E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping |
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E.1.1.1 | Medical condition in easily understood language |
Duchenne muscular dystrophy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013801 |
E.1.2 | Term | Duchenne muscular dystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 ambulation, endurance, and muscle function as measured by change from Baseline at Week 144 on the 6-Minute Walk Test (6MWT) in treated and untreated patients - To assess the biological activity of SRP-4053 via dystrophin expression at Week 48 compared to pre-treatment. |
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E.2.2 | Secondary 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 PK of SRP-4053 administered weekly - To assess respiratory function in treated and untreated patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male aged 6 to 15 years, inclusive. 2. For treated patients (all patients in Part 1 and 12 additional treated patients in Part 2), established clinical diagnosis of DMD with a mutation 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 6MWT distance of ≥250 meters 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 Day 1 and 2) must be within 15% of the Screening mean (average of Screening Day 1 and 2). (Personal assistance or use of any assistive devices for ambulation is not permitted during the 6MWT). 7. Patients must meet at least 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 or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study. Note: patients are allowed to take other medication (excluding other ribonucleic acid [RNA] antisense or gene therapy agents) including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β-blockers, and potassium provided they have been on a stable dose for at least 12 weeks prior Week 1 and the dose is expected to remain constant throughout the study. 9. Have (a) parent(s) or legal guardian(s) who is (are) 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 (are) willing to provide written informed consent for the patient to participate in the study. |
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E.4 | Principal 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. Current or previous treatment with any other experimental treatments within 12 weeks prior to study entry. Untreated patients only can be enrolled concurrently in other non-interventional trials, or in interventional trials in which participants are known to be treated with standard-of-care medication, provided they do not interfere with study assessments performed in Study 4053-101, and the patient meets all the protocol-required entry criteria. 4. A left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional shortening) based on the screening ECHO and QTc (Fridericia’s correction) >450 msec. 5. A forced vital capacity (FVC) <50% of predicted value or requirement for nocturnal ventilation. 6. Major surgery within 3 months prior to Week 1 or orthopedic surgery planned for any time during this study which would interfere with the ability to perform outcome measures. 7. Planned 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, for example significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, behavioral disorder or malignancy. 9. Loss of ≥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 plantigrade 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PART 1: Safety of SRP-4053, assessed as follows: • Incidence of AEs • Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis) • Incidence of abnormalities in vital signs and physical examinations • Incidence of abnormalities on ECGs and ECHOs
PART 2: - Efficacy endpoint: change from Baseline at Week 144 in the 6MWT - Biological endpoint: change from Baseline at Week 48 in dystrophin protein levels determined by Western blot. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PART 1: • AEs: Continuous evaluation • Laboratory abnormalities: Screening (-6 to -4), Baseline (-2 to -1), weekly from Week 1 to 9, Week 12 • Vital signs : Screening (-6 to -4), Baseline (-2 to -1), weekly from Week 1 to 12 • Physical examinations: Screening (-6 to -4), Week 1, 4, 8, and 12 • ECG: Screening, Baseline, Week 12 • ECHO: Screening, Week 12
PART 2: - Efficacy endpoint: • 6-Minute Walk Test (6MWT): Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Weeks 12, 24, 36, 48, 72, 96, 120, 144 - Biological endpoint: • Western blot: Baseline (-2 to -1), Week 48 |
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E.5.2 | Secondary end point(s) |
PART 1&2: - Pharmacokinetic (PK) parameters: • 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), for part 1 only
PART2: - Efficacy endpoint: change from Baseline through Week 144 in forced vital capacity percent predicted (FVC%p)
- Biological endpoint: change from Baseline at Week 48 for the following: • Dystrophin intensity levels determined by immunohistochemistry (IHC) • Percentage of dystrophin-positive fibers as determined by IHC • Exon 53 skipping determined by measurement and sequence verification of exon 53 skipped mRNA.
- 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) • Immunogenicity. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PARTS 1&2: -PK: Part1: W1,3,5,7,12 Part2 treated: W1,24,48,96,144
PART 2: -Efficacy: Screening, Baseline, W12,24,36,48,72,96,120,144 -Biological: Baseline, W48
-Safety: •AEs: continuous •Lab.: Treated: Screening, Baseline, W1 to 4, 8,12,16,20,24,36,48,60,72,84,96,108,120,132,144,FU Untreated: Screening, Baseline, W12, 24, 36, 48, 72, 96, 120, 144 •Vital signs: Treated: Screening, Baseline, every week until FU Untreated: Screening, Baseline, W12,24,36,48,72,96,120,144 •Physical exam.: Treated: Screening, W1,4,8,12,16,20,24,36,48,60,72,84,96,108,120,132,144,FU Untreated: Screening, W12,24,36,48, 72, 96, 120, 144 •ECG: Screening, Baseline, W12,24,36,48,72,96,120,144 •ECHO: Screening, W24,48,72,96,120,144 •Immunogenicity: Baseline, W1(treated),24,48,72,96,120,144 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Study Part 1 : Double blind - Study Part 2 : Open |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Study Part 1 : Placebo ; Study Part 2 : Untreated control group |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |