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    Summary
    EudraCT Number:2019-000601-77
    Sponsor's Protocol Code Number:5051-201
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2020-03-31
    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 ConcernedGermany - BfArM
    A.2EudraCT number2019-000601-77
    A.3Full title of the trial
    A Phase 2, Two-Part, Multiple-Ascending-Dose Study of SRP-5051 for Dose Determination, then Dose Expansion, in Patients with
    Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping
    Treatment
    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.4.1Sponsor's protocol code number5051-201
    A.5.4Other Identifiers
    Name:INDNumber:134648
    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
    B.5.3.3Post codeMA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number1-888-SAREPTA (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 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 nameVesleteplirsen
    D.3.2Product code SRP-5051
    D.3.4Pharmaceutical form Lyophilisate 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 INNVesleteplirsen
    D.3.9.1CAS number 2101569-97-3
    D.3.9.2Current sponsor codeSRP-5051
    D.3.9.3Other descriptive namepeptide-conjugated phosphorodiamidate morpholino oligomer for exon 51 skipping
    D.3.9.4EV Substance CodeSUB197949
    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
    Part A:
    To evaluate the safety and tolerability of multiple ascending doses of SRP-5051 (4 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg), administered
    intravenously (IV) every 4 weeks, and determine the maximum tolerated dose (MTD)

    Part B
    To evaluate dystrophin protein level in skeletal muscle tissue following SRP-5051 treatment, administered IV every 4 weeks at the doses
    selected based on data from Part A
    E.2.2Secondary objectives of the trial
    Part A
    To determine the pharmacokinetics (PK) of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma, at each of the
    aforementioned multiple ascending doses of SRP-5051, administered IV every 4 weeks

    Part B
    • To evaluate exon-skipping level in skeletal muscle tissue following SRP-5051 treatment, administered IV every 4 weeks at the doses selected based on data from Part A
    • To evaluate the ongoing safety and tolerability of SRP-5051 treatment, administered IV every 4 weeks at the doses selected based on data from Part A
    • To determine the PK of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma
    • To evaluate, via immunohistochemistry, percent dystrophin-positive fibers (PDPF) and mean intensity following SRP-5051 treatment,
    administered IV every 4 weeks at the doses selected based on data from Part A
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for Patients Previously Treated with SRP-5051
    Patients previously treated with SRP-5051 must meet all of the following criteria to participate in this study:
    I 1. Has received prior SRP-5051 treatment in Part A of this study or in Study 5051-102.
    I 2. 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 of
    study drug. The sexual partner must also use a highly effective form of contraceptive (refer to Appendix 1 for guidance on highly effective
    contraceptive methods) during this timeframe.
    I 3. Is willing to provide informed consent or 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.

