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    Summary
    EudraCT Number:2021-005139-22
    Sponsor's Protocol Code Number:202009
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-10-19
    Trial 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 number2021-005139-22
    A.3Full title of the trial
    Phase 3 Multicenter, Randomized, Double-Blind, Study to Assess the Efficacy and Safety of Treatment with Bepirovirsen in HBeAg-negative Nucleos(t)ide Analogue-treated Participants with Chronic Hepatitis B Virus (B-Well 1)
    Randomizowane, wieloośrodkowe badanie fazy III prowadzone metodą podwójnie ślepej próby, oceniające skuteczność i bezpieczeństwo leczenia bepirowirsenem u pacjentów z HBeAg-ujemnym przewlekłym zakażeniem wirusem zapalenia wątroby typu B leczonych analogami nukleot(z)ydów (B-Well 1)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Study of Bepirovirsen in Nucleos(t)ide Analogue-treated Participants with Chronic Hepatitis B
    Badanie fazy III oceniające bepirowirsen u pacjentów z przewlekłym wirusowym zapaleniem wątroby typu B leczonych analogami nukleot(z)ydów (B-Well 1)
    A.4.1Sponsor's protocol code number202009
    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+442089909733
    B.5.5Fax numberN/A
    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 nameBepirovirsen
    D.3.2Product code Bepirovirsen
    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.3.9.2Current sponsor codeGSK3228836
    D.3.9.3Other descriptive nameGSK3228836A (free acid)
    D.3.9.4EV Substance CodeSUB208554
    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 infection
    E.1.1.1Medical condition in easily understood language
    Chronic Hepatitis B infection
    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
    Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in HBeAg-negative participants with chronic HBV infection on-NA treatment with baseline HBsAg ≤1000 IU/mL
    E.2.2Secondary objectives of the trial
    Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in HBeAg-negative participants with chronic HBV infection on NA treatment with baseline HBsAg ≤3000 IU/mL

    Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression off-treatment after a finite duration of therapy in HBeAg-negative participants with chronic HBV infection on NA treatment with baseline HBsAg ≤1000 IU/mL

    Efficacy: To assess the treatment effect of 24 weeks bepirovirsen with loading doses in HBV DNA suppression after a finite duration of therapy in HBeAg-negative participants with chronic HBV infection on NA treatment with baseline HBsAg ≤3000 IU/mL

    Safety: To assess the safety and tolerability of bepirovirsen when dosed for 24 weeks duration with loading doses in HBeAg-negative participants with chronic HBV infection on NA treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all of the following criteria apply:
    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 must be HBeAg negative at screening.
    3.Participants who have documented chronic HBV infection ≥6 months prior to Screening AND
    •Currently receiving stable NA therapy 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, but no greater than 3000 IU/mL
    5.Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL
    6.Alanine aminotransferase (ALT) ≤2 x ULN
    7.Participants who are willing and able to cease their NA treatment in accordance with the protocol.

    Sex and Contraceptive/Barrier Requirements
    8.Male and/or female
    a.There are no contraceptive requirements for male participants.
    b.A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
    •Is a woman of non childbearing potential (WONCBP) as defined in Section 10.4
    OR
    Is a WOCBP and using a contraceptive method (for a period of 28 days prior to enrollment [first dose of study drug]) that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 4 during the study intervention period and for at least 7 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
    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 8.2.5).
    •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.
    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
    9.Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
    E.4Principal 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 or coagulopathy) or physical examination
    2.Co-infection with:
    a.Current history of Hepatitis C infection or participants that have been cured for <12 months at the time of screening
    b.Human immunodeficiency virus (HIV)
    c.Hepatitis D virus
    3.History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by
    a.Both APRI >2 and FibroSure/FibroTest result >0.7
    •If only 1 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 1 of the following criteria documented from their medical history, they will be excluded from the study
    •Liver biopsy (i.e., Metavir Score F4)
    •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, cryoglobulinemia, uncontrolled hypertension)
    8.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
    9.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.
    10.Participants to whom immnosuppressive treatment, including therapeutic doses of steroids is contraindicated, should not be considered for enrolment in the study.
    11.Currently taking, or HAS TAKEN within 12 months of Screening, any interferon containing therapy.
    12.Participants requiring anti-coagulation therapies (e.g., warfarin, Factor Xa inhibitors) or anti-platelet agents (like clopidogrel or aspirin) unless treatment can safely be discontinued throughout duration of the study, by the discretion of the investigator. Occasional use is permitted.
    13.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).
    14.Prior treatment with any oligonucleotide or siRNA within 12 months prior to the first dosing day (excluding COVID vaccinations).
    15.Prior treatment with bepirovirsen.
    Diagnostic Assessments
    16.Fridericia’s QT correction formula (QTcF) ≥450 msec (if single ECG at screening shows QTcF 450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
    17.Laboratory results as follows:
    a.Serum albumin ≤3.5 g/dL
    b.Glomerular filtration rate (GFR) ≤60 mL/min/1.73m2 as calculated by the CKD EPI formula (for Japan, JSN CKDI equation)
    c.INR >1.25
    d.Platelet count <140 x 109/L
    e.Total bilirubin >1.25 x ULN

    Please refer protocol for further exclusion criteria from page number 45-48.
    E.5 End points
    E.5.1Primary end point(s)
    Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <1000IU/mL
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 72
    E.5.2Secondary end point(s)
    - Functional cure for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <3000IU/mL
    - Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <1000IU/mL
    - Sustained suppression of HBV DNA (<LLOQ) for 24 weeks after discontinuation of all chronic HBV treatment (bepirovirsen/placebo and NA) in the absence of rescue medication in participants with baseline HBsAg <3000 IU/mL
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 72
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    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 trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Brazil
    Canada
    China
    Hong Kong
    India
    Japan
    Korea, Republic of
    Mexico
    Panama
    Singapore
    Taiwan
    Thailand
    United States
    France
    Poland
    Bulgaria
    Romania
    Spain
    Germany
    Greece
    Italy
    Hungary
    Turkey
    United Kingdom
    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 years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days1
    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: 454
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 534
    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)
    To continue with standard of care.
    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 Decision2022-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-08
    P. End of Trial
    P.End of Trial StatusOngoing
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