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    Summary
    EudraCT Number:2018-001762-42
    Sponsor's Protocol Code Number:4658-402
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-07-08
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-001762-42
    A.3Full title of the trial
    A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of a High Dose of Eteplirsen, Preceded by an Open-label Dose Escalation, in Patients with Duchenne Muscular
    Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to compare different doses of a new investigational medicinal product for treatment of certain patients with Duchenne muscular dystrophy
    A.4.1Sponsor's protocol code number4658-402
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/029/2016
    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 organisationSyneos Health
    B.5.2Functional name of contact pointCarolyn Mills
    B.5.3 Address:
    B.5.3.1Street Address4 The Fleming Buildings, Edinburgh Technopole Milton Bridge
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH26 0BE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441314481303
    B.5.6E-mailCarolyn.mills@syneoshealth.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 Yes
    D.2.1.1.1Trade name Exondys 51
    D.2.1.1.2Name of the Marketing Authorisation holderSarepta Therapeutics, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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/3/08/586
    D.3 Description of the IMP
    D.3.1Product nameEteplirsen
    D.3.2Product code AVI-4658
    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 INNETEPLIRSEN
    D.3.9.1CAS number 1173755-55-9
    D.3.9.2Current sponsor codeAVI-4658
    D.3.9.4EV Substance CodeSUB129287
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Duchenne Muscular Dystrophy
    E.1.1.1Medical condition in easily understood language
    Duchenne muscular dystrophy is a rare, fatal degenerative neuromuscular disease with an X-linked recessive inheritance caused by mutations in the dystrophin gene
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10052655
    E.1.2Term Duchenne muscular dystrophy gene carrier
    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
    Open-label Dose Escalation
    Evaluate the safety and tolerability of weekly IV doses of 100 and 200 mg/kg of eteplirsen.

    Double-blind Dose Finding:
    Evaluate the PK, PD (exon skipping
    quantitation), safety and tolerability of doses higher than 30 mg/kg of eteplirsen, to select a single higher dose of eteplirsen for Dose Comparison

    Double-blind Dose Comparison:
    Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly
    To investigate the effect of a selected high dose of eteplirsen (100 mg/kg or 200 mg/kg) as compared with 30 mg/kg, administered weekly IV, on motor function in ambulant Duchenne muscular dystrophy (DMD) patients with confirmed deletion genotypes amenable to exon 51 skipping
    E.2.2Secondary objectives of the trial
    Double-blind Dose Comparison:

    Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly on:
    -Ambulatory performance
    -Pulmonary function
    -Dystrophin expression
    To evaluate safety and tolerability of a selected high dose as compared with 30 mg/kg of eteplirsen, administered weekly IV
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient must meet all of the following criteria to be eligible to participate in this study.
    1. Be a male with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping (for example, deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, and 52-63).
    2. Be aged 7 to 13 years, inclusive
    3. Have achieved a mean 6-minute walk test (6MWT) distance of ≥300 and ≤450 meters (without assistance) at both the screening and baseline visits for the double-blind.
    4. Have intact right and left biceps muscles (the preferred biopsy site) or an alternative upper arm muscle group that will allow for sufficiently sized (1 cm3) muscle biopsies to be obtained prior to and on treatment.
    5. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to randomization, and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study.
    6. Have stable pulmonary function (forced vital capacity ≥50% of predicted and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate significantly over the duration of the study.
    7. If sexually active, agree 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 (ie, female oral contraceptives) during this timeframe.
    8. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
    9. 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
    A patient who meets any of the following criteria will be excluded from this study:
    1. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to randomization that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if an endocrinologist has documented the diagnosis and medical necessity of treatment and if the patient has been on a stable dose for at least 24 weeks prior to randomization.
    2. Current or previous treatment with any other experimental pharmacologic treatment for DMD or any prior exposure to antisense oligonucleotide, gene therapy or gene editing; exceptions are listed in number 3 below.
    3. Previous treatment with drisapersen, ezutromid, or domagrozumab in the last 24 weeks prior to study enrollment.
    4. Major surgery within 3 months prior to randomization or planned surgery for any time during this study, except for allowed protocol-specified surgery, as applicable.
    5. Presence of any other significant neuromuscular or genetic disease other than DMD (eg, dwarfism).
    6. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease or malignancy.
    7. Has evidence of cardiomyopathy, as defined by LVEF <50% on the screening ECHO or the Fridericia’s correction formula (QTcF) ≥450 milliseconds based on the screening ECGs.
    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.
    9. Is, in the Investigator’s opinion, unable or unwilling to comply with the study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    Open-label Dose Escalation
    Incidence of AEs, adverse events of special interest (AESIs) serious adverse events (SAEs), Safety laboratory assessments, ECGs and ECHO

