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    Summary
    EudraCT Number:2014-002008-25
    Sponsor's Protocol Code Number:4053-101
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-08
    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 number2014-002008-25
    A.3Full title of the trial
    A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study of a new investigational medicinal product for the treatment of Duchenne Muscular Dystrophy patients
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code number4053-101
    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 SponsorSarepta Therapeutics, 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 supportSarepta Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVoisin Consulting
    B.5.2Functional name of contact pointClinical Trial Operations
    B.5.3 Address:
    B.5.3.1Street Address64 avenue Pierre Grenier
    B.5.3.2Town/ cityBoulogne-Billancourt
    B.5.3.3Post code92100
    B.5.3.4CountryFrance
    B.5.6E-mailclinicaltrialinformation@voisinconsulting.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSRP-4053
    D.3.2Product code SRP-4053
    D.3.4Pharmaceutical form Concentrate for 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 INNNot Available
    D.3.9.1CAS number 1422959-91-8
    D.3.9.2Current sponsor codeSRP-4053
    D.3.9.3Other descriptive namePhosphorodiamidate morpholino oligomer for exon 53 skipping
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with Duchenne Muscular Dystrophy Amenable to 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 20.0
    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
    PART 1 : To evaluate the safety and tolerability of four escalating doses of SRP-4053 administered once weekly for at least 2 weeks per dose level compared to placebo

    PART 2 :
    - To assess ambulation, endurance, and muscle function as measured by change from Baseline at Week 144 on the 6-Minute Walk Test (6MWT) in treated and untreated patients
    - To assess the biological activity of SRP-4053 via dystrophin expression at Week 48 compared to pre-treatment.
    E.2.2Secondary objectives of the trial
    PART 1 : To determine the pharmacokinetics of four escalating doses of SRP-4053 administered once weekly for at least 2 weeks per dose level compared to placebo

    PART 2 :
    - To assess the safety, tolerability, and PK of SRP-4053 administered weekly
    - To assess respiratory function in treated and untreated patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male aged 6 to 15 years, inclusive.
    2. For treated patients (all patients in Part 1 and 12 additional treated patients in Part 2), established clinical diagnosis of DMD with a mutation amenable to exon 53 skipping (e.g. deletions of exons such as 42-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, or 54-58) as documented by a genetic report from an accredited laboratory confirming deletion endpoints by multiplex ligation-dependent probe amplification (MLPA) or sequencing.
    3. For Part 2 untreated control patients, established clinical diagnosis of DMD with confirmed genomic deletion of exon(s) not amenable to exon 53 skipping as documented by an accredited laboratory and genomic methodology.
    4. Have intact right and left biceps muscles or an alternative upper arm muscle group.
    5. Have stable cardiac and pulmonary function that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.
    6. Achieve a mean 6MWT distance of ≥250 meters at both the Screening and Baseline visits (prior to Week 1). The mean 6MWT distance at the Screening and Baseline visits is the average of 2 separate assessments on 2 consecutive days at each visit. The Baseline mean (average of Baseline Day 1 and 2) must be within 15% of the Screening mean (average of Screening Day 1 and 2). (Personal assistance or use of any assistive devices for ambulation is not permitted during the 6MWT).
    7. Patients must meet at least one of the following two criteria:
    • NSAA (North Star Ambulatory Assessment) total score >17; or
    • Rise (Gowers') time < 7 seconds
    8. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study. Note: patients are allowed to take other medication (excluding other ribonucleic acid [RNA] antisense or gene therapy agents) including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β-blockers, and potassium provided they have been on a stable dose for at least 12 weeks prior Week 1 and the dose is expected to remain constant throughout the study.
    9. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with the study procedure requirements.
    10. Be willing to provide informed assent and have (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.
    E.4Principal exclusion criteria
    1. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength or function within 12 weeks prior to study entry (e.g., growth hormone, anabolic steroids).
    2. Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.
    3. Current or previous treatment with any other experimental treatments within 12 weeks prior to study entry. Untreated patients only can be enrolled concurrently in other non-interventional trials, or in interventional trials in which participants are known to be treated with standard-of-care medication, provided they do not interfere with study assessments performed in Study 4053-101, and the patient meets all the protocol-required entry criteria.
    4. A left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional shortening) based on the screening ECHO and QTc (Fridericia’s correction) >450 msec.
    5. A forced vital capacity (FVC) <50% of predicted value or requirement for nocturnal ventilation.
    6. Major surgery within 3 months prior to Week 1 or orthopedic surgery planned for any time during this study which would interfere with the ability to perform outcome measures.
    7. Planned use of any aminoglycoside antibiotic or statin within 12 weeks of Week 1 or need for use of an aminoglycoside antibiotic or statin during the study.
    8. Presence of other clinically significant illness, for example significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, behavioral disorder or malignancy.
    9. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to contracture (i.e. fixed loss of >10 degrees plantar flexion from plantigrade assuming normal range of dorsiflexion of 20 degrees).
    10. Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study.
    11. Prior or ongoing medical condition that, in the Investigator’s opinion, could interfere with the patient’s participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    PART 1: Safety of SRP-4053, assessed as follows:
    • Incidence of AEs
    • Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis)
    • Incidence of abnormalities in vital signs and physical examinations
    • Incidence of abnormalities on ECGs and ECHOs

