| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the effect of 12 weeks of GSK3228836 on serum HBsAg
levels in participants with CHB |
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| E.2.2 | Secondary objectives of the trial |
Efficacy:
To assess sustainability of serum HBsAg loss by GSK3228836 for up to 24 weeks off-treatment.
To assess sustainability of serum HBsAg and HBV DNA loss by GSK3228836 for up to 24 weeks off treatment.
To assess the effect of 12 weeks GSK3228836 on biomarkers and virus-specific antibody responses |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
AGE
1. At least 18 years of age at the time of signing the informed consent. [if country/site age requirements for consent differ, the more stringent (e.g., higher age) restriction will be required for that country/site].
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Participants who have documented chronic HBV infection ≥6 months prior to screening AND currently receiving stable nucleos(t)ide analogue therapy, 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
3. Plasma or serum HBsAg concentration >100 IU/mL.
4. Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL
5. HBeAg-negative
6. Alanine Transaminase (ALT) ≤2 X ULN
SEX
7. Male and/or Female
a. 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
i. Refrain from donating sperm
ii. 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
1. 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
b. A female participant is eligible to participate:
i. If she is not pregnant or breastfeeding
ii. AND at least one of the following conditions applies:
1. Is not a woman of childbearing potential (WOCBP)
2. OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment
iii. A WOCBP must have both
1. 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]
2. 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.
Additional requirements for pregnancy testing during and after study intervention are included in Appendix 4 of the protocol
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
INFORMED CONSENT
8. Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
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| E.4 | Principal exclusion criteria |
MEDICAL CONDITIONS
1. 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
2. Co-infection with:
a. Current or past history of Hepatitis C virus (HCV)
b. Human immunodeficiency virus (HIV)
c. Hepatitis D virus (HDV)
3. History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by
a. Both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7
i. 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
b. Regardless of APRI or Fibrosure/FibroTest score participants will be excluded from the study if their past history includes one of the following criteria:
i. Liver biopsy showing Metavir 4 or equivalent
ii. Liver stiffness >12 kPa
4. Diagnosed or suspected hepatocellular carcinoma as evidenced by the following
a. Alpha-fetoprotein concentration ≥200 ng/mL
b. 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 enrolment.
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. Positive (or borderline positive) ANCA at screening by itself won’t be an exclusion criterion - but if results are borderline positive or positive: Participants that meet this criteria may be considered for inclusion following:
a. Analysis of MPO-ANCA [pANCA] and PR3-ANCA [cANCA] and
b. 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
9. Low C3 at screening or baseline AND evidence of past history or current manifestations of vasculitic/inflammatory/auto-immune condition
a. All participants with low C3 at screening should have their medical history discussed with the Medical Monitor prior to enrolment.
10. 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
i. 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
PRIOR/CONCOMITANT THERAPY
11. 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.
12. Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids, will be excluded
13. Currently taking, or took within 12 months of screening, any interferon-containing therapy.
14. Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel)
PRIOR/CONCOMITANT THERAPY
15. 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).
16. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 months prior to the first dosing day
For remaining Exclusions Criteria please refer to the protocol P 39. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary Estimand supporting the primary objective of the study is defined as:
• Population: Participants with CHB who receive at least one dose of IP
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy)
• Variable: Achieving serum HBsAg level <LLOQ at any time point up to and including Week 12 without the use of PEG-interferon or other immunomodulator therapies
• Population-level summary: Percent of participants that achieve serum HBsAg level <LLOQ
• Intercurrent events: Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).
The primary estimand is the percentage of participants with CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) who achieve serum HBsAg level <LLOQ at any time point up to and including Week 12, without the use of PEG-interferon or other immunomodulator therapies, regardless of completing IP, interruptions in IP or adherence to IP.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The Estimand supporting the objective is defined as:
• Population: Participants with CHB who receive at least one dose of IP
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy)
• Variables:
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the planned end of GSK3228836 treatment
-HBsAg from Week 13 to Week 36 will be used to assess sustained HBsAg response after the planned end of GSK3228836 treatment without the use of PEG-interferon or other immunomodulator therapies.
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the actual end of GSK3228836 treatment
- HBsAg for 24 weeks after end of actual treatment will also be used to assess sustained HBsAg response after the actual end of GSK3228836 treatment without the use of PEG-interferon or other immunomodulator therapies.
• Intercurrent events: Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).
The group of estimands supporting this objective in participants with CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the percentage of participants for each variable regardless of completing IP, interruptions in IP or adherence to IP, without the use of PEG-interferon or other immunomodulator therapies.
The Estimand supporting the objective is defined as:
• Population: Participants with CHB who receive at least one dose of IP
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy)
• Variables:
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks after the planned end of GSK3228836 treatment
- HBsAg and HBV DNA from Week 13 to Week 36 will be used to assess sustained virologic response after the planned end of GSK3228836 treatment without the use of PEG-interferon or other immunomodulator therapies.
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks after the actual end of GSK3228836 treatment
- HBsAg and HBV DNA for 24 weeks after end of actual treatment will be used to assess sustained virologic response after the actual end of GSK3228836 treatment without the use of PEG-interferon or other immunomodulator therapies.
• Intercurrent events: Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).
The group of estimands supporting this objective in participants with CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the percentage of participants for each variable regardless of completing IP, interruptions in IP or adherence to IP, without the use of PEG-interferon or other immunomodulator therapies.
Estimands supporting the secondary objective of assessing the effect of 12 weeks GSK3228836 on biomarkers and virus-specific antibody responses are defined as follows:
• Population: Participants with CHB who receive at least one dose of IP
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy)
• Intercurrent events: Discontinuation of, interruption of, adherence to IP will be ignored (treatment policy). PEG-interferon or other immunomodulator therapies will be handled with hypothetical strategy.
1) Categorical Variables:
• Achieving:
o HBsAg <LLOQ over time
o HBV DNA <LLOQ over time
o HBsAg and HBV DNA <LLOQ over time
• Categorical changes from baseline in HBsAg (e.g. <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) over time.
• ALT>3X ULN at over time
. HBe antibody (anti-HBeAg) levels over time
Population summary: percentage of participants in each category.
2) Continuous Variables:
• Actual values and change from baseline over time for HBsAg and HBV DNA
• HBs antibody (anti-HBsAg) and HBe antibody (anti-HBeAg) levels over time
• Area under the curve (AUC) for ALT on treatment (12 weeks), during follow up (24 weeks), and on treatment + follow up (36 weeks).
Population summary: mean values and/or mean changes from baseline for each variable
3) Time to Event Variable
• Time to Maximum ALT (ALT must be greater than 3xULN) during 36 weeks of treatment + follow up
Population summary: Turnbull estimate for median Time to Maximum ALT (>3xULN)
The group of estimands supporting this objective in participants with CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) are the population summary for each variable in the absence of PEG-interferon or other immunomodulator therapies, regardless of completing IP, interruptions in IP, or adherence to IP.
For remaining Endpoints please refer to the protocol P 27-28. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Netherlands |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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