    Double-blind Dose Finding
    Dystrophin expression in biopsied muscle tissue
    Plasma PK parameters of 30, 100, and 200 mg/kg of eteplirsen, administered IV weekly
    Incidence of AEs, AESIs and SAEs
    Abnormal changes from baseline or worsening of vitals or physical examination findings
    Safety laboratory assessments
    ECGs and ECHO
    Tissue concentration of eteplirsen from biopsied muscle tissue

    Dose Comparison
    Change from baseline at Week 144 in North Star Ambulatory Assessment
    (NSAA) total score
    E.5.1.1Timepoint(s) of evaluation of this end point
    Open-label Dose Escalation
    At the completion of every 2-week treatment by 4 subjects at each
    dose level.

    Double-blind Dose Finding
    At baseline all patients undergo muscle biopsy pre-dose. One additional muscle biopsy at either 12, 24, or 48 weeks.
    Interim analyses will be performed on muscle biopsy data at Weeks 12 to assess dystrophin expression for high dose selection; additional interim analyses will be conducted at Week 24 and, if a high dose is not selected, at Week 48.

    AE assessment at baseline and continuous throughout the study. ECG
    at screening, week 1, 4, 8, and 12, and every 12 weeks thereafter.
    ECHO at screening, week 48, 96, and 144.

    Dose Comparison
    Change from baseline at Week 144
    E.5.2Secondary end point(s)
    Change from baseline at Week 144 in
    o 6 MWT
    o 10 meter walk/run time
    o Timed 4 step stair ascend test
    o Time to rise from floor
    Annual decline rate in FVC % predicted Time to LOA
    Change from baseline at Week 48 (also at Week 12 if Dose Finding is not necessary, based on Dose Escalation, and Week 24 if dose selection is at Week 12) in skeletal muscle dystrophin expression by:
    o Western blot (quantitation)
    o IHC fiber intensity
    o Exon skipping quantitation by PCR
    IIncidence of AEs
    Incidence of AESIs
    Incidence of SAEs
    Safety laboratory assessments
    ECGs
    ECHO
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change from baseline at Week 144
    Change from baseline at Week 48 (also at Week 12 if Dose Finding is not necessary, based on Dose Escalation, and Week 24 if dose selection is at Week 12)
    AE assessment at baseline and continuous throughout the study. ECG at
    screening, week 1, 4, 8, and 12, and every 12 weeks thereafter. ECHO at
    screening, week 48, 96, and 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 No
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    The open-label period of the study evaluates the tolerability of the higher dose eteplirsen in DMD patients
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Open-label Dose Escalation followed by a Double-blind Dose Finding and Dose Comparison part
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    different dosage of the same product
    E.8.2.4Number of treatment arms in the trial3
    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 EEA16
    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
    Canada
    Chile
    Colombia
    France
    Germany
    Hong Kong
    Ireland
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Peru
    Russian Federation
    Spain
    Taiwan
    Turkey
    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 years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days18
    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: 152
    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: 125
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 27
    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
    Male subjects 7-13 years old with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping
    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 70
    F.4.2.2In the whole clinical trial 152
    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 completion of the trial the patients will get back to their normal treatment of that condition under their physician
    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 Decision2019-11-19
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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