    PART 2:
    - Efficacy endpoint: change from Baseline at Week 144 in the 6MWT
    - Biological endpoint: change from Baseline at Week 48 in dystrophin protein levels determined by Western blot.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PART 1:
    • AEs: Continuous evaluation
    • Laboratory abnormalities: Screening (-6 to -4), Baseline (-2 to -1), weekly from Week 1 to 9, Week 12
    • Vital signs : Screening (-6 to -4), Baseline (-2 to -1), weekly from Week 1 to 12
    • Physical examinations: Screening (-6 to -4), Week 1, 4, 8, and 12
    • ECG: Screening, Baseline, Week 12
    • ECHO: Screening, Week 12

    PART 2:
    - Efficacy endpoint:
    • 6-Minute Walk Test (6MWT): Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Weeks 12, 24, 36, 48, 72, 96, 120, 144
    - Biological endpoint:
    • Western blot: Baseline (-2 to -1), Week 48
    E.5.2Secondary end point(s)
    PART 1&2:
    - Pharmacokinetic (PK) parameters:
    • Maximum plasma concentration (Cmax)
    • Time to maximum plasma concentration (tmax)
    • Area under the plasma concentration-curve (AUC)
    • Apparent volume of distribution at steady state (Vss)
    • Elimination half-life (t½)
    • Total clearance (CL)
    • Mean residence time (MRT)
    • Urinary clearance (CLR), for part 1 only

    PART2:
    - Efficacy endpoint: change from Baseline through Week 144 in forced vital capacity percent predicted (FVC%p)

    - Biological endpoint: change from Baseline at Week 48 for the following:
    • Dystrophin intensity levels determined by immunohistochemistry (IHC)
    • Percentage of dystrophin-positive fibers as determined by IHC
    • Exon 53 skipping determined by measurement and sequence verification of exon 53 skipped mRNA.

    - Safety:
    • Incidence of adverse events
    • Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis)
    • Incidence of abnormalities in vital signs and physical examinations
    • Incidence of abnormalities on electrocardiograms (ECGs) and echocardiograms (ECHO)
    • Immunogenicity.
    E.5.2.1Timepoint(s) of evaluation of this end point
    PARTS 1&2:
    -PK:
    Part1: W1,3,5,7,12
    Part2 treated: W1,24,48,96,144

    PART 2:
    -Efficacy: Screening, Baseline, W12,24,36,48,72,96,120,144
    -Biological: Baseline, W48

    -Safety:
    •AEs: continuous
    •Lab.:
    Treated: Screening, Baseline, W1 to 4,
    8,12,16,20,24,36,48,60,72,84,96,108,120,132,144,FU
    Untreated: Screening, Baseline, W12, 24, 36, 48, 72, 96, 120, 144
    •Vital signs:
    Treated: Screening, Baseline, every week until FU
    Untreated: Screening, Baseline, W12,24,36,48,72,96,120,144
    •Physical exam.:
    Treated: Screening,
    W1,4,8,12,16,20,24,36,48,60,72,84,96,108,120,132,144,FU
    Untreated: Screening, W12,24,36,48, 72, 96, 120, 144
    •ECG: Screening, Baseline, W12,24,36,48,72,96,120,144
    •ECHO: Screening, W24,48,72,96,120,144
    •Immunogenicity: Baseline, W1(treated),24,48,72,96,120,144
    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 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 Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Study Part 1 : Double blind - Study Part 2 : Open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Study Part 1 : Placebo ; Study Part 2 : Untreated control group
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    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
    Last patient last visit
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 48
    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: 24
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 24
    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 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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 48
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Muscular Dystrophy Campaign
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Action Duchenne
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Duchenne Family Support Group
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 4
    G.4.1Name of Organisation Duchenne Parent Project France
    G.4.3.4Network Country France
    G.4 Investigator Network to be involved in the Trial: 5
    G.4.1Name of Organisation Association Française contre les Myopathies
    G.4.3.4Network Country France
    G.4 Investigator Network to be involved in the Trial: 6
    G.4.1Name of Organisation Italian DMD Parent Project Onlus
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-25
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