Safety Study of Eteplirsen to Treat Early Stage Duchenne Muscular Dystrophy

Study Overview
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Brief Summary
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This is an open-label study to assess the safety, tolerability, efficacy and pharmacokinetics of eteplirsen in patients with early stage Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.

Detailed Description
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Safety, including adverse event monitoring and routine laboratory assessments, will be followed on an ongoing basis for all patients. Clinical efficacy, including functional tests and MRI, will be assessed at regularly scheduled study visits. Patients will undergo one baseline and one follow-up muscle biopsy. Population and serial PK will be collected.

Official Title
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An Open-Label, Multi-Center Study to Evaluate the Safety, Efficacy and Tolerability of Eteplirsen in Early Stage Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy (DMD)

Intervention / Treatment
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* Drug: eteplirsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male 4-6 years of age. Diagnosis of DMD, genotypically confirmed. Stable dose of oral corticosteroids for at least 12 weeks or has not received corticosteroids for at least 12 weeks. Intact right and left biceps muscles or two alternative upper arm muscle groups. Parent that is willing to provide consent and comply with study procedures. Exclusion Criteria: Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks that may have an effect on muscle strength or function (e.g., growth hormone, anabolic steroids). Previous or current treatment with any other experimental treatments within 12 weeks or participation in any other clinical trial within 6 months. Major surgery within 3 months prior to the first dose of study drug, or planned surgery during this study which would interfere with the ability to perform study activities. Presence of other clinically significant illness.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 6 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label<br>Approximately 20 patients will receive weekly infusions of eteplirsen 30 mg/kg . | Drug: eteplirsen<br>* Eteplirsen 30 mg/kg will be administered as an IV infusion once a week for 96 weeks.<br>* Other names: EXONDYS 51®;|
| No Intervention: Control Group<br>Approximately 20 patients with DMD not amenable to exon 51 skipping will be observed for 96 weeks. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Adverse Event (AE) was any untoward medical occurrence in a participant that did not necessarily have a causal relationship with the study drug. Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. Treatment emergent adverse events were events that developed or worsened during the on-treatment period (defined as time from first dose of study drug and up to 28 days after last dose of study drug [up to 100 weeks]) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events. | Baseline up to 100 weeks | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities Reported as TEAEs | Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of participants with at least one potentially clinically significant abnormal findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were clinically significant or not clinically significant. Clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care. | Baseline up to 100 weeks | 
| Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs | Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of participants with at least one potentially clinically significant abnormal vital signs findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were clinically significant or not clinically significant. Clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care. | Baseline up to 100 weeks | 
| Number of Participants With at Least One Abnormal Physical Examination Finding | Physical examinations, full and brief, were performed by the Investigator, a physician Sub-Investigator, or a Nurse Practitioner (if licensed in the state or province to perform physical examinations). Full physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; skin; lymph nodes; and musculoskeletal and neurological systems. Number of participants with at least one abnormal physical examination findings were reported. Abnormality in physical examinations was based on Investigator's discretion. | Baseline up to 100 weeks | 
| Number of Participants With Abnormalities in Electrocardiograms (ECGs) Reported as TEAEs | Twelve-lead ECGs and Holter ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the participant was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel. Number of participants with at least one abnormalities in ECGs were reported as TEAEs. | Baseline up to 96 weeks | 
| Number of Participants With Abnormalities in Echocardiograms (ECHO) Reported as TEAEs | Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. Cardiac function events included cardiomegaly, tachycardia, and dyspnoea. The ECHO was reviewed and interpreted by medically qualified personnel. Number of participants with at least one abnormalities in ECHO were reported as TEAEs. | Baseline up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Dystrophin Protein Levels Quantified by Western Blot at Week 48 and 96 | Change from baseline in dystrophin protein levels (in muscle biopsy samples) were determined by Western blot at Week 48 and 96 was reported. For each time point, 2 blocks of tissues were analyzed by Western blot, each with 2 replicates of gels to determine the dystrophin level as compared to a healthy individual (Percent Normal). The block average value from 2 replicate gels was computed. The overall average was calculated as the mean of the block average values. The overall average values were used for all analyses. In case only 1 gel was available for a block, then that value was used as the block average value. | Baseline, Week 48 and 96 | 
| Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 and 96 | Change from baseline in dystrophin intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry at Week 48 and 96 was reported. | Baseline, Week 48 and 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, Duchenne muscular dystrophy, eteplirsen, Dystrophin, exon 51