Last updated: 06/07/2023 04:00:25
A study of GSK3228836 in participants with chronic hepatitis B (CHB)B-Clear
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study to Assess the Efficacy and Safety of Treatment with GSK3228836 in Participants with Chronic Hepatitis B Virus (B-Clear)
Trial description: Chronic hepatitis B virus (HBV) infection is a significant worldwide medical problem. GSK3228836 demonstrated target engagement in CHB participants who were not on treatment and in CHB participants on stable nucleos(t)ide therapy. This study is intended to evaluate if treatment with GSK3228836 can achieve sustained virologic response (SVR), that is hepatitis B virus surface antigen (HBsAg) less than (<) lower limit of quantitation (LLOQ) and HBV deoxyribonucleic acid (DNA) <LLOQ sustained for 24 weeks post-GSK3228836 treatment end. In addition, the study will also evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of GSK3228836 in the 4 dosing regimens. This study will assess the efficacy and safety of treatment with GSK3228836 in two populations of participants with CHB; participants on stable nucleos(t)ide treatment (Cohort 1) and participants who are not currently on nucleos(t)ide therapy (Cohort 2). For each population, participants will be randomized into one of the 4 different parallel arms to receive treatment. The study will consist of a screening, treatment, and post-treatment follow-up phase. Approximately, 440 participants will be enrolled in the study.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Single (Participant)
Allocation:
Randomized
Primary outcomes:
Percentage of participants achieving SVR
Timeframe: Up to Week 48
Secondary outcomes:
Percentage of participants achieving HBsAg <LLOQ
Timeframe: Up to Week 24
Percentage of participants achieving HBV DNA <LLOQ
Timeframe: Up to Week 24
Percentage of participants with alanine aminotransferase (ALT) normalization over time in absence of rescue medication
Timeframe: Up to Week 48
HBsAg level at indicated time points
Timeframe: Day 1 to Week 48
Change from Baseline in HBsAg over time
Timeframe: Baseline (Day 1) and up to Week 48
HBV DNA level at indicated time points
Timeframe: Day 1 to Week 48
Change from Baseline in HBV DNA over time
Timeframe: Baseline (Day 1) and up to Week 48
Hepatitis B virus e-antigen (HBeAg) level at indicated time points
Timeframe: Day 1 to Week 48
Change from Baseline in HBeAg level over time
Timeframe: Baseline (Day 1) and up to Week 48
Hepatatis B surface antibody (HBsAb) level at indicated time points
Timeframe: Day 1 to Week 48
Change from Baseline in HBsAb level over time
Timeframe: Baseline (Day 1) and up to Week 48
HBeAb level at indicated time points
Timeframe: Day 1 to Week 48
Change from Baseline in HBeAb level over time
Timeframe: Baseline (Day 1) and up to Week 48
Time to ALT normalization in absence of rescue medication
Timeframe: Day 1 to Week 48
Percentage of participants achieving SVR over time
Timeframe: Up to Week 24
Area under the concentration-time curve (AUC) following administration of GSK3228836- Intensive pharmacokinetics (PK)
Timeframe: Any one week between Week 14 to Week 24
AUC following administration of nucleos(t)ide therapy- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Concentration at the end of the dosing interval (Ctau) following administration of GSK3228836- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Ctau following administration of nucleos(t)ide therapy- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Maximum observed concentration (Cmax) following administration of GSK3228836- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Cmax following administration of nucleos(t)ide therapy- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Time of maximum observed concentration (tmax) following administration of GSK3228836- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Tmax following administration of nucleos(t)ide therapy- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Apparent subcutaneous plasma clearance for GSK3228836- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Apparent oral plasma clearance for nucleos(t)ide- Intensive PK
Timeframe: Any one week between Week 14 to Week 24
Terminal half-life (T1/2) following administration of GSK3228836- All participants
Timeframe: From Week 15 to Week 44
T1/2 following administration of nucleos(t)ide therapy- All participants
Timeframe: Any one week between Week 14 to Week 24
Ctau following administration of GSK3228836- All participants
Timeframe: From Week 1 to Week 25
Ctau following administration of nucleos(t)ide therapy- All participants
Timeframe: From Week 1 to Week 25
Interventions:
Drug: GSK3228836
Drug: Placebo
Drug: Nucleos(t)ide therapy
Enrollment:
457
Observational study model:
Not applicable
Primary completion date:
2022-18-03
Time perspective:
Not applicable
Clinical publications:
MF Yuen, SG Lim, R Plesniak, K Tsuji, H Janssen, C Pojoga, A Gadano, CP Popescu, T Stepanova, T Asselah, G Diaconescu, HJ Yim, J Heo, E Janczewska, A Wong, N Idriz, M Imamura, G Rizzardini, K Takaguchi, P Andreone, M Arbune, J Hou, SJ Park, A Vata, J Cremer, R Elston, T Lukic, G Quinn, L Maynard, S Kendrick, H Plein, F Campbell, M Paff, D Theodore.Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection .N Engl J Med.2022;387(21):1957-1968
DOI: 10.1056/NEJMoa2210027
PMID: 36346079
Medical condition
Hepatitis B
Product
Not applicable
Collaborators
Not applicable
Study date(s)
July 2020 to March 2022
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- At least 18 years of age at the time of signing the informed consent.
