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    Summary
    EudraCT Number:2017-001110-29
    Sponsor's Protocol Code Number:56136379HPB2001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-05-24
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-001110-29
    A.3Full title of the trial
    A Phase 2a, Randomized, Partially-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Pharmacokinetics of Treatment With Multiple Doses of JNJ-56136379 as Monotherapy and in Combination With a Nucleos(t)ide Analog in Subjects With Chronic Hepatitis B Virus Infection
    Uno studio di fase 2a randomizzato, parzialmente in cieco, controllato con placebo per valutare l’efficacia, la sicurezza e la farmacocinetica del trattamento con dosi multiple di JNJ-56136379 in monoterapia e in combinazione con un analogo di Nucleos(t)ide in soggetti con infezione da virus dell'epatite B cronica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Assess the Efficacy, Safety, and Pharmacokinetics of Treatment With Multiple Doses of JNJ-56136379 as Monotherapy and in Combination With a Nucleos(t)ide Analog in Subjects With Chronic Hepatitis B Virus Infection
    Uno studio per valutare l'efficacia, la sicurezza e la farmacocinetica del trattamento con dosi multiple di JNJ-56136379 in monoterapia e in combinazione
    con un analogo di Nucleos(t)ide in soggetti con virus dell'epatite B cronica.
    Infezione
    A.3.2Name or abbreviated title of the trial where available
    A Phase 2a, Randomized, Partially-blind, Placebo-controlled Study to Assess the Efficacy, Safety, an
    Uno studio di fase 2a randomizzato, parzialmente in cieco, controllato con placebo per valutare l’ef
    A.4.1Sponsor's protocol code number56136379HPB2001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03361956
    A.5.4Other Identifiers
    Name:56136379HPB2001Number:56136379HPB2001
    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 SponsorJanssen Sciences Ireland Unlimited Company
    B.1.3.4CountryBelgium
    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 supportJanssen-Cilag SpA
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportJanssen Sciencies Ireland UC
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailClinicalTrialsEU@its.jnj.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 nameJNJ-56136379
    D.3.2Product code [JNJ-56136379]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeJNJ-56136379-AAA
    D.3.9.4EV Substance CodeSUB180015
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 2
    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 nameJNJ-56136379
    D.3.2Product code [JNJ-56136379]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeJNJ-56136379-AAA
    D.3.9.4EV Substance CodeSUB180015
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 3
    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 Yes
    D.2.1.1.1Trade name Viread
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences International Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameViread
    D.3.2Product code [Viread]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTENOFOVIR DISOPROXIL FUMARATO
    D.3.9.1CAS number 202138-50-9
    D.3.9.2Current sponsor code202138-50-9
    D.3.9.4EV Substance CodeSUB12607MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 4
    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 Yes
    D.2.1.1.1Trade name Baraclude
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameBaraclude
    D.3.2Product code [Baraclude]
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENTECAVIR
    D.3.9.1CAS number 209216-23-9
    D.3.9.2Current sponsor code209216-23-9
    D.3.9.4EV Substance CodeSUB25434
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral 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 Virus Infection
    infezione cronica da virus dell’epatite B
    E.1.1.1Medical condition in easily understood language
    A serious liver infection caused by the hepatitis B virus
    Una seria infezione del fegato causata dal virus dell’epatite 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 evaluate efficacy of 24 weeks of study treatment, in terms of changes in hepatitis B surface antigen (HBsAg) levels.
    Valutare l’efficacia di 24 settimane di trattamento dello studio in termini di variazioni dei livelli di antigene di superficie dell’epatite B (HBsAg)
    E.2.2Secondary objectives of the trial
    • To evaluate the safety and tolerability of 24 weeks of study treatment.
    • To evaluate efficacy in terms of changes in HBsAg levels.
    • To evaluate efficacy in terms of changes in HBV DNA levels.
    • To evaluate efficacy in terms of changes in HBeAg levels (in HBeAg-positive subjects only).
    • To evaluate efficacy in terms of HBsAg (in all subjects) or HBeAg (in HBeAg-positive subjects only) seroclearance and/or seroconversion.
    • To evaluate the frequency of subjects with biochemical response.
    • To evaluate the frequency of HBV virological breakthrough.
    • To evaluate the potential effect of JNJ-56136379 on the pharmacokinetics of
    nucleos(t)ide analog (NA) when coadministered.
    • To evaluate the pharmacokinetics of JNJ-56136379 when administered as monotherapy.
    • To evaluate the potential effect of NA on the pharmacokinetics of JNJ-56136379 when coadministered.
    • To assess changes in the HBV genome sequence.
    Additional objectives for treatment extension phase are on page 54 of Protocol # 2
    Valutare:
    •la sicurezza e la tollerabilità di 24 settimane di trattamento dello studio
    • l’efficacia in termini di variazioni dei livelli di HBsAg
    • l’efficacia in termini di variazioni dei livelli di HBV DNA
    •l’efficacia in termini di variazioni dei livelli di HBeAg (solo nei soggetti HBeAGpositivi)
    •l’efficacia in termini di clearance sierica e/o sieroconversione di HBsAg (in tutti i soggetti) o HBeAg (solo nei soggetti HBeAgpositivi)
    •la frequenza di soggetti con risposta biochimica
    •la frequenza del breakthrough virologico dell’HBV
    •il potenziale effetto di JNJ56136379 sulla farmacocinetica dell’ analogo nuicleos(t)idico (NA) in caso di co somministrazione
    •la farmacocinetica di JNJ56136379 somministrato in monoterapia
    •il potenziale effetto dell’NA sulla farmacocinetica di JNJ-56136379 in caso di cosomministrazione
    •le variazioni della sequenza del genoma dell’HBV
    Ulteriori obiettivi per la fase di estensione del trattamento sono a pagina 54 del Protocollo # 2
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Liver Biopsy Substudy dated 25th May 2018. A separate liver biopsy substudy may be performed at selected study sites where a liver biopsy will be
    performed at different time points. Details, including objectives and study design, will be described in a separate substudy protocol titled Liver Biopsy Substudy dated 25th May 2018.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio “Biopsia epatica” del 25 maggio 2018 separato può essere effettuato in centri di studio selezionati dove verrà eseguita una biopsia epatica in diversi momenti temporali. I dettagli, inclusi gli obiettivi e la progettazione dello studio, sono descritti nel protocollo separato del sottostudio “Biopsia epatica” del 25 maggio 2018.
    E.3Principal inclusion criteria
    • Subjects must be 18 to 70 years of age, inclusive.
    • Subjects must have CHB infection documented by:
    - Serum HBsAg-positive at screening and at least 6 months prior to screening.
    - Serum IgM anti-HBc antibody negative at screening.

