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    Summary
    EudraCT Number:2018-001968-33
    Sponsor's Protocol Code Number:P171006J
    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:2018-10-30
    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 number2018-001968-33
    A.3Full title of the trial
    Étude ouverte de phase 1/2 évaluant la sécurité et l’efficacité de l’injection de cellules CD34 + autologues transduites ex vivo par le vecteur lentiviral GLOBE1 qui exprime le gène de la globine ╬▓AS3 chez des patients atteints de drépanocytose.
    " A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the Sickle Cell Anemia by Transplantation of an Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the ?AS3 globin gene (GLOBE1 ?AS3 Modified Autologous CD34+ Cells) in Patients with Sickle Cell Disease (SCD) "DREPAGLOBE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    safety éand efficacity of the globe 1 lentiviral vector beta AS3 modified autologous CD34 +cells
    securité et efficacité du vecteur lentiviral globe 1 beta AS3 modifiant les cellule CD34 du patient
    A.3.2Name or abbreviated title of the trial where available
    DREPAGLOBE
    A.4.1Sponsor's protocol code numberP171006J
    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 support
    B.4.2Country
    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-mailchristine.lanau@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 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 nameCellules CD34+modifiées par vecteur globe1beta AS3
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.10 Strength
    D.3.10.3Concentration numbercellules
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Information not present in EudraCT
    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 Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with Sickle Cell disease
    Patient atterint de forme sévère de drépanocytose
    E.1.1.1Medical condition in easily understood language
    Sickle Cell desease
    Sickle Cell desease
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10040644
    E.1.2Term Sickle cell disease
    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
    The primary objective of the study is to assess the initial safety and tolerability of treatment with DREPAGLOBE drug product, including the mobilization procedure with Perixaflor, conditioning regimen and transplantation with GLOBE1 betaAS3 lentiviral vector gene modified autologous CD34+cells in up to 10 severe SCD patients
    Objectif primaire:
    déterminer la Sécurité et la tolérance d'un traitement par DREPAGLOBE associant une procédure de mobilisation, par Périxaflor de conditionnement et de transplantation de celillules CD34+autologues genétiquement modifiées par le vecteur lentiviral globe1 beta AS3-globine de CD34 chez dix patients atteints de forme sévéres de drépanocytose
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    " To assess the initial efficacy of treatment with GLOBE1 beta AS3-globin modified autologous CD34+ stem cells.
    " To assess the long-term safety and efficacy of treatment with DREPAGLOBE drug product

    Les objectifs secondaires de l'étude sont:
    • Évaluer l'efficacité initiale du traitement avec des cellules souches autologues CD34 + modifiées par le vesteur lentiviral GLOBE1 ßAS3-globine.
    • Évaluer la sécurité et l'efficacité à long terme du traitement par DREPAGLOBE
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    iIndividuals eligible to participate in this study must meet all of the following criteria:
    " Age 5 - 35 years
    " Diagnosis of HbSS by Hb electrophoresis or genetic analysis
    " Clinical history or ongoing evidence of severe sickle cell anemia with one OR more of the following clinical complications demonstrating disease severity:
    1. At least 3 vaso occlusive crises requiring hospitalization, under hydroxyurea or transfusion, within 2 years prior to enrollment
    2. One severe acute chest syndrome (ACS) hospitalized in intensive care unit
    3. At least 2 episodes of ACS within the prior 3 years), including one under HU.
    4. Acute priapism (at least 2 episodes > 3h in the preceding year or in the year prior to the start of a regular transfusion program), OR stuttering priapism ? 1 by week under sickle cell treatment (HU, transfusion or phlebotomy).
    5. Cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) without Moya-moya
    6. Presence of sickle cell cardiomyopathy documented by Doppler echocardiography (left ventricular ejection fraction (LVEF) <55% AND tricuspid regurgitation velocity >2.5m/s on cardiac echocardiograph),
    7. Tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP>25mmHg)

    " Failed hydroxyurea (HU) therapy, were unable to tolerate HU therapy, or, if 18 years of age or older, have actively made the choice to not take the recommended daily HU regimen. Inadequate clinical response to HU, defined as any one of the following outcomes, while on HU for at least 3 months: 2 or more acute sickle pain crises requiring hospitalization, no rise in Hb >1.5 g/dl from pre-HU baseline or requires transfusion to maintain Hb > 6.0 g/dL, Has an episode of ACS despite adequate supportive care measures.
    " Karnovsky/Lansky performance score ? 60
    " Sexually active patients must be willing to use an acceptable method of double-barrier contraception for at least 12 months post-infusion (beyond 12 months at the discretion of the investigator)
    " procedure for obtaining consent (adults, dependent minors, to give their consent, , affiliation of a social security regime (or exemption),

    Pour participer à l'étude les patients doivent remplir tous les critères d'inclusion suivants:
    -
    "Âge 5 - 35 ans inclus
    "Diagnostic de HbSS a par électrophorèse de l'Hb ou analyse génétique
    "Antécédents cliniques ou signes persistants d'anémie falciforme grave avec une ou plusieurs des complications cliniques suivantes démontrant la gravité de la maladie:
    -AU moins trois crises vaso-occlusives nécessitant une hospitalisation,sous hydroxyurée ou transfusion,dans les deux année précedent l'inscription
    -n syndrome thoracique aigu sévére (ASC) hospitalisé en soins intensifs
    -A u moins deux épiodes de ACS pendant les trois dernières années,y compris un sous HU.
    -Priapisme récurent (au moins 2 épisodes>3h l'année précédente ou l'année précedent le commencement de transfusion)ou priapisme de begaiement >ou= 1 fois par semaine sous le traitement de drépanocytose (HU,Transfusion ou phlébotomie)
    -Véno-occlusion du SNC sans maladie de Moyamoya confirmée par ARM (angiographie par résonance magnétique).
    -Présence d'une cardiomyopathie drépanocytaire documentée par échocardiographie Doppler (fraction d'éjection ventriculaire gauche (FEVG) <55% ou vitesse de régurgitation tricuspide> 2,5 m / s sur l'échocardiographe cardiaque)
    -Vitesse de régurgitation tricuspidienne>2.8 m/s sur l'échocardiographie cardiaque sans hypertension pulmonaire confirmée par un cathétérisme cardiaque droit (mPAP> 25mmHg)
    -Echec de traitement par hydroxyurée (HU) incapacité à tolérer le traitement par HU, ou, si le sujet est âgé de 18 ans ou plus, ayant activement fait le choix de ne pas suivre le régime d'HU quotidien recommandé.
    Réponse clinique inadéquate à l' HU,définie par un des résultats suivants au cours du traitement par l'HU
    pendant 3 mois:
    2 crises aiguës ou plus de drépanocytose aiguë nécessitant une hospitalisation, aucune élévation de l'Hb> 1,5 g / dl de base pré-HU ou nécessite une transfusion pour maintenir Hb> 6,0 g / dL un épisode de SCA malgré des mesures de soins et de soutien adéquates.
    -"Score de performance Karnovsky / Lansky> ou= à 60
    Les patients sexuellement actifs doivent accepter d' utiliser une méthode de contraception médicalement acceptableà double barrière pendant au moins 12 mois après la perfusion (au-delà de 12 mois à la discrétion de l'investigateur)
    Procédure pour l'obtention du consentement (adultes,mineurs à charge, pour donner leur consentement;
    Affiliation à un régime de sécurité sociale (ou exemption)
    E.4Principal exclusion criteria
    Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:Existence of a matched sibling donor Patients who have started new treatment for SCD within 6months of enrollment
    "Hematologic evaluation: Leukopenia (WBC < 3000 uL) or neutropenia (ANC < 1000 uL) or thrombocytopenia (platelet count < 100,000 uL) within 90 days prior to mobilization or harvest ( not due to an erythrapheresis procedure)
    "PT/INR or PTT > 1.5 times upper limit of normal (ULN) or clinically significant bleeding disorder
    "Evaluations within 6 months prior to screening visit:ALT or AST > 1.5 times ULN
    "Liver Cirrhosis suspicion on echography, CT scan or MRI AND confirmed by histology Liver iron > 125 µmol/g by MRIMeasured GFR < 60 ml/min/1.73 m 2 Cardiac evaluation: LVEF < 40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities;Stroke with significant CNS sequelae i.e., Rankin > 2;Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state
    "Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm>25mmHg). Right heart catheterization is required if tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph OR >2.5m/s with an abnormal Brain Natriuretic Peptide dosage or an important decrease in transcutaneous Hb O2 saturation during the 6 minutes walk test.
    Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR.Pregnancy or breastfeeding in a postpartum female
    "Any current cancer or prior history of a malignant disease, with the exception of curatively treated non-melanoma skin cancer;Immediate family member with an established or suspected Familial Cancer Syndrome;Diagnosis of significant psychiatric disorder of the subject that could seriously impeded the ability to participate in the study;Patients who failed previous HSCT and are severely ill ;Any clinically significant active infection
    "Participation in another clinical study with an investigational drug within 30 days of screening;Any condition, based on perspective of the medical monitor and treating investigator, which may lead to increased safety risk or inability to comply with the protocol;Each patient will receive a single intravenous infusion of the DREPAGLOBE drug product at dose range of 3 to 20 million CD34+ cells/kg post-transduction.Source of CD34+ will be :
    1)Bone- Marrow 2)CD34 + mobilized with Plerixafor after a single or multiple harvests3)The DREPAGLOBE drug product consists in autologous CD34+ hematopoietic stem cells transduced with Self-inactivating lentiviral vector (GLOBE1 AS3) encoding the human ?AS3-globin gene and suspended in HSA (5% Albunorm™) in the final immediate container for the intended medical use. All subjects are to receive the DREPAGLOBE drug product on Day 1 via IV infusion according to applicable SOPs, with vital signs being monitored concurrently. The minimum dose to be administered is 3.0×106 CD34+ cells/kg.Exchange transfusion before the mobilization procedure ;Mobilization by Plerixafor ;Apheresis/ conditioning regimend
    Infusion with GLOBE1 ?AS3 lentiviral vector;This study consists of 5 phases:Screening (4 weeks)Mobilization (6 weeks)Myeloablation (1 week)Treatment (up to 1 week)Follow-up (up to 24 months)
    Up to 10 evaluable patients with severe SCD will be treated in the study to receive a single IV dose of the DREPAGLOBE drug product.
    There will be a sequential enrolment.
    The first three patients enrolled will be the three young adults patients mobilized by Plerixafor (Drepamob protocol) in the order of enrollment into the study, after the previous patient has safely reconstituted the peripheral hematological compartment (i.e., ANC > 500 µL), estimated to occur approximately 4-6 weeks post-treatment. If we assess that the first three treated patients present good clinical results and benefits (Stable hemoglobin production over time), SCD patients between 5 and 35 years old will be enrolled sequentially (no specific cohort for pediatric and adults patients).
    Treatment will not be initiated in patients under fifteen years until the first adult patients treated have been followed up for 3 months and production of therapeutic Hb will be documented.
    Les sujets ne doivent répondre à aucun des critères suivants: patients ayant un donneur familial volontaire HLA identique 10/10
    Patients ayant commencé un nouveau traitement pour la drépanocytose les 6 mois précédent le recrutement ;Evaluation hématologique: Leucopénie (WBC < 3000 uL) ou neutropénie (ANC < 1000 uL) ou thrombocytopénie (taux de plaquettes< 100,000 uL) dans les 90 jours précédant la mobilisation ou la récolte (non-due à une procédure d' erythrapherese )PT/INR ou PTT > 1.5 fois la limite supérieure de la normale (ULN) ou un trouble de la coagulation cliniquement significatif ;Evaluation dans les 6 mois précèdent la visite de screening : 1.ALT ou AST > 1.5 fois ULN2.Suspicion de cirrhose du foie sur l'échographie, le scanner ou l'IRM etconfirmée par histologie
    3.Fer hépatique>125 µmol/g par IRM4.GFR mesuré < 60ml/min/ 1,73 m25.Evaluation cardiaque : (FEVG) < 40% par échocardiographie cardiaque ou par Scan MUGA ou anomalies ECG cliniquement significatives 6.Accident vasculaire cérébral avec séquelles importantes du SNC; c-à-d Rankin >27.Infiltrat interstitiel pulmonaire ET capacité vitale forcée inférieure à 70% ET DLCO inférieure à 60% en l'absence d'infection 8.Hypertension pulmonaire confirmée définie par un cathétérisme cardiaque droit (PAPm>25mmHg). Un cathétérisme cardiaque droit est nécessaire si la vitesse de régurgitation tricuspide est supérieure à 2.8m/s sur échocardiographie cardiaque OU supérieure à 2.5 m/s avec un dosage anormal de Peptide Natriurétique Cérébral ou une diminution importante de la saturation transcutanée Hb O2 pendant le test de marche de 6 minutes.
