiving GSK3739937

Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 25 mg GSK3739937 for 14 days.

Intervention: GSK3739937 (PIB)

Part 2: Cohort 3: Participants receiving Placebo

Eligible participants in part 2 cohort 3, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days.

Intervention: Placebo

Part 2: Cohort 4: Participants receiving GSK3739937

Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 50 mg GSK3739937 for 14 days.

Intervention: GSK3739937 (PIB)

Part 2: Cohort 4: Participants receiving Placebo

Eligible participants in part 2 cohort 4, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 14 days.

Intervention: Placebo

Part 2: Cohort 5: Participants receiving GSK3739937

Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 7 participants will be randomized to receive a once-daily dose of 100 mg GSK3739937 for 18 days.

Intervention: GSK3739937 (PIB)

Part 2: Cohort 5: Participants receiving placebo

Eligible participants in part 2 cohort 5, will consist of approximately 10 participants out of 3 participants will be randomized to receive a once-daily dose of placebo for 18 days.

Intervention: Placebo

Part 2: Cohort 6: Participants receiving GSK3739937

Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 7 participants will be randomized to receive three 500 mg doses of GSK3739937 administered at once weekly intervals over two weeks.

Intervention: GSK3739937 (PIB)

Part 2: Cohort 6: Participants receiving placebo

Eligible participants in part 2 cohort 6, will consist of approximately 10 participants out of 3 participants will be randomized to receive three doses of placebo administered at once weekly intervals over two weeks.

Intervention: Placebo

Part 3: Cohort 7: Participants receiving treatment sequence ABC

Participants will receive Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 1; Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 2; and Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 3.

Intervention: GSK3739937 (PIB)

Part 3: Cohort 7: Participants receiving treatment sequence ABC

Intervention: GSK3739937 (Tablet)

Part 3: Cohort 7: Participants receiving treatment sequence BCA

Participants will receive Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 1; Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 2; and Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 3.

Intervention: GSK3739937 (PIB)

Part 3: Cohort 7: Participants receiving treatment sequence BCA

Intervention: GSK3739937 (Tablet)

Part 3: Cohort 7: Participants receiving treatment sequence CAB

Participants will receive Treatment C: GSK3739937 Tablet, 100 mg administered under fasted conditions in Period 1; Treatment A: GSK3739937 PiB, 100 mg administered under moderate fat conditions in Period 2; and Treatment B: GSK3739937 Tablet, 100 mg administered under moderate fat conditions in Period 3.

Intervention: GSK3739937 (PIB)

Part 3: Cohort 7: Participants receiving treatment sequence CAB

Intervention: GSK3739937 (Tablet)

Outcomes

Primary Outcomes

Part 1 - Number of Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame: Up to 27 weeks

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An 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 and important medical events may jeopardize the participant or may require medical or surgical intervention/Standard of care (SOC) to prevent one of the other outcomes mentioned before.

Part 2 - Number of Any AEs and SAEs

Time Frame: Up to 5 weeks

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An 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 and important medical events may jeopardize the participant or may require medical or surgical intervention/SOC to prevent one of the other outcomes mentioned before.

Part 3 - Number of Any AEs and SAEs

Time Frame: Up to 16 weeks

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An 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 and important medical events may jeopardize the participant or may require medical or surgical intervention/SOC to prevent one of the other outcomes mentioned before.

Part 1 - Change From Baseline in Hematology Parameters - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelets. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 1 - Change From Baseline in Hematology Parameters - Erythrocytes Count

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Erythrocytes count. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameters - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameters - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Hematology Parameters - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets

Time Frame: Baseline (Day -1) and Day 6

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameters - Erythrocytes Count

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameters - Erythrocytes Count

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Hematology Parameters - Erythrocytes Count

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Hematology Parameter - Erythrocytes Mean Corpuscular Hemoglobin (MCH)

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Erythrocytes Mean Corpuscular Hemoglobin (MCH). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameter - Hemoglobin (Hb)

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Blood samples were collected to assess change from baseline in Hemoglobin (Hb). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameter - Erythrocytes Mean Corpuscular Hemoglobin (MCH)

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameter - Hemoglobin (Hb)