    • In subjects currently not being treated (Treatment Arms 1-2-3 and 6-7-8):
    - Subjects must not be receiving any CHB treatment at screening, ie,
    ¿ Have never received treatment with HBV antiviral medicines, including NAs or IFN products, OR
    ¿ Have not been on treatment with HBV antiviral medicines, including NAs or IFN products within 6 months prior to baseline (first intake of study drugs), AND
    - Subjects must be HBeAg-positive and have HBV DNA =20,000 IU/mL, OR be HBeAg-negative and have HBV DNA =2,000 IU/mL at screening, AND
    - Subjects must have HBsAg >250 IU/mL at screening, AND
    - Subjects must have ALT > ULN and =5 x ULN at screening, determined in the central laboratory.
    Note: If subjects were treated with investigational anti-HBV agents more than 6 months before screening, the sponsor should be contacted to discuss the case. Subjects who have received treatment with a CAM for more than 4 weeks any time prior to screening are excluded.

    • In virologically suppressed subjects (Treatment Arms 4-5 and 9-10):
    - Subjects must be virologically suppressed by current NA treatment (ETV or TDF) as defined by HBV DNA <60 IU/mL at screening and at least 6 months prior to screening, AND
    - Subjects must be on the same NA treatment (ETV or TDF) and the same dose for =12 months prior to screening, AND
    - Subjects must have HBsAg >250 IU/mL at screening, AND
    - Subjects must have ALT =2x ULN at screening
    Note: If subjects were treated with investigational anti-HBV agents more than 6 months before screening, the sponsor should be contacted to discuss the case. Subjects who have received treatment with a CAM for more than 4 weeks any time prior to screening are excluded.

