Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients
Condition: Duchenne Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Intervention: AVI-4658 (Eteplirsen); Placebo
Intervention description: Treatment group 1 (n=4): 50.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 2 (n=4): 30.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 3 (n=4): matching placebo once weekly x 24 weeks via a 60-minute i.v. infusion; treatment group 3a will match two placebo subjects to 50.0 mg/kg eteplirsen; treatment group 3b will match two placebo subjects to 30.0 mg/kg eteplirsen; sterile, isotonic, clear, colorless phosphate buffered saline solution of eteplirsen at a concentration of 100 mg/mL in single-use vials containing a nominal volume of 1.0 mL without preservatives.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 12.0
Sex: Male
Minimum age: 7 Years
Maximum age: 13 Years
Healthy volunteers: No
Keywords: DMD

Summary:

      This study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics
      (PK) of AVI-4658 (eteplirsen) in both 50.0 mg/kg and 30.0 mg/kg doses administered over 24
      weeks in subjects diagnosed with Duchenne muscular dystrophy (DMD).
    

Eligibility criteria:

        Major Inclusion and Exclusion Criteria:

        Inclusion Criteria:

        A subject must meet all of the following criteria to be eligible for this study.

          -  Be a male with DMD and have an out-of-frame deletion(s) that may be corrected by
             skipping exon 51 [e.g., deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63],
             as confirmed in a Clinical Laboratory Improvement Act-accredited laboratory by any of
             the peer-reviewed and published methodology that evaluates all exons (including, but
             not limited to, multiplex ligation-dependent probe, comparative genomic hybridization,
             and single condition amplification/internal primer analysis).

          -  Be between the ages of 7 and 13 years, inclusive.

          -  Have stable cardiac function and stable pulmonary function (forced vital capacity
             [FVC] ≥50% of predicted and not require supplemental oxygen) that, in the
             Investigator's opinion, is unlikely to decompensate over the duration of the study.

          -  Be receiving treatment with oral corticosteroids and have been on a stable dose for at
             least 24 weeks before study entry. Subjects may be allowed to take other (non-RNA
             antisense or gene therapy) medication (including angiotensin-converting enzyme [ACE]
             inhibitors, β blockers, losartan potassium, and coenzyme Q) as long as they have been
             on a stable dose of the medication for 24 weeks before the screening visit (Visit 1)
             and the dose will remain constant throughout the study.

          -  Have intact right and left biceps muscles or an alternative upper arm muscle group.

          -  Achieve an average distance within 200m and 400m ±10% (i.e. within 180m and 440m)
             while walking independently over six minutes.

          -  Have a left ventricular ejection fraction (LVEF) of >40% based on the ECHO that is
             obtained at the screening visit (Visit 1). A subject who has abnormal ECHO findings
             but who has an LVEF of >40% may be enrolled in the study at the Investigator's
             discretion; however, the subject must have been receiving stable doses of ACE
             inhibitors or β blockers for at least 24 weeks before study entry.

          -  Have a parent(s) or legal guardian(s) who is able to understand and comply with the
             all of the study procedure requirements.

          -  Be willing to provide informed assent and have a parent(s) or legal guardian(s) who is
             willing to provide written informed consent for the subject to participate in the
             study.

        Exclusion Criteria:

        A subject who meets any of the following criteria will be excluded from this study.

          -  Use of any pharmacologic treatment, other than corticosteroids, that might have an
             effect on muscle strength or function within 12 weeks before study entry (e.g., growth
             hormone, anabolic steroids).

          -  Previous treatment with the experimental agents eteplirsen, BMN-195, or PRO051.

          -  Previous treatment with any other experimental agents or participation in any other
             DMD interventional clinical study within 12 weeks before entry into this study;
             including use of the shock training system or "STS," or planned use during this study.

          -  Surgery within 3 months before study entry or planned surgery at any time during this
             study.

          -  Presence of other clinically significant illness at the time of study entry, including
             significant renal dysfunction (as measured by urinary cystatin C, KIM-1, or urinary
             total protein), or average heart rate during screening Holter monitoring in excess of
             110 bpm (unless subsequently treated and confirmed controlled and stable on a
             β-blocker) or QTc >450 ms.

          -  Use of any aminoglycoside antibiotic within 12 weeks before the screening visit (Visit
             1) or need for use of an aminoglycoside antibiotic during the study (unless discussed
             and agreed with the Principal Investigator and medical monitor).

          -  Prior or ongoing medical condition that, in the Investigator's opinion, could
             adversely affect the safety of the subject or that makes it unlikely that the course
             of treatment or follow-up would be completed or could impair the assessment of study
             results.