Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping MedDRA version: 20.0 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: SRP-4053
Product Code: SRP-4053
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not Available
Sponsors
Sarepta Therapeutics, Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
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 =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 450 msec. 5. A forced vital capacity (FVC) 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ; Secondary Objective: 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 ; 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. ; 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. ; 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 | — |
Countries
France, Italy, United Kingdom, United States
Contacts
Public ContactClinical Trial Operations
Voisin Consulting
Outcome results
None listed