Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection

Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Treatment Emergent Adverse Events (STEAEs), and Treatment Withdrawals Due to TEAEs

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 serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date (i.e., Day 1) till Day 5 after study intervention administration. Any AE which started post Day 5 of study intervention administration was not considered as TEAE.

Time frame: From the start of study intervention (Day 1) up to 12 weeks

Part 2A: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs

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 serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date.

Time frame: From the start of study intervention (Day 1) up to 6 weeks

Part 2B: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs

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 serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset date was on or after study intervention start date (i.e., Day 1) till Day 5 after study intervention administration. Any AE which started post Day 5 of study intervention administration was not considered as TEAE.

Time frame: From the start of study intervention (Day 1) up to 9 weeks

Part 3: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs

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 serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE was considered treatment emergent if the AE onset or worsen date was on or after study intervention start date. Data for the placebo or GSK3965193 monotherapy phase were presented.

Time frame: From the start of study intervention (Day 1) up to 6 weeks

Part 4: Number of Participants With TEAEs, STEAEs, and Treatment Withdrawals Due to TEAEs

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 serious adverse event that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; abnormal pregnancy outcomes or other situations as per the medical or scientific judgment of the investigator. An AE would be considered treatment emergent if the AE onset or worsen date was on or after study intervention start date.

Time frame: From the start of study intervention (Day 1) up to 48 weeks

Part 1: Number of Participants With Clinically Significant Hematology and Clinical Chemistry Parameters

Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, RBC indices (mean corpuscular volume \[MCV\] and mean corpuscular hemoglobin \[MCH\]), white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), blood urea nitrogen (BUN), creatinine, glucose (non-fasting), potassium, sodium, calcium, aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Clinical significance of laboratory parameters was determined by the investigator.

Time frame: At Day 2

Part 2A: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters

Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator.

Time frame: Up to 21 days

Part 2B: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters

Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator.

Time frame: Up to 9 weeks

Part 3: Number of Participants With Clinically Significant Hematology and Clinical Chemistry Parameters

Blood samples were collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Clinical significance of laboratory parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.

Time frame: Up to 35 days

Part 3: Number of Participants With Clinically Significant Urinalysis Parameters

Urine samples were analyzed using automated urinalysis or urine dipstick. Microscopic examination was performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.

Time frame: Up to 28 days

Part 4: Number of Participants With Clinically Significant Hematology, Clinical Chemistry, and Urinalysis Parameters

Blood samples were planned to be collected to analyze hematology and clinical chemistry parameters: platelet count, RBC count, hemoglobin, hematocrit, RBC indices (MCV and MCH), WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), BUN, creatinine, glucose (non-fasting), potassium, sodium, calcium, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, indirect bilirubin, direct bilirubin, total protein, and albumin. Urine samples were planned to be analyzed using automated urinalysis or urine dipstick. Microscopic examination was planned to be performed if abnormal blood or protein was present in the urine sample. Clinical significance of laboratory parameters would be determined by the investigator.

Time frame: Up to 48 weeks

Part 1: Number of Participants With Clinically Significant Vital Sign Findings

Vital signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.

Time frame: Up to 12 weeks

Part 2A: Number of Participants With Clinically Significant Vital Sign Findings

Vital signs included SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.

Time frame: Up to 21 days

Part 2B: Number of Participants With Clinically Significant Vital Sign Findings

Vital signs included SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator.

Time frame: Up to 9 weeks

Part 3: Number of Participants With Clinically Significant Vital Sign Findings

Vital signs included temperature, SBP and DBP, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.

Time frame: Up to 35 days

Part 4: Number of Participants With Clinically Significant Vital Signs Findings

Vital signs were planned to include temperature, SBP and DBP, pulse and respiratory rate and were planned to be measured with the participant in semi-supine position after 5 minutes rest. Clinical significance of the vital sign findings would be determined by the investigator.

Time frame: Up to 48 weeks

Part 1: Number of Participants With Clinically Significant Electrocardiogram [ECG] Findings

A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and corrected QT (QTc) intervals. Clinical significance of ECG parameters was determined by the investigator.

Time frame: Up to 12 weeks

Part 2A: Number of Participants With Clinically Significant ECG Findings

A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG parameters was determined by the investigator.

