A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects

ID: NCT03020745
Status: Recruiting
Phase: Phase 2
Start Date: February 14, 2017
First Submitted: December 05, 2016
Last Updated: February 22, 2018
Results: N/A
Organization: GlaxoSmithKline
Sponsors & Collaborators: GlaxoSmithKline
Location: Hong Kong, Korea, Republic of
Conditions: Hepatitis B
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Study Description

Brief Summary

GSK3389404 is being developed for the treatment of CHB virus infection. The development goal for GSK3389404 is the establishment of a finite duration treatment that results in sustained suppression of hepatitis B virus (HBV) replication and viral antigen production after cessation of all treatments for CHB due to the restoration of a functional immune response in the absence of high antigen levels. This study is a multicenter, randomized double-Blind (sponsor un-blinded in Part 1), Placebo-controlled Study which will evaluate the safety, tolerability, PK, and PD profile of GSK3389404 in subjects with CHB and aim to establish proof-of-mechanism. The study will be conducted in two parts. Part 1 plans to enroll subjects primarily from the Asia-pacific region and will be conducted as a single ascending dose (SAD) study with 5 planned cohorts ranging from 30 milligram (mg) to a maximum of 240 mg GSK3389404. Within each cohort, subjects will be randomized to receive either GSK3389404 or placebo in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an optional cohort and may be dosed after Cohort C or in parallel with Cohort D. Part 2 will be conducted as a multiple-dose, dose-ranging study. Subjects will be randomized to different parallel dose levels and regimens or placebo. The dose levels of Part 2 will be selected after a review of Part 1 safety but will not exceed a total monthly dose of 480 mg. However, the total monthly subcutaneous (SC) dose of 480 mg will only be explored in a once weekly or bi-weekly (every 2 weeks) dosing regimen. An optional Japanese part-2 sub-study is planned. The total study duration for part 1 including screening, treatment, and post-treatment follow-up, will not be expected to exceed 13 weeks for each subject and for part 2, including screening, treatment and post-treatment follow-up, will not be expected to exceed 29 weeks for each subject.

Detailed Description

Condition or disease Intervention/treatment Phase

Hepatitis B

Drug: GSK3389404
Other Names
Drug: Placebo
Other Names
Phase 2

Tracking Information

First Submitted DateDecember 05, 2016
Last Update Posted DateFebruary 22, 2018
Actual Start DateFebruary 14, 2017
Anticipated Completion DateJanuary 28, 2019
Actual Primary Completion DateNovember 04, 2018
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • RR based on reduction of HBsAg level from Baseline: Part 2 [Time Frame: Baseline and up to 171 days]

    A subject will be considered a responder if there is at least a 1.5 times log 10 IU/mL reduction of HBsAg levels from Baseline anytime during the study

  • Response Rate (RR), based on reduction of hepatitis B surface antigen (HBsAg) level from Baseline: Part 1 [Time Frame: Baseline and up to 61 days]

    A subject will be considered a responder if there is at least a 1.5 times log 10 international unit/milliliter (IU/mL) reduction of HBsAg levels from Baseline anytime during the study

  • Apparent SC plasma clearance (CL/F) of GSK3389404: part 1 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating CL/F.

  • Apparent terminal phase half-life(t1/2) of GSK3389404: Part 1 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating T1/2.

  • Tmax of GSK3389404: Part 2 [Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, 29, and 57]

    Blood samples will be collected at specific time points for calculating Tmax

  • Time to achieve Cmax (Tmax) of GSK3389404: Part 1 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating Tmax

  • Cmax of GSK3389404: Part 2 [Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, 29, and 57]

    Blood samples will be collected at specific time points for calculating Cmax

  • Maximum observed plasma concentration (Cmax) of GSK3389404: Part 1 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating Cmax

  • Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinity]) for GSK3389404: Part 1 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating AUC [0-infinity]

  • Area under the plasma concentration-time curve (AUC) for GSK3389404 [Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating AUC.

