| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 |
| Efficacy: To investigate the efficacy of two different durations of GSK3228836 followed by up to 24 weeks of PegIFN therapy in participants with CHB on stable NA therapy |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy: To assess the efficacy of GSK3228836 and PegIFN sequential therapy on biomarkers and virus specific antibody responses
Efficacy: To investigate the durability of virological response after sequential therapy with 12 weeks of GSK3228836 followed by 24 weeks of PegIFN in participants with CHB on stable NA therapy for up to 36 weeks off treatment.
Efficacy: To compare efficacy between different treatment durations: 12 or 24 weeks of GSK3228836 followed by 24 weeks PegIFN |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
AGE
1.At least 18 to 75 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 are eligible to be treated with PegIFN (Table 7)
3.Documented chronic HBV infection ≥6 months prior to screening AND currently receiving stable NA therapy except telbivudine, defined as no changes to their NA regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study
4.Plasma or serum HBsAg concentration >100 IU/mL
5.Plasma or serum HBV DNA <90 IU/mL
6.Alanine Transaminase (ALT) ≤2 X ULN
SEX
1.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) as defined in Section 10.4 Contraception and Barrier Guidance
2.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
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention, see Section 10.2 of protocol
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in Section 10.2 of protocol.
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
INFORMED CONSENT
1.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.
For a full list of inclusion criteria please refer to Section 5.3 for Peg-IFN of the Study Protocol |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
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, autoimmune disease, 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 within 12 months of screening
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, if the participant has historical evidence of 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 randomisation
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.Poorly controlled thyroid dysfunction or abnormal thyroid stimulating hormone (TSH) levels
9.Positive (or borderline positive) Anti-neutrophil cytoplasmic antibody (ANCA) at screening :
a.Participants that meet these criteria may be considered for inclusion in the study following:
i.Analysis of MPO-ANCA [perinuclear anti-neutrophil cytoplasmic
antibodies (pANCA)] and PR3-ANCA [classical anti-neutrophil
cytoplasmic antibodies (cANCA)] AND
ii.A discussion with the Medical Monitor to review participant’s complete medical history to ensure no past history or current manifestations of a vasculitic/inflammatory/auto-immune condition
10.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
11.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
12.Pre-existing severe psychiatric condition or a history of severe psychiatric disorders, including severe depression, suicidal ideation and attempted suicide.
PRIOR/CONCOMITANT THERAPY
13.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.
14.Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids.
15.Patients with prior treatment with Pegylated interferon or interferon are excluded.
16.Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel)
17.Participants currently taking, or took within 6 months of screening, telbivudine
For a full list of exclusion criteria please refer to Section 5.2 of the Study Protocol and Section 5.3 for Exclusion Criteria for Peg-IFN of the Study Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The main Estimand supporting the primary objective is
defined as:
• Population: Participants with CHB on stable NA therapy who received at least one dose of GSK3228836
• Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by up to 24 weeks of PegIFN therapy while on stable NA therapy
• Variable (Categorical): Participants achieving Sustained Virologic Response (SVR) (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks after
the planned end of sequential treatment, without use of any rescue medication
• Intercurrent Events:
o Discontinuation of, interruption in, and nonadherence to GSK3228836 and PegIFN not related to any wide disruptive events (such as COVID-19 pandemic) will be ignored (treatment policy strategy).
o Ineligibility to receive PegIFN will be ignored (treatment policy strategy)
o Use of rescue medication (composite strategy).
o Wide disruptive events (such as COVID-19 pandemic) leading to discontinuation of, interruption in, and non-adherence to GSK3228836 and PegIFN will be handled assuming they had not happened (hypothetical strategy).
• Population Summary: The percentage of participants in each treatment group who achieve SVR, without use of any rescue medication
The main primary estimand supporting the primary objective in participants with CHB on stable NA therapy in each treatment arm is the percentage of participants that achieve SVR (HBsAg <LLOQ and HBV DNA
<LLOQ) for 24 weeks after the planned end of sequential treatment in the absence of rescue medication, regardless of ineligibility to receive PegIFN, discontinuation of, interruption in, and non-adherence to GSK3228836 and PegIFN, had they not been affected by wide disruptive events.
Three supplementary Estimands are defined to support the primary objective:
• The first supplementary Estimand is defined in the same way as the main Estimand, except the assessment time frame for patients 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 NA therapy in each treatment arm is the percentage of participants that achieve SVR (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks after the actual end of sequential treatment in the absence of rescue medication, regardless of ineligibility to receive
PegIFN, discontinuation of, interruption in, and nonadherence to GSK3228836 and PegIFN, had they not been affected by wide disruptive events.
• The second supplementary Estimand is to understand the relationship between the PegIFN duration and achieving SVR for 24 weeks after the
actual end of treatment, defined as:
o Population: Participants with CHB on stable NA therapy who received at least one dose of GSK3228836
o Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by 24 weeks of PegIFN therapy while on stable NA therapy
o Variable: The relationship between SVR for 24 weeks after actual end of treatment and the duration of PegIFN received by participants
o Intercurrent Events: Discontinuation and delayed start of, PegIFN, will be accounted to reflect the actual duration from the first to the last
dose of PegIFN received (while-on treatment strategy).
Interruption in and other non-adherence to PegIFN will be ignored (treatment policy strategy)
Discontinuation of, interruption in and non-adherence to GSK3228836 will be ignored (treatment policy strategy)
Use of rescue medication (composite strategy).
Wide disruptive events (such as COVID-19 pandemic) leading to discontinuation and delayed start of, PegIFN will be handled with while-on treatment strategy; wide disruptive events leading to interruption in and other non-adherence to PegIFN will be ignored (treatment policy strategy); wide disruptive events leading to discontinuation of, interruption in, and non-adherence to GSK3228836 will be
ignored (treatment policy strategy).
o Population Summary: The percentage of participants achieving SVR for 24 weeks after the actual end of treatment by PegIFN
treatment duration categorical grouping in each treatment arm
• The second supplementary Estimand (supporting the primary objective in participants with CHB on stable NA therapy) is the percentage of participants achieving SVR for 24 weeks after the actual end of
treatment by PegIFN treatment duration categorical grouping in each treatment arm, taking into account discontinuation and delayed start of PegIFN, regardless of interruption in and other nonadherence to PegIFN, regardless of discontinuation of, interruption in and non-adherence to
GSK3228836.
Refer other endpoints in protocol |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weekly during the treatment period for up to 48 weeks with additional visits for loading dose on Day 4 and Day 11) and then decrease in frequency during the off-treatment period (9 visits over 36 weeks; Off treatment weeks: Off treatment week 1, week 2, week 4, week 8, week
12, week 20, week 24 and week 36)
|
|
| E.5.2 | Secondary end point(s) |
The Estimand supporting the objective is defined as:
• Population: Participants with CHB on stable NA therapy who received at least one dose of GSK3228836; For the time to ALT normalisation
variable, population will be aforementioned participants with baseline ALT >ULN.
• Treatment: 300 mg GSK3228836 for 12, or 24 weeks followed by 24 weeks of PegIFN therapy while on stable NA therapy
• Categorical Variables:
o Achieving HBsAg <LLOQ and HBV DNA
<LLOQ at two time points: (1) the planned end of treatment and (2) at the end of 24 weeks follow-up
o Categorical changes from baseline in HBsAg (e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) at each scheduled visit or analysis window.
o ALT normalisation (ALT ≤ULN) over time in absence of rescue medication in participants with baseline ALT >ULN
Population summary is the percentage of participants in each category for each treatment group.
• Continuous Variables:
o Actual values and change from baseline over time for HBsAg, HBV DNA and HBeAg
o Actual values and change from baseline over time for HBs antibody (anti-HBsAg) and HBe antibody (anti-HBeAg) levels over time
o Actual values and change from baseline over time for ALT
Population summary is the mean values and the mean changes from baseline of each variable for participants in each treatment
group.
• Time to Event Variable:
o Time to ALT normalisation in absence of rescue medication in participants with baseline ALT>ULN
Population summary is the Turnbull’s estimator for non-parametric estimation of Time to ALT normalisation in each treatment arm
• Intercurrent Events: Discontinuation of, interruption in, and non-adherence to GSK3228836 and PegIFN will be ignored (treatment policy); PegIFN ineligibility will be ignored (treatment policy); Rescue medication will be ignored (treatment policy), except for ALT normalisation which can only be achieved in the absence of rescue medication; Wide disruptive events (such as COVID-19 pandemic) leading to discontinuation of, interruption in, and nonadherence
to GSK3228836 and PegIFN will be handled with Treatment Policy Strategy.
• The group of estimands supporting this objective is the population summary for each variable in each treatment arm in the population regardless of
discontinuation of, interruption in or non-adherence to GSK3228836 and PegIFN, and regardless of rescue medication (except for ALT normalisation which can only be achieved in the absence of rescue medication) or PegIFN ineligibility.
The same definition as the above secondary estimand, focusing on the timepoints following the 24 weeks off treatment period in the treatment arm of 300 mg
GSK3228836 for 12 weeks followed by up to 24 weeks of PegIFN therapy while on stable NA therapy.
The same definition as the primary estimand except
treatments and population summary are defined as:
• Treatments: Arms 1 and 2. One treatment comparison between Arms 1 & 2 up to 24 weeks off treatment
• Population summary: difference in proportion of participants who achieve SVR between treatment arms
The group of estimands supporting this objective in participants with CHB on stable NA therapy is the difference between treatment arms 1 and 2 in the
proportion of participants that achieve SVR for 24 weeks after the planned end of sequential treatment, in the absence of rescue medication, regardless of ineligibility to receive PegIFN, regardless of discontinuation of, interruption in or non-adherence to GSK3228836 and PegIFN had they not been affected by wide disruptive events. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weekly during the treatment period for up to 48 weeks with additional visits for loading dose on Day 4 and Day 11) and then decrease in frequency during the off-treatment period (9 visits over 36 weeks; Off treatment weeks: Off treatment week 1, week 2, week 4, week 8, week
12, week 20, week 24 and week 36)
o
|
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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