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    Summary
    EudraCT Number:2017-001110-29
    Sponsor's Protocol Code Number:56136379HPB2001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-01-26
    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 ConcernedSpain - AEMPS
    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 24 Weeks 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
    Estudio de fase 2a, aleatorizado, parcialmente ciego y controlado con placebo para evaluar la eficacia, la seguridad y la farmacocinética del tratamiento durante 24 semanas con dosis múltiples de JNJ-56136379 en monoterapia y en combinación con un análogo de nucleós(t)idos en pacientes con infección crónica por el virus de la hepatitis B.
    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 24 Weeks 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
    Estudio para evaluar la eficacia, seguridad y farmacocinética de 24 semanas de tratamiento con dosis múltiples de JNJ-56136379 en monoterapia y en combinación con un análogo de Nucleos(t)idos en pacientes con infección crónica por el virus de la hepatitis B
    A.4.1Sponsor's protocol code number56136379HPB2001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03361956
    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 UC
    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 Sciences 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, S.A.
    B.5.2Functional name of contact pointGlobal Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressPº de las Doce Estrellas, 5-7
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28042
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491 7228100
    B.5.5Fax number+3491 7228628
    B.5.6E-mailagonza45@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.3.2Product 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.3.8INN - Proposed INNNot Assigned
    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 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.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.3.2Product 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.3.8INN - Proposed INNNot Assigned
    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 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.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.3.4Pharmaceutical 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 fumarate
    D.3.9.1CAS number 202138-50-9
    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 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.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.3.4Pharmaceutical 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 monohydrate
    D.3.9.1CAS number 209216-23-9
    D.3.9.4EV Substance CodeSUB25434
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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 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
    Infección crónica por el virus de la hepatitis B
    E.1.1.1Medical condition in easily understood language
    A serious liver infection caused by the hepatitis B virus
    Infección hepática grave causada por el virus de la hepatitis B
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10008910
    E.1.2Term Chronic hepatitis B
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate efficacy of 24 weeks of study treatment, in terms of changes in hepatitis B surface antigen (HBsAg) levels.
    Evaluar la eficacia de 24 semanas de tratamiento del estudio, en términos de cambios en los niveles de antígeno de superficie de la hepatitis 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.
    • Evaluar la seguridad y tolerabilidad de 24 semanas de tratamiento del estudio.
    • Evaluar la eficacia en términos de cambios en los niveles de HBsAg.
    • Evaluar la eficacia en términos de cambios en los niveles de ADN del VHB.
    • Evaluar la eficacia en términos de cambios en los niveles de HBeAg (solo en pacientes HBeAg-positivos).
    • Evaluar la eficacia en términos de HBsAg (en todos los sujetos) o HBeAg (solo en pacientes con HBeAg positivo), seroaclaramiento y / o seroconversión.
    • Evaluar la frecuencia de pacientes con respuesta bioquímica.
    • Evaluar la frecuencia de recaída virológica
    Evaluar el posible efecto de JNJ‑56136379 sobre la farmacocinética del NA cuando se administran conjuntamente.
    • Evaluar la farmacocinética de JNJ-56136379 cuando se administra como monoterapia.
    • Evaluar el posible efecto del NA sobre la farmacocinética de JNJ‑56136379 cuando se administran conjuntamente.
    •Evaluar posibles cambios en la secuencia del genoma del VHB.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects must be 18 (or older legal age of consent as per local requirements) 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.
    · Los pacientes deben tener entre 18 (o una edad legal de consentimiento mayor, según la regulación local) y 70 años de edad, ambos inclusive.
    · Los pacientes deben tener hepatitis B crónica documentada mediante:
    - HBsAg positivo en suero en la visita de selección y al menos 6 meses antes de la visita de selección.
    - Anticuerpos de tipo inmunoglobulina M (IgM) anti‑HBc en suero negativos en la visita de selección.
    · Pacientes que no estén recibiendo tratamiento actualmente (grupos de tratamiento 1‑2‑3 y 6‑7‑8):
    -El paciente no debe estar recibiendo ningún tratamiento para la HBC en la selección, es decir,
    o Nunca ha recibido tratamiento con antivirales contra el VHB, incluidos NA o productos a base de interferón (IFN), O
    o No ha recibido tratamiento con antivirales contra el VHB, incluidos NA o productos a base de IFN, en los 6 meses previos a la visita basal (primera toma de los fármacos del estudio), Y
    - El paciente debe tener HBeAg positivo y una concentración de ADN del VHB ³ mayor o igual 20.000 UI/ml, O HBeAg negativo y una concentración de ADN del VHB ³ mayor o igual 2000 UI/ml en la selección, Y
    - El paciente debe tener una concentración de HBsAg > 250 UI/ml en la selección, Y
    - El paciente debe tener una concentración de ALT > límite superior de la normalidad (LSN) y ≤ 5 veces el LSN en la visita de selección, determinada en el laboratorio central.
    Nota: En los pacientes tratados con fármacos contra el VHB en investigación más de 6 meses antes de la visita de selección, deberá contactarse con el promotor para comentar el caso. Se excluirá a los pacientes que hayan recibido tratamiento con un modulador del ensamblaje de la cápsida durante más de 4 semanas en cualquier momento antes de la selección.