  • Number of subjects with AEs, SAEs: Part 2 [Time Frame: Up to 171 days]

    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  • Number of subjects having abnormal routine urinalysis values: Part 2 [Time Frame: Up to 171 days]

    Urine samples will be collected as a measure of safety

  • Number of subjects having abnormal clinical chemistry values: Part 2 [Time Frame: Up to 171 days]

    Samples for clinical laboratory tests will be collected as a measure of safety

  • Number of subjects with abnormal ECG values: Part 2 [Time Frame: Up to 171 days]

    Twelve- lead ECG measurements will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects having abnormal hematology values: Part 2 [Time Frame: Up to 171 days]

    Samples for clinical laboratory tests will be collected as a measure of safety

  • Number of subjects with abnormal findings in physical examination: Part 2 [Time Frame: Up to171 days]

    A complete physical exam will be conducted at the Screening visit and Brief physical exams will be conducted at all other time points. A complete physical exam will include, at a minimum, assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured and recorded (with subject wearing daytime clothing with no shoes). A brief physical exam will include, at a minimum assessments of the dermatologic, cardiovascular, respiratory, and gastrointestinal systems.

  • Number of subjects with abnormal respiratory rate values: Part 2 [Time Frame: Up to 171 days]

    Respiratory rate measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal body temperature values: part 2 [Time Frame: Up to 171 days]

    Body temperature measurements will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal heart rate values: Part 2 [Time Frame: Up to 171 days]

    Heart rate measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal blood pressure values: Part 2 [Time Frame: Up to 171 days]

    Systolic and diastolic blood pressure single measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes.

  • Number of subjects with Adverse Event (AE), Serious Adverse Event (SAE): Part 1 [Time Frame: Up to 61 days]

    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  • Number of subjects having abnormal routine urinalysis values: Part 1 [Time Frame: Up to 61 days]

    Urine samples will be collected as a measure of safety

  • Number of subjects having abnormal clinical chemistry values: Part 1 [Time Frame: Up to 61 days]

    Samples for clinical laboratory tests will be collected as a measure of safety

  • Number of subjects having abnormal hematology values: Part 1 [Time Frame: Up to 61 days]

    Samples for clinical laboratory tests will be collected as a measure of safety

  • Number of subjects with abnormal Electrocardiogram (ECG) values: Part 1 [Time Frame: Up to 61 days]

    Twelve- lead ECG measurements will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal findings in physical examination: Part 1 [Time Frame: Up to 61 days]

    A complete physical exam will be conducted at the Screening visit and Brief physical exams will be conducted at all other time points. A complete physical exam will include, at a minimum, assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will also be measured and recorded (with subject wearing daytime clothing with no shoes). A brief physical exam will include, at a minimum assessments of the dermatologic, cardiovascular, respiratory, and gastrointestinal systems.

  • Number of subjects with abnormal body temperature values: part 1 [Time Frame: Up to 61 days]

    Body temperature measurements will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal respiratory rate values: Part 1 [Time Frame: Up to 61 days]

    Respiratory rate measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal heart rate values: Part 1 [Time Frame: Up to 61 days]

    Heart rate measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes before each reading.

  • Number of subjects with abnormal blood pressure values: Part 1 [Time Frame: up to 61 days]

    Systolic and diastolic blood pressure single measurement will be made with the subject in the semi-supine or supine position having rested in this position for at least 5 minutes.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • HBV DNA level in plasma: Part 1 [Time Frame: Up to 61 days]

    HBV DNA concentration levels to assess the PK effect of GSK3389404

  • HBsAg level in plasma: Part 1 [Time Frame: Up to 61 days]

    HBsAg concentration levels to assess the PK effect of GSK3389404

  • Hepatitis B Virus e-Antigen (HBeAg) level in plasma: Part 1 [Time Frame: Up to 61 days]

    HBeAg concentration levels to assess the PK effect of GSK3389404

  • HBV DNA level in plasma: Part 2 [Time Frame: Up to 171 days]

    HBV DNA concentration levels to assess the PK effect of GSK3389404

  • HBsAg level in plasma: Part 2 [Time Frame: Up to 171 days]

    HBsAg concentration levels to assess the PK effect of GSK3389404

  • HBeAg level in plasma: Part 2 [Time Frame: Up to 171 days]

    HBeAg concentration levels to assess the PK effect of GSK3389404

  • AUC for metabolite of GSK3389404 (ISIS 505358) [Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating AUC.

