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

Phase 2CompletedNCT03020745

GlaxoSmithKline78 enrolled

Overview

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, including Japan 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, Pharmacokinetic (PK) and Pharmacodynamic (PD) data. The treatments selected are 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo. 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 65 weeks for each subject.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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 For Part 2, 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 from at least 28 days prior to the first dose of study treatment until Follow-up visit Day 169 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 Follow-up visit Day 169; 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 Follow-up visit Day 169. * 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. Subjects with prior treatment with interferon (pegylated or non-pegylated) must have ended treatment at least 6 months prior to the Baseline visit (Day 1 pre-dose). * 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 \<lower limit of quantification (LLOQ) * 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 \<=2 times 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 and Investigator judgment. 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 (or \>=30 mg/g). In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement in cases where subjects have low urine albumin and low urine creatinine levels resulting in a urine ACR calculation \>=0.03 mg/mg (or \>=30 mg/g), the investigator should confirm that subject does not have a history of diabetes, hypertension or other risk factors that may affect renal function and discuss with the PPD or GSK medical monitor, or designee. * 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) (single ECG at screening shows QTcF \>=450 msec, a mean of triplicate measurements should be used to confirm that subject meets exclusion criterion). * Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (\<=2 weeks) or topical/inhaled steroid use. * Current alcohol use as judged by investigator to potentially interfere with participant compliance. * A positive pre-study treatment screen and an unwillingness to refrain from use of illicit drugs (or substances with abuse potential) and adhere to other protocol-stated restrictions while participating in the study \[The screen refers to illicit drugs and substances with abuse potential. Medications that are used by the subject as directed, whether over-the-counter or through prescription, are acceptable and would not meet the exclusion criteria\]. . * 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. * For Part 1, females of reproductive potential.

Outcomes

Primary Outcomes

Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points

SBP and DBP were measured in a supine or semi-supine position after approximately 5 minutes rest. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Day 1: 1 hour, Day 1: 2 hours, Day 1: 4 hours, Day 1: 8 hours, Day 3, Day 8 and Day 30

Part 2: Change From Baseline in SBP and DBP at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in SBP and DBP at Indicated Time Points (Up to Day 450-Optional Follow-up)

Time frame: Baseline (Day 1 pre-dose), Day 270 and Day 450

Part 1: Change From Baseline in Heart Rate at Indicated Time Points

Heart rate was measured in a supine or semi-supine position after approximately 5 minutes rest. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Day 1: 1 hour, Day 1: 2 hours, Day 1: 4 hours, Day 1: 8 hours, Day 3, Day 8 and Day 30

Part 2: Change From Baseline in Heart Rate at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Heart Rate at Indicated Time Points (Up to Day 450-Optional Follow-up)

Time frame: Baseline (Day 1 pre-dose), Day 270 and Day 450

Part 1: Change From Baseline in Respiratory Rate at Indicated Time Points

Respiratory rate was measured in a supine or semi-supine position after approximately 5 minutes rest. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 3, 8 and 30

Part 2: Change From Baseline in Respiratory Rate at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Respiratory Rate at Indicated Time Points (Up to Day 450-Optional Follow-up)

Time frame: Baseline (Day 1 pre-dose), Day 270 and Day 450

Part 1: Change From Baseline in Body Temperature at Indicated Time Points

Body temperature was measured in a supine or semi-supine position after approximately 5 minutes rest. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 3, 8 and 30

Part 2: Change From Baseline in Body Temperature at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Body Temperature at Indicated Time Points (Up to Day 450-Optional Follow-up)

Time frame: Baseline (Day 1 pre-dose), Day 270 and Day 450

Part 1: Number of Participants With Abnormal Findings in Physical Examination

Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. Data was not collected and not captured in the database.

Time frame: Up to Day 60

Part 2: Number of Participants With Abnormal Findings in Physical Examination (Up to Day 169-Interim Analysis)

Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. Data was not collected and not captured in the database.

Time frame: Up to Day 169

Part 2: Number of Participants With Abnormal Findings in Physical Examination (Up to Day 450-Optional Follow-up)

Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. Data was not collected and not captured in the database.

Time frame: Up to Day 450

Part 1: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters

Blood samples were collected for the analysis of following hematology and coagulation parameters: Hemoglobin, Leukocytes, Lymphocytes, Neutrophils, Platelets, Activated partial thromboplastin time (aPTT), Prothrombin international normalized ratio (INR) and Prothrombin time (PT). Laboratory parameters were graded according to Division of Acquired Immune Deficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Only those hematology and coagulation parameters with maximum post-Baseline grade (Grade 1 to Grade 4) have been presented.

Time frame: Up to Day 60

Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters (Up to Day 169-Interim Analysis)

Blood samples were collected for the analysis of following hematology and coagulation parameters: Hemoglobin, Leukocytes, Lymphocytes, Neutrophils, Platelets, aPTT, Prothrombin INR and PT. Laboratory parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Only those hematology and coagulation parameters with maximum post-Baseline grade (Grade 1 to Grade 4) have been presented.