- Participants who have documented chronic HBV infection greater than equal to (>=6) months prior to screening and not currently on nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naive) or must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit; OR Currently receiving stable nucleos(t)ide analogue therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
- Clinically significant abnormalities, aside from chronic HBV infection in medical history (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, uncontrolled diabetes, bleeding diathesis or coagulopathy) or physical examination.
- Co-infection with Current or past history of Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Hepatitis D virus (HDV).
Inclusion and exclusion criteria
Inclusion criteria:
- At least 18 years of age at the time of signing the informed consent.
- Participants who have documented chronic HBV infection greater than equal to (>=6) months prior to screening and not currently on nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naive) or must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit; OR Currently receiving stable nucleos(t)ide analogue therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
- Plasma or serum HBsAg concentration >100 international units per milliliter (IU/mL).
- Plasma or serum HBV DNA concentration: Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 IU/mL; Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.
- ALT for treatment naive participants and for participants who are not currently receiving treatment: ALT <3 times ULN will be included initially if agreed by the independent data monitoring committee (IDMC) after review of safety data, the ALT inclusion criteria may be expanded to include participants with ALT <5 times ULN; ALT less than equal to (<=2) times ULN for participants who are receiving stable nucleos(t)ide analogue therapy.
- Male and/or Female: A male participant is eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study treatment: Refrain from donating sperm AND 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. A female participant is eligible to participate: If she is not pregnant or breastfeeding AND at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1 percent per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment; A WOCBP must have both a confirmed menstrual period prior to the first dose of study intervention (additional evaluation [e.g., amenorrhea in athletes, birth control] should also be considered) and a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study treatment.
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- 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.
- Capable of giving signed informed consent.
Exclusion criteria:
- Clinically significant abnormalities, aside from chronic HBV infection in medical history (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, uncontrolled diabetes, bleeding diathesis or coagulopathy) or physical examination.
- Co-infection with Current or past history of Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Hepatitis D virus (HDV).
- History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7. If only one parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted. Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: Liver biopsy (i.e., Metavir Score F4); Liver stiffness >12 kilopascals (kPa).
- Diagnosed or suspected hepatocellular carcinoma as evidenced by the following: Alpha-fetoprotein concentration >=200 nanogram per milliliter (ng/mL); If the screening alpha fetoprotein concentration is >=50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.
- 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.
- 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, cryoglobulinemia, uncontrolled hypertension).
- Anti-neutrophil cytoplasmic antibodies (ANCA) at screening by itself won’t be an exclusion criterion, but if results are borderline positive or positive: myeloperoxidase-ANCA (MPO-ANCA) (Perinuclear antineutrophil cytoplasmic antibodies [pANCA]) and proteinase 3- ANCA (PR3-ANCA) (Cytoplasmic antineutrophil cytoplasmic antibodies [cANCA]) analysis will be conducted; A discussion with the Medical Monitor will be required to review participant’s complete medical history to ensure no past history or current manifestations of a vasculitic/inflammatory/auto-immune condition before inclusion in study is permitted.
