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    Summary
    EudraCT Number:2015-002069-52
    Sponsor's Protocol Code Number:4045-301
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-09-20
    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 ConcernedSweden - MPA
    A.2EudraCT number2015-002069-52
    A.3Full title of the trial
    A Double-Blind, Placebo-Controlled, Multicenter Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy
    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 number4045-301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02500381
    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 Trials
    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-4045
    D.3.2Product code SRP-4045
    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 yet available
    D.3.9.1CAS number 1422958-19-7
    D.3.9.2Current sponsor codeSRP-4045
    D.3.9.3Other descriptive namePhosphorodiamidate morpholino oligomer for exon 45 skipping
    D.3.9.4EV Substance CodeSUB183702
    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.IMP: 2
    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 yet 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.3.9.4EV Substance CodeSUB170839
    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 placeboConcentrate for solution 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 45 or 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
    Double-blind period : Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) compared to placebo on ambulation, endurance, and muscle function, as measured by the 6MWT
    E.2.2Secondary objectives of the trial
    -Double-blind period:
    Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) on:
    1) Dystrophin protein expression in biopsied muscle tissue as measured by:
    •Western blot (quantification)
    •Immunohistochemistry (IHC) fiber intensity
    2) Functional status as measured by:
    •Ability to rise independently from the floor (without external support)
    •Loss of ambulation (LOA)
    •North Star Ambulatory Assessment (NSAA)
    •Respiratory muscle function as measured by forced vital capacity (FVC)% predicted
    3) Safety and tolerability of SRP-4045 and SRP-4053

    -Open-label period:
    4) Evaluate the long-term effects of SRP-4045 and SRP-4053 treatment on functional status up to 144 weeks
    5) Evaluate the long-term safety and tolerability of SRP-4045 and SRP-4053

    -Pharmacokinetics:
    6) Evaluate the PK properties of SRP-4045 and SRP-4053 via a population PK model
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Is a male with an established clinical diagnosis of DMD and an out-of-frame deletion amenable to:
    ● Exon 45 skipping (including but not limited to deletions of exons such as 12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, or 46-55) OR
    ● Exon 53 skipping (including but not limited to deletions of exons such as 42-52, 45-52, 47-52, 48-52,49-52, 50-52, 52, or 54-58) as documented prior to screening by a genetic report from an accredited laboratory defining deletion endpoints by multiplex ligation-dependent probe amplification or sequencing. The patient's amenability to exon 45 or exon 53 skipping must be confirmed prior to first dose using the genotyping results obtained during Screening.
    2. Is between 7 and 13 years of age, inclusive, at randomization.
    3. Has stable pulmonary function (FVC % of predicted ≥50% and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.
    4. Has intact right and left biceps brachii muscles (the preferred biopsy site) or 2 alternative upper arm muscle groups.
    5. Has 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 throughout the study (except for modifications to accommodate changes in weight).
    6. If taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β adrenergic blockers, aldosterone receptor antagonists, potassium, or coenzyme Q, has been on a stable dose for at least 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except modifications to accommodate changes in weight).
    7. Achieved a mean 6MWT distance of ≥300 to ≤450 meters (without assistance) 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 Days 1 and 2) must be within 15% of the Screening mean distance (average of Screening Days 1 and 2).
    8. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive (e.g., female oral contraceptives) during this time frame.
    9. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
    10. Is willing to provide informed assent (if applicable) and has (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. Treatment with any of the following investigational therapies according to the time frames specified:
    ● At any time:
    - Utrophin upregulating agents (except for Ezutromid)
    - CRISPR/Cas9, or any other form of gene editing
    - Gene therapy
    - Cell-based therapy (e.g. stem cell transplantation)
    - Any form of nucleic acid antisense therapy, except PRO045 (BMN 045) or PRO053 (BMN 053) (see below)
    - Exon Skipping Therapies
    - Drisapersen within 36 weeks prior to Week 1
    - PRO045 (BMN 045) Within 24 weeks prior to Week 1
    - PRO053 (BMN 053) Within 24 weeks prior to Week 1
    - PRO051 (BMN 051) Within 24 weeks prior to Week 1
    ● All Anti-Myostatin Therapies within 24 weeks prior to Week 1 including but not limited to:
    - Domagrozumab (PF-06252616)
    - RG-6206 (formally RO-7239361 and BMS-986089)
    ● Small Molecule Therapies:
    - Ezutromid (SMT C1100) within 1 week prior to Week 1
    ● Within 24 weeks prior to Week 1:
    - Anti-fibrotic or anti-inflammatory agents including but not limited to: rimeporide, vamorolone (VBP-15), epigallocatechin-gallate, TAS-205, edasalonexent (CAT-1004), FG-3019, and halofuginone (HT-100)
    - Mast cell activation inhibitor (e.g., CRD007 [pemirolast sodium])
    - Idebenone (Raxone®)
    ● Within 12 weeks prior to Week 1:
    - Nitric oxide (NO)-active agents including, but not limited to, metformin and citrulline, isosorbide dinitrate, tadalafil, sildenafil, pentoxyfilline if taken as part of a DMD clinical trial and not for a medical indication. If taken for a medical indication, must be on a stable dose for at least 12 weeks prior to Week 1.
    ● For any experimental treatment not otherwise specified in Exclusion Criterion 1, consult the medical monitor.
    2. Treatment with any of the following non-investigational therapies according to the time frames specified:
    ● Within 12 weeks prior to Week 1:
    - Any pharmacologic treatment (other than corticosteroids) that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if a physician has documented the diagnosis and medical necessity of treatment, and the patient started dosing at least 24 weeks prior to Week 1.
    ● Within 12 weeks prior to Week 1 or anticipated need during the study:
    - Statins
    - Amynoglycoside antibiotics
    3. Major surgery within 3 months prior to Week 1 or planned surgery for any time during this study, except for protocol-specified surgery, as applicable.
    4. Presence of any other significant genetic disease other than DMD (e.g., dwarfism).
    5. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or malignancy.
    6. LVEF <50% on the Screening echocardiogram (ECHO) or QTcF ≥450 msec on the Screening and Baseline ECG.
    7. Dorsiflexion range of motion will be measured bilaterally and recorded as degrees from neutral (see figure). The subject will be excluded if the average loss of dorsiflexion of both extremities is > -10 degrees. For example, if the subject has -8 degrees on 1 side and -12 degrees on the other side, then he would still qualify
    because the average of the 2 sides is -10 degrees.
    8. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results. Additionally, patients who seem unable / unwilling to comply with the study procedures, in the Investigator’s opinion, are to be excluded.
    E.5 End points
    E.5.1Primary end point(s)
    Double-blind period: Change from Baseline at Week 96 in 6MWT
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96
    E.5.2Secondary end point(s)
    1) • Change from Baseline at Weeks 48 or 96 in the quantity of dystrophin protein expression as measured by Western blot of biopsied muscle tissue
    • Change from Baseline at Weeks 48 or 96 in the intensity of dystrophin expression in biopsied muscle tissue, as measured by IHC

