| 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 efficacy of the three dosing regimens of GSK3228836 in participants with CHB |
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| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of GSK3228836 on biomarkers and virus-specific antibody responses
To compare the efficacy between 12 weeks, 12 weeks + 12 weeks step-down, and 24 weeks of GSK3228836 treatment
To characterize GSK3228836 and nucleos(t)ide PK in participants with CHB |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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].
2. Participants who have documented chronic HBV infection ≥6 months prior to screening AND
a.Not currently on nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naïve) OR must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit
b. 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
3. Plasma or serum HBsAg concentration >100 IU/mL
4. Plasma or serum HBV DNA concentration
a. Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 IU/mL
b. Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL
5. Alanine Transaminase (ALT)
a. ALT for treatment naïve participants and for participants who are not currently receiving treatment
i. ALT <3 X ULN will be included initially
1. If agreed by the IDMC after review of safety data, the ALT inclusion criteria may be expanded to include participants with ALT <5 X ULN
b. ALT ≤2 X ULN for participants who are receiving stable nucleos(t)ide analogue therapy
6. 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 located in Appendix 2.
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
7. Capable of giving signed informed consent 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 |
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 of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study
I. Liver biopsy (i.e., Metavir Score F4)
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 randomization
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 :
a. Participants that meet this criteria may be considered for inclusion in the study following:
i. Analysis of MPO-ANCA [pANCA] and PR3-ANCA [cANCA] analysis will be conducted
ii. 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
9. Low C3 at screening AND evidence of past history or current manifestations of vasculitic/inflammatory/auto-immune conditions
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
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)
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
17. Fridericia’s QT correction formula (QTcF) ≥450 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).
For a full list of exclusion criteria please refer to Section 5.2 of the Study Protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary estimands supporting the primary objective are defined as:
Population: separate assessment for participants with CHB on stable nucleos(t)ide therapy and participants with CHB not currently on nucleos(t)ide therapy.
Variable: Participants achieving Sustained virologic response for 24 weeks after the planned end of GSK3228836 treatment in the absence of rescue medication.
Treatments: arms 1, 2, & 3. Estimation of the within-arm response rate.
Intercurrent events: use of rescue medication and discontinuation of/interruption of/adherence to IP. The use of rescue medication has been incorporated into the definition of variable (composite strategy). Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy). Wide disruptive events leading to discontinuation of interruption in, and non-adherance to GSK3228836 will be handled assuming they had not happened (hypothetical strategy)
Population summary: proportion of participants who achieve SVR for each treatment arm.
The primary estimands for each sub-population is the proportion of participants in each treatment arm 1, 2, & 3 who achieve SVR for 24 weeks after the planned end of GSK3228836 treatment in the absence of rescue medication regardless of completing IP, interruptions in IP or adherence to IP had they not been affected by wide disruptive events.
A supplementary estimand is defined to support the primary objective:
- the supplementary estimand is defined in the same way as the main estimand, except the assessment time frame for participants achieving SVR will be 24 weeks after the actual end of treatment. Therefore, the strategy for intercurrent events of treatment discontinuation will be while-on-treatment. This supplementary estimand supporting the primary objective in participants with CHB on stable nucloes(t)ide therapy and participants with CHB not currently on nucleos(t)ide therapy is the proportion of participants in each treatment arm 1, 2, and 3
who achieve SVR for 24 weeks after the actual end of GSK3228836 treatment in the absence of rescue medication, regardless of completing IP, interruptions in IP or adherence to IP, had they not been affected by wide disruptive events.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weekly during the treatment period (Day 1 to Day 162; with additional visits for loading dose on Day 4 and Day 11) and then decrease in frequency during the off-treatment period (8 visits over 24 weeks; Off-treatment weeks: Off treatment week 1, week 2, week 4, week 8, week 12, week 20, and week 24) |
|
| E.5.2 | Secondary end point(s) |
1) Categorical Variables:
-Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the end of treatment.
-Categorical changes from baseline in HBsAg (e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) and in HBV DNA (e.g., <1, ≥1, ≥2, ≥3 log IU/mL)
-ALT normalization over time in absence of rescue medication
-HBe antibody (anti-HBeAg) levels
- Population summary: proportion of participants in each category for each treatment arm.
2) Continuous Variables: Actual values and change from baseline over time of HBsAg and HBV DNA and actual values and change from baseline of HBeAg levels; HBs antibody (anti-HBsAg) and HBe antibody (anti-HBeAg) levels; Time to ALT normalization
- Population summary: mean values and mean changes from baseline for each variable in each treatment arm
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weekly during the treatment period (Day 1 to Day 162; with additional visits for loading dose on Day 4 and Day 11) and then decrease in frequency during the off-treatment period (8 visits over 24 weeks; Off-treatment weeks: Off treatment week 1, week 2, week 4, week 8, week 12, week 20, and week 24) |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| 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 |
| China |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Malaysia |
| Philippines |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Thailand |
| Turkey |
| United States |
| Bulgaria |
| France |
| Germany |
| Italy |
| Poland |
| Romania |
| Spain |
| United Kingdom |
| Argentina |
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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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