Time frame: Up to Day 169

Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters (Up to Day 450-Optional Follow-up)

Time frame: Up to Day 450

Part 1: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points

Blood samples were collected from participants to assess complement C3 and complement C4 levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 60

Part 2: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose) and Up to Day 169

Part 2: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points (Up to Day 450-Optional Follow-up)

Blood samples were planned to be collected from participants to evaluate change from Baseline in complement C3 and complement C4 levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Complement Bb Level at Indicated Time Points

Blood samples were collected from participants to assess complement Bb levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 60

Part 2: Change From Baseline in Complement Bb Level at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose) and Up to Day 169

Part 2: Change From Baseline in Complement Bb Level at Indicated Time Points (Up to Day 450-Optional Follow-up)

Blood samples were collected from participants to evaluate change from Baseline in complement Bb levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Complement C5a Level at Indicated Time Points

Blood samples were collected from participants to assess complement C5a levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 60

Part 2: Change From Baseline in Complement C5a Level at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose) and Up to Day 169

Part 2: Change From Baseline in Complement C5a Level at Indicated Time Points (Up to Day 450-Optional Follow-up)

Blood samples were collected from participants to evaluate change from Baseline in complement C5a levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters

Blood samples were collected for the analysis of following clinical chemistry parameters: Alanine aminotransferase, Albumin, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, Calcium (high), Calcium (low), Creatine kinase, Creatinine, Glucose (high), Glucose (low), Magnesium, Phosphate, Potassium (high), Potassium (low), Sodium (high), Sodium (low) and Urate. Laboratory parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Only those clinical chemistry parameters with maximum post-Baseline grade (Grade 1 to Grade 4) have been presented.

Time frame: Up to Day 60

Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters (Up to Day 169-Interim Analysis)

Blood samples were collected for the analysis of following clinical chemistry parameters: Alanine aminotransferase, Albumin, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, Calcium (high), Calcium (low), Creatine kinase, Creatinine, Glucose (high), Glucose (low), Magnesium, Phosphate, Potassium (high), Potassium (low), Sodium (high), Sodium (low), Urate and glomerular filtration rate (GFR). Laboratory parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Only those clinical chemistry parameters with maximum post-Baseline grade (Grade 1 to Grade 4) have been presented.

Time frame: Up to Day 169

Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters (Up to Day 450-Optional Follow-up)

Blood samples were collected for the analysis of following clinical chemistry parameters: Alanine aminotransferase, Albumin, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, Calcium (high), Calcium (low), Creatine kinase, Creatinine, Glucose (high), Glucose (low), Magnesium, Phosphate, Potassium (high), Potassium (low), Sodium (high), Sodium (low), Urate and glomerular filtration rate (GFR). Laboratory parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Only those clinical chemistry parameters with maximum post-Baseline grade (Grade 1 to Grade 4) have been presented.

Time frame: Up to Day 450

Part 1: Change From Baseline in Urine Albumin at Indicated Time Points

Urine samples were collected from participants to assess urine albumin levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 8, 30 and Follow-up (Day 60)

Part 2: Change From Baseline in Urine Albumin at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 15, 29, 43, 57, 71, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Urine Albumin at Indicated Time Points (Up to Day 450-Optional Follow-up)

Urine samples were planned to be collected from participants to evaluate change from Baseline in urine albumin levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Urine Creatinine at Indicated Time Points

Urine samples were collected from participants to assess urine creatinine levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 8, 30 and Follow-up (Day 60)

Part 2: Change From Baseline in Urine Creatinine at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 15, 29, 43, 57, 71, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Urine Creatinine at Indicated Time Points (Up to Day 450-Optional Follow-up)

Urine samples were planned to be collected from participants to evaluate change from Baseline in urine creatinine levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Urine Potential of Hydrogen (pH) at Indicated Time Points

Urine samples were collected from participants to assess urine pH levels. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 3, 8, 30 and Follow-up (Day 60)

Part 2: Change From Baseline in Urine pH at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Urine pH at Indicated Time Points (Up to Day 450-Optional Follow-up)

Urine samples were planned to be collected from participants to evaluate change from Baseline in urine pH levels. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Urine Specific Gravity at Indicated Time Points

Urine samples were collected from participants to assess urine specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 3, 8, 30 and Follow-up (Day 60)

Part 2: Change From Baseline in Urine Specific Gravity at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Urine Specific Gravity at Indicated Time Points (Up to Day 450-Optional Follow-up)

Urine samples were planned to be collected from participants to evaluate change from Baseline in urine specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in Urobilinogen at Indicated Time Points

Urine samples were collected from participants to assess urobilinogen levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose), Days 3, 8, 30 and Follow-up (Day 60)

Part 2: Change From Baseline in Urobilinogen at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose), Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 113, 141 and 169

Part 2: Change From Baseline in Urobilinogen at Indicated Time Points (Up to Day 450-Optional Follow-up)

Urine samples were planned to be collected from participants to evaluate change from Baseline in urobilinogen. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Change from Baseline was to be calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Number of Participants With Abnormal Electrocardiogram (ECG) Findings

Electrocardiograms were obtained after 5 minutes of rest in the semi-supine or supine position using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings have been presented. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee.