    ·Pacientes con supresión virológica (grupos de tratamiento 4‑5 y 9‑10):
    -El paciente debe mostrar supresión virológica con el tratamiento presente con NA (ETV o TDF), definida como una concentración de ADN del VHB < 60 UI/ml en la visita de selección y al menos 6 meses antes de la visita de selección, Y
    -El paciente debe recibir el mismo tratamiento con NA (ETV o TDF) y la misma dosis durante ≥ 12 meses antes de la visita de selección, Y
    -El paciente debe tener una concentración de HBsAg > 250 UI/ml en la visita de selección, Y
    -El paciente debe tener una concentración de ALT ≤ 2 veces el LSN en la visita de selección.
    Nota: En los pacientes tratados con fármacos contra el VHB en investigación más de 6 meses antes de la visita de selección, deberá contactarse con el promotor para comentar el caso. Se excluirá a los pacientes que hayan recibido tratamiento con un modulador del ensamblaje de la cápsida durante más de 4 semanas en cualquier momento antes de la visita de selección.

    ·Los pacientes deben presentar:
    -Un resultado de biopsia hepática clasificado como Metavir F0‑F2 en el año previo a la visita de selección o en el momento de la visita de selección, O
    -Medición de la rigidez hepática con FibroScan™ < 8,0 kPa en los 6 meses previos a la visita de selección o en el momento de la visita de selección.
    Las mujeres en edad fértil deben tener una prueba de embarazo en suero negativa altamente sensible (beta-gonadotropina coriónica humana) en la evaluación.

    • Las mujeres deben ser:
    - No tener capacidad de procrear
    - Tener capacidad de procrear y practicar un método anticonceptivo altamente eficaz, preferiblemente independiente del usuario (tasa de fracaso de <1% por año cuando se usa de manera consistente y correcta) y aceptar permanecer en un método altamente eficaz mientras reciba el tratamiento del estudio y hasta 90 días después de la última dosis de JNJ -56136379.

    • Una mujer debe aceptar no donar óvulos (óvulos, ovocitos) durante el estudio hasta al menos 90 días después de la última dosis de JNJ-56136379.

    • El paciente masculino debe aceptar usar un condón al participar en cualquier actividad que permita el paso de la eyaculación a otra persona durante el estudio hasta al menos 90 días después de la última dosis de JNJ-56136379.

    • El paciente masculino debe aceptar no donar esperma durante el estudio y durante al menos 90 días después de recibir la última dosis de JNJ-56136379.