    Inclusion Criteria for Patients Treatment-Naïve to SRP-5051
    Patients who are treatment-naïve to SRP-5051 must meet all of the following criteria to participate in this study:
    I 1. Is male.
    I 2. Is 7 to 21 years of age, inclusive.
    I 3. Has a genetic diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51-skipping treatment.
    I 4. Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug administration or has not received
    corticosteroids for at least 12 weeks prior to study drug administration.
    I 5. Has stable pulmonary function (FVC ≥ 40% of predicted and no requirement for nocturnal ventilation as a result of the complications of DMD) that, in the Investigator's opinion, is unlikely to decompensate significantly over the duration of the study. NOTE: patients on nocturnal ventilation because of sleep apnea, obesity, or other conditions caused by corticosteroid use are allowed to participate in the study if FVC % predicted is ≥ 40.
    I 6. 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 of
    study drug. The sexual partner must also use a highly effective form of contraceptive (refer to Appendix 1 for guidance on highly effective
    contraceptive methods) during this timeframe.
    I 7. Is willing to provide informed consent or 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
    Exclusion Criteria for Patients Previously Treated with SRP-5051:
    E 1. Has a current infection, or history of an infection within 12 weeks prior to Day -1 requiring intravenous treatment with an antibiotic, or oral antibiotics that may affect renal or cardiac function.
    E 2. Has a known kidney disease (identified by eGFR [calculated using Schwartz 2012 cystatin C equation] of < 90 mL/min/1.73 m2) or had an acute kidney injury within 24 weeks prior to Screening.
    E 3. Major surgery within 12 weeks prior to Screening, or planned surgery or procedures that would interfere with the conduct of the study.
    E 4. Presence of other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy.
    E 5. Any other condition that, in the Investigator's opinion, could interfere with the patient's participation in the trial, including body weight loss to < 18 kg.
    E 6. Inability to comply with the study protocol.
    E 7. Is an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees or the Investigator.
    E 8. Any patient who is taking medications that increase the risk of bleeding, in the Investigator's opinion
    E 9. Platelet count < 150 × 10^3/μL.
    E 10. Known hypersensitivity to the study drug (ie, SRP-5051) or to any of its components.
    E 11. Has:
    a. Hypomagnesemia (< lower limit of normal) at Screening
    b. Other abnormal electrolyte values considered clinically significant by the Investigator upon medical review and in consultation with the Medical Monitor at Screening;
    c. Serum creatinine > upper limit of normal (ULN) at Screening.
    E 12. Has quantitative urinalysis or urine microscopy findings above the ULN for RBCs or WBCs.
    E 13. Urine Protein/Creatinine Ratio ≥ 200 mg/g and UACR ≥ 30 mg/g OR 24-hour urine values for protein ≥ 200 mg/24 hr at Screening and albumin ≥ 30 mg/24 hr. (Note that 24-hour urine protein does not need to be performed during screening if the UPCR/UACR criteria are met).
    E 14. GGT > 3 × ULN at Screening
    E 15. Is being treated with a proton pump inhibitor, loop diuretic, or thiazide diuretic at the time of study initiation.
    E 16. Treatment with any exon 51-skipping therapy within 4 weeks prior to Screening, or with any experimental gene therapy for the treatment of DMD at any time. For other exclusion criteria please refer to Protocol
    Exclusion Criteria for Patients Treatment-Naïve to SRP-5051:
    E 1. History of hypomagnesemia within 12 weeks prior to Screening.
    For TN Cohort patients entering the study in Part B
    E 2. Has body weight < 18 kg.
    E 3. Has a diagnosis of diabetes (any type).
    E 4. Initiation or change of dosing (except for modifications to accommodate changes in weight or changes in standard of care) within 12 weeks prior to Screening for any of the following: angiotensinconverting enzyme inhibitors, angiotensin receptor-blocking agents, β- blockers, or potassium.
    E 5. Requires anti-arrhythmic and/or diuretic therapy for heart failure.
    E 6. Has a current infection, or history of an infection within 12 weeks prior to Day -1 requiring intravenous treatment with an antibiotic, or oral antibiotics that may affect renal or cardiac function.
    E 7. Has a known kidney disease (identified by eGFR [calculated using Schwartz cystatin C equation] of < 90 mL/min/1.73 m2) or had an acute kidney injury within 24 weeks prior to Screening.
    E 8. Major surgery within 12 weeks prior to Screening, or planned surgery or procedures that would interfere with the conduct of the study.
    E 9. Presence of other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy.
    E 10. Any other condition that, in the Investigator's opinion, could interfere with the patient's participation in the trial.
    E 11. Inability to comply with the study protocol.
    E 12. Is an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees or the Investigator.
    E 13. Any patient who is taking medications that increase the risk of bleeding, in the Investigator's opinion
    E 14. Platelet count < 150 × 10^3/μL
    E 15. Known sensitivity to the study drug (ie, SRP-5051) or to any of its components
    E 16. Has:
    a. Hypomagnesemia (< lower limit of normal) at Screening
    b. Other abnormal electrolyte values considered clinically significant by the Investigator upon medical review and in consultation with the Medical Monitor at Screening;
    c. Serum creatinine > upper limit of normal (ULN) at Screening
    E 17. Has quantitative urinalysis or urine microscopy findings above the ULN for RBCs or WBCs
    For other exclusion criteria please refer to Protocol
    E.5 End points
    E.5.1Primary end point(s)
    Part A
    • Incidence of adverse events (AEs)
    • Clinically significant laboratory abnormalities (eg, hematology, chemistry [including electrolytes], coagulation, urinalysis)

    Part B
    Change from Baseline in dystrophin protein level (as measured by Western blot) at 28 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A
    All AEs will be reported from the time of providing signed informed consent/assent through the last follow-up visit.
    All the routine clinical laboratory tests will be performed during clinic visits at the time points specified in the Schedule of Events for Part A as
    stated in the Table 1 of the protocol

    Part B
    Change from Baseline in dystrophin protein level (as measured by Western blot) at 28 weeks
    E.5.2Secondary end point(s)
    Part A
    PK parameters of SRP-5051 in plasma and urine, and of its major metabolite SRP-5051A in plasma, at each dose level

    Part B
    • Change from Baseline in exon-skipping level (as measured by ddPCR) at 28 weeks
    • Incidence of AEs
    • Incidence, severity, and reversibility of hypomagnesemia
    • Clinically significant laboratory abnormalities (eg, hematology, chemistry [including electrolytes], coagulation, urinalysis)
    • PK parameters of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma
    • Change from Baseline in PDPF and mean intensity, as measured by immunofluorescence assay
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A – Multiple-Ascending-Dose (MAD) for Dose Determination
    • PK assessments will be collected at the time points specified in the Schedule of Events in Table 1 of the protocol.

    Part B – Dose Expansion
    •PK, muscle and skin biopsy, routine laboratory assessments and functional assessments will be collected at the time points specified in the Schedule of Events in Table 1 and Table 2 of the protocol.
    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 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
    Immunogenicity and Circulating Biomarker. Multiple-Ascending-Dose Study for Dose Determination, then Dose Expansion
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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
    Multiple-Ascending-Dose Study for Dose Determination, then Dose Expansion
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Canada
    United Kingdom
    United States
    Belgium
    Germany
    Italy
    Netherlands
    Spain
    E.8.7Trial has a data monitoring committee No
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months7
    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: 57
    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: 44
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 26
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    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 Yes
    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
    This study will be conducted in both ambulatory and nonambulatory patients, aged 7 to 21 years, inclusive, with DMD amenable to exon 51-skipping treatment.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 29
    F.4.2.2In the whole clinical trial 57
    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)
    Sponsor will assess the need for a potential long-term extension study of SRP-5051 at the conclusion of this trial.
    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 Decision2020-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-17
    P. End of Trial
    P.End of Trial StatusRestarted
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