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    Summary
    EudraCT Number:2015-005215-33
    Sponsor's Protocol Code Number:CLJN452A2202
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-05
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-005215-33
    A.3Full title of the trial
    A randomized, double-blind, placebo controlled, 2- part, adaptive design, multicenter 12-week study to assess safety, tolerability and efficacy of LJN452 in patients with non-alcoholic steatohepatitis (NASH) FLIGHT-FXR
    Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo, de 2 partes, diseño adaptativo y 12 semanas de duración para evaluar la seguridad, tolerabilidad y eficacia de LJN452 en pacientes con
    esteatohepatitis no alcohólica (EHNA).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 2 part clinical study that will evaluate the safety and effectiveness of LJN452A to treat patients with fatty liver disease for a period of 12 weeks. The first part will be used for LJN452 dose selection for the second part of the study.
    Estudio de 2 partes que evalúa la seguridad y eficacia de LJN452 en pacientes con enfermedad hepática en un periodo de 12 semanas. La primera parte se usará para selección de dosis de LJN452 para la segunda parte del estudio.
    A.4.1Sponsor's protocol code numberCLJN452A2202
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico (ICRO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+34900353036
    B.5.5Fax number+34932479903
    B.5.6E-maileecc.novartis@novartis.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 nameLJN452
    D.3.2Product code LJN452
    D.3.4Pharmaceutical form Capsule, hard
    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 available yet
    D.3.9.2Current sponsor codeLJN452
    D.3.9.3Other descriptive nameLJN452
    D.3.9.4EV Substance CodeSUB174477
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.3.1Product nameLJN452
    D.3.2Product code LJN452
    D.3.4Pharmaceutical form Capsule, hard
    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 available yet
    D.3.9.2Current sponsor codeLJN452
    D.3.9.3Other descriptive nameLJN452
    D.3.9.4EV Substance CodeSUB174477
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 placeboCapsule, hard
    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
    Non-alcoholic Steatohepatitis (NASH)
    Esteatohepatitis no alcohólica (EHNA)
    E.1.1.1Medical condition in easily understood language
    Fatty liver disease not related to alcohol intake
    Hepatopatía grasa no relacionada con el consumeo de alcohol.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine safety and tolerability of different doses of LJN452 by monitoring adverse events up to the end of the study.
    Moreover, the study will determine the dose-response relationship of LJN452 on markers of hepatic inflammation in NASH by changes in ALT and AST from baseline to Week 12
    El objetivo principal del estudio es determinar la seguridad y tolerabilidad de diferentes dosis de LJN452 monitorizando los acontecimientos adversos hasta el final del estudio.
    Asimismo, en el estudio se determinará la relación dosis-respuesta de LJN452 en los marcadores de inflamación hepática en EHNA según los cambios en ALT y AST desde la basal hasta la semana 12.
    E.2.2Secondary objectives of the trial
    To determine the dose-response relationship of LJN452 on liver fat content by quantitative MRI
    To determine the effect of different doses of LJN452 on weight, BMI, waist-to-hip (WTH) ratio) after 12 weeks of treatment
    To determine the dose-response relationship of LJN452 on markers of target engagement
    To determine the dose-response relationship of LJN452 on markers of liver fibrosis
    To determine the dose-response relationship of LJN452 on GGT, a cholestasis marker
    To determine the effect of LJN452 on fasting lipid profile
    To determine the pharmacokinetics of LJN452
    To determine the effect of LJN452 compared to placebo with respect to occurrence of potential itch based on a visual analog scale (VAS) rating scale
    To determine effects of LJN452 on primary endpoints in the subset of patients who have historical biopsy data, both overall and by subsets defined by fibrosis score and/or NAS score as feasible (based on extent of available data)
    Determinar la relación dosis-respuesta de LJN452 en el contenido de grasa en el hígado por métido cuantitativo RM
    Determinar el efecto de diferentes dosis de LJN452 en (peso, IMC, índice cintura/cadera [ICC]) después de 12 semanas de tratamiento.
    Determinar la relación dosis-respuesta en los marcadores diana.
    Determinar la relación dosis-respuesta de LJN452 en marcadores de fibrosis hepatica
    Determinar la relación dosis-respuesta de LJN452 en GGT, un marcador de colestasis.
    Determinar el efecto de LJN452 en el perfil lipídico en ayunas.
    Determinar la farmacocinética de LJN452
    Determinar el efecto de LJN452 vs placebo con relación a la aparición de posibles picores según una escala visual analógica (EVA).
    Determinar los efectos de LJN452 en las variables principales en el subgrupo de pacientes que presenten datos históricos de biopsias, tanto globalmente como por subgrupos definidos por puntuación de fibrosis y/o puntuación NAS si es factible (según los datos disponibles).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Written informed consent must be obtained before any assessment is performed

    Male and female patients 18 years or older (at the time of the screening visit)

    Presence of NASH as demonstrated by ONE of the following:
    - Histologic evidence of NASH based on liver biopsy obtained 2 years or less before randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, no diagnosis of alternative chronic liver diseases
    AND
    ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)

    OR
    Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
    o ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND
    o BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or ≥23 kg/m2 (in patients with a self-identified Asian race)
    AND
    o Diagnosis of Type 2 diabetes mellitus by having either:
    - HbA1C ≥ 6.5% or
    - Drug therapy for Type 2 diabetes mellitus

    Liver fat ≥ 10% at screening as determined by the central MRI laboratory

    Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate in the study
    El consentimiento informado por escrito se debe obtener antes de realizar cualquier evaluación.

