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    Summary
    EudraCT Number:2018-001747-31
    Sponsor's Protocol Code Number:P160907
    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:2018-12-28
    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 number2018-001747-31
    A.3Full title of the trial
    A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Tranplant (LTx) recipients with bronchiolitis obliterans sydrome (BOS) grade 1-2
    Essai multicentrique, randomisé contre placebo, de l’utilisation du Nintedanib dans le traitement de la bronchiolite obliterante/dysfonction chronique du greffon chez les patients transplantés pulmonaires.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Transplant (LTx) recipients with bronchiolitis obliterans syndrome (BOS) grade 1-2

    Essai multicentrique, randomisé double aveugle contre placebo, évaluant l'efficacité du Nintedanib dans le traitement du Syndrome de Bronchiolite Oblitérante de grade 1-2 chez les patients transplantés pulmonaires.
    A.3.2Name or abbreviated title of the trial where available
    INFINITX BOS
    A.4.1Sponsor's protocol code numberP160907
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailfadila.amerali@aphp.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
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 Capsule
    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 INNNintedanib
    D.3.9.3Other descriptive nameNintedanib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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
    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
    Bronchiolitis Obliterating Syndrome (SBO) grade 1 or 2 in patients with pulmonary transplantation.
    Syndrome de Bronchiolite Oblitérante (SBO) de grade 1 ou 2 chez des patients patients greffés pulmonaires .
    E.1.1.1Medical condition in easily understood language
    bronchiolitis obliterans syndrome
    Syndrome de Bronchiolite Oblitérante de grade 1-2
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029888
    E.1.2Term Obliterative bronchiolitis
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    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 Nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 sec) in BOS post-LTx at a dose of 150 mg twice daily (bid) compared to placebo over 6 months.
    évaluer l'efficacité du Nintedanib dans le traitement du SOB post-TxP en comparant le déclin du VEMS (Volume Expiré en 1 sec, mL) sur 6 mois chez les patients greffés pulmonaires porteurs d'une BO traités par Nintedanib à une dose de 150 mg (1 gélule) deux fois par jour par rapport à ceux traités par placebo.
    E.2.2Secondary objectives of the trial
    1- to assess the efficacy of Nintedanib on exercise tolerance as assessed by the change of 6-minute walking test (6-WT) over 6 months
    2- to assess the efficacy of Nintedanib on quality of life (QOL) improvement as assessed by change in the SGRQ (Saint George's Respiratory Questionnaire) over 6 months
    3- to assess the efficacy of Nintedanib to hamper FEV1 decrease, as assessed by a repeated FEV1 measurements method over 6 months
    4-to assess the efficacy of Nintedanib to hamper progression of BOS, as assessed by change in BOS grade and graft failure (defined as death or retransplantation)
    5-to assess the efficacy of Nintedanib on the change of Oxygen saturation (SpO2) over 6 months
    6-to assess Nintedanib tolerance in lung-transplant recipients over 6 months, comparing occurrence of adverse events between both arms

    1- évaluer l'efficacité du Nintedanib sur la tolérance à l'exercice/effort, mesurée par le changement au test de marche de 6 minutes (T6M) à 6 mois
    2- évaluer l'efficacité du Nintedanib sur l'amélioration de la qualité de vie (QDV), mesurée par la variation du score du questionnaire SGRQ (Saint George's Respiratory Questionnaire) à 6 mois
    3- évaluer l'efficacité du Nintedanib à réduire le déclin du VEMS, par la mesure répétée du VEMS sur 6 mois
    4- évaluer l'efficacité du Nintedanib à limiter la progression du SOB, mesuré par le changement dans le grade de sévérité et l'échec de la greffe (défini par le décès du patient ou une re-transplantation pulmonaire)
    5- évaluer l'efficacité du Nintedanib sur (l'évolution de) la saturation en oxygène (SPO2) à 6 mois
    6- évaluer la tolérance du Nintedanib chez les patients transplantés pulmonaires à 6 mois en comparant la survenue des évènements indésirables entre les deux bras
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) - Written informed consent signed prior to entry into the trial
    2) - Patients > ou = à18 years of age when signing his/her informed consent
    3) - Patients at least at 6 months post-LTx
    4) - Single- or double-LTx or combined cardio-pulmonary LTx are elligible.
    5) - Patients must have diagnosis of BOS defined as a decrement of 20% or more in forced expiratory volume in 1 seconde (FEV1) compared to post-transplant baseline FEV1 individualized for each patient according to ISHLT definition [9]. The documented post-LTx baseline value of FEV1 is defined as the mean of the 2 highest values measured at least 3 weeks apart according to ISHLT criteria, and post-LTx VC measurements [9].