  • Cmax of GSK3389404 metabolite (ISIS 505358): Part 1 [Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating Cmax

  • Cmax of GSK3389404 metabolite (ISIS 505358): Part 2 [Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, 29, and 57]

    Blood samples will be collected at specific time points for calculating Cmax

  • Tmax of GSK3389404 metabolite (ISIS 505358): Part 1 [Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating Tmax

  • Tmax of GSK3389404 metabolite (ISIS 505358): Part 2 [Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, 29, and 57]

    Blood samples will be collected at specific time points for calculating Tmax

  • t1/2 of GSK3389404 metabolite (ISIS 505358): Part 1 [Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose]

    Blood samples will be collected at specific time points for calculating T1/2

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleA Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects
Official TitleA Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 in Chronic Hepatitis B Subjects
Brief Summary

GSK3389404 is being developed for the treatment of CHB virus infection. The development goal for GSK3389404 is the establishment of a finite duration treatment that results in sustained suppression of hepatitis B virus (HBV) replication and viral antigen production after cessation of all treatments for CHB due to the restoration of a functional immune response in the absence of high antigen levels. This study is a multicenter, randomized double-Blind (sponsor un-blinded in Part 1), Placebo-controlled Study which will evaluate the safety, tolerability, PK, and PD profile of GSK3389404 in subjects with CHB and aim to establish proof-of-mechanism. The study will be conducted in two parts. Part 1 plans to enroll subjects primarily from the Asia-pacific region and will be conducted as a single ascending dose (SAD) study with 5 planned cohorts ranging from 30 milligram (mg) to a maximum of 240 mg GSK3389404. Within each cohort, subjects will be randomized to receive either GSK3389404 or placebo in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an optional cohort and may be dosed after Cohort C or in parallel with Cohort D. Part 2 will be conducted as a multiple-dose, dose-ranging study. Subjects will be randomized to different parallel dose levels and regimens or placebo. The dose levels of Part 2 will be selected after a review of Part 1 safety but will not exceed a total monthly dose of 480 mg. However, the total monthly subcutaneous (SC) dose of 480 mg will only be explored in a once weekly or bi-weekly (every 2 weeks) dosing regimen. An optional Japanese part-2 sub-study is planned. The total study duration for part 1 including screening, treatment, and post-treatment follow-up, will not be expected to exceed 13 weeks for each subject and for part 2, including screening, treatment and post-treatment follow-up, will not be expected to exceed 29 weeks for each subject.

Detailed Description

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
150
Allocation
Randomized
Interventional Model
Single Group Assignment
Masking
Double
Primary Purpose
Treatment
Conditions
Hepatitis B
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: GSK3389404

GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Other Names
Drug: Placebo

Placebo is available as a Clear colorless solution.

Other Names
Study Groups/Cohorts
Part 1, Cohort A : GSK3389404 30 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo

Part 1, Cohort B: GSK3389404 60 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo

Part 1, Cohort C: GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo

Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo

Part 1, Cohort D: GSK3389404
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 <= 240 mg or matching placebo

Part 2: GSK3389404 or placebo SC
Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1 and will not exceed total monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same but divided into a once weekly or bi weekly (every 2 weeks) dosing regimens for a planned treatment duration of 3 months.

Study Arms
Experimental Part 1, Cohort A : GSK3389404 30 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Experimental Part 1, Cohort A : GSK3389404 30 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 1, Cohort B: GSK3389404 60 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 1, Cohort B: GSK3389404 60 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Experimental Part 1, Cohort C: GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Experimental Part 1, Cohort C: GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Experimental Part 1, Cohort D: GSK3389404
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 <= 240 mg or matching placebo
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Experimental Part 1, Cohort D: GSK3389404
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 <= 240 mg or matching placebo
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 2: GSK3389404 or placebo SC
Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1 and will not exceed total monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same but divided into a once weekly or bi weekly (every 2 weeks) dosing regimens for a planned treatment duration of 3 months.
Drug : Placebo
Placebo is available as a Clear colorless solution.