    Etre positifs pour la présence d'anticorps dirigés contre le virus de l'immunodéficience humaine (VIH), Virus de l'Hépatite C (HCV), Virus T-lymphotropique Humain (HTLV-1), ou Virus actif de l'Hépatite B, ou une infection active par le CMV ou le parvovirus B19, basé sur un PCR sanguin positif. Grossesse ou allaitement chez une femme post-partumTumeur maligne existante ou antérieure à l'exception du cancer de la peau non mélanome traité. Membre de la famille proche atteint d'un cancer familial connu ou soupçonné Diagnostic d'un trouble psychiatrique significatif du sujet susceptible de nuire significativement à sa capacité à participer à l'étude.Les patients qui ont échoué à une greffe de cellules souches hématopoïétiques précédente et qui sont gravement malades.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints of this study are safety.
    Safety in the first 6 months following IV infusion of DREPAGLOBE drug product, as assessed by:
    " Incidence of transplant related mortality up to 100 days post treatment
    " Incidence of the need for rescue autologous bone marrow transplant up to 100 days post treatment
    " Frequency and severity of clinical AEs and laboratory parameters
    " Incidence of RCL
    Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    o In vivo engraftment through hematopoietic reconstitution after IV infusion of the DREPAGLOBE drug product, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    o Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    o Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    o Absence of RCL
    o Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    o Protein expression through percentage of anti-sickling Hb
    o Percentage HbAS3
    Le critère pricipal d'évaluation primaire est la sécurité
    la sécurité dans les six premiers mois suivant la perfusion de DREPAGLOBE est évalué par:.
    • Incidence de la mortalité liée à la greffe dans les 100 jours suivant le traitement
    • Incidence de la nécessité d'une greffe de moelle osseuse autologue de secours jusqu'à 100 jours après le traitement
    Surveillance des paramètres de laboratoire ainsi que la fréquence des ei cliniques
    • Incidence de RCL
    • Incidence de la malignité cliniquement détectable et / ou de la dominance clonale anormale évaluée comme étant liée au traitement de l'étude

    Les critères secondaires sont la sécurité et l'efficacité , évalués dans les six premiers mois suivant la transplantation sont :
    Prise de greffe in vivo par reconstitution hématopoïetique après perfusion iv de Drepaglobe c.a.d la récupération des neutrophiles et des plaquettes (la récupération des neutrophiles et des plaquettes est définie par le premier de trois jours concéqcutifs avec un ANC de >500/uL,et la récupération des plaquettes est définie par le premier de trois jours concecutifs avec un taux de plaquettes> à 20000/uL,maintenu sans transfusion plaquettaire pendant au moins sept jours)
    Pourcentage de HbAS3
    Les autres critères secondaires sontla sécurité et l'efficcacité à long terme (tout au long de la phase de suivi de 24 mois)mesurés par:

    Surveillance de la fréquence et de la séverité des ei (s)cliniques,tels qu'ils sont évalués par les critères de terminologie standart pour les évenements indésirables de National Cancer Institute(NCI CTAE)version 4.03
    Absence de RCL
    Absence de malignité cliniquement détectable ou de dominance clonale anormale évaluée comme étant liée au traitement de l'étude
    Expression protéique par le pourcentage de Hb anti-falciformation
    • Pourcentage HbAS3


    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety in the first 6 months following IV infusion of DREPAGLOBE drug product
    la sécurité dans les six premiers mois suivant la perfusion de DREPAGLOBE
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are:
    • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days)
    • Percentage HbAS3.
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by:
    • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03
    • Absence of RCL
    • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment
    • Protein expression through percentage of anti-sickling Hb
    • Percentage HbAS3
    E.5.2.1Timepoint(s) of evaluation of this end point
    The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase
    securité et efficacité pendant les 24 mois de suivi
    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 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) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    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 Yes
    F.1.1Number of subjects for this age range: 6
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception 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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    mineurs
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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)
    after the gene therapy,the patient will undergo a close clinical follow-up and monitoring;However ,there will not be other treatment after the gen therapie.
    après la thérapie génique, le patient subira un suivi et une surveillance cliniques étroits, mais il n’y aura pas d’autre traitement après la thérapie génique.
    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 Decision2019-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-13
    P. End of Trial
    P.End of Trial StatusOngoing
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