    6) - Patients must have BOS grade 1 or 2 [9]
    7) - Patients must have documented progressive BOS as demonstrated by the following criteria: at least 3 FEV1 and VC measurements in the last 12 months prior V1, each at least 3 weeks apart, with a total decline of at least 200ml in FEV1 in these last 12 months AND FEV1/VC<0.7 [3]
    8) - Azithromycin therapy for at least 4 weeks prior to V1, with an Azithromycin dose of minimum 250 mg/day at least 3 times per week as this is considered standard therapy for bronchiolitis obliterans syndrome [16] [34].
    1)- consentement éclairé écrit du patient
    2) - âge > ou = à 18 ans à la date de la signature du consentement
    3) - transplantation pulmonaire ayant été réalisée il y a au moins 6 mois
    4) - transplantation pulmonaire (mono- ou bi-pulmonaire) ou transplantation cardiopulmonaire combinée
    5) - diagnostic de SBO défini par une diminution de 20% ou plus du Volume Expiratoire Maximal par Seconde (VEMS1) comparé à la valeur de base post-transplantation du VEMS1 du patient (selon les critères de l'International Society for Heart and Lung Transplantation [1,2]). La valeur de base post-greffe documentée du VEMS1 est définie comme la moyenne des deux valeurs les plus élevées mesurées à un intervalle d'au moins trois semaines selon critères de l'ISHLT et les mesures de Capacité Vitale (CV) post-transplantation [1,2].
    6) - diagnostic de SBO de grade 1 ou 2 [1,2]
    7) -SBO progressif documenté par les critères suivants : au moins 3 mesures de VEMS et CV dans les 12 mois précédant la visite V1, chaque mesure à au moins 3 semaines d'intervalle, avec un déclin total du VEMS d'au moins 200 mL dans ces 12 derniers mois [3]
    8) -traitement par Azitromycine débuté au moins depuis 4 semaines avant la visite V1, à la dose minimum de 250 mg/jour au moins 3 fois/semaine, considéré comme traitement standard du SBO [1,2].
    E.4Principal exclusion criteria
    - Patients with lung redo transplantation (combined lung transplantation, included heart-lung transplantation are permitted)
    - Criteria of restrictive allograft syndrome (RAS) at V0, including the following: (1) Decline of VC > 10% of best post-LTx value (FVCBest is defined as the average of the two FVCs associated with the two PFTs used in FEV1 baseline calculation for CLAD diagnosis) AND FEV1/VC > 0.7 AND (2) Thorax HRCT at entry demonstrate new significant findings which are compatible with RAS like interstitial fibrosis, consolidation, appearances suggesting Restrictive Allograft Syndrome (RAS) [3].
    - FEV1 and/or FV and/or TLC decline related to other nonCLAD causes (eg Diaphragm dysfunction, pneumothorax or pleural effusion, evolutive bronchial stricture within the previous 3 months)
    - At V0, patients who already have developed severe BOS grade 3
    - Patients with severe comorbidity complicating CLAD which might determine the prognosis and functional level of the patient (e.g. evolutive invasive aspergillosis or mycobacterial infection within the last 3 months, active malignant disease within the last 12 months).
    - At visit V1 , diagnosis of documented acute cellular (AR) perivascular rejection higher than grade A1 within the 4 prior weeks OR diagnosis of acute antibody-mediated rejection within the 4 prior weeks, based on presence of all 4 following criteria: 1) acute lung allograft dysfunction, 2) detection of donor-specific antibodies, 3) histological findings compatible with AMR on transbronchial lung biopsy TBBx, and 4) detection of C4d > 50% on TBBx [35] [36].
    - At visit V1 (end of screening period), diagnosis of documented acute pulmonary infection within the 2 prior weeks, on the basis of the following: 1) clinical, radiological and physiological deterioration; 2) isolation of an organism from a clinically relevant BAL fluid culture; 3) antibiotic therapy resulting in a full recovery and return to pre-morbid lung function.
    - Previous treatment with Nintedanib after the date of lung transplantation (Treatment with Nintedanib before lung transplantation is not an exclusion criteria).
    -Within the 2 weeks prior to V1, renal insufficiency with following criteria: Creatinine clearance <30 ml/min estimated by the Cockcroft-Gault equation.
