A Study to Compare Safety and Efficacy of a High Dose of Eteplirsen in Participants With Duchenne Muscular Dystrophy (DMD) (MIS51ON)

Study Overview
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Brief Summary
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This study will be comprised of 2 parts: Part 1 (dose escalation) will be conducted to evaluate the safety and tolerability of 2 doses (100 milligrams/kilogram [mg/kg] and 200 mg/kg) of eteplirsen in approximately 10 participants with DMD; Part 2 (dose finding and dose comparison) will be conducted for the selection of a high dose (100 mg/kg versus 200 mg/kg) and its comparison with the 30 mg/kg dose of eteplirsen, in approximately 144 participants with genetically confirmed deletion mutations amenable to treatment by skipping exon 51.

Official Title
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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

Conditions
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Muscular Dystrophy, Duchenne

Intervention / Treatment
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* Drug: Eteplirsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Ambulatory participant, able to perform TTRISE in 10 seconds or less at the time of screening visit. Able to walk independently without assistive devices. Have intact right and left biceps muscles or an alternative upper arm muscle group. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 12 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 the recently published guidelines throughout the study. For ages 7 years and older, has stable pulmonary function (forced vital capacity ≥50 percent (%) of predicted and no requirement for nocturnal ventilation). For ages 4 to 6 years, does not require support from ventilator or non-invasive ventilation at time of screening. Exclusion Criteria: Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to randomization. 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 in the last 12 weeks prior to first dose; Drisapersen in the last 36 weeks prior to first dose; Suvodirsen in the last 12 weeks prior to first dose; Vamorolone in the last 12 weeks prior to first dose; and Eteplirsen (previous or current use). Major surgery within 3 months prior to randomization. Presence of any other significant neuromuscular or genetic disease other than DMD. Presence of any known impairment of renal function and/or other clinically significant illness. Has evidence of cardiomyopathy, as defined by left ventricular ejection fraction less than <50% on the screening echocardiogram or Fridericia's correction formula (QTcF) ≥450 millisecond based on the screening electrocardiograms (ECGs). Other inclusion/exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 4 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: Part 1: Eteplirsen<br>Participants will receive eteplirsen 100 mg/kg once weekly for at least 4 weeks, followed by eteplirsen 200 mg/kg once weekly for at least 4 weeks. | Drug: Eteplirsen<br>* Solution for intravenous (IV) infusion.<br>* Other names: EXONDYS;|
| Active Comparator: Part 2: Eteplirsen 30 mg/kg<br>Randomized participants will receive eteplirsen 30 mg/kg once weekly for up to 144 weeks. | Drug: Eteplirsen<br>* Solution for intravenous (IV) infusion.<br>* Other names: EXONDYS;|
| Experimental: Part 2: Eteplirsen 100 mg/kg<br>Randomized participants will receive eteplirsen 100 mg/kg once weekly before the selection of the high dose occurs and then will receive the selected high dose once weekly for up to 144 weeks. | Drug: Eteplirsen<br>* Solution for intravenous (IV) infusion.<br>* Other names: EXONDYS;|
| Experimental: Part 2: Eteplirsen 200 mg/kg<br>Randomized participants will receive eteplirsen 200 mg/kg once weekly before the selection of the high dose occurs and then will receive the selected high dose once weekly for up to 144 weeks. | Drug: Eteplirsen<br>* Solution for intravenous (IV) infusion.<br>* Other names: EXONDYS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Incidence of Adverse Events (AEs) |  | Up to Week 148 | 
| Part 2: Change From Baseline in the NSAA Total Score at Week 144 |  | Baseline, Week 144 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Change From Baseline in Time to Rise From the Floor, Time to Complete 10-Meter Walk/Run, and the Timed Stair Ascend Test |  | Baseline, Week 144 | 
| Part 2: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) |  | Baseline, Week 144 | 
| Part 2: Change from Baseline in Forced Vital Capacity Percent Predicted (FVC%p) at Week 144 |  | Baseline, Week 144 | 
| Part 2: Time to Loss of Ambulation (LOA) |  | Baseline up to Week 144 | 
| Part 2: Change From Baseline in Skeletal Muscle Dystrophin Expression |  | Baseline, Postdose (at Week 24, Week 48, or Week 144) | 
| Part 2: Incidence of Adverse Events (AEs) |  | Baseline up to Week 148 | 
| Part 2: Pharmacokinetic (PK) Plasma Concentration of Eteplirsen |  | 0 (predose) to 2 hours postdose up to Week 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, Duchenne muscular dystrophy, Exon Skipping, Exon 51, North Star Ambulatory Assessment, Ambulatory, Pediatric, Duchenne, EXONDYS, MIS51ON