- Low complement C3 (C3) at screening by itself won’t be an exclusion criterion, but if it is present: A discussion with the Medical Monitor is required to review participant’s complete medical history to ensure no past history or current manifestations of vasculitic/inflammatory/auto-immune conditions.
- History of alcohol or drug abuse/dependence: Current alcohol use as judged by investigator to potentially interfere with participant compliance; History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance. Refers to illicit drugs and substances with abuse potential. Medications that are used by the participant as directed, whether over-the-counter or through prescription, are acceptable and would not meet the exclusion criteria.
- Currently taking, or took 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 for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids, will be excluded.
- Currently taking, or took within 12 months of screening, any interferon-containing therapy.
- Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel).
- 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).
- Prior treatment with any oligonucleotide or small interfering ribonucleic acid (RNA) (Small interfering RNA [siRNA]) within 12 months prior to the first dosing day.
- Fridericia’s QT correction formula (QTcF) >=450 milliseconds (msec) (if single electrocardiogram [ECG] at screening shows QTcF>=450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
- Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL), Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula (for Japan, Japanese Society of Nephrology Chronic Kidney Disease Initiative [JSN-CKDI equation]), International normalized ratio (INR) >1.25. Platelet count <140 times 10^9 cells/L, Total bilirubin >1.25 times ULN. For participants with benign unconjugated hyperbilirubinemia with total bilirubin >1.25 times ULN, discussion for inclusion to the study is required with the Medical Monitor, Urine albumin to creatinine ratio (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. In cases where participants have low urine albumin and low urine creatinine levels resulting in a urine ACR calculation >=0.03 mg/mg (or >=30 mg/g), the investigator should confirm that the participant does not have a history of diabetes, hypertension or other risk factors that may affect renal function and discuss with the Medical Monitor, or designee.
- History of/sensitivity to GSK3228836 or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
Trial location(s)
Location
GSK Investigational Site
Decatur, Georgia, United States, 30033
Status
Study Complete
Location
GSK Investigational Site
Victoria, British Columbia, Canada, V8V 3M9
Status
Study Complete
Location
GSK Investigational Site
Port Elizabeth, Eastern Cape, South Africa, 6001
Status
Study Complete
Location
GSK Investigational Site
Kwaguqa Emalahleni, Mpumalanga, South Africa, 1039
Status
Study Complete
Location
GSK Investigational Site
Lenasia Johannesburg, Gauteng, South Africa, 1827
Status
Study Complete
Location
GSK Investigational Site
Pittsburg, Pennsylvania, United States, 15213
Status
Study Complete
Location
GSK Investigational Site
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1181ACH
Status
Study Complete
Location
GSK Investigational Site
Los Angeles, California, United States, 90089
Status
Study Complete
Location
GSK Investigational Site
Richmond, Virginia, United States, 23249
Status
Study Complete
Location
GSK Investigational Site
New York, New York, United States, 10016
Status
Study Complete
Location
GSK Investigational Site
Buenos Aires, Buenos Aires, Argentina, C1280AEB
Status
Study Complete
Location
GSK Investigational Site
Newcastle-upon-Tyne, United Kingdom, NE7 7DN
Status
Study Complete
Location
GSK Investigational Site
Ennerdale, Gauteng, South Africa, 1830
Status
Study Complete
Location
GSK Investigational Site
Durban, KwaZulu- Natal, South Africa, 4052
Status
Study Complete
Location
GSK Investigational Site
Boston, Massachusetts, United States, 02114
Status
Study Complete
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2022-18-03
Actual study completion date
2022-18-03
Plain language summaries
Summary of results in plain language
Available language(s): English, Afrikaans, Bulgarian, Chinese (China), French (Canadian), French, German, Italian, Japanese, Korean, Malay (Malaysia), Polish, Romanian, Russian, Sesotho, Chinese (Singapore), Spanish (Argentina), Spanish, Spanish (United States), Tagalog, Thai, Vietnamese, Xhosa, Zulu, Chinese (Traditional)
To view plain language summaries on trialsummaries.com click here.
Additional information about the trial
Additional information
Not applicable
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