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    Summary
    EudraCT Number:2019-002593-31
    Sponsor's Protocol Code Number:69HCL19_0003
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-09-05
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-002593-31
    A.3Full title of the trial
    Efficacy of Nintedanib per os as a treatment for epistaxis in HHT disease
    A national, randomized, multicenter phase II study

    EPICURE
    EPICURE : Efficacité du Nintedanib par voie orale pour le traitement des épistaxis dans la maladie de Rendu-Osler. Etude nationale, randomisée, multicentrique de phase II.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Nintedanib per os as a treatment for epistaxis in HHT disease
    EPICURE
    EPICURE : Efficacité du Nintedanib par voie orale pour le traitement des épistaxis dans la maladie de Rendu-Osler.
    A.4.1Sponsor's protocol code number69HCL19_0003
    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 SponsorHospices Civils de Lyon
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinistry of Health
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospices Civils de Lyon
    B.5.2Functional name of contact pointRegulatory Project Manager
    B.5.3 Address:
    B.5.3.1Street Address3 QUAI DES CELESTINS
    B.5.3.2Town/ cityLYON
    B.5.3.3Post code69002
    B.5.3.4CountryFrance
    B.5.4Telephone number472406829+33
    B.5.5Fax number472115190+33
    B.5.6E-maildrci_promo@chu-lyon.fr
    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 Yes
    D.2.1.1.1Trade name OFEV
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namenintédanib
    D.3.4Pharmaceutical form Capsule, soft
    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 656247-17-5
    D.3.9.3Other descriptive nameNINTEDANIB
    D.3.9.4EV Substance CodeSUB120728
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    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
    Hereditary Hemorrhagic Telangiectasia
    E.1.1.1Medical condition in easily understood language
    Hereditary Hemorrhagic Telangiectasia
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10019887
    E.1.2Term Hereditary hemorrhagic telangiectasia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    evaluate efficacy, at the end of the treatment period, on epistaxis duration of nintedanib treatment per os (300 mg/day for 12 weeks) versus placebo in patients with HHT complicated by moderate to severe epistaxis.
    Evaluer l’efficacité sur la durée des épistaxis d’un traitement Nintedanib (300 mg par jour en deux prises) administré per os pendant 12 semaines à des patients atteints de la maladie de Rendu-Osler.
    E.2.2Secondary objectives of the trial
    1. To evaluate nintedanib safety in HHT patients.
    2. To evaluate efficacy of nintedanib treatment on epistaxis (duration, frequency and severity).
    3. To evaluate efficacy of nintedanib treatment on other clinical criteria: Quality of life: SF36, number of red blood cell transfusions and number of iron infusions.
    4. To evaluate efficacy of nintedanib treatment on biological criteria: hemoglobin and ferritin levels.
    1- Evaluer la tolérance, tout au long de l’étude, du nintedanib chez les patients Rendu-Osler.
    2- Evaluer l’efficacité du Nintedanib sur les épistaxis (durée, fréquence et sévérité).
    3- Evaluer l’efficacité du Nintedanib sur l’évolution des autres paramètres cliniques : qualité de vie : SF36, nombre de transfusions de globules rouges, nombre de perfusion de fer.
    4- Evaluer l’efficacité du Nintedanib sur l’évolution des paramètres biologiques : anémie (hémoglobinémie et ferritinémie)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
     Age > 18 years old
     Patients who have given their free informed and signed consent
     Patients affiliated to a social security scheme or similar
     Patients monitored for clinically confirmed HHT and/or with molecular biology confirmation
     Patient with an Epistaxis Severity Score (ESS) > 4 (target population of patients with important consequences on quality of life)
    • Age > 18 ans
    • Patient ayant donné son consentement libre, éclairé et signé.
    • Patient affilié à un régime de sécurité sociale ou assimilé.
    • Patient suivi pour une maladie de Rendu-Osler confirmée cliniquement (présence d’au moins 3 critères de Curaçao) et/ou en biologie moléculaire.
    • Patient présentant des épistaxis avec un score de sévérité (ESS) > 4
    E.4Principal exclusion criteria
    • Pregnant woman or woman of child bearing potential not using two effective methods of birth control (one barrier and one highly effective non-barrier) for at least 1 month prior to trial and/or committing to using it until 3 months after the end of treatment.
    • Woman who are breast feeding.
    • Patient who are protected adults under the terms of the law (French Public Health Code).
    • Participation in another interventional clinical trial which may interfere with the proposed trial (judgment of the investigator).
    • Clinical evidence of active infection.
    • (AST, ALT > 1,5 fold upper limit of normal (ULN) and/or Bilirubin > 1,5 fold upper limit of normal (ULN).
    • Severe renal impairment (Creat Clearance <30 mL/min) estimated by the Cockcroft-Gault equation.