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameter - Erythrocytes Mean Corpuscular Hemoglobin (MCH)

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Blood samples were collected to assess change from baseline in Mean Corpuscular Hemoglobin (MCH). Blood samples were collected to assess change from baseline in Erythrocytes Mean Corpuscular Hemoglobin (MCH). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 3 - Change From Baseline in Hematology Parameter - Erythrocytes Mean Corpuscular Hemoglobin (MCH)

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Hematology Parameter - Hematocrit

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Hematocrit. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameter - Hematocrit

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameter - Hematocrit

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Hematology Parameter - Hematocrit

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Hematology Parameter - Reticulocytes

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Reticulocytes. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Hematology Parameter - Reticulocytes

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Hematology Parameter - Reticulocytes

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Hematology Parameter - Reticulocytes

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Hematology Parameter - Hemoglobin (Hb)

Time Frame: Baseline (Day -1) and Day 6

Part 3 - Change From Baseline in Hematology Parameter - Hemoglobin (Hb)

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Clinical Chemistry Parameter - Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphate (ALP) and Serum Creatine Phosphokinase (CPK)

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphate (ALP) and Serum Creatine Phosphokinase (CPK). Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Clinical Chemistry Parameter - ALT, AST, ALP and Serum CPK

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Clinical Chemistry Parameter -ALT, AST, ALP and Serum CPK

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Clinical Chemistry Parameter - ALT, AST, ALP and CPK

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Clinical Chemistry Parameters- Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Potassium, Sodium, Blood Urea Nitrogen, Cholesterol, High Density Lipoprotein, Low Density Lipoprotein, Triglycerides

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Potassium, Sodium, Blood Urea Nitrogen (BUN), Cholesterol, High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL) and Triglycerides. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Clinical Chemistry Parameters- Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Potassium, Sodium, BUN, Cholesterol, HDL, LDL, Triglycerides

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 - (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Clinical Chemistry Parameter - Total Protein

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Blood samples were collected to assess change from baseline in Total Protein. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Clinical Chemistry Parameters- Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Potassium, Sodium, BUN, Cholesterol, HDL, LDL, Triglycerides

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Clinical Chemistry Parameter - Total Protein

Time Frame: Baseline (Day -1) and Day 6

Part 3 - Change From Baseline in Clinical Chemistry Parameters- Bicarbonate, Calcium, Glucose, Chloride, Magnesium, Phosphate, Potassium, Sodium, BUN, Cholesterol, HDL, LDL, Triglycerides Edit Properties | Duplicate Measure

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Clinical Chemistry Parameters - Amylase and Lipase

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Amylase and Lipase. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Clinical Chemistry Parameters - Amylase and Lipase

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Clinical Chemistry Parameters - Amylase and Lipase

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Clinical Chemistry Parameters - Amylase and Lipase

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Clinical Chemistry Parameter - Total Bilirubin, Direct Bilirubin and Creatinine

Time Frame: Baseline (Day -1) and Day 6

Blood samples were collected to assess change from baseline in Total Bilirubin, Direct Bilirubin and Creatinine. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Clinical Chemistry Parameter - Total Bilirubin, Direct Bilirubin and Creatinine

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Clinical Chemistry Parameter - Total Bilirubin, Direct Bilirubin and Creatinine

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Clinical Chemistry Parameter - Total Bilirubin, Direct Bilirubin and Creatinine

Time Frame: Baseline (Day -1) and Day 6

Part 1 - Change From Baseline in Clinical Chemistry Parameter - Total Protein

Time Frame: Baseline (Day -1) and Day 6

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Clinical Chemistry Parameter - Total Protein

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 1 - Number of Participants With Abnormal Urinalysis Parameters

Time Frame: Up to 27 weeks

Urine samples were collected to detect presence of occult blood and protein through dipstick and random method respectively. The results presented are worst case abnormal urinalysis results post-baseline relative to baseline.

