Background of Duchenne Muscular Dystrophy. 21 5.2. Phosphorodiamidate Morpholino Oligomers (PMOs) for the Treatment of Duchenne Muscular Dystrophy 21 5.3. Clinical Experience with Eteplirsen 22 5.4. Rationale for the Current Study 22 6. STUDY OBJECTIVES 23 6.1. Primary Objective 23 6.2. CCI 7. INVESTIGATIONAL PLAN 24 7.1. Overall Study Design 24 7.2. Dose Selection Rationale 25 7.3. Study Endpoints 25 7.3.1. Safety Endpoints 25 7.3.2. CCI 7.4. Discussion of Study Design 26 8. SELECTION AND WITHDRAWAL OF PATIENTS 27 8.1. Number of Patients 27 8.2. Patient Inclusion Criteria 27 8.3. Patient Exclusion Criteria 28 8.4. Completion of a Patient’s Participation in the Study 28 8.5. Patient Withdrawal Criteria 29 8.6. Study Discontinuation 29 9. TREATMENT OF PATIENTS 31 9.1. Investigational Product 31 9.1.1. Packaging and Labeling 31 9.1.2. Storage 31 9.2. Treatments Administered 31 9.2.1. Dose Modification, Reduction, or Delay 32 9.3. Randomization and Blinding 32 9.4. Prior and Concomitant Medications 32 9.5. Treatment Compliance 33 10. STUDY ASSESSMENTS 34 10.1. Study Schedule of Events 34 10.2. Assessments at the Screening/Baseline Visits 34 10.2.1. Informed Consent 34 10.2.2. Medical History 34 10.2.3. Blood samples for DMD Genotyping and CCI 34 10.2.4. CCI 10.3. Safety Assessments 34 10.3.1. Physical Examination 34 10.3.2. Xxxxx Xxxxx and Weight 35 10.3.3. Clinical Laboratory Evaluations 35 10.3.4. Height and Ulnar Length 36 10.3.5. Electrocardiogram 36 10.3.6. Echocardiogram 36 10.3.7. Concomitant Medications and Therapies 36 10.3.8. Adverse Events 36 CCI CCI CCI CCI 10.4.6. Immunogenicity Assessment 38 11. ADVERSE EVENTS 39 11.1. Collection of Adverse Events 39 11.2. Definition of Adverse Events 39 11.2.1. Adverse Event (AE) 39
Background of Duchenne Muscular Dystrophy. Duchenne muscular dystrophy (DMD) is a rare (estimated incidence of 1 in 3,500 to 5,000 live male births; CDC 2009; Xxxxx 1991), degenerative, X-linked recessive genetic disorder caused by mutations in the dystrophin gene. In DMD, mutations in the dystrophin gene disrupt the open reading frame, resulting in an absence of functional dystrophin, a critically important part of the protein complex that connects the cytoskeletal actin of a muscle fiber to the extracellular matrix. In the absence of dystrophin, the stress of repeated muscle contraction causes cellular degeneration, regeneration, and inflammation, and, over time, myonecrosis. The progression of DMD follows a highly predictable course. Significant motor deficits may be present during the first year of life, but diagnosis is usually made between the ages of 3 to 5 years when toddlers begin to show functional symptoms (e.g., waddling gait, toe walking, and difficulty climbing stairs). Over time, ambulation becomes increasingly abnormal, and by 8 years of age, most patients lose the ability to rise from the floor and climb stairs, and often fall while walking. By 10 to 14 years of age, most lose the ability to walk. Upper limb, cardiac, and diaphragmatic muscles progressively weaken during adolescence. Historically, patients died from respiratory or cardiac failure in their late teens or early 20s (Xxxxxx 1989, Eagle 2002). Recent research suggests that use of ventilation support and steroids may increase life span by several years; however, DMD still has a mortality rate of 100% (Kohler 2009). There are currently no disease-modifying treatments for DMD. Existing interventions are largely supportive in nature and include bracing, muscle-stretching exercises to avoid onset of contractures, tendon-release surgery, and eventual wheelchair use and assisted ventilation. Current pharmacologic treatments, such as corticosteroids, focus on alleviation of symptoms, but do not address the underlying cause of the disease. Corticosteroids may prolong ambulation, delay the onset of scoliosis, and improve performance on some measures of clinical function (Beenakker 2005, Xxxxxx 2006, Pradhan 2006). However, their benefits are only temporary, and their use is often limited by numerous side effects, including growth inhibition, effects on pubertal changes, weight gain, behavioral changes, osteoporosis, Cushingoid facies and habitus, and cataracts (Biggar 2006, Manzur 2004).
