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    Summary
    EudraCT Number:2011-005042-35
    Sponsor's Protocol Code Number:PRO053-CLIN-01
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-03-18
    Trial results View 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 number2011-005042-35
    A.3Full title of the trial
    A Phase I/II, open-label, dose escalating with 48 week treatment study to assess the safety and tolerability, pharmacokinetics, pharmacodynamics and efficacy of BMN 053 (previously known as PRO053) in subjects with Duchenne muscular dystrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test if BMN 053 is safe and effective in people who suffer from Duchenne muscular dystrophy
    A.4.1Sponsor's protocol code numberPRO053-CLIN-01
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/247/2013
    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 Kingdom
    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 department
    B.5.3 Address:
    B.5.3.1Street Address105 Digital Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post codeCA94949
    B.5.3.4CountryUnited States
    B.5.4Telephone number+4414382418292105
    B.5.5Fax number31713322088
    B.5.6E-mailwailing.mo@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/3/12/992
    D.3 Description of the IMP
    D.3.1Product nameBMN 053
    D.3.2Product code BMN 053
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPS524
    D.3.9.2Current sponsor codePS524
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense oligonucleotide
    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
    Duchenne muscular dystrophy resulting from a mutation correctable by BMN 053-induced DMD exon 53 skipping
    E.1.1.1Medical condition in easily understood language
    Duchenne muscular dystrophy
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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 efficacy of BMN 053 at recommended dosing regimen after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of BMN 053 after single intravenous (IV) and subcutaneous (SC) dose in subjects with Duchenne muscular dystrophy.

    To investigate the pharmacokinetics BMN 053 at different dosing regimens in subjects with Duchenne muscular dystrophy.

    - To assess the safety and tolerability at different dosing regimens in subjects with Duchenne muscular dystrophy

    To assess the pharmacodynamics of BMN 053 at different dosing regimens levels in subjects with Duchenne muscular dystrophy.

    To assess efficacy and safety of BMN 053 in subjects with Duchenne Muscular Dystrophy not included in the primary analysis after 48 weeks of dosing and/or dosing extension
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN 053 confirmed by a state-of-the-art DNA diagnostic technique covering all DMD gene exons, including but not limited to MLPA (Multiplex Ligation-dependent Probe Amplification), CGH (Comparative Genomic Hybridisation), SCAIP (Single Condition Amplification/Internal Primer) or HRMCA (High-Resolution Melting Curve Analysis).
    2. Ambulant boys aged at least 5 years on the day of first dosing able to walk for at least 300 metres in the 6 minute walking distance (6MWD) test at the first screening visit and also at the baseline visit. In addition, results of 2 of any of the 3 pretreatment 6MWD tests (assessed screen 1, screen 2, baseline) must be within ±30 metres of each other prior to first BMN 053 administration. Subjects must also be able to rise from the
    floor in ≤ 7 seconds at the first screening visit and also at the baseline visit.