    -Within the 2 weeks prior to V1, any of the following liver test criteria above the specified limit: Total bilirubin > 1.5 above the upper limit of the normal range (ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert's syndrome). Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN
    - Cardiac disease: (1) History of myocardial infarction within 6 months of visit 1 or unstable angina within 6 months of visit 1; (2) Presence of aortic stenosis (AS) per investigator judgement at visit 1; (3) Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25% per investigator judgement at visit 1;
    - Bleeding Risk: Known genetic predisposition to bleeding; Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelet therapy (acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day) [NB: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited]; History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1; History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1; International normalised ratio (INR) > 2 at visit 1; Prothrombin time (PT) and activated partial thromboplastin time (aPTT) > 150% of institutional ULN at visit 1;
    -Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment)
    -Second-degree or third-degree atrioventricular (AV) block on electrocardiogram (ECG) per investigator judgement at visit 1;
    - Hypotension (systolic blood pressure [SBP] < 90 mm Hg or diastolic blood pressure [DBP] < 50 mm Hg)
    - Uncontrolled systemic hypertension (SBP > 160 mmHg; DBP > 100 mmHg) at visit 1;
    -
    - re-transplantation pulmonaire
    - à V0, diagnostic de RAS (Restrictif allograft syndrome) représentant un phénotype restrictif de dysfonction chronique du greffon incluant l'ensemble des critères suivants : (1) déclin de la capacité vital (CV) > 10% par rapport à la meilleure valeur post-transplantation (valeur définie comme la moyenne des deux CV des deux tests de la fonction pulmonaire utilisés dans le calcul du VEMS1 de base pour le diagnostic du CLAD) ET VEMS/CV > 0.7 ET (2) scanner du thorax montrant l'apparition de nouvelles opacités scannographiques compatibles avec un RAS telles que épaississement sous-pleural, fibrose interstitielle, consolidation parenchymateuses du greffon [9]
    - déclin du VEMS et/ou de la CV (capacité vitale) et/ou de la CPT (Capacité Pulmonaire Totale) lié à une autre cause que le SBO (telle que dysfonction diaphragmatique, pneumothorax/épanchement pleural, ou sténose bronchique évolutive dans les 3 derniers mois).
    - à V0, critères de SBO de grade 3 déjà atteint selon la définition de l'ISHLT (1,2)
    - co-morbidité sévère compliquant le SBO, pouvant mettre en jeu le pronostic vital ou fonctionnel du patient à court terme (pour exemple, tels que : diagnostic d'Aspergillose invasive évolutive non contrôlée ou mycobactériose pulmonaire évolutive dans les 3 derniers mois, néoplasie évolutive dans les 12 derniers mois)
    - à la visite V1, diagnostic de rejet aigu cellulaire documenté histologiquement de grade > A1 dans les 4 semaines précédentes V1 OU diagnostic de rejet humoral documenté sur l'ensemble des 4 critères suivant dans les 4 semaines précédentes la V1: 1) dysfonction aiguë du greffon ET 2) détection d'anticorps anti-HLA anti-greffon (= DSA, donor-specific antibodies) ET 3) histologie compatible avec un rejet médié par anticorps sur biopsies trans-bronchiques ET 4) détection de C4d (fraction C4d du complément) >50% au sein des biopsies transbronchiques (1,2,3,9)
    - à la visite V1 , infection pulmonaire aiguë documentée dans les 2 semaines précédentes, diagnostiquée sur les éléments suivants : 1) dégradation clinique, radiologique et fonctionnelle ET 2) isolement d'un agent infectieux sur lavage broncho-alvéolaire ET 3) antibiothérapie permettant un retour à l'état clinique antérieur du patient (récupération complète et fonction pulmonaire pré-morbide)
    - traitement antérieur par Nintedanib après la date de la transplantation pulmonaire (un traitement par Nintedanib avant la transplantation pulmonaire n'est pas un critère de non-inclusion)
    - au cours des deux semaines précédant la visite V1, insuffisance rénale : clairance de la créatinine < 30 mL/min selon la formule de Cockcroft & Gault
    - au cours des deux semaines précédant la visite V1, toute augmentation - au-dessus du seuil défini - des marqueurs de la fonction hépatique suivants : bilirubine totale > 1.5 LSN (Limite Supérieure à la Normale), excepté chez les patients présentant une augmentation prédominante de la bilirubine non conjuguée (Syndrome de Gilbert) ; Aspartate ou Alanine Aminotransferases (ASAT ou ALAT) > 3 LSN
    - maladie cardiaque : i) antécédent d'infarctus du myocarde dans les 6 mois précédant la visite V1 ou angine de poitrine non stabilisée dans les 6 mois précédant la visite V1 ; ii) sténose aortique jugée par l'investigateur à la visite V1 ; iii) insuffisance cardiaque sévère chronique définie par une fraction d'éjection ventriculaire gauche < 25%, selon l'investigateur à la visite V1
