Four-part, Randomized, Double-blind (Parts 1, 2A, 3 and 4), Multi-center, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK3965193 Monotherapy in Healthy Participants and in Participants Living With Chronic Hepatitis B Infection; and GSK3965193 in Combination With Bepirovirsen in Participants Living With Chronic Hepatitis B Infection

GlaxoSmithKline15 个研究点分布在 6 个国家目标入组 74 人开始时间: 2022年4月14日最近更新: 2026年6月16日

适应症

干预措施

试验速览

阶段: 1 期
状态: 终止
发起方: GlaxoSmithKline
入组人数: 74
试验地点: 15
主要终点: Parts 1 and 2B: Number of participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This Phase 1/2a multiple part study is a first time-in-human (FTIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single (Part 1) and repeat doses (Part 2) of GSK3965193 in healthy participants. Part 3 will evaluate the ability of GSK3965193 to lower hepatitis B virus surface antigen (HBsAg) in participants living with chronic hepatitis B infection (PLWCHB) and will be given the option to subsequently receive treatment with open label bepirovirsen. Part 4 will evaluate the safety and tolerability of combination therapy with GSK3965193 and bepirovirsen and the potential to effect sustained virologic response in PLWCHB.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Crossover
主要目的: Treatment
盲法: Triple (Participant, Care Provider, Investigator)

盲法说明

This is a double-blind study

入排标准

年龄范围: 18 Years 至 65 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 是

入选标准

•Parts 1 and 2: Participants between 18 and 55 years of age inclusive, at the time of signing the informed consent.
•Parts 3 and 4: Participants between 18 and 65 years of age inclusive, at the time of signing the informed consent.
•Body weight >=50 kilograms (kg) and body mass index within the range 18-32 kilograms per square meter (kg/m^2) (inclusive).
•Male or female participant: a. Parts 1 and 2: woman of nonchildbearing potential only. b. Parts 3 and 4: woman of nonchildbearing potential or woman of child-bearing potential who is not pregnant or breastfeeding and is using a contraceptive method that is highly effective.
•Capable of giving signed informed consent.
•Additional Inclusion Criteria for PLWCHB (Parts 3 and 4).
•Participants who have documented chronic hepatitis B virus (HBV) infection >=6 months prior to screening.
•Participants currently receiving stable NA therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, entecavir).
•Plasma or serum HBsAg concentration >100 IU/mL.
•Plasma or serum HBV deoxyribonucleic acid (DNA) concentration <90 IU/mL.
•Hepatitis B virus e-antigen (HBeAg) positive or negative.
•Alanine aminotransferase (ALT) <=2 times the upper limit of normal (ULN)

排除标准

•Exclusion Criteria for Healthy Participants:
•Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening
•A current diagnosis of migraine headache
•ALT >1 times ULN.
•Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%])
•Corrected QT interval (QTc) >450 milliseconds (msec)
•Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19)
•Participants with known COVID-19 positive contacts in the past 14 days.
•For participants in Part 2A: i. Personal history or family history of peripheral neuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy
•Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of >5 pack years
•Exclusion Criteria for PLWCHB:
•Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination, aside from chronic HBV infection.
•Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).
•History of or suspected liver cirrhosis and/or evidence of cirrhosis.
•Diagnosed or suspected hepatocellular carcinoma.
•History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer).
•History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause] or history/presence of other diseases Exclusion Criteria for Healthy Participants:
•Positive Hepatitis A virus antibody (HAV Ab immunoglobulin M [IgM]), or positive for HBV, hepatitis C virus (HCV) or human immunodeficiency virus (HIV) at screening.
•A current diagnosis of migraine headache
•ALT >1 times ULN.
•Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%]).
•Corrected QT interval (QTc) >450 milliseconds (msec).
•Signs and symptoms suggestive of Coronavirus Disease 2019 (COVID-19).
•Participants with known COVID-19 positive contacts in the past 14 days.
•For participants in Part 2A: i. Personal history or family history of peripheral neuropathy. ii. A score ≥4 on the Toronto clinical scoring system for polyneuropathy.
•Current or previous use of tobacco- or nicotine-containing products (for example (e.g.) cigarettes, nicotine patches or electronic devices) within 6 months before screening and/or have a smoking pack history of >5 pack years
•Exclusion Criteria for PLWCHB:
•Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination, aside from chronic HBV infection.
•Co-infection with or past history of HCV, HIV or Hepatitis D virus (HDV).
•History of or suspected liver cirrhosis and/or evidence of cirrhosis.
•Diagnosed or suspected hepatocellular carcinoma.
•History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer).
•History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause] or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).
•History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinaemia, uncontrolled hypertension).
•History of alcohol or drug abuse/dependence: a. Current alcohol use as judged by investigator to potentially interfere with participant compliance. b. History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance.
•History or other evidence of bleeding from esophageal varices.
•Documented history or other evidence of metabolic liver disease within 1 year of randomization.
•Personal history or family history of peripheral neuropathy.
•A score >4 on the Toronto clinical scoring system for polyneuropathy.
•History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral corticosteroids, interferon or pegylated interferon) within the 3 months prior to randomization or the expectation that such treatment will be needed at any time during the study.
•Abnormal and clinically significant 12-lead ECG finding.
•Currently taking, or taken within 3 months prior to randomization, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use.
•Participants requiring anti-coagulation therapies.
•Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 months prior to the first dosing day.
•Positive test for COVID-19 infection.

研究组 & 干预措施

Part 1: Cohort 1 - Placebo/GSK3965193 Dose 2/Dose 3/Dose 4

Experimental

Healthy participants received a single dose of placebo oral solution on Day 1 in Treatment Period 1; followed by a single dose of GSK3965193 Dose 2 oral solution on Day 1 in Treatment Period 2; followed by a single dose of GSK3965193 Dose 3 oral solution on Day 1 in Treatment Period 3; further followed by a single dose of GSK3965193 Dose 4 oral solution on Day 1 in Treatment Period 4. Dose 4 of GSK3965193 was higher than Dose 3 and Dose 3 was higher than Dose 2.