Part 2 - Number of Participants With Abnormal Urinalysis Parameters

Time Frame: Up to 5 weeks

Part 3 - Number of Participants With Abnormal Urinalysis Parameters

Time Frame: Up to 16 weeks

Part 1 - Change From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Blood pressure (SBP and DBP) was assessed in semi-supine position with a completely automated device. Blood pressure measurement preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline is defined as the average of the triplicate predose assessments within each treatment. Change from Baseline was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Vital Signs - Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Vital Signs - Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Vital Signs - Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Part 1 - Change From Baseline in Vital Signs - Pulse Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Pulse rate was assessed in semi-supine position with a completely automated device. Pulse rate measurement preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Vital Signs - Pulse Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Vital Signs - Pulse Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Maximum Observed Concentration (Cmax) of GSK3739937

Time Frame: Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period

Blood samples were collected at indicated time points for PK analysis of GSK3739937. PK parameters were analyzed using standard non-compartmental analysis.

Part 3 - Change From Baseline in Vital Signs - Pulse Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Part 1 - Change From Baseline in Vital Signs - Body Temperature

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Temperature was assessed in the semi-recumbent position with a completely automated device, preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Vital Signs - Body Temperature

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Body temperature were assessed at indicated time-points. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Vital Signs - Body Temperature

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Vital Signs - Body Temperature

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Part 1 - Change From Baseline in Vital Signs - Respiratory Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Respiratory rate was assessed in the semi-recumbent position with a completely automated device, preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline value was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, before the first dose of study drug administration. Change from Baseline value is presented and was calculated as post-dose visit value minus Baseline value.

Part 2 (QD PBO and Cohort 3, 4 and 5) - Change From Baseline in Vital Signs - Respiratory Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 14

Part 2 (QW PBO and Cohort 6) - Change From Baseline in Vital Signs - Respiratory Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 15

Part 3 - Change From Baseline in Vital Signs - Respiratory Rate

Time Frame: Baseline (Day 1, pre-dose) and Day 6

Part 1 - Number of Participants With Worst Case Post-Baseline Electrocardiogram (ECG) Findings

Time Frame: Up to 27 weeks

Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. ECG findings were categorized as Normal, Abnormal clinically significant (CS) and Abnormal 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 ECG findings have been presented.

Part 2 - Number of Participants With Worst Case Post-Baseline ECG Findings

Time Frame: Up to 5 weeks

Part 3 - Number of Participants With Worst Case Post-Baseline ECG Findings

Time Frame: Up to 16 weeks

Part 3 - Area Under the Plasma Concentration Time Curve (AUC) From Zero to 24 Hours (AUC[0-24]) of GSK3739937

Time Frame: Pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 12, 16 and 24 hours post-dose in each treatment period

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3739937. PK parameters were analyzed using standard non-compartmental analysis.

Part 3 - AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK3739937

Time Frame: Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period

Blood samples were collected at indicated time points for PK analysis of GSK3739937. PK parameters were analyzed using standard non-compartmental analysis.