Time frame: Up to 21 days

Part 3: Number of Participants With Clinically Significant ECG Findings

A 12-lead ECG was recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG parameters was determined by the investigator. Data for the placebo or GSK3965193 monotherapy phase were presented.

Time frame: Up to 35 days

Part 4: Number of Participants With Clinically Significant ECG Findings

A 12-lead ECG was planned to be recorded with the participant in a semi-supine position after 5 minutes of rest using an ECG machine. The parameters planned to be collected were PR, QRS, QT, and QTc intervals. Clinical significance of ECG findings would be determined by the investigator.

Time frame: Up to 25 weeks

Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 7

Sensory nerve conduction testing was performed to detect neuropathy in participants. Nerve conduction velocity (NCV) and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25 percent (%) decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 7 was reported.

Time frame: Baseline and Day 7

Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 14

Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 14 was reported.

Time frame: Baseline and Day 14

Part 2A: Number of Participants With Changes in Sensory Nerve Conduction at Day 42

Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. Sensory nerve conduction studies at Baseline were collected twice, one at the time of screen and one prior to dosing. Mean (arithmetic mean) of two measurements were considered as Baseline. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 42 was reported.

Time frame: Baseline and Day 42

Part 3: Number of Participants With Changes in Sensory Nerve Conduction at Day 15

Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. The best measurement out of Screening and Day -1 was considered as Baseline, best being the higher measurement. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 15 for the placebo or GSK3965193 monotherapy phase was reported.

Time frame: Baseline and Day 15

Part 3: Number of Participants With Changes in Sensory Nerve Conduction at Day 29

Sensory nerve conduction testing was performed to detect neuropathy in participants. NCV and nerve conduction amplitude were determined. The best measurement out of Screening and Day -1 was considered as Baseline, best being the higher measurement. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from Baseline at Day 29 for the placebo or GSK3965193 monotherapy phase was reported.

Time frame: Baseline and Day 29

Part 4: Number of Participants With Changes in Sensory Nerve Conduction

Sensory nerve conduction testing was planned to be performed to detect neuropathy in participants. NCV and nerve conduction amplitude were planned to be determined. Number of participants with 25% decrease in NCV and 50% decrease in nerve conduction amplitude from baseline was planned to be reported.

Time frame: Baseline up to 29 days

Part 1: Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK3965193 Following Single Dose Administration

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours (h) post-dose

Part 2A: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3965193 Following Repeat Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods. As the dosing interval Tau was 12 hours, AUC(0-tau) is the same as AUC from time zero to 12 hours after dosing (AUC\[0-12\]).

Time frame: Pre-dose and 15 minutes (min), 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, and 12 h post-first dose on Day 14

Part 1: Maximum Observed Concentration (Cmax) of GSK3965193 Following Single Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose

Part 2A: Cmax of GSK3965193 Following Repeat Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14

Part 1: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK3965193 Following Single Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose

Part 2A: Tmax of GSK3965193 Following Repeat Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14

Part 1: Apparent Terminal Half-life (T1/2) of GSK3965193 Following Single Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose

Part 2A: T1/2 of GSK3965193 Following Repeat Dose Administration

Blood samples were collected at indicated time points for PK analysis of GSK3965193. PK analysis was conducted using standard non-compartmental methods.

Time frame: Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4, h, 8 h, and 12 h post-first dose on Day 1; pre-morning dose on Days 2 through 6 and Days 12 through 13; pre-dose and 15 min, 30 min, 1 h, 2h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h post-first dose on Day 14

Part 3: Maximum Reduction of Serum HBsAg Levels From Baseline

Blood samples were collected from participants to assess HBsAg levels for the placebo or GSK3965193 monotherapy phase. Baseline was the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Posterior mean and associated 95 percent (%) credible interval were derived for maximum reduction of serum HBsAg levels from Baseline using Bayesian mixed model repeated measures. The data presented are mean referring to posterior mean, with 95% confidence interval referring to 95% credible interval.

Time frame: From Baseline (Pre-dose on Day 1) up to 6 weeks

Part 4: Number of Participants Achieving Complete Response

Blood samples were planned to be collected to assess HBsAg and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Complete response is defined HBsAg and HBV DNA below lower limit of quantification (LLOQ) for 6 consecutive months after the planned end of treatment.

Time frame: Up to 48 weeks