Last updated: 08/18/2025 10:30:07
Study of GSK3965193 in Healthy Participants and Participants Living with Chronic Hepatitis B Infection
GSK study ID
214760
Clinicaltrials.gov ID
EudraCT ID
EU CT Number
Trial status
Recruitment complete
Recruitment complete
Trial overview
Official title: 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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Cross-over
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:
Parts 1 and 2B: Number of participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs
Timeframe: Up to 14 days
Part 2A: Number of participants with AEs, SAEs, and withdrawals due to AEs
Timeframe: Up to 42 Days
Parts 1: Number of participants with clinically significant changes in laboratory parameters
Timeframe: Up to 2 days
Parts 2B: Number of participants with clinically significant changes in laboratory parameters
Timeframe: Up to 14 days
Parts 1 and 2B: Number of participants with clinically significant changes in vital signs and cardiac parameters (electrocardiogram [ECG])
Timeframe: Up to 14 days
Part 2A: Number of participants with clinically. significant changes in laboratory parameters, vital signs, cardiac parameters (ECG)
Timeframe: Up to 21 days
Part 2A: Number of participants with clinically. significant nerve changes
Timeframe: Up to 42 days
Part 1 and 2B: Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) of GSK3965193 following single dose administration
Timeframe: Up to 4 days
Part 2A: AUC(0-tau) of GSK3965193 following repeat dose administration
Timeframe: Up to 17 days
Part 1 and 2B: maximum observed concentration (Cmax) of GSK3965193 following single dose administration
Timeframe: Up to 4 days
Part 2A: Cmax of GSK3965193 following repeat dose administration
Timeframe: Up to 17 days
Part 1 and 2B: Time to maximum observed plasma drug concentration (Tmax) of GSK3965193 following single dose administration
Timeframe: Up to 4 days
Part 2A: Tmax of GSK3965193 following repeat dose administration
Timeframe: Up to 17 days
Part 1 and 2B: Apparent terminal half-life (T1/2) of GSK3965193 following single dose administration
Timeframe: Up to 4 days
Part 2A: T1/2 of GSK3965193 following repeat. dose administration
Timeframe: Up to 17 days
Part 3: Number of participants with AEs, SAEs, and withdrawals due to AEs
Timeframe: Up to 42 days
Part 4: Number of participants with AEs, SAEs, and withdrawals due to AEs
Timeframe: Up to 48 weeks
Part 3: Number of participants with clinically. significant changes in laboratory parameters and vital signs
Timeframe: Up to 42 days
Part 3: Number of participants with clinically. significant changes in cardiac parameters (ECG)
Timeframe: Up to 42 days
Part 4: Number of participants with clinically. significant changes in laboratory parameters and vital signs
Timeframe: Up to 48 weeks
Part 4: Number of participants with clinically. significant changes in cardiac parameters (ECG)
Timeframe: Up to 48 weeks
Part 3: Number of participants with clinically. significant nerve changes
Timeframe: Up to 42 days
Part 4: Number of participants with clinically. significant nerve changes
Timeframe: Up to 48 weeks
Part 3: Maximum reduction of serum HBsAg levels from Baseline
Timeframe: Baseline and up to 6 weeks
Part 4: Number of participants achieving. complete response
Timeframe: Up to 48 weeks
Secondary outcomes:
Part 2B: AUC (0-inf) of GSK3965193 following. single dose administration
Timeframe: Up to 4 days
Part 2B: Cmax of GSK3965193 following single dose administration
Timeframe: Up to 4 days
Part 3: AUC(0-tau) of GSK3965193 following. repeat dose administration
Timeframe: Up to 42 days
Part 3: Cmax of GSK3965193 following repeat dose administration
Timeframe: Up to 42 days
Part 3: Tmax of GSK3965193 following repeat. dose administration
Timeframe: Up to 42 days
Part 3: T1/2 of GSK3965193 following repeat. dose administration
Timeframe: Up to 42 days
Part 3: Change from baseline in serum HBsAg levels from baseline (greater than or equal to [≥] 0.5 times log international units per milliliters [IU/mL])
Timeframe: Baseline and up to 42 days
Part 3, Sub cohort 7: Number of participants with AEs, SAEs, and withdrawals due to AEs
Timeframe: Week 7 to 54 weeks
Part 3, Sub cohort 7: Number of participants with clinically significant changes in laboratory parameters and vital signs
Timeframe: Week 7 to 54 weeks
Part 4: Number of participants with HBsAg loss
Timeframe: Up to 48 weeks
Interventions:
Enrollment:
74
Primary completion date:
2025-19-05
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Hepatitis B
Product
Not applicable
Collaborators
Not applicable
Study date(s)
April 2022 to April 2026
Type
Interventional
Phase
1/2
Participation criteria
Sex
Female & Male
Age
18 - 65 Years
Accepts healthy volunteers
Yes
- 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.
- 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
Inclusion and exclusion criteria
Inclusion criteria:
- 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)
Exclusion criteria:
- 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.
Trial location(s)
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Study documents
No study documents available.
Results overview
Study Results yet to be posted
Recruitment status
Recruitment complete
Actual primary completion date
2025-19-05
Actual study completion date
Not applicable
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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