    3. Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. Only under exceptional circumstances will an alternative muscle (preferably brachii) be considered for biopsy and only following discussion between the Principal Investigator and the BioMarin Medical Monitor.
    4. Life expectancy of at least 3 years after inclusion in the study.
    5. Glucocorticosteroid use which is stable for at least 3 months prior to first BMN 053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN 053 administration.
    6. Willing and able to adhere to the study visit schedule and other protocol requirements.
    7. Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations).
    8. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
    9. Anticipated adequate vein access for intravenous (IV) infusion.
    E.4Principal exclusion criteria
    1. Current or history of liver disease or impairment.
    2. Current or history of renal disease or impairment.
    3. Screening aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN 053.
    4. Screening platelet count below the lower limit of normal (LLN).
    5. Acute illness within 4 weeks prior to first dose of BMN 053 which may interfere with the study assessments.
    6. Severe mental retardation and/or behavioural problems which, in the opinion of the Investigator, prohibit participation in this study.
    7. Severe cardiomyopathy which, in the opinion of the Investigator prohibits participation in this study. If a subject has a left ventricular ejection fraction <45% at screening, the Investigator should discuss inclusion of the subject with the Medical Monitor.
    8. Expected need for daytime mechanical ventilation within the next year.
    9. Use of anticoagulants, antithrombotics or antiplatelet agents.
    10. Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
    11. Use of nutritional or herbal supplements which, in the opinion of the Investigator, may influence muscle performance within 1 month prior to first dose of BMN 053.
    12. Use of any other investigational product or participation in another trial with an investigational product, within 6 months prior to the start of the screening for the study.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in 6MWD after 48 weeks of treatment phase for primary evaluation at recommended regimen
    E.5.1.1Timepoint(s) of evaluation of this end point
    At screening, baseline, at weeks 13, 25, 37 and 49
    E.5.2Secondary end point(s)
    Efficacy:
    • Muscle function (North Star Ambulatory Assessment, Timed tests, 6MWD)
    • Muscle strength (handheld myometry)
    • Pulmonary function (spirometry)
    • Performance of upper limb (PUL)
    • DMD Functional Outcomes Questionnaire (DMD-FOS)
    • Exploratory efficacy endpoints:
    - Accelerometry
    - Myotools (grip strength, key pinch, moviplate)

    Safety parameters:
    • Adverse events
    • Local tolerability
    • Laboratory assessments including:
    - Routine biochemistry and haematology
    - Urinalysis (routine parameters plus 1-microglobulin, microscopy) and 24-hour urine (additionally including protein electrophoresis, urine cystatin and KIM-1
    - Coagulation parameters (aPTT, PTT [INR], fibrinogen)
    - Complement C3 and split products (C3a, SC5b-9, Bb)
    - Pro-inflammatory markers (cytokines IL-6, TNF- and chemokine MCP-1)
    • Anti-dystrophin antibodies
    • ECG parameters
    • Vital signs (temperature, blood pressure, pulse rate, respiration rate)
    • Echocardiography
    • Physical examination
    • DEXA
    • Standard renal ultrasound

    Pharmacokinetic parameters:
    • t ½ (if reliable)
    • AUC: 0-24h, 0-72h, 0-7d, 0- (where applicable)
    • Cmax, Ctrough, 7d
    • tmax
    • Vd (for IV) or Vd/F (for SC)
    • CL (for IV) or CL/F (for SC)
    • BMN 053 concentrations in urine
    • BMN 053 concentrations in muscle tissue

    Pharmacodynamic parameters:
    • Presence of (BMD-like) dystrophin expression after treatment (in muscle biopsy)
    • Histological and immunological staining on cross-sections of muscle tissue
    • Production of exon skip 53 mRNA (in muscle biopsy)
    • Exploratory PD endpoints:
    - Nuclear Magnetic Resonance imaging and spectroscopy (MRI and MRS)
    - Exploratory biomarkers(e.g. MMP-9, miR-1, miR-133)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy: at all available study visits
    Safety: at all time points
    Pharmacokinetic parameters: per protocol
    Pharmacodynamic parameters: per protocol
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 EEA15
    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
    Argentina
    Australia
    Belgium
    Brazil
    Bulgaria
    Chile
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Netherlands
    Poland
    Turkey
    United Kingdom
    United States
    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
    The end of the study is defined as the last subject undergoing the last
    follow-up visit of the dose extension phase.
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    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 Yes
    F.1.1Number of subjects for this age range: 45
    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: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) No
    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 Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children under the age of 18.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 45
    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 subjects have finished study treatment standard care to continue OR dependent on emerging safety and/or PD data from the BMN 053 development programme, the subjects in this study may be offered the potential for further longer-term dosing with BMN 053. Any further dosing and assessments after completion of the 48-week treatment phase will be presented and justified either within an amendment to this protocol or by a new clinical study protocol.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-09-09
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