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    Summary
    EudraCT Number:2014-002008-25
    Sponsor's Protocol Code Number:4053-101
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-10
    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 ConcernedItaly - Italian Medicines Agency
    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 Address3 rue des Longs Prés
    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 17.0
    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 the effect of SRP-4053 administered weekly on ambulation, endurance, and muscle function as measured by change from Baseline to Week 48 on the 6-Minute Walk Test (6MWT) compared to untreated control patients
    - To assess the biological activity (dystrophin expression) 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 pharmacokinetics of SRP-4053 administered weekly compared to untreated control patients
    - To assess the effect of SRP-4053 on respiratory muscle strength as measured by change from Baseline to Week 48 in maximal inspiratory and expiratory pressure % predicted as compared to untreated control patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male aged 6 to 15, inclusive.
    2. For treated patients (all patients in Part 1 + 12 additional treated patients in Part 2), established clinical diagnosis of DMD 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 distance of two separate assessments on two consecutive days at screening and again at baseline (prior to investigational drug product administration) ≥250 meters on the 6MWT with the two means being ±15% of each other. (Personal assistance or use of any assistive devices for ambulation is not permitted during the 6MWT.)
    7. Patients must meet 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 of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study. Note: patients may be allowed to take other (non-RNA antisense or gene therapy) medication including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β blockers, and potassium provided they have been on a stable dose for 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study.
    9. Have a parent(s) or legal guardian(s) who is 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 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. Previous or current treatment with any other experimental treatments within 12 weeks prior to study entry or participation in any other clinical trial within 6 months prior to study entry.
    4. Have a left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional shortening) based on the screening ECHO and QTc (Fredericia’s correction) >450 msec.
    5. Have a forced vital capacity [FVC] <50% of predicted value or require nocturnal ventilation.
    6. Major surgery within 3 months prior to Week 1 or planned orthopedic surgery for any time during this study which would interfere with the ability to perform outcome measures.
    7. 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 including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, behavioral disease or malignancy.
    9. Loss ≥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 plantagrade 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:
    • Incidence of adverse events (AEs)
    • 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)

    PART 2:
    - Functional efficacy endpoint:
    change from Baseline to Week 48 in the 6-Minute Walk Test (6MWT)
    - Biological endpoint:
    change from Baseline at Week 48 in the percentage of dystrophin-positive fibers as determined by immunohistochemistry (IHC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    PART 1:
    • Continuous evaluation of the AEs.
    • laboratory abnormalities: Screening (-6 to -4), Baseline (-2 to -1), weekly from week 1 to 9, week 12
    • vital signs : every week from screening to week 12
    • physical examinations : Screening (D1814), week 1, week 4, week 8, week 12
    • ECG: Screening , Baseline, week 7 and 12
    • ECHO: Screening, week 12

    PART 2:
    - Functional efficacy endpoint:
    • 6-Minute Walk Test (6MWT): Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Week 12 (only control arm), Week 24, Week 36, Week 48, Week 60
    - Biological endpoint:
    • IHC: Baseline (-2 to -1), Week 60
    E.5.2Secondary end point(s)
    PART 1 and PART 2:

    - Pharmacokinetic:
    • 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)

    PART2:
    - Functional efficacy endpoint:
    change from Baseline to Week 48 for the following:
    • Pulmonary function tests (PFT): maximum expiratory pressure % predicted (MEP % predicted) and maximum inspiratory pressure % predicted (MIP % predicted)

    - Biological endpoint:
    change from Baseline at Week 48 for the following:
    • Dystrophin intensity levels determined by IHC
    • Dystrophin protein levels determined by Western blot (WB)
    • Exon 53 skipping determined by reverse transcription-polymerase chain reaction (RT-PCR)

    - 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)
    E.5.2.1Timepoint(s) of evaluation of this end point
    PART 1 & 2:
    - Pharmacokinetic:
    Part 1 : Week 1, 3, 5, 7 & 12;
    Part 2: Week 13, 36 & 60

    PART 2 :
    - Efficacy: Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Week 12 (Only control arm), 24, 36,48,60

    - Biological: Baseline, Week 60

    - Safety:
    • Continuous evaluation of the AEs
    • laboratory abnormalities: Screening (new patients only), Baseline, weekly from week 13 to 16, week 20, 24, 28, 32, 36, 48 (excluded control arm), 60 & follow-up
    • vital signs: every week from screening (new patients only) and baseline to follow-up
    • physical examinations: Screening (new patients only), week 13, 16, 20, 24, 28, 32,36,48,60 & follow-up
    • ECG: Screening, Baseline, week 24, 36, 48 & 60
    • ECHO: Screening, week 36 & 60
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    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 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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    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 Decision2014-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-13
    P. End of Trial
    P.End of Trial StatusCompleted
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