    • Subjects must have:
    - A liver biopsy result classified as Metavir F0-F2 within 1 year prior to screening or at the time of screening, OR
    - FibroScan™ liver stiffness measurement <8.0 kPa within 6 months prior to screening or at the time of screening.

    • Female subjects of childbearing potential must have a negative highly sensitive serum pregnancy test (beta-human chorionic gonadotropin) at screening.

    • Female subjects must be:
    - Not of childbearing potential
    - Of childbearing potential and
    o Practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study treatment and until 90 days after last dose of JNJ-56136379.

    • A female subject must agree not to donate eggs (ova, oocytes) during the study until at least 90 days after the last dose of JNJ-56136379.

    • A male subject must agree to wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study until at least 90 days after the last dose of JNJ-56136379.

    • A male subject must agree not to donate sperm during the study and for at least 90 days after receiving the last dose of JNJ-56136379.

    • Subject must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

    • Subject must sign a separate ICF if he or she agrees to provide an optional DNA sample for research. Refusal to give consent for the optional DNA research sample does not exclude a subject from participation in the study.

    • In the investigator's opinion, the subject must be able to understand and comply with protocol requirements, instructions, and lifestyle restrictions (Section 4.3) and be likely to complete the study as planned.
    •sogg.con età tra 18-70 anni,inclusi.
    •sogg.con infezione cronica HBV documentata da:
    -Positività sierica HBsAg allo screening e almeno 6 mesi prec. lo screening;
    -Anticorpo anti-HBc IgM nel siero negativo allo screening.
    •Nei sogg.attualmente non trattati(bracci di trattamento 1-2-3 e 6-7-8):
    -I sogg.non devono essere in trattamento con alcuna terapia per inf. cronica HBV allo screening,ovvero non devono essere mai stati trattati con farmaci antivirali per HBV,inclusi NA e prodotti a base di interferone(IFN)OPPURE non devono essere stati trattati con farmaci antivirali per HBV,inclusi NA e prodotti a base di IFN,entro 6 mesi prec. al basale(prima assunzione dei farmaci dello studio) E
    -Sogg.devono essere HBeAg-positivi e presentare HBV DNA=20.000 UI/mL OPPURE
    devono essere HBeAg-negativi e presentare HBV DNA=2000 UI /mL allo screening E
    -Sogg.devono presentare HBsAg>250 UI/mL allo screening E
    -Sogg.devono presentare ALT>limite superiore della norma(ULN)e =5xULN allo screening,det. dal laboratorio centrale.
    Nota: se i sogg.sono stati trattati con agenti anti-HBV sperimentali più di 6 mesi prima dello screening,contattare lo sponsor per discutere il caso. I sogg.che hanno ricevuto il trattamento con CAM per oltre 4 sett. in qualsiasi momento prima dello screening sono esclusi.
    •Nei sogg.virologicamente soppressi(bracci di trattamento 4-5 e 9-10):
    -sogg.devono essere virologicamente soppressi dall’attuale trattamento con NA(ETV o TDF) come determinato dalla presenza di HBV DNA<60 UI/mL allo screening e almeno 6 mesi prec. lo screening E
    -sogg.devono assumere lo stesso trattamento con NA(ETV o TDF)alla stessa dose da=12 mesi prec. lo screening E
    -sogg.devono presentare HBsAg>250 UI/mL allo screening E
    -sogg.devono presentare ALT=2x ULN allo screening.
    Nota: se i sogg.sono stati trattati con agenti anti-HBV sperimentali più di 6 mesi prec. lo screening,contattare lo sponsor per discutere il caso. I sogg.che hanno ricevuto trattamento con CAM per oltre 4 sett. in qualsiasi momento prec. lo screening sono esclusi.
    •sogg.devono presentare:
    -biopsia del fegato Metavir F0-F2 entro l’anno precedente allo screening o al momento dello screening OPPURE
    -misurazione FibroScan™ della rigidità del fegato <8,0 kPa entro i 6 mesi precedenti allo screening o al momento dello screening.
    •sogg.di sesso femminile potenz.fertili devono avere un test di gravidanza sierico altamente sensibile negativo(beta-HCG umana)allo screening.
    •sogg.di sesso femminile devono essere:
    -non fertili
    -fertili e o praticare un metodo contraccettivo altamente efficace,preferibilmente indipendente dall'utente(tasso di fallimento<1% all'anno se usato in modo coerente e corretto)e accettare di continuare con un metodo altamente efficace durante il trattamento di studio e fino a 90 giorni dopo l'ultima dose di JNJ -56136379.
    •il sogg.di sesso femminile deve accettare di non donare uova(ovuli, ovociti)durante lo studio fino a 90 giorni dopo l'ultima dose di JNJ-56136379.
    •il sogg.di sesso maschile deve accettare di utilizzare un preservativo quando intraprende qualsiasi attività che consenta il passaggio dell'eiaculato a un'altra persona durante lo studio fino a 90 giorni dopo l'ultima dose di JNJ-56136379.
    •il sogg.di sesso maschile deve accettare di non donare sperma durante lo studio e per almeno 90 giorni dopo aver ricevuto ultima dose di JNJ-56136379.
    •Il sogg.deve firmare un consenso informato indicando di comprendere lo scopo e le procedure richieste per lo studio ed è disposto a partecipare allo studio.
    •il sogg.deve firmare un consenso informato separato se accetta di fornire un campione di DNA facoltativo per la ricerca.Il rifiuto di dare consenso per il campione facoltativo di DNA non esclude il sogg. dalla partecipazione allo studio.
    •Secondo parere dello sperimentatore,il sogg.deve essere in grado di capire e attenersi ai requisiti del protocollo,istruzioni,restrizioni sullo stile di vita(sez4.3)ed è probabile che completi lo studio come previsto.
    E.4Principal exclusion criteria
    • Subjects who test positive for anti-HBs antibodies.

