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    Summary
    EudraCT Number:2017-000662-29
    Sponsor's Protocol Code Number:270-203
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-10-09
    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 ConcernedUK - MHRA
    A.2EudraCT number2017-000662-29
    A.3Full title of the trial
    A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤ 1 IU/dL and Pre-existing Antibodies Against AAV5
    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 pre-existing antibodies to AAV5
    A.4.1Sponsor's protocol code number270-203
    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.5.6E-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.3.9.3Other descriptive nameAAV5-hFVIII-SQ
    D.3.9.4EV Substance CodeSUB174200
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2E13
    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
    Haemophilia A
    E.1.1.1Medical condition in easily understood language
    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
    - Assess the safety of a single intravenous administration of BMN 270 in severe Haemophilia A subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody
    E.2.2Secondary objectives of the trial
    - Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26
    - Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy
    - Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy
    - Evaluate the pharmacodynamics of FVIII expression following intravenous infusion of BMN 270
    - Assess the impact of BMN 270 on patient-reported outcomes (PROs)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent.
    2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total antibody ELISA
    3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs)
    4. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry.
    5. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures.
    6. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart within the past 12 months (at least one of which should be tested at the central laboratory)
    7. Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection.
    8. Willing to abstain from consumption of alcohol for at least the first 52 weeks following BMN 270 infusion.
    E.4Principal exclusion criteria
    1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection.
    2. Significant liver dysfunction with any of the following abnormal laboratory results:
    o ALT (alanine aminotransferase) > 1.25x ULN;
    o AST (aspartate aminotransferase) > 1.25x ULN;
    o GGT (gamma-glutamyltransferase) > 1.25x ULN;
    o Total bilirubin > 1.25x ULN;
    o Alkaline phosphatase > 1.25x ULN; or
    o INR (international normalized ratio) ≥ 1.4
    Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing of the entire liver test panel within the same Screening window and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.
    3. Most recent, prior FibroScan or liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used
    4. Evidence of any bleeding disorder not related to hemophilia A
    5. Platelet count of < 100 x 10^9/L
    6. Creatinine ≥ 1.5 mg/dL
    7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.
    8. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results .
    9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy
    10. Active malignancy, except non-melanoma skin cancer
    11. History of hepatic malignancy
    12. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing.
    13. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.
    14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis).
    15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study
    16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including corticosteroid treatment and/or the use of alternative immunosuppressive agents outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result.
    17. Prior treatment with any vector or gene transfer agent
    18. Major surgery planned in the 52-week period following the infusion with BMN 270
    19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the BMN 270 infusion
    20. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 and with prior consultation with the Medical Monitor
    21. Known allergy or hypersensitivity to investigational product formulation
    22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed
    E.5 End points
    E.5.1Primary end point(s)
    - The following safety outcome measurements will be assessed:
    • Incidence of adverse events (AEs), including serious AEs (SAEs)
    • Change in clinical laboratory tests (serum chemistry and hematology)
    • Change in vital signs
    • Change in physical examination
    • Vector shedding (blood, urine, semen, feces, saliva)
    • Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase)
    • Immune response to FVIII transgene product and AAV5 vector capsid
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 26
    E.5.2Secondary end point(s)
    - The efficacy goal is to achieve FVIII activity ≥ 5 IU/dL at 26 weeks post-BMN 270 administration.
    Other efficacy measures:
    - assessment of the impact of BMN 270 on the use of FVIII replacement therapy and on the number of bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the sponsor, to record the relevant details.
    - Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-BMN 270 infusion
    - Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 infusion.
    - Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 of the study post-BMN 270 infusion.
    - Change from baseline in the Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the study post-BMN 270 infusion.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 26
    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
    safety, tolerability, efficacy of BMN 270 in haemophilia A patients w/ pre-existing AAV5 antibodies
    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.8.2.4Number of treatment arms in the trial1
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    South Africa
    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
    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 months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months1
    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: 10
    F.1.3Elderly (>=65 years) No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 10
    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 Decision2017-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-01
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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