Clinical trial NCT05330455: Study of GSK3965193 in Healthy Participants and Participants Living With Chronic Hepatitis B Infection
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hepatitis B
Keywords: Bepirovirsen
Chronic hepatitis B
First-time-in-human
GSK3965193
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2022-04-15
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Parts 1 and Part 2B are crossover and Part 2A, Part 3 and Part 4 are parallel group
Primary purpose: TREATMENT

Brief 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) 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.


Eligibility 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.

Primary outcomes:
measure: 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
measure: Part 2A: Number of participants with AEs, SAEs, and withdrawals due to AEs
timeFrame: Up to 42 Days
measure: Parts 1: Number of participants with clinically significant changes in laboratory parameters
timeFrame: Up to 2 days
measure: Parts 2B: Number of participants with clinically significant changes in laboratory parameters
timeFrame: Up to 14 days
measure: Parts 1 and 2B: Number of participants with clinically significant changes in vital signs and cardiac parameters (electrocardiogram [ECG])
timeFrame: Up to 14 days
measure: Part 2A: Number of participants with clinically. significant changes in laboratory parameters, vital signs, cardiac parameters (ECG)
timeFrame: Up to 21 days
measure: Part 2A: Number of participants with clinically. significant nerve changes
timeFrame: Up to 42 days
measure: 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
measure: Part 2A: AUC(0-tau) of GSK3965193 following repeat dose administration
timeFrame: Up to 17 days
measure: Part 1 and 2B: maximum observed concentration (Cmax) of GSK3965193 following single dose administration
timeFrame: Up to 4 days
measure: Part 2A: Cmax of GSK3965193 following repeat dose administration
timeFrame: Up to 17 days
measure: Part 1 and 2B: Time to maximum observed plasma drug concentration (Tmax) of GSK3965193 following single dose administration
timeFrame: Up to 4 days
measure: Part 2A: Tmax of GSK3965193 following repeat dose administration
timeFrame: Up to 17 days
measure: Part 1 and 2B: Apparent terminal half-life (T1/2) of GSK3965193 following single dose administration
timeFrame: Up to 4 days
measure: Part 2A: T1/2 of GSK3965193 following repeat. dose administration
timeFrame: Up to 17 days
measure: Part 3: Number of participants with AEs, SAEs, and withdrawals due to AEs
timeFrame: Up to 42 days
measure: Part 4: Number of participants with AEs, SAEs, and withdrawals due to AEs
timeFrame: Up to 48 weeks
measure: Part 3: Number of participants with clinically. significant changes in laboratory parameters and vital signs
timeFrame: Up to 42 days
measure: Part 3: Number of participants with clinically. significant changes in cardiac parameters (ECG)
timeFrame: Up to 42 days
measure: Part 4: Number of participants with clinically. significant changes in laboratory parameters and vital signs
timeFrame: Up to 48 weeks
measure: Part 4: Number of participants with clinically. significant changes in cardiac parameters (ECG)
timeFrame: Up to 48 weeks
measure: Part 3: Number of participants with clinically. significant nerve changes
timeFrame: Up to 42 days
measure: Part 4: Number of participants with clinically. significant nerve changes
timeFrame: Up to 48 weeks
measure: Part 3: Maximum reduction of serum HBsAg levels from Baseline
timeFrame: Baseline and up to 6 weeks
measure: Part 4: Number of participants achieving. complete response
timeFrame: Up to 48 weeks
Secondary outcomes:
measure: Part 2B: AUC (0-inf) of GSK3965193 following. single dose administration
timeFrame: Up to 4 days
measure: Part 2B: Cmax of GSK3965193 following single dose administration
timeFrame: Up to 4 days
measure: Part 3: AUC(0-tau) of GSK3965193 following. repeat dose administration
timeFrame: Up to 42 days
measure: Part 3: Cmax of GSK3965193 following repeat dose administration
timeFrame: Up to 42 days
measure: Part 3: Tmax of GSK3965193 following repeat. dose administration
timeFrame: Up to 42 days
measure: Part 3: T1/2 of GSK3965193 following repeat. dose administration
timeFrame: Up to 42 days
measure: 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
measure: Part 3, Sub cohort 7: Number of participants with AEs, SAEs, and withdrawals due to AEs
timeFrame: Week 7 to 54 weeks
measure: Part 3, Sub cohort 7: Number of participants with clinically significant changes in laboratory parameters and vital signs
timeFrame: Week 7 to 54 weeks
measure: Part 4: Number of participants with HBsAg loss
timeFrame: Up to 48 weeks
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Grenoble Cedex 9
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Nantes cedex 1
country: France
facility: GSK Investigational Site
city: Rennes
country: France
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
city: Monza MB
country: Italy
facility: GSK Investigational Site
city: Daegu
country: Korea, Republic of
facility: GSK Investigational Site
city: Pusan
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: