Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Efficacy, Safety, Tolerability and Pharmacokinetics Study of AVI-4658(Eteplirsen),in the Treatment of Ambulant Subjects With Duchenne Muscular Dystrophy
Brief 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).


Options:
A: Inclusion Criteria:

* Duchenne muscular dystrophy patients of all ages
* Null mutation of the dystrophin gene or muscle with \<5% dystrophin
* Doppler echocardiogram with ejection fraction (EF) \<55% within 30 days of enrollment
* Ability to cooperate for testing
* Glucocorticoid treatment acceptable including daily or weekend administration of prednisone or deflazacort

Exclusion Criteria:

* Patients with EF 55% or greater
* Patients with EF \<40% after washout
* Patients taking \>5 mg lisinopril, or \>25 mg losartan or \>5 mg enalapril
* Skeletal deformities or pulmonary anatomical variants that preclude consistent measures of Doppler echocardiography
B: Inclusion Criteria:

* Patient has ACC/AHA Stage C heart failure and remains in NYHA Class III - ambulatory Class IV despite optimal medical therapy.
* ACE inhibitor or ARB (Angiotensin Receptor Blocks) at least 30 days preceding implant or nitrate/hydralazine at the investigators discretion
* Beta-blocker for at least 90 days and stable for 30 days preceding implant
* Patient has left ventricular ejection fraction (LVEF) ≤ 35%
* Patient has had Cardiac Resynchronization Therapy (CRT) for at least 90 days prior to enrollment or is not indicated for a CRT device
* Patient has had an implanted cardio-defibrillator (ICD) at least 30 days prior to enrollment or is not indicated for ICD implantation.
* Patient is at least 18 years of age and not older than 75 years
* Patient six minute hall walk assessment between 100-350 meters
* Patient understands the nature of the procedure, is willing to comply with associated follow-up evaluations, and provide written informed consent prior to the procedure

Exclusion Criteria:

* Patient has any evidence of:

  * Ascending aortic calcification on posterior-anterior or lateral chest x-ray at initial screening OR
  * Atherosclerotic ascending aortic disease, specifically intimal thickening greater than 3mm or mobile atheroma (moderate) or mural calcification (severe) as detected by CT scan or echocardiography (Echo)
* Patient has ascending aorto-coronary artery bypass grafts, history of aortic dissection, Marfans disease or other connective tissue disorder or has had an aortic root replacement
* Patient aorta not conforming to specified dimensional constraints defined by CT scan, most specifically mid ascending aortic outside diameter less than 29mm or greater than 40mm
* Patient has severe mitral valve incompetence, grade 4+
* Patient has moderate to severe aortic valve incompetence, grade 2-4+
* Patient has systolic blood pressure less than 90 or greater than 140 mmHg
* Patient has a Serum Sodium less than 130 mEq/L
* Patient has a Estimated Glomerular Filtration Rate (GFR) less than 40 ml/min/1.73m2
* Patient has any two of three of Bilirubin, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) greater than three times upper limit of normal
* Patient has a serum Albumin less than 3.0 g/dL
* Patient has Body Mass Index (BMI) less than 18 or greater than 40 kg/m2
* Men with Peak Oxygen Uptake (VO2) of greater than 18 ml/kg/min or less than 10 ml/kg/min OR -Women with Peak VO2 of greater than 16 ml/kg/min or less than 9 ml/kg/min
* Patient has any active infection
* Patient has had a myocardial infarction (MI), stroke, transient ischemic attack (TIA), cardiac or other major surgery, in the 90 days prior to enrollment
* Patient has severe Chronic Obstructive Pulmonary Disease (COPD) as evidenced by Forces Expiratory Volume (FEV1) less than or equal to 0.9 L/min
* Patient requires a concomitant surgical procedure \[i.e. coronary artery bypass graft (CABG), Valve repair\]
* Patient is supported with a left ventricular assist device or IABP
* Severe Right Heart Dysfunction with systemic venous congestion evidenced by clinical signs/symptoms such as Central Venous Pressure (CVP) ≥ 20 mmHg, Cardiac Index (CI) \< 2.0 l/min./m2, elevated liver function tests beyond three time the upper limit of normal and presence of ascites
* Patient has reversible causes of heart failure that may be remedied by conventional surgery or other intervention
* Patient is pregnant; Note: Negative pregnancy test required in all women of child bearing potential
* Patient has any other condition that, in the opinion of the investigators, would disqualify the patient for inclusion in the study, limits survival to less than one year, or not permit valid consideration
* Patient is currently enrolled or has participated in the last 30 days in another therapeutic or interventional clinical study that is likely to confound study results
* Patient has symptomatic Carotid artery disease or asymptomatic disease with a stenosis greater than 70%.
C: 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.
D: Inclusion Criteria:

1. DBMD as determined by either a skeletal muscle biopsy demonstrating absence or lack of dystrophin, and/or genetic testing showing a mutation in the dystrophin gene predictive of DBMD, as well as a consistent physical examination
2. Male gender
3. Age greater than or equal to 18 years
4. Cardiac dysfunction with ejection fraction less than or equal to 50% as determined by echocardiogram, cardiac MRI, or multi-gated acquisition (MUGA) scan
5. On a stable dose of ACE-inhibitor or angiotensin receptor blocker (ARB) for at least 3 months; beta-adrenergic receptor blockers and glucocorticosteroids are not required but if used, a stable dose for at least 3 months is required.
6. Ability of the subject or legal guardian to provide informed consent
7. Ability to adhere with study follow-up
8. Willingness to abstain from food and alcohol for 8 hours prior to FMD

Exclusion Criteria:

1. Use of nitrates or alpha-adrenergic receptor blockers
2. Known intolerance or allergy to sildenafil, or a history of any severe allergic or anaphylactic reactions
3. Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable
4. Known hereditary retinal disorder such as retinitis pigmentosa
5. History of priapism or conditions that may predispose to priapism such as sickle cell anemia, multiple myeloma, or leukemia
6. Bleeding disorders
7. Active tobacco use
8. Chronic atrial fibrillation or frequent arrhythmia that would result in an irregular pulse
9. Factors that would preclude obtaining an MRI study - (e.g. implantable pacemaker or cardioverter-defibrillator; body habitus cannot fit into scanner)
10. Systolic blood pressure (SBP) less than 85 mmHg at baseline evaluation
11. Chronic kidney disease stages 4 and 5: GFR\< 30 mL/min/1.73 m2 as determined by serum cystatin C level and the equation eGFRcys = 76.7 x (serum cystatin C-1.18)
12. Current use of sildenafil.

Answer: C