Experimental Part 2: GSK3389404 or placebo SC
Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1 and will not exceed total monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same but divided into a once weekly or bi weekly (every 2 weeks) dosing regimens for a planned treatment duration of 3 months.
Drug : GSK3389404
GSK3389404 is available as Clear colorless to slightly yellow solution for injection.

Arm Intervention/Treatment
Experimental Part 1, Cohort A : GSK3389404 30 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo
Drug : GSK3389404
Experimental Part 1, Cohort A : GSK3389404 30 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo
Drug : Placebo
Experimental Part 1, Cohort B: GSK3389404 60 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo
Drug : Placebo
Experimental Part 1, Cohort B: GSK3389404 60 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo
Drug : GSK3389404
Experimental Part 1, Cohort C: GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : GSK3389404
Experimental Part 1, Cohort C: GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : Placebo
Experimental Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : Placebo
Experimental Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo
Drug : GSK3389404
Experimental Part 1, Cohort D: GSK3389404
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 <= 240 mg or matching placebo
Drug : GSK3389404
Experimental Part 1, Cohort D: GSK3389404
Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 <= 240 mg or matching placebo
Drug : Placebo
Experimental Part 2: GSK3389404 or placebo SC
Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1 and will not exceed total monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same but divided into a once weekly or bi weekly (every 2 weeks) dosing regimens for a planned treatment duration of 3 months.
Drug : Placebo
Experimental Part 2: GSK3389404 or placebo SC
Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1 and will not exceed total monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same but divided into a once weekly or bi weekly (every 2 weeks) dosing regimens for a planned treatment duration of 3 months.
Drug : GSK3389404

Recruitment Information

Recruitment Status:Recruiting
Enrollment150
Completion DateJanuary 28, 2019
Eligibility Criteria: Inclusion Criteria:
- Subject is able to understand and is capable of giving written informed consent, is willing to comply with protocol requirements, instructions and protocol-stated restrictions, and is likely to complete the study as planned.
- Between 18 and 70 years of age, inclusive, at the time of signing the informed consent form.
- A body mass index (BMI) between 18 to 30 kilogram (Kg)/meter (m^2), inclusive.
- Male or female if they satisfy the following: All females must meet the following criteria: Non-pregnant (as confirmed by a negative serum Human Chorionic Gonadotropin [hCG] test); AND Non-lactating at screening and prior to dosing; AND females of reproductive potential (FRP) must agree to follow (or confirm that they have and are currently following) one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP (see Appendix 4) from at least 28 days prior to the first dose of study treatment until the final Follow-up visit in conjunction with partner's use of male condom. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. For females of non-reproductive potential at least one of the following conditions must apply: Premenopausal females without reproductive potential defined by Documented salpingectomy, Hysterectomy or Documented bilateral oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea; A blood sample for simultaneous Follicle-Stimulating Hormone (FSH) and estradiol levels may be collected at the discretion of the investigator or site to confirm non-reproductive potential; Male subjects with a female partner of child-bearing potential must agree to meet one of the contraception requirements from the time of first dose of study treatment until the final Follow-up visit; Vasectomy; Male condom plus partner's use of one of the contraceptive options below that meets the Standard Operating Procedure (SOP) effectiveness criteria including a <1 percent rate of failure per year, as stated in the product label: Contraceptive subdermal implant, Intrauterine device or intrauterine system, Combined estrogen and progestogen oral contraceptive, Injectable progestogen, Contraceptive vaginal ring, or Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Male subjects must refrain from donating sperm from the time of first dose of study treatment until the final Follow-up visit.
- Documented chronic HBV infection >=6 months prior to screening.
- Subjects with HBV treatment history as follows: Part 1: Treatment naive or have had prior treatment with interferon (pegylated or non pegylated) that must have ended at least 6 months prior to the Baseline visit (Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have ended at least 6 months prior to the Baseline visit or currently receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study. Part 2: Subjects with CHB receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
- Plasma or serum HBV DNA concentration: treatment naïve subjects or subjects not currently receiving treatment, there is no minimum HBV DNA requirement; Subjects who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA - Plasma or serum HBsAg concentration >50 IU/mL.
- Alanine aminotransferase (ALT) concentration: ALT < 5 X Upper Limit of Normal (ULN) for treatment naïve subjects and for subjects who are not currently receiving treatment. ALT <=ULN for subjects who are receiving stable nucleos(t)ide analogue therapy.

