Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection

Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05330455
• Other study ID #: 214760
• Secondary ID: 2021-005117-13
• Status: Recruiting
• Phase: Phase 2
• Start date: April 14, 2022
• Est. completion date: January 1, 2026

Study information

• Verified date: June 2023
• Source: GlaxoSmithKline
• Contact: US GSK Clinical Trials Call Center
• Phone: 877-379-3718
• Email: GSKClinicalSupportHD[@]gsk.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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). 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 132
• Est. completion date: January 1, 2026
• Est. primary completion date: January 1, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 non-childbearing potential only. b. Parts 3 and 4: woman of non-childbearing 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 in medical history, 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 8 weeks prior to the first dose of study drug 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 of screening, 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.

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• GSK3965193
GSK3965193 will be administered
• Placebo to match GSK3965193
Placebo to match GSK3965193 will be administered
• Bepirovirsen
Bepirovirsen will be administered

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	Cambridge

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parts 1 and 2B: Number of participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs		Up to 14 days
Primary	Part 2A: Number of participants with AEs, SAEs, and withdrawals due to AEs		Up to 42 Days
Primary	Parts 1 and 2B: Number of participants with clinically significant changes in laboratory parameters		Up to 2 days
Primary	Parts 1 and 2B: Number of participants with clinically significant changes in vital signs and cardiac parameters (electrocardiogram [ECG])		Up to 14 days
Primary	Part 2A: Number of participants with clinically significant changes in laboratory parameters, vital signs, cardiac parameters (ECG)		Up to 21 days
Primary	Part 2A: Number of participants with clinically significant nerve changes		Up to 6 weeks
Primary	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		Up to 4 days
Primary	Part 2A: AUC(0-tau) of GSK3965193 following repeat dose administration		Up to 17 days
Primary	Part 1 and 2B: maximum observed concentration (Cmax) of GSK3965193 following single dose administration		Up to 4 days
Primary	Part 2A: Cmax of GSK3965193 following repeat dose administration		Up to 17 days
Primary	Part 1 and 2B: Time to maximum observed plasma drug concentration (Tmax) of GSK3965193 following single dose administration		Up to 4 days
Primary	Part 2A: Tmax of GSK3965193 following repeat dose administration		Up to 17 days
Primary	Part 1 and 2B: Apparent terminal half-life (T1/2) of GSK3965193 following single dose administration		Up to 4 days
Primary	Part 2A: T1/2 of GSK3965193 following repeat dose administration		Up to 17 days
Primary	Part 3: Number of participants with AEs, SAEs, and withdrawals due to AEs		Up to 85 days
Primary	Part 4: Number of participants with AEs, SAEs, and withdrawals due to AEs		Up to 36 weeks
Primary	Part 3: Number of participants with clinically significant changes in laboratory parameters and vital signs		Up to 85 days
Primary	Part 3: Number of participants with clinically significant changes in cardiac parameters (ECG)		Up to 36 days
Primary	Part 4: Number of participants with clinically significant changes in laboratory parameters and vital signs		Up to 36 weeks
Primary	Part 4: Number of participants with clinically significant changes in cardiac parameters (ECG)		Up to 13 weeks
Primary	Part 3: Number of participants with clinically significant nerve changes		Up to 85 days
Primary	Part 4: Number of participants with clinically significant nerve changes		Up to 13 weeks
Primary	Part 3: Change from Baseline in HBsAg levels		Baseline and up to 6 weeks
Primary	Part 4 : Number of participants achieving sustained virologic response		Up to 36 weeks
Primary	Parts 1 and 2B: Number of participants with. adverse events (AEs), serious adverse events. (SAEs), and withdrawals due to AEs		Up to 14 days
Primary	Parts 1 and 2B: Number of participants with. clinically significant changes in laboratory. parameters		Up to 2 days
Primary	Parts 1 and 2B: Number of participants with. clinically significant changes in vital signs and. cardiac parameters (electrocardiogram [ECG])		Up to 14 days
Primary	Part 2A: Number of participants with clinically. significant changes in laboratory parameters, vital signs, cardiac parameters (ECG)		Up to 21 days
Primary	Part 2A: Number of participants with clinically. significant nerve changes		Up to 42 Days
Primary	Part 2A: T1/2 of GSK3965193 following repeat. dose administration		Up to 17 days
Primary	Part 3: Number of participants with clinically. significant changes in laboratory parameters and vital signs		Up to 85 days
Primary	Part 3: Number of participants with clinically. significant changes in cardiac parameters (ECG)		Up to 36 days
Primary	Part 4: Number of participants with clinically. significant changes in laboratory parameters and vital signs		Up to 36 weeks
Primary	Part 4: Number of participants with clinically. significant changes in cardiac parameters (ECG)		Up to 13 weeks
Primary	Part 3: Number of participants with clinically. significant nerve changes		Up to 85 days
Primary	Part 4: Number of participants with clinically. significant nerve changes		Up to 13 weeks
Primary	Part 3: Maximum reduction of serum HBsAg levels from Baseline		Baseline and up to 6 weeks
Primary	Part 4: Number of participants achieving. sustained virologic response		Up to 36 weeks
Secondary	Part 2B: AUC(0-inf) of GSK3965193 following single dose administration		Up to 5 days
Secondary	Part 2B: Cmax of GSK3965193 following single dose administration		Up to 5 days
Secondary	Part 3: AUC(0-tau) of GSK3965193 following repeat dose administration		Up to 29 days
Secondary	Part 3: Cmax of GSK3965193 following repeat dose administration		Up to 29 days
Secondary	Part 3: Tmax of GSK3965193 following repeat dose administration		Up to 29 days
Secondary	Part 3: T1/2 of GSK3965193 following repeat dose administration		Up to 29 days
Secondary	Part 3: Change from Baseline in HBsAg levels (greater than or equal to [>=] 0.5 times log international units per milliliters [IU/mL])		Baseline and up to 85 days
Secondary	Part 4: Number of participants with HBsAg loss		Up to 36 weeks
Secondary	Part 2B: AUC (0-inf) of GSK3965193 following. single dose administration		Up to 4 days
Secondary	Part 2B: Cmax of GSK3965193 following single. dose administration		Up to 4 days
Secondary	Part 3: AUC(0-tau) of GSK3965193 following. repeat dose administration		Up to 29 days
Secondary	Part 3: Tmax of GSK3965193 following repeat. dose administration		Up to 29 days
Secondary	Part 3: T1/2 of GSK3965193 following repeat. dose administration		Up to 29 days
Secondary	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])		Baseline and up to 85 days
Secondary	Number of participants with HBsAg loss		Up to 36 weeks