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    Summary
    EudraCT Number:2019-004475-39
    Sponsor's Protocol Code Number:73763989HPB2003
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-21
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-004475-39
    A.3Full title of the trial
    A Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Response to Combination Regimens Containing JNJ-73763989 and Nucleos(t)ide Analog With or Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection.
    Uno studio multicentrico di fase 2 randomizzato, in aperto, a gruppi paralleli, per valutare le variazioni intraepatiche e periferiche dei marcatori immunologici e virologici in risposta a regimi di combinazione contenenti JNJ-73763989 e analoghi nucleos(t)idici con o senza JNJ-56136379 in pazienti con infezione cronica da virus dell’epatite B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study to Assess Immunologic and Virologic Changes in the Liver in Response to Combination Regimens Containing JNJ-73763989 and Nucleos(t)ide Analog With or Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection.
    Studio per valutare le variazioni intraepatiche e periferiche dei marcatori immunologici e virologici in risposta a regimi di combinazione contenenti JNJ-73763989 e analoghi nucleos(t)idici con o senza JNJ-56136379 in pazienti con infezione cronica da virus dell’epatite B
    A.3.2Name or abbreviated title of the trial where available
    INSIGHT
    INSIGHT
    A.4.1Sponsor's protocol code number73763989HPB2003
    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.1.3.4CountryIreland
    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 Sciences Ireland Unlimited Company
    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 pointDavid Wright
    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.5.6E-mailJCI-Office@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-73763989
    D.3.2Product code [JNJ-73763989]
    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.3.9.2Current sponsor codeJNJ-73763989-AAM
    D.3.9.4EV Substance CodeSUB197801
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.3.9.1CAS number 1638266-40-6
    D.3.9.2Current sponsor codeJNJ-56136379
    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: 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 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.3.9.1CAS number 1638266-40-6
    D.3.9.2Current sponsor codeJNJ-56136379
    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: 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 Entecavir Mylan 0.5 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMylan S.A.S.
    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 nameEntecavir Mylan 0.5 mg film-coated tablets
    D.3.2Product code [Entecavir Mylan 0.5 mg film-coated tablets]
    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 INNENTECAVIR
    D.3.9.2Current sponsor codeJ05AF10
    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 number5000
    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: 5
    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 Vemlidy 25 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences Ireland UC
    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 nameTenofovir alafenamide
    D.3.2Product code [Tenofovir alafenamide]
    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 ALAFENAMIDE
    D.3.9.1CAS number 379270-37-8
    D.3.9.2Current sponsor codenap
    D.3.9.4EV Substance CodeSUB121761
    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: 6
    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 Tenofovir disoproxil Mylan 245 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMYLAN S.A.S
    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 nameTenofovir disoproxil
    D.3.2Product code [Tenofovir disoproxil]
    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.3.9.2Current sponsor codeTENOFOVIR DISOPROXIL
    D.3.9.4EV Substance CodeSUB20643
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number245
    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
    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
    Chronic Hepatitis B Virus Infection
    Infezione cronica da virus dell’epatite B
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    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 changes in intrahepatic HBsAg between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment
    Valutare le variazioni dell'HBsAg intraepatico tra il basale e la biopsia epatica durante il trattamento, in risposta al trattamento associato a base di JNJ-3989
    E.2.2Secondary objectives of the trial
    1. To assess changes in intrahepatic immune response between baseline and on-treatment liver biopsy.
    2. To assess changes in intrahepatic viral nucleic acids and proteins between baseline and on-treatment liver biopsy.
    3. To evaluate the efficacy of the study intervention as measured in the periphery.
    4. To evaluate the frequency of virologic breakthrough during study intervention.
    5. To assess HBV-specific T-cell responses.
    6. To evaluate the safety and tolerability of the study intervention.
    7. To evaluate the plasma PK of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379, and optionally of NA, as applicable.
    1.Valutare le variazioni della risposta immunitaria intraepatica tra il basale e la biopsia epatica durante il trattamento
    2.Valutare le variazioni delle proteine e degli acidi nucleici intraepatici virali tra il basale e la biopsia epatica durante il trattamento
    3.Valutare l'efficacia dell'intervento dello studio con misurazioni periferiche
    4.Valutare la frequenza del breakthrough virologico durante l'intervento dello studio
    5.Valutare le risposte delle cellule T specifiche per l'HBV
    6.Valutare la sicurezza e la tollerabilità dell'intervento dello studio
    7.Valutare la PK plasmatica di JNJ-3989 (ossia, JNJ 3976 e JNJ-3924), JNJ-6379, e facoltativamente dell'AN, secondo quanto applicabile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult participants =18 years of age to =65 years of age.