    • Subjects with current hepatitis A virus infection (confirmed by hepatitis A antibody IgM), HCV infection (confirmed by HCV antibody), HDV infection (confirmed by HDV antibody), hepatitis E virus infection (confirmed by hepatitis E antibody IgM), or HIV-1 or HIV-2 infection (confirmed by antibodies) at screening. Evidence of other active infection (bacterial, viral, fungal, including acute tuberculosis) deemed clinically relevant by the investigator that would interfere with study conduct or its interpretation will also lead to exclusion.

    • Subjects with any evidence of hepatic decompensation at any time point prior to or at the time of screening:
    - Direct bilirubin >1.2x ULN, or
    - International normalized ratio >1.5x ULN, or
    - Serum albumin < lower limit of normal (LLN), or
    - Documented history or current evidence of variceal bleeding, ascites, or hepatic encephalopathy.

    • Subjects with any evidence of liver disease of non-HBV etiology. This includes but is not limited to hepatitis virus infections mentioned above, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, Gilbert’s syndrome, a-1 antitrypsin deficiency, primary biliary cirrhosis, primary sclerosing cholangitis, or any other non-HBV liver disease considered clinically significant by the investigator.

    • Subjects who have signs of hepatocellular carcinoma (HCC) on an abdominal ultrasound performed within 2 months prior to screening or at the time of screening. In case of suspicious findings on conventional ultrasound, subject may still be eligible if HCC has been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
    Additional exclusions criteria are listed on page 68 and 69 of Protocol Amendment #2
    • Soggetti risultati positivi agli anticorpi anti-HBs.
    • Soggetti con attuale infezione da virus dell’epatite A (confermata dall’anticorpo IgM dell’epatite A),
    attuale infezione da virus dell’epatite C (HCV) (confermata dall’anticorpo per l’HCV), attuale
    infezione da virus dell’epatite D (HDV) (confermata dall’anticorpo per l’HDV), attuale infezione da
    virus dell’epatite E (confermata dall’anticorpo IgM dell’epatite E) o infezione da virus
    dell’immunodeficienza umana di tipo 1 (HIV-1) o di tipo 2 (HIV-2) (confermata dagli anticorpi) allo
    screening. Anche l’evidenza di un’altra infezione attiva (batterica, virale o fungina, inclusa la
    tubercolosi attiva), considerata clinicamente rilevante dallo sperimentatore, che interferirebbe con la
    conduzione dello studio o con la sua interpretazione sarà motivo di esclusione.