    • Presence of non-treated pulmonary arteriovenous malformations accessible to a treatment on CT scan within 5 years.
    • Patients with hemoptysis or hematuria within 12 weeks prior to inclusion.
    • Patients with active gastro-intestinal (GI) bleeding or GI ulcers.
    • Presence of cerebral arteriovenous malformation on MRI done within 5 years prior inclusion.
    • Patients who require full-dose therapeutic anticoagulation (e.g. vitamin K antagonist or heparin, dabigatran) or high dose antiplatelet therapy.
    • Patients with known coronary artery disease or recent history of myocardial infarction (within 1 year).
    • Known inherited predisposition to thrombosis or thrombotic events (including stroke and transient ischemic attack) within 12 months prior to inclusion.
    • Patients with QTc prolongation (on ECG, less than 3 months).
    • Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients.
    • Patient who incompletely filled in epistaxis grids within 8 weeks prior to inclusion.
    • Patient who have received intravenous bevacizumab within 6 months prior to inclusion.
    • Patient who had surgery (including ENT surgery) within 12 weeks prior to inclusion.
    • Unhealed wound.
    • Planned major surgery within the next 3 months, including liver transplantation, major abdominal or intestinal surgery.
    • Femme enceinte ou femme en âge de procréer sans une double contraception (barrière + autre méthode efficace) depuis un mois avant le traitement jusqu’à 3 mois après la fin du traitement.
    • Femme en cours d’allaitement
    • Patient majeur protégé selon les termes de la loi (Code de la Santé Public)
    • Participation à un autre essai clinique qui peut interférer avec l’essai proposé (jugement de l’investigateur)
    • Episode infectieux en cours
    • ASAT, ALAT supérieures à 1,5 fois la limite normale et/ ou bilirubine supérieure à 1,5 fois la limite supérieure
    • Insuffisance rénale (Clairance créatinine < 30 mL/min selon Cockcroft-Gault)
    • Présence de malformation artério-veineuse pulmonaire non traitée et accessible à un traitement sur scanner thoracique de moins de 5 ans
    • Patient ayant présenté des épisodes d’hémoptysie ou d’hématurie dans les 12 semaines précédant l’inclusion
    • Patient avec des saignements digestifs actifs ou des ulcères gastro-intestinaux
    • Présence de malformation artério-veineuse cérébrale sur IRM de moins de 5 ans
    • Patient nécessitant un traitement anticoagulant à dose complète (par exemple antagoniste de la vitamine K ou héparine, dabigatran) ou un traitement antiplaquettaire à forte dose
    • Patient atteint d’une coronaropathie connue ou avec des antécédents récents (moins d’un an) d’infarctus du myocarde
    • Prédisposition connue aux thromboses ou évènements thrombotiques (y compris accident vasculaire cérébral et accident ischémique transitoire) dans les 12 mois précédant l’inclusion
    • Patient présentant un ECG avec QT long (ECH de moins de 3 mois)
    • Hypersensibilité au nintedanib, arachide ou soja ou à l’un des excipients
    • Patient qui a complété ses d’épistaxis de façon incomplète dans les 8 semaines précédant l’inclusion
    • Patient qui a reçu du bevacizumab par voie IV dans les 6 mois précédant l’inclusion
    • Patient qui a eu une chirurgie (y compris ORL) dans les 12 semaines précédant l’inclusion
    • Patient qui présente une plaie non cicatrisée
    • Chirurgie planifiée dans les 3 prochains mois, y compris transplantation hépatique, chirurgie abdominale ou intestinale
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of participants reporting a response at the end of the treatment. A response is defined by a reduction of at least 50% on epistaxis monthly mean duration during the last 8 weeks of treatment (day 29 to day 84 included) as compared to the 8 weeks before treatment (day -55 to day 0 included). Monthly mean duration is defined as total duration recorded X (28/number of day available for the reporting period).
    Proportion de patient ayant présenté une réponse à la fin du traitement. Une réponse est définie comme une réduction d’au moins 50% de la durée moyenne mensuelle des épistaxis au cours des 8 dernières semaines de traitement par rapport aux 8 semaines précédant le traitement.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 56
    Jour 56
    E.5.2Secondary end point(s)
    1.All adverse events and severe adverse events observed during the study will be collected.
    2.Epistaxis will be assessed through
     Proportion of patients reporting a response at the end of follow-up. A response is defined by a reduction of at least 50% on epistaxis monthly mean duration during the last 8 weeks of follow-up (day 113 to day 168 included) as compared to the 8 weeks before treatment (day-55 to day 0 included). Assessment by epistaxis grids filled in by patients (collected at each visit or filled in online).