    2. Participants must be medically stable on the basis of physical examination, medical history, vital signs, and triplicate 12-lead ECG performed at screening.
    3. Participants must have HBV infection documented by serum HBsAg positivity at screening. In addition, chronicity must be documented by any of the following at least 6 months prior to screening: serum HBsAg positivity, HBeAg positivity or HBV DNA positivity, ALT elevation above ULN without another cause than HBV infection, documented transmission event, liver biopsy with changes consistent with chronic HBV.
    4. Participants who are not currently treated, including treatment-naïve participants should:
    a. be HBeAg positive, AND b. have serum HBV DNA at screening =20,000 IU /mL, AND c. have ALT levels at screening <10x ULN, AND d. have indication for NA treatment according to local standard practice.
    5. Virologically suppressed participants should: a. be HBeAg negative, AND b. be on stable HBV treatment, defined as currently receiving NA treatment (ETV, tenofovir disoproxil, or TAF) for at least 6 months prior to screening and have been on the same NA treatment regimen for at least 3 months at the time of screening, AND c. have serum HBV DNA <60 IU/mL on 2 measurements at least 3 months apart (one of which is at screening), AND d. have documented ALT values <2.0x ULN on 2 measurements at least 3 months apart .
    6. Participants must have HBsAg >100 IU/mL at screening.
    7. Participants must have a body mass index between 18.0 and 35.0 kg/m2, extremes included.
    8. Participants must have fibroscan liver stiffness measurement =9.0 kPa within 6 months prior to screening or at the time of screening.
    9.Female participants of childbearing potential must have a negative highly sensitive serum pregnancy test (B-human chorionic gonadotropin [B-hCG]) at screening and a negative urine pregnancy test on Day 1 before the first dose of study intervention.
    10. A woman must be (as defined in Section 10.8, Appendix 8, Contraceptive and Barrier Guidance and Collection of Pregnancy Information):
    Examples of highly effective methods of contraception are located in Section 10.8, Appendix 8, Contraceptive and Barrier Guidance and Collection of Pregnancy Information.
    11. Male participants must agree to wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study intervention period and until 90 days after last dose of study intervention.
    12. Female participants must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study intervention period and until 90 days after last dose of study intervention.
    13. Male participants must agree not to donate sperm for the purpose of reproduction during the study intervention phase and until 90 days after last dose of study intervention.
    14. Participants 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.
    15. Participants must separately consent if he or she agrees to undergo optional study procedures (ie, leukapheresis, intensive PK, and/or optional biopsy). Refusal to give consent to one or all of these optional study procedures does not exclude from participation in the study.
    16. In the investigator’s opinion, the participant is able to understand and comply with protocol requirements, instructions, and study restrictions and is likely to complete the procedures as planned for this this study.

    Please refer to the protocol for a full list of the inclusion criteria.
    1. Partecipanti adulti di età = 18 anni e = 65 anni.
    2. Condizioni mediche stabili evidenziate da esame obiettivo, anamnesi medica, segni vitali e triplo ECG a 12 derivazioni eseguito allo screening.
    3. L’infezione cronica da HBV deve essere documentata dalla positività a HBsAg nel siero allo screening.
    4. I partecipanti attualmente non trattati compresi anche i partecipanti naïve al trattamento , devono presentare i seguenti valori:
    a. positività all’HBeAg,
    b. DNA HBV sierico allo screening =20,000 IU /mL,
    c. livelli di ALT allo screening <10x ULN E
    d. indicazione per il trattamento con AN secondo le pratiche standard locali.
    5. I partecipanti virologicamente soppressi devono:
    a. essere HBeAg-negativi,
    b. assumere un trattamento stabile per l’HBV
    c. presentare DNA HBV nel siero <60 UI/mL in due misurazioni eseguite ad almeno 3 mesi di distanza (una delle quali deve avvenire allo screening) E
    d. presentare valori di ALT < 2,0x ULN in due misurazioni eseguite ad almeno 3 mesi di distanza (una delle quali deve avvenire allo screening).
    6. I partecipanti devono presentare HBsAg >100 UI/mL allo screening.
    7. I partecipanti devono avere un indice di massa corporea compreso tra 18,0 e 35,0 kg/m2, estremi inclusi.
    8. Deve essere rilevato mediante Fibroscan un valore di rigidità del fegato =9,0 kPa nei 6 mesi precedenti allo screening o al momento dello screening.