    • Soggetti con evidenza di scompenso epatico in qualsiasi momento prima dello screening o al
    momento dello screening:
    - Bilirubina diretta >1,2x ULN oppure
    - Rapporto normalizzato internazionale >1,5x ULN oppure
    -Albumina sierica < limite inferiore di normalità (LLN) oppure
    - Storia documentata o attuale evidenza di sanguinamento da varici, ascite o encefalopatia
    epatica.

    • Soggetti con evidenza di malattia epatica con eziologia diversa dall’HBV tra cui, a titolo
    esemplificativo, infezioni da virus dell’epatite sopra indicate, patologia epatica correlata al consumo
    di farmaci o alcol, epatite autoimmune, emocromatosi, malattia di Wilson, sindrome di Gilbert, deficit di a1-antitripsina, cirrosi biliare primitiva, colangite sclerosante primaria o altre patologie epatiche non dovute all’HBV considerate clinicamente significative dallo sperimentatore.

    • Soggetti che presentano segni di carcinoma epatocellulare (HCC) all’ecografia addominale eseguita entro i 2 mesi precedenti allo screening o al momento dello screening. In caso di risultati sospetti
    dell’ecografia tradizionale, il soggetto sarà considerato idoneo se la presenza di carcinoma
    epatocellulare sarà esclusa da una procedura di imaging più specifica (ecografia, tomografia
    computerizzata [TC] o risonanza magnetica [RM] con mezzo di contrasto).
    Ulteriori criteri di esclusione sono elencati a pagina 68 e 69 del Protocollo Emendamento n. 2
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in HBsAg levels at Week 24
    Variazioni rispetto al basale dei livelli di HBsAg alla settimana 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and Week 24
    Baseline e Settimana 24
    E.5.2Secondary end point(s)
    • Safety and tolerability data including but not limited to (S)AEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, and urinalysis) throughout the study. • Change from baseline in HBsAg levels during study treatment and follow-up. • Proportion of subjects with HBsAg levels by response subcategory, such as HBsAg <1,000 or <100 IU/mL, or with >0.5 or >1 log10 IU/mL reduction in HBsAg from baseline as detailed in the Statistical Analysis Plan (SAP) during study treatment and follow-up. • Change from baseline in HBV DNA levels during study treatment and follow-up. • Proportion of subjects with HBV DNA levels by response subcategory as detailed in the SAP during study treatment and follow-up. • Change from baseline in HBeAg levels during study treatment and follow-up. • Proportion of subjects with HBeAg levels by response subcategory as detailed in the SAP during study treatment and follow-up. • Proportion of subjects with HBsAg or HBeAg seroclearance (defined as HBsAg or HBeAg negativity, respectively, based on the assay used) during study treatment and follow-up. • Proportion of subjects with HBsAg or HBeAg seroconversion (defined as HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively) during study treatment and follow-up. • Proportion of subjects with ALT improvement and normalization during study treatment and follow-up. • Proportion of subjects with virological breakthrough during study treatment defined as confirmed on-treatment HBV DNA increase by >1 log10 from nadir level or confirmed on-treatment HBV DNA level >200 IU/mL in subjects who had HBV DNA level below the lower limit of quantification (LLOQ) of the HBV DNA assay. • Pharmacokinetics of NA when administered as monotherapy or when coadministered with JNJ-56136379. • Pharmacokinetics of JNJ-56136379 when administered as monotherapy or when coadministered with an NA. • Emergence of treatment-associated mutations during study treatment and follow-up. Please note: Endpoints applicable to the treatment extension phase only are listed on page 60 of protocol amendment #3
    • Dati sulla sicurezza e sulla tollerabilità comprendenti, a titolo esemplificativo, gli eventi avversi (seri) [(S)AE], gli esami obiettivi, i segni vitali, gli elettrocardiogrammi (ECG) a 12 derivazioni e le analisi cliniche di laboratorio (inclusi esami ematologici e biochimici, test di coagulazione ematica e analisi delle urine) nell’arco dello studio • Variazione dei livelli di HBsAg rispetto al basale durante il trattamento dello studio e il follow-up • Percentuale di soggetti con livelli di HBsAg in base alla sottocategoria di risposta, come ad esempio HBsAg <1000 o <100 UI/mL, o con riduzione >0,5 o >1 log10 UI/mL di HBsAg rispetto al basale, come descritto dettagliatamente nel Piano di analisi statistica (SAP), durante