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    Summary
    EudraCT Number:2019-003213-34
    Sponsor's Protocol Code Number:270-205
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-07
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-003213-34
    A.3Full title of the trial
    A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an AdenoAssociated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Active or Prior Inhibitors
    Studio di fase 1/2 volto a valutare la sicurezza, la tollerabilità e l'efficacia di BMN 270, un trasferimento genico del fattore VIII umano mediato da vettore di virus adeno-associato in pazienti affetti da emofilia A con inibitori attivi o pregressi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 study to evaluate the safety and efficacy of BMN 270 gene transfer in patients with severe hemophilia A and active or prior inhibitors
    Studio di fase 1/2 volto a valutare la sicurezza e l'efficacia del trasferimento genico BMN270 in pazienti affetti da emofilia A con inibitori attivi o pregressi
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code number270-205
    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 SponsorBIOMARIN PHARMACEUTICAL INC.
    B.1.3.4CountryUnited States
    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 supportBioMarin Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin Pharmaceutical Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address105 Digital Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.4Telephone number00000000
    B.5.5Fax number0000000
    B.5.6E-mailmedinfo@bmrn.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1622
    D.3 Description of the IMP
    D.3.1Product nameAAV5-hFVIII-SQ
    D.3.2Product code [BMN 270]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNValoctocogene roxaparvovec
    D.3.9.1CAS number 1819334-78-5
    D.3.9.2Current sponsor codeBMN 270
    D.3.9.4EV Substance CodeSUB198084
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 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 Yes
    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
    Hemophilia A
    Emofilia A
    E.1.1.1Medical condition in easily understood language
    Bleeding Disorder
    Bleeding Disorder
    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 10060612
    E.1.2Term Hemophilia A
    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
    To assess the safety of a single IV administration of BMN 270 in HA subjects with active inhibitors (Part A), or prior inhibitors (Part B)
    • Valutare la sicurezza di una singola somministrazione EV di BMN 270 in soggetti affetti da HA con inibitori attivi (Parte A) o inibitori pregressi (Parte B)
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of BMN 270 as measured by FVIII activity together with the level of inhibitor titer (Part A) and the recurrence of inhibitors (Part B)
    - To assess the impact of BMN 270 on the use of emicizumab (Part A) and FVIII prophylaxis (Part B)
    - To assess the impact of BMN 270 on the number of bleeding episodes requiring pharmacologic intervention
    - To assess the impact of BMN 270 on quality of life as measured by the Haemo-QoL-A questionnaire
    • Valutare l'efficacia di BMN 270 misurata in base all'attività del FVIII insieme al livello del titolo di inibitori (Parte A) e alla recidiva degli inibitori (Parte B).
    • Valutare l'impatto di BMN 270 sull'uso di emicizumab (Parte A) e della profilassi con FVIII (Parte B).
    • Valutare l'impatto di BMN 270 sul numero di episodi di sanguinamento che richiedono un intervento farmacologico
    • Valutare l'impatto di BMN 270 sulla qualità della vita misurata con il questionario Haemo-QoL-A
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males = 18 years of age with hemophilia A and documented prior residual FVIII activity = 1 IU/dL including, but not limited to, at the time of detected inhibitors, at the time of signing the informed consent.
    2. History of a positive inhibitor result with the first positive result in the last 12 months. Part A: Positive FVIII inhibitor titer = 0.6 BU. Part B: Negative FVIII inhibitor screening titer < 0.6 BU.
    3. Part A: Emicizumab prophylaxis at least 6 months prior to screening; Part B: FVIII replacement prophylaxis for 12 months. Bleeding, inhibitor & hemophilia therapy Hx over previous 12 months.
    4. Sexually active participants must agree to use an acceptable method of effective contraception. Participants must agree to contraception use for at least 12 weeks post-infusion.
    5. Willing to abstain from consumption of alcohol for at least the first 52 weeks following BMN 270 infusion.
    1. Soggetti di sesso maschile di = 18 anni di età affetti da emofilia A e documentazione di attività residua del FVIII = 1 IU/dL precedente, compreso a titolo di esempio il momento del rilevamento degli inibitori, all'atto della firma del consenso informato.
    2. Anamnesi documentata di un precedente risultato positivo relativo agli inibitori (risultati di un test di Bethesda o di Nijmegen-Bethesda = 0,6 BU), con il primo rilevamento degli inibitori almeno 12 mesi prima dello Screening.
    Per la Parte A: Test degli inibitori del FVIII positivo in base al laboratorio centrale allo Screening, definito come titolo degli inibitori = 0,6 BU secondo il test cromogenico di Nijmegen-Bethesda (cNBA). I primi 3 soggetti arruolati nella Parte A devono avere un titolo degli inibitori = 5 BU.
    Per la Parte B: Test degli inibitori del FVIII negativo in base al laboratorio centrale allo Screening, definito come titolo degli inibitori < 0,6 BU secondo il test cNBA.
    3. Per la Parte A: Il soggetto deve essere in profilassi con emicizumab da almeno 6 mesi prima dello Screening. I soggetti devono assumere emicizumab a una dose di mantenimento di 1,5 mg/kg alla settimana, o essere disposti a passare a questo regime, prima della somministrazione di BMN 270. Devono essere disponibili dati storici di alta qualità e ben documentati riguardanti gli episodi di sanguinamento, l'anamnesi degli inibitori e la terapia per l'emofilia nei 12 mesi precedenti.
    Per la Parte B, il soggetto deve essere in terapia profilattica sostitutiva con FVIII da almeno 12 mesi prima dello Screening. Devono essere disponibili dati storici di alta qualità e ben documentati riguardanti gli episodi di sanguinamento, l'anamnesi degli inibitori e la terapia per l'emofilia nei 12 mesi precedenti.
    4. I partecipanti sessualmente attivi devono accettare di utilizzare un metodo di contraccezione efficace accettabile, sia esso costituito da contraccezione a doppia barriera (ovvero preservativo + diaframma; o preservativo o diaframma + gel o schiuma spermicida) oppure dall'uso da parte della partner di contraccettivi ormonali o di un dispositivo intrauterino. I partecipanti devono accettare di utilizzare i metodi di contraccezione per almeno 12 settimane dopo l'infusione; dopo 12 settimane, i soggetti potranno interrompere l'uso della contraccezione solo se sono stati ottenuti 3 campioni di sperma consecutivi con DNA del vettore virale al di sotto del limite di rilevamento.
    5. Volontà di astenersi dal consumo di alcol almeno per le prime 52 settimane dopo l'infusione di BMN 270.
    E.4Principal exclusion criteria
    1. Detectable pre-existing antibodies to the AAV5 capsid.
    2. Any evidence of active infection or any immunosuppressive disorder, including HIV infection.
    3. Currently undergoing, or plan to receive during the study, immune tolerance induction therapy or prophylaxis with FVIII (Part A only).
    4. Significant renal dysfunction or liver dysfunction, infection or history of hepatic malignancy.
    5. Evidence of any bleeding disorder not related to hemophilia A.
    1. Anticorpi preesistenti contro il capside dell'AAV5 rilevabili.
    2. Qualsiasi evidenza di infezione attiva, tra cui COVID-19, o qualsiasi disturbo immunosoppressivo, inclusa l'infezione da HIV.
    3. Il soggetto riceve attualmente, o prevede di ricevere durante lo studio, terapia di induzione dell'immunotolleranza o profilassi con FVIII (solo Parte A).
    4. Significativa disfunzione renale o epatica, infezione o storia di tumore maligno del fegato.
    5. Evidenza di qualsiasi disturbo di sanguinamento non correlato all'emofilia A.
    E.5 End points
    E.5.1Primary end point(s)
    •FVIII inhibitors
    •Incident of AEs and SAEs
    •Change in clinical laboratory tests (serum chemistry and hematology)
    •Change in vital signs
    •Change in physical examination
    •Vector shedding (blood, urine, semen, stool, saliva)
    •Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase)
    •Immune responses to AAV5 capsid proteins
    •Immunological assessments, including hFVIII TAb, IFN¿ ELISpot, PBMC for exploratory immunogenicity assessments, a complement panel (C3, C3a, C4, Bb, and sC5b-9), and an exploratory biomarker panel.
    • Inibitori del FVIII (cNBA)
    • Incidenza di eventi avversi (AE) e AE seri (SAE)
    • Variazioni nei test clinici di laboratorio (analisi chimiche del siero e analisi ematologiche)
    • Variazioni nelle funzioni vitali
    • Variazioni nell'esame obiettivo
    • Shedding del vettore (sangue, urina, sperma, feci, saliva)
    • Test epatici (LT, incluse ALT, AST, GGT, LDH, bilirubina totale e fosfatasi alcalina)
    o La frequenza e la durata dei test LT possono subire variazioni sulla base della discussione tra Medical Monitor e Sperimentatore, della revisione dei dati del soggetto e/o del feedback del DMC indipendente.
    • Risposta immunitaria alle proteine del capside dell'AAV5
    • Valutazioni immunologiche, tra cui hFVIII TAb, IFN¿ ELISpot, PBMC per valutazioni di immunogenicità esplorative, un pannello relativo al complemento (C3, C3a, C4, Bb, e sC5b-9) e un pannello di biomarcatori esplorativi.
    E.5.1.1Timepoint(s) of evaluation of this end point
    •cNBA for FVIII inhibitor level; Throughout the weeks 1-52 and then q4w on Year 2 and q6w on Year 3-5
    •Adverse events; Day 8, then throughout the weeks 2-52 and then q4w on Year 2 and q6w on Year 3-5
    •Vital Signs; Day 8 and then throughout the weeks 2-52 and then q12w
    •Physical examination; Throughout the weeks 4-52 and then q12w
    •Clinical laboratory tests; Throughout the weeks 2-52 and then q12w
    •Vector shedding; Day 8 and then throughout the weeks 4-52 and then q12w
    •Liver tests; Day 2, 4 and 8, and then throughout the weeks 2-52 and then q4w on Year 2 and q6w on Year 3-5
    •Immune response to AAV5 capsid proteins; Throughout the weeks 4-52 and then annually until the study end
    •Immunological assessments; Throughout the weeks 2-52 then q24w and at End of Year visits
    Fare riferimento al testo in Inglese.
    E.5.2Secondary end point(s)
    •hFVIII activity
    •Decrease in anti-FVIII inhibitory titer post infusion (Part A)
    •Absence of anti-FVIII inhibitors (Part B)
    •Change in the annualized utilization of emicizumab post-BMN 270 infusion from the baseline utilization of emicizumab (Part A)
    •Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy post-BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy (Part B)
    •Change in the annualized number of bleeding episodes requiring treatment (annualized bleeding rate, ABR) post-BMN 270 infusion from the baseline ABR
    •Change from baseline on quality of life as measured by Haemo-QoL-A questionnaire
    Fare riferimento al testo in Inglese.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Measured FVIII concentration/activity will be used for plasma profiles to determine PD parameters.
    • cNBA for hFVIII inhibitor level; Part A: Day 4 and 8, weeks 2-26 then per the protocol schedule q2w or q4w or q6w and Part B: Weeks 1-26 then per the protocol schedule q2w or q4w, or q6w
    • Change in utilization of emicizumab (Part A); Day 8, Weeks 2-26, then per the protocol schedule q2w or q4w or q6w
    • Change in utilization of exogenous FVIII replacement therapy (Part B); Day 8, Weeks 2-26, then per the protocol schedule q2w or q4w or q6w
    • Change in bleeding episodes; Throughout the study every week
    • Impact of BMN 270 on quality of life as measured by the Haemo-QoL-A questionnaire; throughout the weeks 4-52 and then q12w
    Fare riferimento al testo in Inglese.
    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 Yes
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Fase I/II
    Fase I/II
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    In Aperto
    Open
    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.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    France
    Germany
    Italy
    United Kingdom
    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
    LSVS
    LSVS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    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: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    F.2 Gender
    F.2.1Female No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 20
    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
    Nessuno
    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 Decision2021-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-08
    P. End of Trial
    P.End of Trial StatusOngoing
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