    • El paciente debe firmar un ICF que indique que entiende el propósito y los procedimientos requeridos para el estudio y está dispuesto a participar en el estudio.

    • El paciente debe firmar un ICF por separado si acepta proporcionar una muestra de ADN opcional para la investigación. La negativa a dar consentimiento para la muestra de investigación de ADN opcional no excluye a un sujeto de la participación en el estudio.

    • En la opinión del investigador, el paciente debe ser capaz de comprender y cumplir con los requisitos del protocolo, las instrucciones y las restricciones de estilo de vida (Sección 4.3) y ser previsiblemente capaz de completar el estudio según lo planificado.
    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, α-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).
    ·Pacientes que den positivo para anticuerpos anti‑HBs.
    ·Pacientes con infección presente por el virus de la hepatitis A (confirmada por la presencia de anticuerpos IgM contra el virus de la hepatitis A), el virus de la hepatitis C (VHC) (confirmada por la presencia de anticuerpos contra el VHC), el virus de la hepatitis D (VHD) (confirmada por la presencia de anticuerpos contra el VHD), el virus de la hepatitis E (confirmada por la presencia de anticuerpos IgM contra el virus de la hepatitis E) o el virus de la inmunodeficiencia humana de tipo 1 (VIH‑1) o VIH‑2 (confirmada por la presencia de anticuerpos) en la visita de selección. Los datos de otra infección activa (bacteriana, vírica, fúngica, incluida tuberculosis aguda) que el investigador considere clínicamente relevante y que podría interferir en la realización del estudio o en su interpretación también darán lugar a la exclusión.
    ·Pacientes con cualquier dato de descompensación hepática en cualquier momento antes de o en el momento de la visita de selección:
    -Bilirrubina directa > 1,2 veces el LSN, o
    -Cociente internacional normalizado > 1,5 veces el LSN, o
    -Albúmina sérica < límite inferior de la normalidad (LIN), o
    -Antecedentes documentados o signos presentes de varices hemorrágicas, ascitis o encefalopatía hepática.
    ·Pacientes con cualquier indicio de hepatopatía con una etiología distinta del VHB. Ello incluye, aunque no exclusivamente, las infecciones por virus de la hepatitis mencionadas anteriormente, la hepatopatía relacionada con fármacos o alcohol, la hepatitis autoinmunitaria, la hemocromatosis, la enfermedad de Wilson, el síndrome de Gilbert, la deficiencia de α‑1 antitripsina, la cirrosis biliar primaria, la colangitis esclerosante primaria o cualquier otra hepatopatía no debida al VHB que el investigador considere clínicamente significativa.
    ·Pacientes con signos de carcinoma hepatocelular (CHC) en una ecografía abdominal realizada en los dos meses previos a la visita de selección o en el momento de la visita de selección. En caso de hallazgos sospechosos en una ecografía convencional, el paciente podrá seguir siendo elegible siempre que se descarte un CHC mediante un procedimiento de imagen más específico (ecografía con contraste, tomografía computarizada [TC] o resonancia magnética [RM]).
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in HBsAg levels at Week 24
    Variación de la concentración de HBsAg entre la visita basal y la semana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and Week 24
    Visita basal y semana 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.
    · Datos de seguridad y tolerabilidad, entre otros, acontecimientos adversos (AA) y acontecimientos adversos graves (AAG), exploraciones físicas, constantes vitales, electrocardiograma (ECG) de 12 derivaciones y análisis clínicos (incluyendo hematología, bioquímica, coagulación y análisis de orina), durante todo el estudio.
    · Variación con respecto al momento basal de la concentración de HBsAg durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con concentraciones de HBsAg según la subcategoría de respuesta, como HBsAg < 1000 o < 100 UI/ml, o con una reducción > 0,5 o > 1 log10 de la concentración de HBsAg con respecto al momento basal, tal como se indica en el plan de análisis estadístico (PAE), durante el tratamiento del estudio y el seguimiento.
    · Variación con respecto al momento basal de la concentración de ADN del VHB durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con concentraciones de ADN del VHB según la subcategoría de respuesta, tal como se indica en el PAE, durante el tratamiento del estudio y el seguimiento.
    · Variación con respecto al momento basal de la concentración de HBeAg durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con concentraciones de HBeAg según la subcategoría de respuesta, tal como se indica en el PAE, durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con seroaclaramiento del HBsAg o HBeAg (definido como negatividad del HBsAg o HBeAg, respectivamente, según el análisis utilizado) durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con seroconversión del HBsAg o HBeAg (definida como negatividad del HBsAg o HBeAg y positividad de anticuerpos anti‑HBs o anti‑HBe, respectivamente) durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con mejoría y normalización de la alanina aminotransferasa (ALT) durante el tratamiento del estudio y el seguimiento.
    · Proporción de pacientes con recaída virológica durante el tratamiento del estudio, definida como un aumento de la concentración de ADN del VHB durante el tratamiento > 1 log10 con respecto al valor mínimo o una concentración confirmada de ADN del VHB durante el tratamiento > 200 UI/ml en pacientes que han presentado una concentración de ADN del VHB por debajo del límite inferior de cuantificación (LIC) del análisis de ADN del VHB.
    · Farmacocinética del NA cuando se administra en monoterapia o conjuntamente con JNJ‑56136379.
    · Farmacocinética de JNJ‑56136379 cuando se administra en monoterapia o conjuntamente con un NA.
    · Aparición de mutaciones asociadas al tratamiento durante el tratamiento del estudio y el seguimiento.
    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
    Seguridad: durante todo el estudio