    - risque de saignement : prédisposition génétique aux hémorragies, patients requérant une fibrinolyse, ou sous anticoagulation thérapeutique à dose efficace (tels que antagoniste de la vitamine K (AVK), inhibiteur direct de la thrombine, héparine, hirudine…) ou sous antiagrégant plaquettaire à haute dose (acide acétylsalicylique > 325 mg/jour ou clopidogrel > 75 mg/jour) [NB : sont autorisés : l'héparine à dose prohylactique ou administrée en flush pour la maintenance d'un dispositif intraveineux à demaure (par exemle enoxaparine 4000 UI en injection S/C/jour) ; une thérapie antiplaquettaire à dose prophylactique (par exemple acide acétylsalicylique jusqu'à 325 mg/jour ou clopidogrel à 75 mg/jour ou doses équivalentes de d'autres médicaments antiplaquettaires) ; antécédent d'hémorragie du système nerveux central dans les 12 mois précédant la visite V1 ; antécédent d'hémoptysie ou hématurie ; saignement gastro-intestinal actif ou ulcères et/ou blessure importante ou chirurgie dans les 3 mois précédant la visite V1 ; International Normalised Ratio (INR) > 2 à la visite V1 ; Temps de Prothrombine (PT) et Temps de Thromboplastine Partielle activé (aPTT) > 150% LSN à la visite V1
    - maladie hépatique chronique sous-jacente (Child Pugh classe A, B ou C)
    - hypotension (Pression Artérielle Systolique [PAS] < 90 mm Hg ou Pression Artérielle Diastolique [PAD] < 50 mm Hg)
    - hypertension artérielle non contrôlée (PAS > 160 mmHg, PAD > 100 mmHg) à la visite V1


    E.5 End points
    E.5.1Primary end point(s)
    The absolute difference of FEV1 in mL over 6 months of treatment defined by the rate of decline between inclusion (V1) and month 6 (V4) will be compared between Nintedanib versus placebo groups.
    la différence absolue du VEMS (en mL) sur 6 mois de traitement, défini comme la pente du VEMS mesuré à l'inclusion (V1) et le VEMS mesuré à 6 mois (V4) sera comparée entre les deux groupes (Nintedanib vs. placebo).
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 month
    6 mois
    E.5.2Secondary end point(s)
    (i) Absolute change from baseline in the 6-min walking test (6-WT) at month six (V4).
    (ii) Absolute change from baseline in SGRQ total score at month six (V4).
    (iii) Absolute change of FEV1 in mL at month 6 by a repeated FEV1 measurements (Month 0 (V1), month 1 (V2), month 3 (V3), month 6 (V4)).
    (iv) Proportion of patients with disease progression of BOS disease, as assessed by change in BOS grade and graft failure (defined as death or retransplantation).
    (v) Absolute change from baseline in SPO2 (Oxygen saturation, expressed in percent) rest evaluated from baseline at month six (V4).
    (vi) Incidence of adverse events of observed with Nintedanib versus placebo over 6 months in LTx recipients
    (vii) Explanatory parameters: absolute change of 1) biomarkers of alveolar cells injury: Krebs von den Lungen-6 (KL6), surfactant apoprotein D (SPD), and growth factors as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) since baseline at month 6.
    i)variation absolue par rapport à la valeur initiale de la distance parcourue du test de marche de 6 minutes (T6M) à 6 mois (V4)
    ii)variation absolue par rapport à la valeur initiale du score total du questionnaire SGRQ (Saint George's Respiratory Questionnaire) à 6 mois (V4)
    iii)variation absolue du VEMS (en mL) à 6 mois par des mesures répétées du VEMS (à l'inclusion/0 mois (V1), à 1 mois (V2), à 3 mois (V3), à 6 mois (V4))
    iv)proportion de patients montrant une progression du SBO, mesuré par le changement de grade de sévérité fonctionnel du SBO (critères de l'International Society for Heart and Lung Transplantation (ref 1,2)) et l'échec de la greffe (défini par le décès du patient ou la retransplantation pulmonaire)
    v)variation absolue par rapport à la valeur initiale de la SPO2 au repos (saturation en oxygène exprimée en pourcentage) à 6 mois
    vi)incidence des évènements indésirables observés avec le Nintedanib versus placebo à 6 mois chez les patients transplantés pulmonaires
    vii)critères pharmacocinétiques et paramètres exploratoires : variation absolue à 6 mois de la valeur de base de biomarqueurs des lésions des cellules alvéolaires : Krebs von den Lungen-6 (KL6), apoprotéine D du surfactant (SPD) et facteurs de croissance tels le facteur de croissance de l'endothélium vasculaire (VEGF) et le facteur de croissance dérivé des plaquettes (PDGF).
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 month
    6 mois
    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 No
    E.6.5Efficacy No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 concerned7
    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 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
    Derniere visite du dernier patient inclus
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned 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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 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 state80
    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
    Non
    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 Decision2019-02-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-09
    P. End of Trial
    P.End of Trial StatusOngoing
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