Time frame: Day 1: 2 hours, Day 1: 4 hours, Day 1: 8 hours, Day 3, Day 8 and Day 30

Part 2: Number of Participants With Abnormal ECG Findings (Up to Day 169-Interim Analysis)

Electrocardiogram were obtained after 5 minutes of rest in the semi-supine or supine position using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. CS and NCS abnormal ECG findings have been presented. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee.

Time frame: Days 29, 57, 85 and 169

Part 2: Number of Participants With Abnormal ECG Findings (Up to Day 450-Optional Follow-up)

ECGs were planned to be obtained after 5 minutes of rest in the semi-supine or supine position using ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTcF intervals.

Time frame: Days 270, 360 and 450

Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is any untoward medical occurrence in a clinical investigation participant, 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 were categorized as SAE.

Time frame: Up to Day 60

Part 2: Number of Participants With AEs and SAEs (Up to Day 169-Interim Analysis)

Time frame: Up to Day 169

Part 2: Number of Participants With AEs and SAEs (Up to Day 450-Optional Follow-up)

Time frame: Up to Day 450

Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the Time of the Last Quantifiable Concentration (AUC[0-t]) for GSK3389404

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: AUC (0-t) for GSK3389404

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) for GSK3389404

Blood samples were collected to measure AUC (0-infinity) at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: AUC (0-infinity) for GSK3389404

Blood samples were collected to measure AUC (0-infinity) at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3389404

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: Cmax of GSK3389404

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Time to Achieve Cmax (Tmax) of GSK3389404

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: Tmax of GSK3389404

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Apparent Terminal Phase Half-life(t1/2) of GSK3389404

Blood samples were collected to measure t1/2 at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: t1/2 of GSK3389404

Blood samples were collected to measure t1/2 at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Apparent Subcutaneous Plasma Clearance (CL/F) of GSK3389404

Blood samples were collected to measure CL/F at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose), Days 3, 8 and 30

Part 2: CL/F of GSK3389404

Blood samples were collected to measure CL/F at indicated time-points. Pharmacokinetic parameters were determined using standard non-compartmental methods.

Time frame: Day 1 (Pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose), Days 29 and 57 (Pre-dose and at 1, 2, 3 hours post-dose), Day 169

Part 1: Number of Participants Achieving Response Rate (RR) Based on Reduction of Hepatitis B Surface Antigen (HBsAg) Level From Baseline

The RR was based on the proportion of participants with at least a 1.5 logarithm to the base 10 (log10) international units per milliliter (IU/mL) reduction of HBsAg levels from Baseline at any time up to Day 60. Number of participants who achieved \>1.5 log10 IU/mL decrease in HBsAg levels at any time up to Day 60 are presented.

Time frame: Up to Day 60

Part 2: Number of Participants Achieving RR Based on Reduction of HBsAg Level From Baseline

The RR was based on the proportion of participants with at least a 1.5 log10 IU/mL reduction of HBsAg levels from Baseline at any time up to Day 85. Number of participants who achieved \>1.5 log10 IU/mL decrease in HBsAg levels at any time up to Day 85 are presented.

Time frame: Up to Day 85

Secondary Outcomes

Part 1: Change From Baseline in log10 Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Indicated Time Points

Blood samples were collected from participants to assess HBV DNA viral load. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Log10 change from Baseline was calculated as log10(Post-Dose Visit Value/Baseline).

Time frame: Baseline (Day 1 pre-dose), Day 1: 8 hours, Days 3, 8, 15, 22, 30 and 60

Part 2: Change From Baseline in log10 HBV DNA Viral Load in Plasma at Indicated Time Points (Up to Day 169-Interim Analysis)

Time frame: Baseline (Day 1 pre-dose) and Up to Day 169

Part 2: Change From Baseline in log10 HBV DNA Viral Load in Plasma at Indicated Time Points (Up to Day 450-Optional Follow-up)

Time frame: Baseline (Day 1 pre-dose) and Up to Day 450

Part 1: Change From Baseline in log10 Hepatitis B Virus Surface Antigen (HBsAg) Levels in Plasma at Indicated Time Points

Blood samples were collected from participants to assess HBsAg levels. Baseline was defined as the last assessment before the first dose of the study treatment (Day 1 pre-dose). Log10 change from Baseline was calculated as log10(Post-Dose Visit Value/Baseline).

Time frame: Baseline (Day 1 pre-dose) and Day 1: 8 hours, Days 3, 8, 15, 22, 30 and 60

Part 2: Change From Baseline in log10 HBsAg Levels in Plasma at Indicated Time Points (Up to Day 169-Interim Analysis)

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

Overview

Conditions

Interventions

Eligibility

Locations (21)

Outcomes

Primary Outcomes

Secondary Outcomes