    HBsAg, HBeAg, ADN del VHB: Selección, Fase de tratamiento: Día 1, Semanas 1, 2, 4, 8, 12 (D84), 16, 20, 24, y Fase de seguimiento: Semanas 2, 4, 12, 24

    Anti-HBs y anti-HBe: Selección, fase de tratamiento: día 1 y semana 24, y fase de seguimiento: semanas 2, 4, 12, 24

    Muestras PK: Fase de tratamiento: Día 1, Semanas 1, 2, 4, 8, 12 (D84), 20, 24, y Fase de seguimiento: Semanas 2 y 4

    Bioquímica sanguínea (ALT): Selección, fase de tratamiento: día 1, semana 1, 2, 4, 8, 12 (D84), 16, 20, 24 y fase de seguimiento: semanas 2, 4, 12, 24

    Secuenciación del genoma viral: Selección, fase de tratamiento: día 1, semanas 2, 4, 8, 12 (D84), 16, 20, 24 y fase de seguimiento: semanas 2, 4, 12, 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy 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
    Análisis de biomarcadores y de resultados comunicados por los pacientes.
    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 concerned5
    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 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
    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 months7
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days12
    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 state15
    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)
    Where approved, JNJ-56136379-treated subjects who have successfully completed 24 weeks of treatment and who have HBV DNA levels <LLOQ and evidence of HBsAg decline at Week 20, may be invited to enroll in a treatment extension study, in which the JNJ-56136379 treatment will be prolonged. NA treatment (either ETV or TDF as per local practice) may be continued or, in case of JNJ-56136379 monotherapy, started at Week 24 until the end of the follow-up phase at the investigator’s discretion.
    Si aprobado, los pacientes tratados con JNJ‑56136379 que hayan completado 24 semanas de tratamiento y con concentraciones de ADN del VHB < LIC y disminución del HBsAg en semana 20 podrán ser invitados a participar en un estudio de ampliación del tratamiento de JNJ‑56136379. El tratamiento con NA (ETV o TDF según práctica local) podrá mantenerse o, en caso de JNJ‑56136379 en monoterapia, iniciarse en semana 24 hasta el final de la fase de seguimiento, a criterio del investigador.
    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 Decision2018-05-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-21
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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