     Nosebleeds monthly mean duration (continuous variable) will be computed during the 8 weeks before treatment (day -55 to day 0 included), during the last 8 weeks of the treatment period (day 29 to day 84 included) and during the last 8 weeks of the follow-up period (day 113 to day 168 included). Differences from baseline will be assessed. Assessment by epistaxis grids filled in by patients (collected at each visit or completed online).
     Nosebleeds monthly mean duration (continuous variable) will be computed all over the study period using 4 weeks periods. Assessment by epistaxis grids completed by patients (collected at each visit or filled in online).
     Nosebleeds frequency (considered as continuous variable) will be computed during the 8 weeks before treatment (day -55 to day 0 included), during the last 8 weeks of the treatment period (day 29 to day 84 included) and during the last 8 weeks of the follow-up (day 113 to day 168 included). Differences from baseline will be assessed. Assessment by epistaxis grids filled in by patients (collected at each visit or completed online).
     Epistaxis score = ESS (continuous variable) will be calculated from questionnaire filled by patients at inclusion visit, at the end of the treatment period and at the end of the follow-up.
    3.Other clinical criteria :
     Quality of life = SF36 score based on questionnaire filled in by patients at inclusion visit (baseline), at the end of the treatment and end of the follow up will be calculated.
     Number of red blood cell transfusions (discrete variable) is collected for 8 weeks before treatment (day -55 to day 0 included), during the last 8 weeks of the treatment period (day 29 to day 84 included) and during the last 8 weeks of the follow-up period (day 113 to day 168 included).
     Number of iron infusions (discrete variable) is collected for 8 weeks before treatment (day -55 to day 0 included), during the last 8 weeks of the treatment period (day 29 to day 84 included) and during the last 8 weeks of the follow-up period (day 113 to day 168 included).
    4. Biological criteria:
     Hemoglobin level (continuous variable) will be measured at inclusion, at the end of the treatment visit and at the end of follow-up visit.
     Ferritin level (continuous variable) will be measured at inclusion visit, at the end of the treatment visit and at the end of follow-up visit.
    1. Tous les évènements indésirables et évènements indésirables graves observés pendant l’étude seront recueillis.
    2. Evaluation des épistaxis sur:
     Proportion de patients présentant une réponse à la fin du suivi. Une réponse est définie par une réduction d’au moins 50% de la durée moyenne mensuelle des épistaxis au cours des 8 dernières semaines de suivi par rapport aux 8 semaines précédant le traitement. Evaluation à partir des grilles d’épistaxis complétées par les patients (recueillies à chaque visite ou renseignées en ligne).
     La durée moyenne mensuelle des saignements de nez (variable continue) : sera calculée pour les 8 semaines avant traitement, pour les 8 dernières semaines de traitement et pour les 8 dernières semaines de suivi après le traitement. Evaluation à partir des grilles d’épistaxis complétées par les patients (recueillies à chaque visite ou renseignées en ligne).
     La durée moyenne mensuelle des saignements de nez (variable continue) sera calculée tout au long de l’étude sur des périodes de 4 semaines. Evaluation à partir des grilles d’épistaxis complétées par les patients (recueillies à chaque visite ou renseignée en ligne).
     La fréquence des saignements de nez (considéré comme une variable continue): sera calculée pour les 8 semaines avant traitement, les 8 dernières semaines de la période de traitement et les 8 dernières semaines de suivi après le traitement. Evaluation à partir des grilles d’épistaxis complétées par les patients (recueillies à chaque visite ou renseignée en ligne).
     Le score d’épistaxis = ESS (variable continue) : sera calculée à partir du questionnaire rempli par les patients avant le traitement, à la fin de la période de traitement et à la fin du suivi.
    3. Autres paramètres cliniques :
     Qualité de vie = le score SF36 basé sur le questionnaire rempli par les patients sera calculé avant le traitement, à la fin du traitement et à la fin du suivi.
     Le nombre de transfusions de culots de globules rouges (variable discrète) sera recueilli pour les 8 semaines avant traitement, pendant les 8 dernières semaines de traitement, et pendant les 8 dernières semaines de suivi.
     Le nombre de perfusions de fer (variable discrète) sera recueilli pour les 8 semaines avant traitement, pendant les 8 dernières semaines de traitement, et pendant les 8 dernières semaines de suivi.

    4. Critères biologiques :
     Le taux d’hémoglobine (variable continue) sera dosé à l’inclusion, à la fin de la période de traitement et à la fin du suivi.
     Le taux de Ferritine (variable continue) sera dosé à l’inclusion, à la fin de la période de traitement et à la fin du suivi.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 0 , Day 14, Day 28, Day 56, D84, Day 168
    J0, J14, J28, J56, J84, J168
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    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: 50
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state60
    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 Decision2019-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-05
    P. End of Trial
    P.End of Trial StatusOngoing
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