    9. Le partecipanti di sesso femminile in età fertile devono presentare un test di gravidanza sul siero altamente sensibile (¿ gonadotropina corionica umana [¿ hCG]) negativo allo screening e un test di gravidanza sull’urina negativo il Giorno 1 prima della prima dose di intervento dello studio.
    10. Le donne partecipanti (secondo la definizione contenuta nella Sezione 10.8, Appendice 8, Guida a metodi contraccettivi e di barriera e raccolta di informazioni sulla gravidanza):
    a. non devono essere potenzialmente fertili;
    b. se potenzialmente fertili, dovranno utilizzare un metodo contraccettivo altamente efficace, Esempi di metodi contraccettivi altamente efficaci sono indicati alla Sezione 10.8, Allegato 8, Guida a metodi contraccettivi e di barriera e raccolta di informazioni sulla gravidanza.
    11. I partecipanti di sesso maschile devono accettare di indossare un profilattico
    12. Le partecipanti di sesso femminile devono accettare di non donare ovuli (ovociti) per scopi di riproduzione assistita durante il trattamento con l’intervento dello studio e fino a quando non saranno trascorsi 90 giorni dall’ultima dose di intervento dello studio.
    13. I partecipanti di sesso maschile devono accettare di non donare lo sperma per scopi di riproduzione assistita durante il trattamento con l’intervento dello studio e fino a quando non saranno trascorsi 90 giorni dall’ultima dose di intervento dello studio.
    14. I partecipanti devono firmare un ICF nel quale dichiarano di aver compreso lo scopo dello studio e le relative procedure e che intendono prendervi parte.
    15. I partecipanti che acconsentono a sottoporsi a procedure facoltative. Il mancato consenso a una o tutte le procedure facoltative dello studio non preclude la partecipazione allo studio.
    16. Secondo il giudizio dello sperimentatore, i partecipanti sono in grado di comprendere e rispettare i requisiti del protocollo, le istruzioni e le limitazioni e sono propensi a completare le procedure programmate per questo studio.
    E.4Principal exclusion criteria
    1. Participants with evidence of hepatitis A virus infection (hepatitis A antibody IgM), HCV infection (HCV antibody), hepatitis D virus (HDV) infection (HDV antibody), or hepatitis E virus (HEV) infection (HEV antibody IgM), or HIV-1 or HIV-2 infection (confirmed by antibodies) at screening.
    2. Participants with any of the following laboratory abnormalities within 12 months prior to screening or at the time of screening: a. Total bilirubin >1.5x ULN, OR b. Direct bilirubin >1.2x ULN, OR c. Serum albumin <3.2 g/dL,
    3. History or evidence of clinical signs/symptoms of hepatic decompensation including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices.
    4. Participants with evidence of liver disease of non-HBV etiology. This includes but is not limited to hepatitis virus infections mentioned in exclusion criterion 1, drug- or alcohol related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, a 1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, Gilbert’s syndrome , or any other non HBV liver disease considered clinically significant by the investigator.
    5. Participants with history or signs of cirrhosis or portal hypertension, signs of HCC or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening.
    6. Participants with one or more of the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity Grading Scale:
    a. Estimated glomerular filtration rate (eGFR) =grade 3 (<60 mL/min/1.73m²), calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula;
    b. Pancreatic lipase elevation =grade 3;
    c. Pancreatic amylase elevation =grade 3
    d. Hemoglobin =10.9 g/dL (males), =10.4 g/dL (females);
    e. Platelet count =lower limit of normal (LLN);
    f. Alpha-fetoprotein (AFP) >100 ng/mL;
    g. Any other laboratory abnormality considered to be clinically significant by the investigator.
    7. Participants with presence of coagulopathy or bleeding disorder as indicated by:
    a. International normalized ratio (INR) =1.1 x ULN;
    b. Partial thromboplastin time > 1.1 x ULN;
    c. Any signs of prolonged bleeding (>10 minutes).
    8. Participants with presence of hemoglobinopathy (including sickle cell disease, thalassemia).
    9. Participants who had a liver biopsy performed prior to screening that led to complications and that in the opinion of the investigator would prohibit another liver biopsy.
    10. Participants with history of amyloidosis.
    11. Participant refusal to accept blood transfusions.
    12. Participants with hemoglobin A1c >8% at screening.
    13. Participants with a history of malignancy within 5 years prior to screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which are considered cured with minimal risk of recurrence).
    14. Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute [bpm]); QT interval corrected for heart rate according to Fridericia’s formula (QTcF) >450 ms for males and >470 ms for females; QRS interval =120 ms; PR interval >220 ms ; abnormal conduction; or any other clinically significant abnormalities on a 12-lead ECG at screening.
