A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects
Condition: Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Intervention: GSK3389404; Placebo
Intervention description: GSK3389404 is available as Clear colorless to slightly yellow solution for injection.; Placebo is available as a Clear colorless solution.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Pharmacokinetics; Safety; Pharmacodynamics; Efficacy; Chronic Hepatitis B; GSK3389404

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, 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.
    

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 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.