    2) • Ability to rise independently from the floor (without external support) at Week 96, as indicated by an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver)
    • Time to LOA from randomization through Week 96
    • Change from Baseline at Week 96 in:
    − NSAA total score
    − FVC% predicted

    3) Review and evaluation of:
    • AEs, SAEs, deaths, and discontinuations due to AEs
    • Laboratory testing including hematology, coagulation, chemistry (including serum cystatin C), and urinalysis (including urinary kidney injury molecule-1 [KIM-1])
    • Immunogenicity
    • Electrocardiogram (ECG)
    • Vital signs
    • Physical examination findings

    4) • Change from Baseline at Week 144 (Week 48 of the OL period) in 6MWT
    • Ability to rise independently from the floor (without external support) at Week 144, as indicated by an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver)
    • Time to LOA from randomization through Week 144
    • Change from Baseline at Week 144 in:
    − NSAA total score
    − FVC% predicted

    5) Review and evaluation of:
    • AEs, SAEs, deaths, and discontinuations due to AEs
    • Laboratory testing including hematology, coagulation, chemistry (including serum cystatin C), and urinalysis (including urinary kidney injury molecule-1 [KIM-1])
    • Immunogenicity
    • Electrocardiogram (ECG)
    • Vital signs
    • Physical examination findings

    6) Standard population PK parameters will be estimated by population PK analysis. The effects of potential covariates such as standard dosing, demographic characteristics, concomitant medications, laboratory values, and others on SRP-4045 and SRP-4053 PK will be evaluated
    E.5.2.1Timepoint(s) of evaluation of this end point
    ● Quantity of dystrophin protein expression: Baseline, weeks 48 or 96
    ● 6MWT: weeks 108, 120, 132 and 144
    ● Intensity of dystrophin expression: Baseline, weeks 48 or 96
    ● Ability to rise independently from the floor: Screening, Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144
    ● LOA status: Week 96 and Week 144
    ● NSAA total score and FVC% predicted: Week 96 and Week 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 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) No
    E.7.1.1First administration to humans No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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
    Patients may participate in an open-label treatment extension period of up to 48 weeks
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    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
    Australia
    Belgium
    Bulgaria
    Canada
    Chile
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Ireland
    Israel
    Italy
    Norway
    Poland
    Portugal
    Russian Federation
    Serbia
    Spain
    Sweden
    Ukraine
    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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    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: 222
    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: 190
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 32
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 133
    F.4.2.2In the whole clinical trial 222
    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)
    A long term extension trial will be proposed to the patients at the end of the open label extension.
    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 Decision2016-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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