    15. Participants with a history of or current cardiac arrhythmias (eg, extrasystole, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome) or history or other clinical evidence of significant or unstable cardiac disease (eg, angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia and/or coronary heart disease), moderate to severe valvular disease, or uncontrolled hypertension at screening.

    Please refer to the protocol for a full list of the exclusion criteria.
    Partecipanti:
    1.con evidenza di infezione da virus dell’epatite A, infezione da HCV , infezione da virus dell’epatite D , infezione da virus dell’epatite E o infezione da HIV-1 o HIV-2 allo screening.
    2.che hanno presentato una qualsiasi delle anomalie di laboratorio elencate di seguito entro i 12 mesi precedenti allo screening o al momento dello screening:a. bilirubina totale >1,5x ULN,b. bilirubina diretta >1,2x ULN OPPUREc. albumina sierica <3,2 g/dL
    3.Anamnesi o evidenza di segni/sintomi clinici di scompenso epatico.
    4.con evidenza di malattia epatica di eziologia diversa dall’HBV
    5.con anamnesi o segni di cirrosi o di ipertensione portale o segni di HCC o anomalie renali clinicamente significative all’ecografia addominale eseguita entro i 6 mesi precedenti allo screening o al momento dello stesso.
    6.con una o più delle seguenti anomalie di laboratorio allo screening secondo la definizione della scala di classificazione delle tossicità DAIDS :a. Stima della velocità di filtrazione glomerulare (eGFR) = grado 3 (<60 mL/min/1,73m²) calcolata con la formula CKD-EPIb. Innalzamento della lipasi pancreatica = grado 3c. Innalzamento dell’amilasi pancreatica = grado 3d. Emoglobina =10,9 g/dL (maschi), =10,4 g/dL (femmine)e. Conta piastrinica = limite inferiore della norma (LLN) f. Alfa-fetoproteina (AFP) >100 ng/mL g.
    7.con coagulopatie o disturbi emorragici,:a.Rapporto internazionale normalizzato (INR) >1,1 x ULN b.Tempo di tromboplastina parziale > 1,1 x ULN c.Qualsiasi segno di sanguinamento prolungato (>10 minuti)
    8.con emoglobinopatia
    9.sottoposti a biopsia epatica prima dello screening.
    10.con anamnesi di amiloidosi
    11.che non acconsentono alla trasfusione di sangue
    12. con emoglobina A1c >8% allo screening
    13.con anamnesi di neoplasia maligna entro i 5 anni precedenti allo screening
    14.con ritmo sinusale anomalo
    15.con aritmia cardiaca attuale o pregressa
    16.con qualsiasi patologia attuale o pregressa
    17.che sono stati sottoposti a un trapianto d’organo
    18.con patologia cutanea clinicamente significativa, attuale o pregressa, che richieda un trattamento regolare o periodico
    19.con un quadro di abuso clinicamente significativo di alcol o farmaci entro i 12 mesi precedenti allo screening
    20.con anamnesi di eruzione cutanea da farmaci clinicamente significativa.
    21.che hanno assunto una delle terapie non consentite
    22.che hanno utilizzato un dispositivo medico sperimentale invasivo nei 3 mesi antecedenti alla prima dose programmata di intervento dello studio
    23.di sesso femminile che sono in gravidanza o allattano al seno o pianificano una gravidanza durante l’arruolamento in questo studio o entro i 90 giorni successivi all’ultima dose di intervento dello studio
    24.di sesso maschile che intendono concepire un figlio durante l’arruolamento in questo studio o entro i 90 giorni successivi all’ultima dose di intervento dello studio
    25.che si sono sottoposti a un intervento chirurgico di notevole entità, entro le 12 settimane precedenti allo screening
    26.Il partecipante è un dipendente dello sperimentatore o del centro di sperimentazione direttamente coinvolto nello studio proposto o in altri studi sotto la direzione di detto sperimentatore o centro di sperimentazione oppure è un familiare di un dipendente o dello sperimentatore
    27.Soggetti vulnerabili
    28.con allergie, ipersensibilità o intolleranza note a JNJ-3989 and JNJ-6379 o ai relativi eccipienti
    29.con controindicazioni all’uso di ETV, tenofovir disoproxil o TAF secondo le informazioni di prescrizione locali
    30.Per i partecipanti che si sottoporranno alla leucoaferesi facoltativa: controndicazioni all’uso di anticoagulanti a base di citrato secondo le informazioni di prescrizione locali
    E.5 End points
    E.5.1Primary end point(s)
    Changes in the proportion of HBsAg positive hepatocytes between baseline and on-treatment Week 40.
