Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy of SRP-4045 (casimersen) and SRP-4053 (golodirsen) compared to placebo in participants with DMD with out-of-frame deletion mutations amenable to skipping exon 45 and exon 53, respectively.

Detailed Description
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This is a double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of SRP-4045 and SRP-4053. Eligible participants with out-of-frame deletion mutations amenable to exon 45 or 53 skipping will be randomized to receive once weekly intravenous (IV) infusions of 30 milligrams/kilograms (mg/kg) SRP-4045 or 30 mg/kg SRP-4053 respectively (combined-active group) or placebo for up to 96 weeks (the placebo-controlled period of the trial). This will be followed by an open-label extension period in which all participants will receive open-label active treatment for 48 weeks (up to Week 144 of study). The study will enroll approximately 222 participants. Twice as many participants will be randomized to receive active treatment as will receive placebo (2:1 randomization). Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests, such as the 6-minute walk test (6MWT). All participants will undergo a muscle biopsy at baseline and a second muscle biopsy either at Week 48 or Week 96. Safety will be assessed through the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations throughout the study. Blood samples will be taken periodically throughout the study to assess the pharmacokinetics of both drugs.

Official Title
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A Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: SRP-4045
* Drug: SRP-4053
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genotypically confirmed DMD, with genetic deletion amenable to exon 45 or exon 53 skipping Stable dose of oral corticosteroids for at least 24 weeks prior to Week 1, and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight). Intact right and left biceps or 2 alternative upper muscle groups Mean 6MWT ≥300 meters and ≤450 meters Stable pulmonary function: forced vital capacity (FVC) ≥50% predicted Exclusion Criteria: Treatment with gene therapy at any time Previous treatment with SMT C1100 within 1 week prior to Week 1 and previous treatment with PRO045 (BMN 045), PRO053 (BMN 053), or PRO051 (BMN 051) within 24 weeks prior to Week 1 Current or previous treatment with any other experimental treatment within 12 weeks prior to Week 1 Major surgery within 3 months prior to Week 1 Presence of other clinically significant illness Other inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 13 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SRP-4045<br>Participants amenable to exon 45 skipping will receive SRP-4045 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study). | Drug: SRP-4045<br>* SRP-4045 solution for IV infusion<br>* Other names: AMONDYS 45;|
| Experimental: SRP-4053<br>Participants amenable to exon 53 skipping will receive SRP-4053 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study). | Drug: SRP-4053<br>* SRP-4053 solution for IV infusion<br>* Other names: VYONDYS 53;|
| Placebo Comparator: Placebo followed by SRP-4045 or SRP-4053<br>Participants amenable to exon 45 or 53 skipping will receive SRP-4045 or SRP-4053 placebo-matching IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 or SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study). | Drug: SRP-4045<br>* SRP-4045 solution for IV infusion<br>* Other names: AMONDYS 45;Drug: SRP-4053<br>* SRP-4053 solution for IV infusion<br>* Other names: VYONDYS 53;Drug: Placebo<br>* SRP-4045 or SRP-4053 placebo-matching solution for IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Distance Walked During 6MWT at Week 96 |  | Baseline, Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the Total Distance Walked During 6MWT at Week 144 (Week 48 of the Open-Label Extension Period) |  | Baseline, Week 144 | 
| Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96 |  | Baseline, Week 48 or Week 96 | 
| Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96 |  | Baseline, Week 48 or Week 96 | 
| Participant's Ability to Rise Independently From the Floor, as indicated by a North Star Ambulatory Assessment (NSAA) Subscore | The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, the participant's ability to rise independently from the floor (without external support) will be reported as an NSAA subscore of 2 (without modification) or 1 (Gower's maneuver). | Week 96, Week 144 | 
| Time to Loss of Ambulation (LOA) |  | Baseline, Week 96, and Week 144 | 
| Change From Baseline in the NSAA Total Score at Week 96 and Week 144 | The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, participants will be asked to perform 17 different functional activities, including a 10 meter walk/run, rising from a sit to standing, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. Participants will be graded as follows: 2 = achieves goal without any assistance; 1 = modified method but achieves goal independent of physical assistance from another person; and 0 = unable to achieve goal independently. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function. | Baseline, Week 96 and Week 144 | 
| Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 96 and Week 144 |  | Baseline, Week 96 and Week 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne muscular dystrophy, Exon Skipping, DMD, Exon 53, Exon 45, Ambulatory, Pediatric, Duchenne