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    Summary
    EudraCT Number:2018-001762-42
    Sponsor's Protocol Code Number:4658-402
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2019-10-30
    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 ConcernedDenmark - DHMA
    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
    Et randomiseret, dobbeltblindet dosisfindings- og dosissammenligningsforsøg med henblik på sikkerhed og virkning af en høj dosis eteplirsen, med forudgående åben dosiseskalering, hos patienter med Duchennes muskeldystrofi med deletionsmutationer, der er modtagelige for overspringning af exon 51
    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 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 organisationSarepta Therapeutics, Inc.
    B.5.2Functional name of contact pointPatient Recruitment
    B.5.3 Address:
    B.5.3.1Street Address215 First Street
    B.5.3.2Town/ cityCambridge/ MA
    B.5.3.3Post code02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number1888SAREPTA (1-888-727-3782)
    B.5.6E-mailclinicaltrials@sarepta.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 20.0
    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
    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 and Dose Comparison Part:
    • 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 DMD patients with confirmed deletion genotypes amenable to Exon 51 skipping
    • To select a single higher dose of eteplirsen for dose comparison
    E.2.2Secondary objectives of the trial
    Double-Blind Dose Finding and Dose Comparison Part:
    • To evaluate the effect of a selected high dose as compared with 30 mg/kg of eteplirsen, administered weekly IV, on
    oAmbulatory performance
    oPulmonary function
    oDystrophin expression
    • To evaluate the PK and PD of doses higher than 30 mg/kg of eteplirsen
    • To evaluate safety and tolerability of doses higher than 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 4 to 13 years, inclusive
    3. Ambulatory patient, able to perform TTRISE in 10 seconds or less at the time of screening visit.
    4. Able to walk independently without assistive devices.
    5. Has 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 (for patients in the double-blind part of the study).
    6. 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 and stress-related needs as per recently published guidelines [Birnkrant 2018, Kinnett 2017] throughout the study).
    7. For ages 7 years and older, has 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. For ages 4 to 6 years, does not require support from ventilator or non-invasive ventilation at time of screening.
    8. 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. Acceptable methods of contraception include combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progesteroneonly hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intra-uterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence (True abstinence: When this is in line with the preferred an usual lifestyle of the patient. Periodic abstinence [such as calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.); or condom in combination with either cap, diaphragm, or sponge with spermicide (double-barrier contraception).
    9. Have (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
    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; except the following:
    Ezutromid administered at least 12 weeks prior to first dose.
    Drisapersen administered at least 36 weeks prior to first dose.
    Suvodirsen administered at least 12 weeks prior to first dose.
    Vamorolone administered at least 12 weeks prior to first dose.
    Eteplirsen (previous or current use)
    Tamoxifen administered at least 4 weeks prior to first dose.
    3. 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.
    4. Presence of any other significant neuromuscular or genetic disease other than DMD (eg, dwarfism).
    5. Gamma-glutamyl transpeptidase (GGT) > 3 × the upper limit of normal (ULN) or serum bilirubin > ULN unexplained by Gilbert's Syndrome.
    6. Any known impairment of renal function (eg, estimated glomerular filtration rate [eGFR] ≤ 60 mL/min as assessed by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin C based equation [Inker, 2012, Filler 2012]), or dipstick protein result +2, or persistent and unexplained dipstick protein result +1
    7. Platelet count < the lower limit of normal (LLN).
    8. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease or malignancy.
    9. Has evidence of cardiomyopathy, as defined by left ventricular ejection fraction (LVEF) <50% on the screening ECHO or the Fridericia’s correction formula (QTcF) ≥450 milliseconds based on the screening ECGs.
    10. 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.
    11. Known hypersensitivity to eteplirsen or any excipients of eteplirsen.
    12. 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, Incidence of adverse events of special interest (AESIs), Abnormal changes from Baseline or worsening of vitals or physical examination findings, Incidence of SAEs, Safety laboratory assessments, Electrocardiograms (ECGs) and Echocardiograms (ECHO)

    Double-blind Dose Finding and Dose Comparison Part
    - Change from Baseline at Week 72 in NSAA total score (for conditional efficacy interim analysis)
    - Change from Baseline at Week 96 in NSAA total score (for conditional efficacy interim analysis)
    Change from baseline at Week 144 in NSAA total score (for final analysis)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Open-label Dose Escalation
    week 1-8 safety and tolerability data will be assessed to determine if the dose 100 mg/ kg and escalation dose 200 mg/kg are safe.

    Double-blind Dose Finding and Dose Comparison
    At baseline all patients undergo muscle biopsy pre-dose
    One additional muscle biopsy at either 24, 48, or 144 weeks.
    Dose selection analyses will be performed on muscle biopsy data from Week 24. Additionally, an efficacy interim analysis will be performed (See Section 13.5 for details).
    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.
    Change from baseline at Week 144
    E.5.2Secondary end point(s)
    Change from baseline at Week 144 in
    o TTRISE from floor
    o 10-meter walk/run time
    o 6 MWT
    o Timed 4-step stair ascend test
    o Forced vital capacity percent predicted (FVC%p)
    o Time to LOA through Week 144
    o Change from baseline at either Week 24, Week 48 or Week 144 in skeletal muscle dystrophin expression by:
    o Western blot (quantitation)
    o IHC fiber intensity
    o Exon skipping quantitation by ddPCR
    o PDPF by Immunofluorescence
    o PK parameters (plasma and muscle biopsy)
    o Incidence of AEs
    o Incidence of AESIs
    o Incidence of SAEs
    o Safety laboratory assessments
    o ECGs
    o ECHO
    o Abnormal changes from Baseline or worsening of vital signs and physical examination findings
    E.5.2.1Timepoint(s) of evaluation of this end point
    Change from baseline at Week 144
    Change from baseline at Week 24, Week 48 or 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 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 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 EEA26
    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
    Colombia
    New Zealand
    Switzerland
    Taiwan
    India
    Jordan
    Korea, Republic of
    Mexico
    Serbia
    United Kingdom
    United States
    Czechia
    Denmark
    France
    Germany
    Greece
    Hungary
    Ireland
    Italy
    Netherlands
    Norway
    Poland
    Romania
    Slovenia
    Spain
    Türkiye
    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 years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days14
    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: 154
    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: 144
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    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 4-13 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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 154
    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 Decision2019-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-18
    P. End of Trial
    P.End of Trial StatusRestarted
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