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

NCT05330455 | Terminated Phase 1 Results DMC

• 3 other identifiers: 2147602021-005117-132023-509684-24
• Study Type: interventional
• Target: 74
• Locations: 6 countries
• Sites: 14

Brief Summary

This Phase 1/2a multiple part study is a first time-in-human (FTIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single (Part 1) and repeat doses (Part 2) of GSK3965193 in healthy participants. Part 3 will evaluate the ability of GSK3965193 to lower hepatitis B virus surface antigen (HBsAg) in participants living with chronic hepatitis B infection (PLWCHB) and will be given the option to subsequently receive treatment with open label bepirovirsen. Part 4 will evaluate the safety and tolerability of combination therapy with GSK3965193 and bepirovirsen and the potential to effect sustained virologic response in PLWCHB.

Conditions

Hepatitis B

Keywords

Bepirovirsen; Chronic hepatitis B; First-time-in-human; GSK3965193

Outcome Measures

Primary Outcomes (36)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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\[0-12\]).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Up to 48 weeks

Secondary Outcomes (11)

• Part 2B: AUC(0-inf) of GSK3965193 Following Single Dose Administration

  Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 48 h, and 72 h post-dose

• Part 2B: Cmax of GSK3965193 Following Single Dose Administration

  Pre-dose and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 48 h, and 72 h post-dose

• Part 3: AUC(0-tau) of GSK3965193 Following Repeat Dose Administration

  Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28

• Part 3: Cmax of GSK3965193 Following Repeat Dose Administration

  Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28

• Part 3: Tmax of GSK3965193 Following Repeat Dose Administration

  Pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 1; pre-dose on Day 4, Day 8, Day 11, Day 15, Day 22; pre-dose and 0.25 h, 0.5 h, 1 h, 2, h, 3 h, 4 h, 6 h, 8 h, and 12 h post-dose on Day 28

Study Arms (18)

Part 1: Cohort 1 - Placebo/GSK3965193 Dose 2/Dose 3/Dose 4

EXPERIMENTAL

Healthy participants received a single dose of placebo oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 3 and Dose 3 was higher than Dose 2.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 1 - GSK3965193 Dose 1/Placebo/Dose 3/Dose 4

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 3 and Dose 3 was higher than Dose 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Placebo/Dose 4

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 2 and Dose 2 was higher than Dose 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Dose 3/Placebo

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 1 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of placebo oral solution on Day 1 in Treatment Period 4. Dose 3 of GSK3965193 was higher than Dose 2 and Dose 2 was higher than Dose 1.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 2 - Placebo/GSK3965193 Dose 6/Dose 7/Dose 8

EXPERIMENTAL

Healthy participants received a single dose of placebo oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 7 and Dose 7 was higher than Dose 6.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 2 - GSK3965193 Dose 5/Placebo/Dose 7/Dose 8

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 7 and Dose 7 was higher than Dose 5.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Placebo/Dose 8

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of placebo oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 8 oral solution on Day 1 in Treatment Period 4. Dose 8 of GSK3965193 was higher than Dose 6 and Dose 6 was higher than Dose 5.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Dose 7/Placebo

EXPERIMENTAL

Healthy participants received a single dose of GSK3965193 Dose 5 oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 6 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 7 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of placebo oral solution on Day 1 in Treatment Period 4. Dose 7 of GSK3965193 was higher than Dose 6 and Dose 6 was higher than Dose 5.

Drug: GSK3965193; Drug: Placebo to match GSK3965193

Part 2A: Placebo

PLACEBO COMPARATOR

Healthy participants received repeat doses of placebo oral solution twice daily (BID) for 14 days.

Drug: Placebo to match GSK3965193

Part 2A: Cohort 5 - GSK3965193 Dose 9 BID

EXPERIMENTAL

Healthy participants received repeat doses of GSK3965193 Dose 9 oral solution BID for 14 days. Dose 9 of GSK3965193 was higher than Dose 4 but lower than Dose 5.

Drug: GSK3965193

Part 2A: Cohort 3 - GSK3965193 Dose 5 BID

EXPERIMENTAL

Healthy participants received repeat doses of GSK3965193 Dose 5 oral solution BID for 14 days. Dose 5 of GSK3965193 was higher than Dose 9 but lower than Dose 10.

