Hepatitis B
Conditions
Interventions
investigational material(s)
Generic name etc : GSK3389404
INN of investigational material : -
Therapeutic category code : 391 Agents for liver disease
Dosage and Administration for Investigational mat
Sponsors
GlaxoSmithKline
Eligibility
Sex/Gender
All
Inclusion 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/meter, 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 less than 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 or more 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
Exclusion criteria
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 more than 200 nanogram (ng)/mL. If the screening alpha-fetoprotein concentration is 50 or more ng/mL and less than 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 more than 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 more than 1.25 X ULN. Serum albumin concentration less than 3.5 grams (g)/deciliter (dL). International normalized ratio (INR) more than 1.25. Platelet count less than 140 X 10^9/L. Serum creatinine concentration greater than the ULN. Glomerular Filtration Rate (GFR) = 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,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| efficacy safety 1.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. 2.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. 3.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. 4.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. 5.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. 6.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 ea | — |
Secondary
| Measure | Time frame |
|---|---|
| safety efficacy 1.HBV DNA level in plasma: Part 1 [ Time Frame: Up to 61 days ] HBV DNA concentration levels to assess the PK effect of GSK3389404 2.HBsAg level in plasma: Part 1 [ Time Frame: Up to 61 days ] HBsAg concentration levels to assess the PK effect of GSK3389404 3.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 4.HBV DNA level in plasma: Part 2 [ Time Frame: Up to 457 days ] HBV DNA concentration levels to assess the PK effect of GSK3389404 5.HBsAg level in plasma: Part 2 [ Time Frame: Up to 457 days ] HBsAg concentration levels to assess the PK effect of GSK3389404 6.HBeAg level in plasma: Part 2 [ Time Frame: Up to 457 days ] HBeAg concentration levels to assess the PK effect of GSK3389404 7.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. 8.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 9.Cmax of GSK3389404 metabolite (ISIS 505358): Part 2 [ Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, Day 29, Day 57 and Day 169 ] Blood samples will be collected at specific time points for calculating Cmax 10.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 11.Tmax of GSK3389404 metabolite (ISIS 505358): Part 2 [ Time Frame: Pre-dose and 1, 2, and 3 hours post dose on Day 1, Day 29, Day 57 and Day 169 ] Blood samples will be collected at specific time points for calculating Tmax 12.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 ] | — |
Countries
Asia except Japan, Japan
Outcome results
None listed