Exclusion Criteria:
- Medical history: History of or active diagnosis of moderate to severe liver disease other than CHB, such as autoimmune hepatitis, non alcoholic steatohepatitis, hemochromatosis, or liver failure. History or other clinical evidence of significant or unstable cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease and/or clinically significant ECG abnormalities). Uncontrolled or history of difficult to control hypertension. History of, or active diagnosis of, primary or secondary renal disease (e.g., renal disease secondary to diabetes, hypertension, vascular disease, etc.). History of extrahepatic disorders possibly related to HBV immune complexes (e.g., glomerulonephritis and polyarteritis nodosa). History of bleeding diathesis or coagulopathy. History of or suspected presence of vasculitis. History of Gilbert's Syndrome. History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer), subjects under evaluation for possible malignancy are not eligible.
- History of/sensitivity to GSK3389404 or components thereof or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
- Confirmed or suspected hepatocellular carcinoma (HCC) as evidenced by: Alpha-fetoprotein concentration >=200 nanogram (ng)/mL. If the screening alpha-fetoprotein concentration is >=50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.
- Liver cirrhosis or evidence of cirrhosis as determined by any of the following: Positive liver biopsy (i.e., Metavir Score F4) within 12 months of screening. Fibroscan >12 kilopascals (kPa) within 12 months of screening. AST-Platelet Index (APRI) >2 and FibroSure result >0.7 within 12 months of screening. For subjects without a test for cirrhosis in the above timeframes, APRI and FibroSure should be performed during the screening period to rule out cirrhosis.
- Hepatitis C Virus (HCV) co-infection.
- Human Immunodeficiency Virus (HIV) co-infection.
- Hepatitis D Virus (HDV) co-infection.
- Laboratory results as follows: Total bilirubin concentration >1.25 X ULN. Serum albumin concentration <3.5 grams (g)/deciliter (dL). International normalized ratio (INR) >1.25. Platelet count <140 X 10^9/L. Serum creatinine concentration greater than the ULN. Glomerular Filtration Rate (GFR) <90 mL/min as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula. Subjects with GFR <90 mL/min but >= 60 mL/min may be considered after consultation with the GlaxoSmithKline medical monitor. Urine Albumin to Creatinine Ratio (ACR)>=0.03 mg/mg. In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement.
- Positive test for blood in urine. In the event of a positive test, the test may be repeated once, and if repeat is negative or if urine microscopy reveals <5 RBC per High-Power Field (HPF), the subject is considered eligible.
- Fridericia's QT correction formula (QTcF) >=450 milliseconds (msec) (mean of triplicate measurements).
- Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (<=2 weeks).
- Current alcohol use as judged by investigator to potentially interfere with participant compliance.
- A positive pre-study treatment screen or an unwillingness to refrain from use of the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
- Prior treatment with any non-GSK oligonucleotide or small interfering ribonucleic acid (RNA) (siRNA) within 12 months prior to the first dosing day or prior treatment with GSK oligonucleotide within 3 months prior to the first dosing day.
- Pregnant or lactating females at screening and prior to dosing.
GenderAll
Age18 Years to 70 Years
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
Hong Kong
Korea, Republic of

Administrative Information

NCT Number:NCT03020745
Other Study ID Numbers
205670
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
GlaxoSmithKline
Collaborators
Not Available
Investigators
Study Director
GSK Clinical Trials
GlaxoSmithKline