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    Summary
    EudraCT Number:2020-001083-29
    Sponsor's Protocol Code Number:209668
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-05-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-001083-29
    A.3Full title of the trial
    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)
    Randomizowane, wieloośrodkowe, częściowo zaślepione badanie kohortowe fazy IIb prowadzone w grupach równoległych, oceniające skuteczność i bezpieczeństwo leczenia preparatem GSK3228836 u pacjentów z przewlekłym zakażeniem wirusem zapalenia wątroby typ
    u B (B-Clear).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase IIb study of GSK3228836 in Participants with Chronic Hepatitis B (B-Clear)
    Badanie fazy IIb oceniające GSK3228836 u pacjentów z przewlekłym wirusowym zapaleniem wątroby typu B (B-Clear
    A.4.1Sponsor's protocol code number209668
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline Research & Development Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline Research & Development Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trials Help Desk
    B.5.3 Address:
    B.5.3.1Street Address980 Great West Road
    B.5.3.2Town/ cityBrentford, Middlesex
    B.5.3.3Post codeTW8 9GS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 208 990 4466
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGSK3228836
    D.3.2Product code GSK3228836
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNbepirovirsen
    D.3.9.1CAS number 1403787-62-1
    D.3.9.3Other descriptive nameGSK3228836A
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Hepatitis B
    E.1.1.1Medical condition in easily understood language
    Hepatitis B
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10008910
    E.1.2Term Chronic hepatitis B
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of the three dosing regimens of GSK3228836 in participants with CHB
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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. ANCA at screening by itself won’t be an exclusion criterion, but if results are borderline positive or positive:
    a. MPO-ANCA [pANCA] and PR3-ANCA [cANCA] analysis will be conducted
    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 before inclusion in study is permitted
    9. Low C3 at screening by itself won’t be an exclusion criterion, but if it is present
    a. 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
    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
    E.5 End points
    E.5.1Primary 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: Sustained virologic response for 24 weeks after the 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 preventing assessment of primary outcome 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 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.
    E.5.1.1Timepoint(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.5.2Secondary 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
    - 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
    E.5.2.1Timepoint(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.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Partial-Blind
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial8
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA74
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Canada
    China
    Hong Kong
    Japan
    Korea, Republic of
    Malaysia
    Philippines
    Russian Federation
    Singapore
    South Africa
    Taiwan
    Thailand
    Turkey
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 340
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 440
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No intervention is planned at the end of the study, although participants may be asked to enrol in a long-term roll-over study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-18
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