Drug: GSK3965193

Part 2A: Cohort 4 - GSK3965193 Dose 6 BID

EXPERIMENTAL

Healthy participants received repeat doses of GSK3965193 Dose 6 oral solution BID for 14 days. Dose 6 of GSK3965193 was higher than Dose 10 but lower than Dose 7.

Drug: GSK3965193

Part 2B: Cohort 6 - GSK3965193 Dose 10 Fasted/Fed

EXPERIMENTAL

Healthy participants received GSK3965193 Dose 10 oral tablets under fasted condition in Treatment Period 1, followed by GSK3965193 Dose 10 oral tablets under fed condition in Treatment Period 2. Dose 10 of GSK3965193 was higher than Dose 5 but lower than Dose 6.

Drug: GSK3965193

Part 2B: Cohort 6 - GSK3965193 Dose 10 Fed/Fasted

EXPERIMENTAL

Healthy participants received GSK3965193 Dose 10 oral tablets under fed condition in Treatment Period 1, followed by GSK3965193 Dose 10 oral tablets under fasted condition in Treatment Period 2. Dose 10 of GSK3965193 was higher than Dose 5 but lower than Dose 6.

Drug: GSK3965193

Part 3: Cohort 7 - Placebo

PLACEBO COMPARATOR

Participants living with chronic hepatitis B infection (PLWCHB) on stable nucleos(t)ide analog (NA) therapy received repeat doses of placebo oral tablets for 28 days. Participants who completed placebo monotherapy were given the option to receive subsequent treatment of optional open label bepirovirsen subcutaneous (SC) injection from Day 43.

Drug: Placebo to match GSK3965193; Drug: Bepirovirsen

Part 3: Cohort 7 - GSK3965193 Dose 9

EXPERIMENTAL

PLWCHB on stable NA therapy received repeat doses of GSK3965193 Dose 9 oral tablets for 28 days. Participants who completed GSK3965193 monotherapy were given the option to receive subsequent treatment of optional open label bepirovirsen SC injection from Day 43. Dose 9 of GSK3965193 was higher than Dose 4 but lower than Dose 5.

Drug: GSK3965193; Drug: Bepirovirsen

Part 4: Cohort 8 - Placebo + Bepirovirsen

EXPERIMENTAL

PLWCHB on stable NA therapy were planned to receive placebo oral tablets plus bepirovirsen SC injection for 28 days. All participants were further planned to continue receiving bepirovirsen SC injection after 28 days.

Drug: Placebo to match GSK3965193; Drug: Bepirovirsen

Part 4: Cohort 8 - GSK3965193 + Bepirovirsen

EXPERIMENTAL

PLWCHB on stable NA therapy were planned to receive GSK3965193 oral tablets plus bepirovirsen SC injection for 28 days. All participants were further planned to continue receiving bepirovirsen SC injection after 28 days.

Drug: GSK3965193; Drug: Bepirovirsen

Interventions

GSK3965193 DRUG

GSK3965193 was administered

Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Dose 3/Placebo; Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Placebo/Dose 4; Part 1: Cohort 1 - GSK3965193 Dose 1/Placebo/Dose 3/Dose 4; Part 1: Cohort 1 - Placebo/GSK3965193 Dose 2/Dose 3/Dose 4; Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Dose 7/Placebo; Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Placebo/Dose 8; Part 1: Cohort 2 - GSK3965193 Dose 5/Placebo/Dose 7/Dose 8; Part 1: Cohort 2 - Placebo/GSK3965193 Dose 6/Dose 7/Dose 8; Part 2A: Cohort 3 - GSK3965193 Dose 5 BID; Part 2A: Cohort 4 - GSK3965193 Dose 6 BID; Part 2A: Cohort 5 - GSK3965193 Dose 9 BID; Part 2B: Cohort 6 - GSK3965193 Dose 10 Fasted/Fed; Part 2B: Cohort 6 - GSK3965193 Dose 10 Fed/Fasted; Part 3: Cohort 7 - GSK3965193 Dose 9; Part 4: Cohort 8 - GSK3965193 + Bepirovirsen

Placebo to match GSK3965193 DRUG

Placebo to match GSK3965193 was administered

Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Dose 3/Placebo; Part 1: Cohort 1 - GSK3965193 Dose 1/Dose 2/Placebo/Dose 4; Part 1: Cohort 1 - GSK3965193 Dose 1/Placebo/Dose 3/Dose 4; Part 1: Cohort 1 - Placebo/GSK3965193 Dose 2/Dose 3/Dose 4; Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Dose 7/Placebo; Part 1: Cohort 2 - GSK3965193 Dose 5/Dose 6/Placebo/Dose 8; Part 1: Cohort 2 - GSK3965193 Dose 5/Placebo/Dose 7/Dose 8; Part 1: Cohort 2 - Placebo/GSK3965193 Dose 6/Dose 7/Dose 8; Part 2A: Placebo; Part 3: Cohort 7 - Placebo; Part 4: Cohort 8 - Placebo + Bepirovirsen

Bepirovirsen DRUG

Bepirovirsen was administered

Part 3: Cohort 7 - GSK3965193 Dose 9; Part 3: Cohort 7 - Placebo; Part 4: Cohort 8 - GSK3965193 + Bepirovirsen; Part 4: Cohort 8 - Placebo + Bepirovirsen

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Parts 1 and 2: Participants between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Parts 3 and 4: Participants between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Body weight \>=50 kilograms (kg) and body mass index within the range 18-32 kilograms per square meter (kg/m\^2) (inclusive).
• Male or female participant: a. Parts 1 and 2: woman of nonchildbearing potential only. b. Parts 3 and 4: woman of nonchildbearing potential or woman of child-bearing potential who is not pregnant or breastfeeding and is using a contraceptive method that is highly effective.
• Capable of giving signed informed consent.
• Participants who have documented chronic hepatitis B virus (HBV) infection \>=6 months prior to screening.
• Participants currently receiving stable NA therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, entecavir).
• Plasma or serum HBsAg concentration \>100 IU/mL.
• Plasma or serum HBV deoxyribonucleic acid (DNA) concentration \<90 IU/mL.
• Hepatitis B virus e-antigen (HBeAg) positive or negative.
• Alanine aminotransferase (ALT) \<=2 times the upper limit of normal (ULN)

You may not qualify if:

• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M \[IgM\]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening
• A current diagnosis of migraine headache
• ALT \>1 times ULN.
• Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\])
• Corrected QT interval (QTc) \>450 milliseconds (msec)
• Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19)
• Participants with known COVID-19 positive contacts in the past 14 days.
• For participants in Part 2A: i. Personal history or family history of peripheral neuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy
• Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of \>5 pack years
• Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination, aside from chronic HBV infection.
• Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).
• History of or suspected liver cirrhosis and/or evidence of cirrhosis.
• Diagnosed or suspected hepatocellular carcinoma.
• History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer).
• Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M \[IgM\]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (14)

GSK Investigational Site

Calgary, Alberta, T2N 4Z6, Canada

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Grenoble, 38043, France

Location

GSK Investigational Site

Nantes, 44000, France

Location

GSK Investigational Site

Rennes, 35033, France

Location

GSK Investigational Site

Milan, 20122, Italy

Location

GSK Investigational Site

Monza MB, 20900, Italy

Location

GSK Investigational Site

Daegu, 41944, South Korea

Location

GSK Investigational Site

Pusan, 49241, South Korea

Location

GSK Investigational Site

Seoul, 05505, South Korea

Location

GSK Investigational Site

Bangkok, 10330, Thailand

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

GSK Investigational Site

London, SW17 0QT, United Kingdom

Location

GSK Investigational Site

London, W2 1NY, United Kingdom

Location

MeSH Terms

Conditions

Hepatitis B; Hepatitis B, Chronic

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: This is a double-blind study
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Parts 1 and Part 2B are crossover and Part 2A, Part 3 and Part 4 are parallel group

Study Record Dates

• First Submitted: April 8, 2022
• First Posted: April 15, 2022
• Study Start: April 14, 2022
• Primary Completion: May 19, 2025
• Study Completion: April 8, 2026
• Last Updated: June 16, 2026
• Results First Posted: June 16, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

KR (3); FR (3); TH (1); GB (3); IT (2); CA (2)