il trattamento dello studio e il follow-up • Variazione dei livelli di HBV DNA rispetto al basale durante il trattamento dello studio e il follow-up • Percentuale di soggetti con livelli di HBV DNA in base alla sottocategoria di risposta, come descritto dettagliatamente nel SAP, durante il trattamento dello studio e il follow-up • Variazione dei livelli di HBeAg rispetto al basale durante il trattamento dello studio e il follow-up • Percentuale di soggetti con livelli di HBeAg in base alla sottocategoria di risposta, come descritto dettagliatamente nel SAP, durante il trattamento dello studio e il follow-up • Percentuale di soggetti con clearance sierica di HBsAg o HBeAg (definita rispettivamente come negatività di HBsAg o HBeAg in base al test utilizzato) durante il trattamento dello studio e il follow-up • Percentuale di soggetti con sieroconversione di HBsAg o HBeAg (definita rispettivamente come negatività di HBsAg o HBeAg e positività dell’anticorpo anti-HBs o anti-HBe) • Percentuale di soggetti con miglioramento e normalizzazione dell’alanina aminotransferasi (ALT) durante il trattamento dello studio e il follow-up • Percentuale di soggetti con breakthrough virologico durante il trattamento dello studio, definito come aumento confermato durante il trattamento di HBV DNA >1 log10 rispetto al livello nadir o livello confermato durante il trattamento di HBV DNA >200 UI/mL in soggetti che presentavano un livello di HBV DNA più basso del limite inferiore di quantificazione (LLOQ) del test del HBV DNA • Farmacocinetica dell’NA somministrato in monoterapia o in co-somministrazione con JNJ56136379 • Farmacocinetica di JNJ-56136379 somministrato in monoterapia o in co-somministrazione con un NA • Comparsa di mutazioni associate al trattamento durante il trattamento dello studio e il follow-up. Nota: endpoint applicabili solo alla fase di estensione del trattamento sono elencati a pagina 60 dell'emendamento n. 3 del protocollo
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety: throughout the study: HBsAg, HBeAg, HBV DNA: Screening, Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24 Anti-HBs and anti-HBe: Screening, Treatment phase: Day 1 and Week 24, and Follow-up phase: Weeks 2, 4, 12, 24 PK samples: Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 20, 24, and Follow-up phase: Weeks 2 and 4 Blood chemistry (ALT): Screening, Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24 Viral genome sequencing: Screening, Treatment phase: Day 1, Weeks 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24. Evaluations relating to the treatment extension phase of the study are described in the protocol for Amendment #3.; Sicurezza:Durante lo st
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker and Patient-Reported Outcome Analyses
    Analisi dei Biomarker e dei risultati riportati dai pazientii (Patient-Reported Outcome)
    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 Yes
    E.8.1.5Parallel group Yes
    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 trial10
    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.8.4.1Number 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 EEA38
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    China
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Thailand
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    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 months11
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    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: 210
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 121
    F.4.2.2In the whole clinical trial 220
    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)
    The sponsor will provide treatment or care up to the end of follow up period in the trial only. Medical treatment care beyond the follow up period (i.e. after the end of participation in the trial) will be up to subject's physician as per local/regional treatment guidelines and subject's medical insurance.
    Lo Sponsor fornirà il trattamento solo fino alla fine del periodo di follow-up previsto dallo Studio. Le cure mediche oltre il periodo di follow-up (dopo la fine della partecipazione allo studio) saranno a carico del medico del soggetto secondo le linea guida locali e regionali e l'assicurazione del soggetto.
    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 Decision2018-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-15
    P. End of Trial
    P.End of Trial StatusCompleted
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