    Variazioni della proporzione di epatociti HBsAg positivi tra il basale e la Settimana 40 durante il trattamento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 40
    settimana 40
    E.5.2Secondary end point(s)
    1.Changes between baseline and on-treatment liver biopsy in intrahepatic immune response (eg, CD45+ T-cells, CD4+ T-cells, CD8+ T-cells, Natural Killer cells, and dendritic cells) in terms of proportion of cells, cell types, and spatial redistribution.
    2a. Changes from baseline in intrahepatic viral parameters (such as cccDNA, pgRNA, intrahepatic RNA, or HBsAg in terms of copy number, or number of positive cells).
    2b. Changes from baseline in intrahepatic cccDNA levels and transcriptional activity (pgRNA/cccDNA ratio).
    3a. The proportion of participants during the study intervention and follow-up phases with:
    -HBsAg seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment.
    -(Sustained) Reduction, suppression, and/or seroclearance considering single and multiple markers (such as HBsAg, HBeAg, HBV DNA and ALT)
    -HBsAg and HBeAg seroconversion
    -Flares (virologic, biochemical, and clinical)
    3b. Time to first HBsAg seroclearance
    4. Proportion of participants with virologic breakthrough.
    5. Changes from baseline in HBV-specific peripheral blood T-cell responses during the study intervention and follow-up phases.
    6. Proportion of participants with (S)AEs and abnormalities in clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal biomarkers), 12-lead ECGs, vital signs, and physical examinations throughout the study.
    7. Plasma PK parameters of JNJ-3976, JNJ-3924, JNJ-6379, and optionally of NA, as applicable.
    1. Variazioni, tra il basale e la biopsia epatica durante il trattamento, della risposta immunitaria intraepatica (ad es. cellule T CD45+, CD4+ e CD8+, cellule natural killer e cellule dendritiche) in termini di proporzione e tipi di cellule e di ridistribuzione spaziale.
    2a. Variazioni rispetto al basale dei parametri virali intraepatici (quali cccDNA, pgRNA, RNA intraepatico o HBsAg in termini di numero di copie o numero di cellule positive)
    2b.Variazioni rispetto al basale dei livelli di cccDNA intraepatico e dell'attività trascrizionale (rapporto pgRNA/cccDNA)
    3a.La proporzione dei partecipanti che, durante l'intervento dello studio e le fasi di follow-up, presentano:
    -Clearance sierica di HBsAg alla Settimana 72 (ossia, 24 settimane dopo il completamento di tutti gli interventi dello studio alla Settimana 48) senza iniziare nuovamente il trattamento con l'AN.
    -Riduzione, soppressione, e/or clearance sierica (duratura) considerando marcatori singoli e molteplici (quali HBsAg, HBeAg, DNA HBV e ALT)
    -Sieroconversione HBsAg e HBeAg
    -Riacutizzazioni (virologiche, biochimiche, e cliniche)
    3b.Tempo alla prima clearance sierica di HBsAg
    4.Proporzione dei partecipanti con breakthrough virologico
    5.Variazioni rispetto al basale delle risposte delle cellule T del sangue periferico specifiche per l'HBV durante le fasi di intervento dello studio e di follow-up
    6.Proporzione di partecipanti che presentano (S)AE e anomalie negli esami clinici di laboratorio (incluse analisi ematologiche, analisi ematobiochimiche, test di coagulazione ematica, analisi delle urine, esami chimici delle urine e biomarcatori renali), ECG a 12 derivazioni, segni vitali ed esami obiettivi durante lo studio
    7.Parametri farmacocinetici plasmatici di JNJ-3976, JNJ-3924, JNJ-6379 e facoltativamente dell'AN, secondo quanto applicabile
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study duration.
    Durante tutta la durata dello studio
    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 Yes
    E.6.7Pharmacodynamic Yes
    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 Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Canada
    New Zealand
    United States
    Belgium
    France
    Germany
    Italy
    United Kingdom
    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 years5
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    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: 24
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 14
    F.4.2.2In the whole clinical trial 24
    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)
    Participants will be instructed that study intervention will not be made available to them after they have completed/discontinued study intervention and that they should return to their primary physician to determine standard of care.
    I soggetti saranno informati che il farmaco di studio non sarà reso disponibile per loro dopo aver completato / interrotto il trattamento di studio e che dovrebbero tornare dal proprio medico primario per determinare una cura standard.
    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 Decision2020-06-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-21
    P. End of Trial
    P.End of Trial StatusOngoing
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