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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Hepatitis B

Treatments: Drug: GSK3389404; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03020745

205670

Details and patient eligibility

About

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.

Enrollment: 78 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Double Blind

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78 participants in 6 patient groups

Part 1, Cohort A : GSK3389404 30 mg SC or Placebo

Experimental group

Description:

Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo

Treatment:

Drug: Placebo

Drug: GSK3389404

Part 1, Cohort B: GSK3389404 60 mg SC or Placebo

Experimental group

Description:

Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo

Treatment:

Drug: Placebo

Drug: GSK3389404

Part 1, Cohort C: GSK3389404 120 mg SC or Placebo

Experimental group

Description:

Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo

Treatment:

Drug: Placebo

Drug: GSK3389404

Part 1, Cohort C1 (optional): GSK3389404 120 mg SC or Placebo

Experimental group

Description:

Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo

Treatment:

Drug: Placebo

Drug: GSK3389404

Part 1, Cohort D: GSK3389404 </= 240 mg SC or Placebo

Experimental group

Description:

Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 \<= 240 mg or matching placebo

Treatment:

Drug: Placebo

Drug: GSK3389404

Part 2: GSK3389404 or placebo SC

Experimental group

Description:

Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1. The treatments for Part 2 are 60 mg GSK3389404 weekly, 120 mg bi-weekly GSK3389404, 120 mg GSK3389404 weekly or placebo.

Treatment:

Drug: Placebo

Drug: GSK3389404