    Pacientes de ambos sexos ≥ 18 años de edad (en el momento de la visita de selección).
    Presencia de EHNA demostrada por UNO de los siguientes:Signo histológico de EHNA basado en biopsia hepática obtenida como máximo dos años antes de la aleatorización con un diagnóstico que coincida con EHNA, fibrosis de niveles F1, F2 o F3, sin diagnóstico de hepatopatía crónica alternativa Y
    ALT ≥ 60 UI/l (hombres) o ≥ 40 UI/l (mujeres).

    Diagnóstico fenotípico de EHNA basado en la presencia de ESTAS TRES circunstancias:
    ALT ≥ 60 UI/l (hombres) o ≥ 40 UI/l (mujeres) Y
    o IMC ≥ 27 kg/m2 (en pacientes que se identifiquen a sí mismos como de origen racial no asiático) o ≥ 23 kg/m2 (en pacientes que se identifiquen a sí mismos como de origen racial asiático) Y
    o Diagnóstico de diabetes mellitus de tipo 2 con:
    - HbA1C ≥ 6,5% o
    - Tratamiento farmacológico para la diabetes mellitus de tipo 2

    Grasa en el hígado ≥ 10% en la selección determinada por el laboratorio central de RM.

    Los pacientes deben pesar un mínimo de 40 kg y un máximo de 150 kg para participar en el estudio.
    E.4Principal exclusion criteria
    Previous exposure to obeticholic acid (OCA)

    Patients taking medications prohibited by the protocol

    Pregnant or nursing (lactating) women

    Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the AUDIT questionnaire ≥8
    Uncontrolled diabetes defined as HbA1c ≥ 9.5% within 60 days prior to enrollment

    Presence of cirrhosis on liver biopsy or clinical diagnosis

    Clinical evidence of hepatic decompensation or severe liver impairment

    Previous diagnosis of other forms of chronic liver disease

    Patients with contraindications to MRI imaging
    Exposición previa a ácido obeticólico (AO).

    Pacientes que estén recibiendo medicación prohibida por el protocolo.

    Mujeres embarazadas o en periodo de lactancia

    Consumo significativo de alcohol o antecedentes durante un periodo superior a 3 meses consecutivos durante un año antes de la selección (se entiende por consumo significativo de alcohol más de 20 g/día en mujeres y más de 30 g/día en hombres como media) y/o una puntuación en el cuestionario AUDIT ≥ 8.

    Presencia de cirrosis en biopsia hepática o diagnóstico clínico.

    Signos clínicos de descompensación hepática o deterioro hepático grave.

    Diagnóstico previo de otras formas de hepatopatía crónica.

    Pacientes con contraindicaciones para el diagnóstico por RM.
    E.5 End points
    E.5.1Primary end point(s)
    Safety (to be assessed in the SAF):
    - Occurrence of SAE
    - Occurrence of AE resulting in permanent discontinuation or dose reduction of study treatment
    - Occurrence of AE of special interest

    Efficacy (to be assessed in the FAS):
    - Change from baseline to Week 12 in ALT
    - Change from baseline to Week 12 in AST
    Seguridad:
    - Ocurrencia de AAG
    - Ocurrencia de EA que resulte en la discontinuación permanente o reducción de dosis del tratamiento del estudio.
    - Ocurrencia de EA de especial interés.

    Eficacia:
    - Cambios en ALT desde basal hasta la semana 12.
    - Cambios en AST desde basal hasta la semana 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks of treatment
    12 semanas de tratamiento
    E.5.2Secondary end point(s)
    Relative change from baseline to Week 12 in percentage of fat in the liver assessed using MRI

    Absolute change from baseline to Week 12 in percentage of fat in the liver assessed using MRI

    Weight, BMI, waist-to-hip (WTH) ratio

    FGF19, C4

    Liver stiffness (in kPa) by Fibroscan®, enhanced liver fibrosis panel (ELF) score, and score of fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)

    GGT

    Fasting lipids (total cholesterol, trigylcerides, LDL and HDL cholesterol, free glycerol, free fatty acids)

    Itch VAS
    Cambios relativos desde basal hasta la semana 12 en el contenido de grasa en el hígado mediante los cambios en la grasa determinada por RM.

    Cambios absolutos desde basal hasta la semana 12 en el contenido de grasa en el hígado mediante los cambios en la grasa determinada por RM.

    Peso, IMC, índice cintura/cadera [ICC]

    Marcador de unión con la diana FXR en el intestine FGF19 y C4 marcador de unión con la diana hepática.

    Marcadores de fibrosis hepática habitualmente disponibles, como Fibroscan® (en un subgrupo de pacientes), prueba Enhanced Liver Fibrosis (ELF) o prueba de biomarcadores de fibrosis (originalmente conocida como Fibrotest®/FibroSure®).

    GGT

    Perfil lipídico (cholesterol total, triglicéridos, LDH y HDL, glycerol libre, acidos grasos libres)

    Picores según una escala visual analógica (EVA).
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 weeks of treatment
    12 semanas de tratamiento
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind 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 trial5
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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
    Australia
    Austria
    Belgium
    Canada
    France
    Germany
    Italy
    Korea, Republic of
    Netherlands
    Slovakia
    Spain
    Taiwan
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Visit Last Patient Last Site (LPLVLS)
    Ultimo paciente de ultima visita en el ultimo centro.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    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: 138
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 112
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 250
    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)
    None
    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 Decision2016-10-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-04-06
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