Secondary Outcomes

Part 1 (Cohort 1 and 2) - AUC From Zero (Pre-dose) to Time of the Last Quantifiable Concentration (t) (AUC [0-t]) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - AUC(0-24) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 and 24 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Apparent Terminal Phase Half-life (T1/2) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Apparent Oral Clearance (CL/F) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Cmax of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Concentration of GSK3739937 at 24 Hours (C24) of GSK3739937(Pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 12, 16 and 24 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Last Quantifiable Concentration (Clast) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2 ) - Time of Occurrence of Cmax (Tmax) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Lag Time (Tlag) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 1 (Cohort 1 and 2) - Time to Reach Clast (Tlast) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period.)
Part 2 (Cohort 3, 4 and 5) - AUC (0-24) of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 1 (Cohort 1 and 2) - AUC(0-inf) of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72, 96, 120, 192, 264 and 360 hours post-dose in each treatment period)
Part 2 (Cohort 3, 4 and 5) - Cmax of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 3, 4 and 5) - C24 of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 3, 4 and 5) - Tmax of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 3, 4 and 5) - Tlag of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 3 and 4) - Tmax of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 3 and 4) - Cmax of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 3 and 4) - AUC From Pre-dose to the End of the Dosing Interval at Steady State (AUC[0-tau]) of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 3 and 4) - Plasma Trough Concentration (Ctau) of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 3 and 4) - T1/2 of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 3 and 4) - CL/F of GSK3739937 on Day 14(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 14)
Part 2 (Cohort 5) - Tmax of GSK3739937 on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 5) - Cmax of GSK3739937 on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 5) - AUC From Pre-dose to the End of the Dosing Interval at Steady State (AUC[0-tau]) on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 5) - Plasma Trough Concentration (Ctau) of GSK3739937 on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 5) - T1/2 of GSK3739937 on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 5) - CL/F of GSK3739937 on Day 18(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 18)
Part 2 (Cohort 6) - AUC From Zero to 168 Hours (AUC[0-168]) of GSK3739937 From Day 1(Pre-dose (within 15 minutes prior to dosing) and up to 168 hours post-dose from Day 1)
Part 2 (Cohort 6) - Cmax of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 6) - Concentration of GSK3739937 at 168 Hours (C168) From Day 1(Pre-dose (within 15 minutes prior to dosing) and up to 168 hours post-dose from Day 1)
Part 2 (Cohort 6) - Tmax of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 6) - Tlag of GSK3739937 on Day 1(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 1)
Part 2 (Cohort 6 ) - AUC(0-t) of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 2 (Cohort 6) - Cmax of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 2 (Cohort 6) - Ctau of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 2 (Cohort 6) - Tmax of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 2 (Cohort 6) - T1/2 of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 2 (Cohort 6) - CL/F of GSK3739937 on Day 15(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on Day 15)
Part 3 (Cohort 7) - C24 of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24 hours post-dose in each treatment period)
Part 3 (Cohort 7) Clast of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 3 (Cohort 7) - Tmax of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 3 (Cohort 7) - Tlag of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 1 - Dose Proportionality of GSK3739937 for Dose Levels 10 mg to 800 mg Using Cmax After Single Dose Administration of GSK3739937(Up to day 16)
Part 2 - Dose Proportionality of GSK3739937 for Dose Levels 25 mg to 100 mg Using AUC(0-24) After Repeated Dose Administration of GSK3739937(Up to day 33)
Part 2 - Dose Proportionality of GSK3739937 for Dose Levels 25 mg to 100 mg Using Cmax After Repeated Dose Administration of GSK3739937(Up to day 33)
Part 2 - Dose Proportionality of GSK3739937 for Dose Levels 25 mg to 100 mg Using Ctau After Repeated Dose Administration of GSK3739937(Up to day 33)
Part 2 (Cohort 3 and 4) - Accumulation Ratio of AUC(0-tau) (R [AUC{0-TAU}])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 14)
Part 2 (Cohort 5) - Accumulation Ratio of AUC(0-tau) (R [AUC{0-TAU}])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 18)
Part 2 (Cohort 6) - Accumulation Ratio of AUC(0-tau) (R [AUC{0-TAU}])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 15)
Part 2 (Cohort 3 and 4) - Accumulation Ratio of Cmax (R [CMAX])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 14)
Part 3 (Cohort 7) - Tlast of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 3 (Cohort 7) - T1/2 of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 1 - Dose Proportionality of GSK3739937 for Dose Levels 30 mg to 800 mg Using AUC(0-infinity) After Single Dose Administration of GSK3739937(Up to day 16)
Part 2 (Cohort 5) - Accumulation Ratio of Cmax (R [CMAX])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 18)
Part 2 (Cohort 6) - Accumulation Ratio of Cmax (R [CMAX])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 15)
Part 2 (Cohort 3 and 4) - Accumulation Ratio of C(Tau) (R[CTAU])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 14)
Part 3 (Cohort 7) - CL/F of GSK3739937(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, 120, 192, 264, and 360 hours post-dose in each treatment period)
Part 2 (Cohort 5) - Accumulation Ratio of C(Tau) (R[CTAU])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 18)
Part 2 (Cohort 6) - Accumulation Ratio of C(Tau) (R[CTAU])(Pre-dose (within 15 minutes prior to dosing) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 16 hours post-dose on both Day 1 and Day 15)
Part 2 (Cohort 3 and 4) - Pre-dose Concentration of GSK3739937(Up to day 15)
Part 2 (Cohort 5) - Pre-dose Concentration of GSK3739937(Up to day 19)