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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

31 Oct 2024 → 8 Apr 2026

Decision date (initial)

2024-08-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509684-24-00

ClinicalTrials.gov

NCT05330455

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic

•To assess the safety and tolerability of oral administration of GSK3965193 monotherapy (Part 3) and in combination with bepirovirsen (Part 4). • To evaluate pharmacodynamic (PD) effect of GSK3965193 monotherapy in PLWCHB (Part 3). • To evaluate efficacy of GSK3965193 in combination with bepirovirsen in PLWCHB (Part 4)

Secondary objectives 3

1. To evaluate the PK characteristics of repeat doses of GSK3965193 in PLWCHB (Part 3)
2. To assess the safety and tolerability of bepirovirsen monotherapy in PLWCHB who have completed GSK3965193/placebo monotherapy (Part 3)
3. To evaluate PD effect of GSK3965193 in combination with bepirovirsen in PLWCHB (Part 4)

Conditions and MedDRA coding

Hepatitis B

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Between 18 (or local legal age of consent) and 65 years of age inclusive, at the time of signing the informed consent
2. Body weight >=50 kg and body mass index within the range 18-32 kg/m2 (inclusive)
3. a. A male participant is eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study treatment (GSK3965193) in Parts 1, 2 and 3 and at least 90 days after the last dose of bepirovirsen in Part 4 or the optional Part 3 extension: i. Refrain from donating sperm AND ii. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below: Agree to use a male condom [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential who is not currently pregnant
4. b. A female participant is eligible to participate in Parts 3 and 4 if she is not pregnant or breastfeeding AND at least 1 of the following conditions applies: 1. Is a WONCBP as defined in Section 10.4 (Appendix 4), OR 2. is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year) as described in Section 10.4.2, preferably with low user dependency during the intervention period and for at least 7 days after the last dose of study treatment in Part 3 and 90 days after the last dose of bepirovirsen in Part 4 or if the participant chooses to continue with the optional bepirovirsen extension in Part 3. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention). ii. A WOCBP must have 1. A negative highly sensitive pregnancy test (serum) at screening and on Day -1, see Section 8.2.8 (Pregnancy Testing). iii. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.2.8. iv. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
5. Participants who have documented chronic HBV infection ≥6 months prior to screening
6. Participants currently receiving stable nucleos(t)ide analog (NA) therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, entecavir). “Stable” is defined as no changes to the nucleos(t)ide regimen for at least 6 months prior to screening and with no planned changes to the regimen for the duration of the study
7. Plasma or serum HBsAg concentration >100 IU/mL
8. Plasma or serum HBV DNA concentration <90 IU/mL
9. ALT <=2 x the upper limit of normal (ULN)

Exclusion criteria 23

1. Clinically significant abnormalities affecting physical or mental health in medical history or on physical examination (e.g., moderate-severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant/unstable cardiac disease (including pacemaker or AICD), uncontrolled diabetes, bleeding diathesis or coagulopathy), apart from chronic HBV infection.
2. Co-infection with: a. Current or past history of HCV b. HIV c. Hepatitis D virus (HDV)
3. History of or suspected liver cirrhosis and/or evidence of cirrhosis
4. Diagnosed or suspected hepatocellular carcinoma
5. History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer). Participants under evaluation for possible malignancy are not eligible
6. 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)
7. History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinaemia, uncontrolled hypertension)
8. History of alcohol or drug abuse/dependence judged by investigator to potentially interfere with participant compliance
9. History of or other evidence of bleeding from esophageal varices
10. Documented history or other evidence of metabolic liver disease within 1 year of randomization
11. Documented history or other evidence of diabetes (regardless of insulin-dependence)
12. Personal history or family history of peripheral neuropathy
13. A score >4 on the Toronto Clinical Scoring System for Polyneuropathy
14. History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral corticosteroids) within the 3 months prior to randomization or the expectation that such treatment will be needed at any time during the study
15. Abnormal and clinically significant 12-lead ECG finding
16. Currently taking, or taken within 3 months prior to randomisation, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or topical/inhaled steroid use
17. Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids, will be excluded
18. Participants requiring anti-coagulation therapies
19. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 months prior to the first dosing day. Patients who have received a course of bepirovirsen, even if it has been more than 12 months, are excluded
20. Positive test for COVID-19 infection
21. Currently taking, or has taken within 12 months of randomization, any interferon-containing therapy.
22. The participant 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)
23. Laboratory results as follows: a. Serum albumin ≤3.5 g/dL b. Glomerular filtration rate (GFR) ≤60 mL/min /1.73m2 as calculated by the chronic kidney diseases epidemiology collaboration (2021 CKD-EPI) formula c. INR >1.25 d. Platelet count <140 X 109 /L e. Total bilirubin >1.25 x ULN f. Urine 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Incidence of AEs, SAEs, withdrawals due to AEs
2. Incidence of clinically significant laboratory parameters (haematology, clinical chemistry, urinalysis), vital signs, cardiac parameters (electrocardiogram), and sensory nerve conduction
3. In Part 3 - Maximum reduction of serum HBsAg levels from baseline over 6 weeks (4 weeks on treatment and 2 weeks post-treatment)
4. In Part 4 - Achieving complete response (undetectable serum HBV DNA and HBsAg for 6 consecutive months after the planned end of treatment of bepirovirsen)

Secondary endpoints 4

1. In Part 3 - AUC(0-tau), Cmax, Tmax, and apparent terminal half-life (T1/2) will be calculated as data permits
2. In Part 3 - >=0.5x log IU/mL reduction of serum HBsAg levels from baseline anytime during the study (on-treatment and post-treatment)
3. In Part 3 - Incidence of AEs, SAEs, withdrawals due to AEs and incidence of clinically significant laboratory parameters (haematology, clinical chemistry, urinalysis) and vital signs occurring in participants taking bepirovirsen monotherapy after completing GSK3965193/placebo monotherapy
4. In Part 4 - HBsAg loss (defined by two consecutive measurements of HBsAg below the limit of quantification) anytime during the study (on-treatment and post-treatment)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 14

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications