Clinical trial NCT02286947
Conditions: Muscular Dystrophy, Duchenne
Keywords: DMD exon 51 dystrophin dystrophy eteplirsen Duchenne
Sponsor: Sarepta Therapeutics, Inc.
Start date: 2014-11-01; Completion date: 2018-03-23
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to explore safety and tolerability of eteplirsen in participants with advanced stage Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.

Detailed description:
This is an open-label, multi-center study to explore the safety and tolerability of eteplirsen injection in participants with advanced stage DMD with confirmed genetic mutations amenable to treatment by exon 51 skipping.

Participants will be evaluated for inclusion during a Screening/Baseline period of up to 4 weeks. Eligible participants will receive once weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for 96 weeks, followed by a safety extension (not to exceed 48 weeks).

Safety will be regularly assessed throughout the study via the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations.

Arms: arm 1: Participants will receive eteplirsen 30 mg/kg/week intravenous (IV) infusions, weekly, for up to 96 weeks.
Interventions: intervention 1: Eteplirsen
Intervention descriptions: intervention 1: Eteplirsen solution for IV infusion

Protocol documents:
Prot_000.pdf: 
Sarepta Therapeutics, Inc.
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CLINICAL STUDY PROTOCOL
DRUG:
Eteplirsen (Eteplirsen Injection)
STUDY NUMBER:
4658-204
STUDY TITLE:
An Open-Label, Multi-Center Study to Evaluate the Safety 
and Tolerability of Eteplirsen in Patients with Advanced 
Stage Duchenne Muscular Dystrophy
IND NUMBER:
SPONSOR:
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA
Phone: +1-617-274-4000
CURRENT VERSION DATE:
Amendment 1, 05 July 2016
PRIOR VERSION DATE:
Original, 30 June 2014
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INVESTIGATOR’S AGREEMENT
I have read Study No. 4658-204 Amendment 1 and agree to conduct the study as outlined. I
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol.
Printed Name of Investigator
Signature of Investigator
Date


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PROCEDURES IN CASE OF EMERGENCY
Table 1:
Emergency Contact Information
Role in Study
Name
Address and Telephone number
Responsible Physician
, MD, PhD
Sarepta Therapeutics, Inc.
215 First Street
Cambridge, MA 02142
Telephone:
Mobile: 
PPD
PPD
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1.
SYNOPSIS
NAME OF COMPANY
Sarepta Therapeutics Inc.
215 First Street
Cambridge, MA 02142 USA
Phone: +1-617-274-4000
NAME OF FINISHED PRODUCT
Eteplirsen Injection
NAME OF ACTIVE INGREDIENT
Eteplirsen
TITLE: An Open-Label, Multicenter Study to Evaluate the Safety and Tolerability of Eteplirsen in 
Patients with Advanced Stage Duchenne Muscular Dystrophy
Study Number: 4658-204
Phase of Study: Phase 2
INVESTIGATOR STUDY SITES: This study will be conducted at approximately 10 sites in the 
United States.
OBJECTIVES:
The primary objective of this study is to explore safety and tolerability of eteplirsen in patients with 
advanced stage Duchenne muscular dystrophy (DMD) patients who are amenable to exon 51 skipping.
METHODOLOGY:
This is an open-label, multi-center study to explore the safety and tolerability of eteplirsen injection in 
patients with advanced stage DMD with confirmed genetic mutations amenable to treatment by exon 51
skipping.
Patients will be evaluated for inclusion during a Screening/Baseline period of up to 4 weeks. Eligible 
patients will receive once weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for 96 weeks, 
followed by a safety extension (not to exceed 48 weeks), until the product is commercially available or 
until patients can transition into a separate eteplirsen study.
Safety will be regularly assessed throughout the study via the collection of adverse events (AEs), 
laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical 
examinations.
DURATION OF STUDY:
Screening/Baseline Period:  Up to approximately 4 weeks
Treatment Period:  96 weeks 
Safety Extension Period: Up to 48 additional weeks until product is commercially available or until 
patients can transition into a separate eteplirsen study.
Safety Follow-up Period: Four weeks following last infusion (as applicable) 
Total patient participation:  Up to 148 weeks 
NUMBER OF PATIENTS: Approximately 20 patients will be enrolled in this study.
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NAME OF COMPANY
Sarepta Therapeutics Inc.
215 First Street
Cambridge, MA 02142 USA
Phone: +1-617-274-4000
NAME OF FINISHED PRODUCT
Eteplirsen Injection
NAME OF ACTIVE INGREDIENT
Eteplirsen
INCLUSION/EXCLUSION CRITERIA:
Inclusion Criteria: 
A patient must meet all of the following criteria to be eligible for this study.
1.
Be a male with DMD with a mutation that may be amenable to exon 51 skipping (e.g., deletions 
of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63) as documented by a genetic report from an 
accredited laboratory confirming mutation endpoints by multiplex ligation-dependent probe 
amplification (MLPA) or sequencing.
2.
Be between 7 and 21 years of age.
3.
Has been on a stable dose of oral corticosteroids for at least 24 weeks prior to study drug 
administration and the dose is expected to remain constant (except for modifications to 
accommodate changes in weight) throughout the study, or has not received corticosteroids for at 
least 24 weeks prior to study drug administration and does not expect to start corticosteroids 
throughout the study. 
4.
5.
Has a score of ≤4 on the Brooke Score for Arms and Shoulders. 
6.
Has cardiac and pulmonary function that, in the opinion of the investigator, is unlikely to 
decompensate over the study period.
7.
Patients who are post-pubertal and sexually active must agree to use, for the entire duration of 
the study and for 90 days post last dose, a male condom and the female sexual partner must also 
use a medically acceptable form of birth control (e.g., oral contraceptives).
8.
Able to understand and comply with all study requirements, in the Investigator’s opinion, or if 
under the age of 18 years, must have a parent(s) or legal guardian(s) who is able to understand
and comply with all the study requirements.
9.
Willing to provide informed consent to participate in the study, or if under the age of 18 years, 
be willing to provide informed assent, if applicable, and have a parent(s) or legal guardian(s) 
who is willing to provide written informed consent for the patient to participate in the study.
Exclusion Criteria
A patient who meets any of the following criteria will be excluded from this study.
1.
Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks of study drug 
administration that in the opinion of the Investigator might have an effect on muscle strength or 
function (e.g., growth hormone, anabolic steroids).
2.
Previous treatment with SMT C1100/BMN 195 at any time. 
3.
Previous treatment with drisapersen (PRO051) within the last 6 months. Participation in any 
other DMD interventional clinical study within 12 weeks of study drug administration, or use of 
the shock training system or “STS,” or planned use during this study. Concurrent participation 
in an interventional clinical study or observational trial is not permitted. 
4.
Major change in physiotherapy regimen within the past 3 months or expected change over the 
study period.
5.
Major surgery within 3 months of study drug administration or planned major surgery for any 
time during this study.
6.
Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, 
renal, hematologic, immunologic, behavioral disease or malignancy.
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NAME OF COMPANY
Sarepta Therapeutics Inc.
215 First Street
Cambridge, MA 02142 USA
Phone: +1-617-274-4000
NAME OF FINISHED PRODUCT
Eteplirsen Injection
NAME OF ACTIVE INGREDIENT
Eteplirsen
7.
Systemic use of any aminoglycoside antibiotic within 12 weeks of study drug administration or 
anticipated need for use of an aminoglycoside antibiotic or statin during the study.
8.
.
9.
Must not require antiarrhythmic and/or antidiuretic therapy for heart failure. Patients are 
allowed to take other medication including angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin receptor blocking agents (ARBs), β blockers or potassium, provided they have been 
on a stable dose for 24 weeks prior to study drug administration and the dose is expected to 
remain constant throughout the study.
10.
.
11. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the 
safety of the patient, make it unlikely that the course of treatment would be completed, or impair 
the assessment of study results.
DOSE/ROUTE/REGIMEN (TEST ARTICLE):
Eteplirsen 30 mg/kg will be administered as an IV infusion over approximately 35-60 minutes once a 
week for up to 96 weeks, followed by a safety extension (not to exceed 48 weeks), until the product is 
commercially available or until patients can transition into a separate eteplirsen study.
REFERENCE TREATMENT:
None
CRITERIA FOR EVALUATION:
Safety Endpoints
The incidence of the following:
x
Adverse events
x
Clinical laboratory abnormalities
x
Abnormalities in vital signs and physical examinations
x
Abnormalities on ECGs and ECHOs
Exploratory Endpoints:
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NAME OF COMPANY
Sarepta Therapeutics Inc.
215 First Street
Cambridge, MA 02142 USA
Phone: +1-617-274-4000
NAME OF FINISHED PRODUCT
Eteplirsen Injection
NAME OF ACTIVE INGREDIENT
Eteplirsen
SAMPLE SIZE:
There is no formal sample size calculation. The sample size is based on qualitative considerations and is 
sufficient to provide safety evaluation of eteplirsen in the studied population.
STATISTICAL METHODS:
Safety Analyses
Treatment emergent adverse events (TEAEs) will be summarized by system organ class (SOC) and 
preferred term (PT). Non-emergent events will be recorded in the data listings. For all AE tables, the 
number and percentage of patients reporting AEs will be grouped by the Medical Dictionary for 
Regulatory Activities (MedDRA) SOC and PT.
Descriptive statistics for ECG, ECHO, vital signs, and clinical laboratory parameters will be generated.
Summary statistics for each parameter at the specific visits, as well as the change from Baseline to that 
visit, will also be displayed. All safety data will be presented in data listings.
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Footnotes for Table 2 Schedule of Events: Screening through Week 48
Functional assessments, 
, ECG, Holter ECG, and ECHO have a ±2 weeks window 
a For infusion visits, vital signs are to be collected within approximately 30 minutes prior to infusion and approximately 5, 30, and 60 minutes after the end of the 
infusion. If the patient has not experienced an infusion reaction after the first year of treatment, vital signs may be collected only 30 minutes after the end of the 
infusion.
b Blood samples for the safety laboratory assessments must be obtained within 2 weeks prior to the Baseline/Week 1 visit, and results must be available prior to 
dosing at Baseline/Week 1. If more than 2 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, it must be 
repeated. If less than 2 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, additional safety laboratory 
assessments do not need to be performed.
c Patients may start dosing based on local genotyping results provided that these results fulfill the required inclusion criteria; however, all patients must undergo 
genetic testing to confirm the exon 51 skippable mutation and 
.
.
f Screening ECG, Holter ECG, and ECHO may be performed at any time during the Screening period; however results must be available on Day 1, prior to dosing.
g In the event of early termination prior to Week 96, the Week 96 assessments should be completed as the Early Termination Visit.
h End of Study visit should occur within 4 weeks after last dose
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Footnotes for Table 2 Schedule of Events: Week 52 through End of Study
Functional assessments, 
, ECG, Holter ECG, and ECHO have a ± 2 weeks window 
a For infusion visits, vital signs are to be collected within approximately 30 minutes prior to infusion and approximately 5, 30, and 60 minutes after the end of the 
infusion. If the patient has not experienced an infusion reaction after the first year of treatment, vital signs may be collected only 30 minutes after the end of the 
infusion.
b Blood samples for the safety laboratory assessments must be obtained within 2 weeks prior to the Baseline/Week 1 visit, and results must be available prior to 
dosing at Baseline/Week 1. If more than 2 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, it must be
repeated. If less than 2 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, additional safety laboratory 
assessments do not need to be performed.
c Patients may start dosing based on local genotyping results provided that these results fulfill the required inclusion criteria; however, all patients must undergo 
genetic testing to confirm the exon 51 skippable mutation and 
.
d
e
.
f Screening ECG, Holter ECG, and ECHO may be performed at any time during the Screening period; however results must be available on Day 1, prior to 
dosing.
g In the event of early termination prior to Week 96, the Week 96 assessments should be completed as the Early Termination visit.
h End of Study visit should occur within 4 weeks after last dose
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3.
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS
SIGNATURE PAGE FOR SPONSOR............................................................................................2 
INVESTIGATOR’S AGREEMENT...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY...............................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
SCHEDULE OF EVENTS...........................................................................................9 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION......................................................................................................21 
5.1. 
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. 
 
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. 
 
7.4. 
Discussion of Study Design........................................................................................26 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS..............................................27 
8.1. 
Number of Patients .....................................................................................................27 
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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 
...........................................34 
10.2.4. 
 
10.3. 
Safety Assessments.....................................................................................................34 
10.3.1. 
Physical Examination .................................................................................................34 
10.3.2. 
Vital Signs 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 
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10.3.7. 
Concomitant Medications and Therapies ...................................................................36 
10.3.8. 
Adverse Events...........................................................................................................36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
11.2.2. 
Serious Adverse Event (SAE) ....................................................................................39 
11.3. 
Classification of Adverse Events................................................................................40 
11.3.1. 
Relationship to Investigational Product......................................................................40 
11.3.2. 
Relationship to Study Procedures...............................................................................40 
11.3.3. 
Relationship to Underlying Disease ...........................................................................41 
11.3.4. 
Severity of Adverse Events ........................................................................................41 
11.3.5. 
Outcome......................................................................................................................41 
11.3.6. 
Action Taken Regarding the Investigational Drug Product .......................................41 
11.3.7. 
Expectedness of an Adverse Event.............................................................................41 
11.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ...................................41 
11.4. 
Recording Adverse Events .........................................................................................42 
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11.5. 
Reporting Serious Adverse Events.............................................................................42 
11.6. 
Special Situations........................................................................................................42 
11.6.1. 
Overdose.....................................................................................................................42 
11.6.2. 
Death...........................................................................................................................42 
11.6.3. 
Responsibilities of the Investigator ............................................................................42 
11.6.4. 
Responsibilities of the Sponsor ..................................................................................43 
12. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT..........44 
12.1. 
Recording of Data.......................................................................................................44 
12.2. 
Quality Assurance.......................................................................................................44 
12.3. 
Retention of Study Documents...................................................................................44 
13. 
STATISTICS..............................................................................................................46 
13.1. 
General Considerations...............................................................................................46 
13.2. 
Determination of Sample Size....................................................................................46 
13.3. 
Analysis Sets...............................................................................................................46 
13.4. 
Protocol Deviations ....................................................................................................46 
13.5. 
Disposition, Demographics, and Baseline Characteristics .........................................47 
13.6. 
Medical History ..........................................................................................................47 
13.7. 
Dosing and Compliance..............................................................................................47 
13.8. 
Safety Analysis...........................................................................................................47 
13.8.1. 
Safety Variables..........................................................................................................47 
13.8.2. 
Safety Analyses ..........................................................................................................47 
13.8.2.1. 
Adverse Events...........................................................................................................47 
13.8.2.2. 
Physical Examination, Vital Signs, Weight, and Height/Ulnar Length .....................48 
13.8.2.3. 
Clinical Laboratory Tests ...........................................................................................48 
13.8.2.4. 
Electrocardiograms and Holter Electrocardiograms...................................................48 
13.8.2.5. 
Echocardiograms ........................................................................................................49 
13.8.2.6. 
Prior and Concomitant Medications and Physiotherapeutic Interventions.................49 
13.9. 
 
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13.9.1. 
 
13.9.2. 
 
13.10. 
Interim Analysis..........................................................................................................49 
13.11. 
Other Statistical Issues................................................................................................50 
14. 
SPECIAL REQUIREMENTS AND PROCEDURES................................................51 
14.1. 
Compliance with Ethical and Regulatory Guidelines.................................................51 
14.2. 
Institutional and Ethics Review..................................................................................51 
14.3. 
Informed Consent/Assent and Authorization for Use and Disclosure of 
Protected Health Information .....................................................................................51 
14.4. 
Compliance with the Protocol ....................................................................................51 
14.5. 
Confidentiality............................................................................................................52 
14.5.1. 
Data.............................................................................................................................52 
14.5.2. 
Patient Confidentiality................................................................................................52 
15. 
STUDY DOCUMENTATION AND GENERAL INFORMATION.........................53 
15.1. 
Essential Study Documents ........................................................................................53 
15.2. 
General Information....................................................................................................53 
15.3. 
Dissemination of Study Results..................................................................................53 
15.4. 
Product Handling and Complaints Reporting.............................................................53 
16. 
LIST OF REFERENCES............................................................................................54 
LIST OF TABLES
Table 1: 
Emergency Contact Information...................................................................................4 
Table 2: 
Treatment Period ..........................................................................................................9 
Table 3: 
Safety Extension.........................................................................................................13 
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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
2D
2 dimensional
ACE
angiotensin-converting enzyme
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ARB
angiotensin receptor blocking agent
AST
aspartate aminotransferase
BMD
Becker muscular dystrophy
BMI
body mass index
BUN
blood urea nitrogen
CD
compact disc
CFR
Code of Federal Regulations
CK
creatine kinase
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CS
clinically significant
CSR
clinical study report
DMD
Duchenne muscular dystrophy
DNA
deoxyribonucleic acid
ECG(s)
electrocardiogram(s)
ECHO(s)
echocardiogram(s)
EDC
electronic data capture
EF
ejection fraction
ET
early termination
GCP
Good Clinical Practices
GGT
gamma-glutamyl transferase
HEENT
head, ears, eyes, nose, throat
HIPAA
Health Insurance Portability and Accountability Act
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Abbreviation
Definition
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IV
intravenous, intravenously
KIM-1
kidney injury molecule-1
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction
MedDRA®
Medical Dictionary for Regulatory Activities®
MPLA
multiplex ligation-dependent probe amplification
mRNA
messenger ribonucleic acid
NCS
Not clinically significant
PMO
phosphorodiamidate morpholino oligomer
PT
Preferred Term
RBC
red blood cells
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
System Organ Class
STS
shock training system
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
US FDA
United States Food and Drug Administration
WBC
white blood cell
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5.
INTRODUCTION
5.1.
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; Emery 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 (Brooke 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, Biggar 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).
5.2.
Phosphorodiamidate Morpholino Oligomers (PMOs) for the 
Treatment of Duchenne Muscular Dystrophy
Phosphorodiamidate morpholino oligomers (PMOs) are a class of synthetic molecules based on a 
redesign of the natural nucleic acid structure. PMOs are distinguished from 2′-O-methyl and 
other antisense oligonucleotide platforms by the use of a six-membered morpholinyl ring which 
replaces the five-membered ribofuranosyl ring found in natural ribonucleic acid (RNA) and
deoxyribonucleic acid (DNA), and by the linkage of each morpholinyl ring through an uncharged 
phosphorodiamidate moiety (as opposed to negatively-charged phosphorothioate and other 
backbones used in most other RNA therapeutics). As a result of the combination of the 
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have decreased nonspecific protein binding, with no detectable innate immune activation. The
uniformity of the PMO backbone allows common synthetic, purification, formulation, and 
analytical methods to be used for all PMO drug candidates.
Approximately 80% of boys with DMD have mutations in the dystrophin gene that could be 
amenable to exon skipping therapies (Aartsma-Rus 2009). Thus, modulation of pre-messenger
RNA (mRNA) splicing by exon skipping is a potentially useful treatment for DMD.
The active pharmaceutical ingredient of the investigational product (IP) eteplirsen injection is a 
 PMO that selectively binds to exon 51 of the dystrophin pre-mRNA. In doing so, 
it causes the exon to be skipped during processing and restores the mRNA open reading frame in 
patients with mutations amenable to skipping exon 51 of the dystrophin gene, which is 
approximately 13% of all DMD patients (Aartsma-Rus 2009). This is expected to enable the 
production of an internally deleted, yet partially functional, dystrophin protein, similar to that 
observed in Becker muscular dystrophy (BMD), a much less severe form of dystrophinopathy. In
contrast to DMD, most BMD patients remain ambulatory and have a near-normal life expectancy 
(Bushby 1993).
5.3.
Clinical Experience with Eteplirsen
Two Phase 1 clinical studies of eteplirsen have provided initial support and proof-of-concept for 
the safety and potential efficacy of eteplirsen in the treatment of DMD. In light of the positive 
findings from the two Phase 1 studies, a 28-week, double-blind, placebo-controlled Phase 2
study (Study 4658-us-201) was initiated to assess efficacy, safety, tolerability, and 
pharmacokinetics (PK) of eteplirsen. Twelve patients aged 7 to 13 years were randomized to 
receive once-weekly intravenous (IV) infusions of eteplirsen (30 or 50 mg/kg) for 28 weeks, or 
once-weekly placebo infusions for 24 weeks followed by eteplirsen infusion (30 or 50 mg/kg) for 
4 weeks. At Week 28, these same 12 patients were enrolled in the extension study 
(Study 4658-us-202) where they continued open-label eteplirsen at the same dose they were 
receiving upon completion of the parent study. 
Two other eteplirsen 
studies are ongoing (Study 4658-203, a Phase 2 study in patients 4 to 6 years of age; and Study
4658-301, a Phase 3 confirmatory safety and efficacy study).
Based on the cumulative available safety data from these studies, eteplirsen has been shown to be 
well tolerated, with low rates of serious or severe adverse events (AEs). The following common 
AEs are categorized as adverse drug reactions given their frequency relative to placebo: 
headache, arthralgia, vomiting, nausea, upper respiratory tract infection, nasopharyngitis, and 
cough. In addition, the following events are also categorized as adverse drug reactions given 
their temporal relationship to eteplirsen administration: erythema, flushing, and mild temperature 
elevation.
.
5.4.
Rationale for the Current Study
The purpose of this study is to evaluate the safety of eteplirsen in patients with advanced stage 
DMD with genetic mutations amenable to treatment by exon 51 skipping.
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6.
STUDY OBJECTIVES 
6.1.
Primary Objective
The primary objective of this study is to explore safety and tolerability of eteplirsen in patients 
with advanced stage DMD who are amenable to exon 51 skipping.
6.2.
Exploratory Objectives
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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design
This is an open-label, multicenter study to explore the safety and tolerability of eteplirsen 
injection in approximately 20 patients with advanced stage DMD with confirmed genetic 
mutations amenable to treatment by exon 51 skipping.
Patients will be evaluated for inclusion during a Screening/Baseline period of up to 4 weeks.
Written informed consent from the patient and/or parent/legal guardian and assent, if applicable, 
to participate in the study must be obtained prior to beginning any study-related procedures.
x
Once eligibility is confirmed, patients will undergo Screening Assessments as 
indicated in Section 2 (Schedule of Events).
x
Blood samples collected at the Screening Visit for the safety lab assessments must be 
obtained within 2 weeks prior to the Baseline/Week 1 visit, and results must be 
available prior to dosing at Baseline/Week 1.

However, if more than 2 weeks have elapsed since the collection of blood samples 
for the Screening safety lab assessments, it must be repeated.

If less than 2 weeks have elapsed since the collection of blood samples for the 
Screening safety lab assessments, additional safety lab assessments do not need to 
be performed, and the patient may proceed with Baseline/Week 1 assessments as 
indicated in Section 2.
Starting at Week 1, enrolled patients will receive once weekly IV infusions of 30 mg/kg 
eteplirsen for 96 weeks, followed by a safety extension (not to exceed 48 weeks), until the 
product is commercially available or until patients can transition into a separate eteplirsen study.
Safety will be regularly assessed throughout the study via the collection of AEs, laboratory tests, 
electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations.
Following the end of the weekly infusions, patients will be required to return to the study site for 
End of Study on-treatment safety evaluations.
The total duration including Screening, Treatment, Safety Extension, and End of Study 
Follow-up periods is approximately 148 weeks. The Safety Extension will start following 
completion of the Week 96 visit and is not to exceed 48 weeks. Dosing in the Safety Extension 
will continue until product is commercially available or until patients can transition into another 
study to receive eteplirsen.
Refer to Section 10 for the detailed list of study assessments.
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7.2.
Dose Selection Rationale
The dose of eteplirsen used in this study is 30 mg/kg. This dose was chosen based on results 
from the Phase 2, double-blind, placebo-controlled, multiple-dose study, Study 4658-us-201, and 
its open-label extension, Study 4658-us-202. As described in Section 5.3, these studies assessed
the efficacy, safety, tolerability, and PK of 2 eteplirsen doses (50 and 30 mg/kg) administered as 
IV infusions in twelve 7- to 13-year-old pediatric patients diagnosed with DMD with out of 
frame mutations amenable to treatment by skipping exon 51.
Once weekly treatment with 30 mg/kg eteplirsen for 24 weeks significantly increased the mean 
percentage of dystrophin-positive muscle fibers as percent (%) of normal in DMD patients 
compared to placebo.
At Week 48, increases in the percent of dystrophin-positive fibers were similar for patients who 
had received weekly 30 and 50 mg/kg eteplirsen without interruption from Week 1 (52% and 
42% of normal, respectively or 47% for the combined groups). These data suggest that the effect 
of eteplirsen on the production of novel dystrophin is not significantly different between the two 
doses tested in this study. Therefore, the lower dose was selected as the more conservative 
choice, because patients presumably would receive this drug as a life-long treatment.
7.3.
Study Endpoints
7.3.1.
Safety Endpoints
Incidence of: 
x
Adverse events
x
Clinical laboratory abnormalities 
x
Abnormalities in vital signs and physical examinations
x
Abnormalities on electrocardiograms (ECGs) and echocardiograms (ECHO)
7.3.2.
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7.4.
Discussion of Study Design
This is an open-label study to provide safety data in patients with advanced stage DMD. The
study focuses on safety assessments; however, because a majority of patients with advanced 
stage DMD are non-ambulatory, 
The 96-week duration of the study provides sufficient follow-up time to obtain safety data in this 
population. The safety extension (not to exceed 48 weeks) will allow patients who have been 
receiving once weekly infusions of eteplirsen in Study 4658-204 to continue treatment until the 
product is commercially available or they are able to transition to another eteplirsen study.
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8.
SELECTION AND WITHDRAWAL OF PATIENTS
8.1.
Number of Patients
Approximately 20 patients will be enrolled in this study.
8.2.
Patient Inclusion Criteria
A patient must meet all of the following criteria to be eligible for this study.
1. Be a male with DMD with a mutation that may be amenable to exon 51 skipping 
(e.g., deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63) as documented by a 
genetic report from an accredited laboratory confirming mutation endpoints by multiplex 
ligation-dependent probe amplification (MLPA) or sequencing.
2. Be between 7 and 21 years of age.
3. Has been on a stable dose of oral corticosteroids for at least 24 weeks prior to study drug 
administration and the dose is expected to remain constant (except for modifications to 
accommodate changes in weight) throughout the study, or has not received 
corticosteroids for at least 24 weeks prior to study drug administration and does not 
expect to start corticosteroids throughout the study. 
4.
5. Has a score of ≤4 on the Brooke Score for Arms and Shoulders.
6. Has cardiac and pulmonary function that, in the opinion of the investigator, is unlikely to 
decompensate over the study period.
7. Patients who are post-pubertal and sexually active must agree to use, for the entire 
duration of the study and for 90 days post last dose, a male condom and the female sexual 
partner must also use a medically acceptable form of birth control (e.g., oral 
contraceptives).
8. Able to understand and comply with all study requirements, in the Investigator’s opinion, 
or if under the age of 18 years, must have a parent(s) or legal guardian(s) who is able to 
understand and comply with all the study requirements.
9. Willing to provide informed consent to participate in the study, or if under the age of 
18 years, be willing to provide informed assent, if applicable, and have a parent(s) or 
legal guardian(s) who is willing to provide written informed consent for the patient to 
participate in the study.
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8.3.
Patient Exclusion Criteria
A patient who meets any of the following criteria will be excluded from this study.
1. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks of study 
drug administration that in the opinion of the Investigator might have an effect on muscle 
strength or function (e.g., growth hormone, anabolic steroids).
2. Previous treatment with SMT C1100/BMN 195 at any time. 
3. Previous treatment with drisapersen (PRO051) within the last 6 months. Participation in 
any other DMD interventional clinical study within 12 weeks of study drug 
administration, or use of the shock training system or “STS,” or planned use during this 
study. Concurrent participation in an interventional clinical study or observational trial is 
not permitted. 
4. Major change in physiotherapy regimen within the past 3 months or expected change 
over the study period.
5. Major surgery within 3 months of study drug administration or planned major surgery for 
any time during this study.
6. Presence of other clinically significant illness including significant cardiac, pulmonary, 
hepatic, renal, hematologic, immunologic, behavioral disease or malignancy.
7. Systemic use of any aminoglycoside antibiotic within 12 weeks of study drug 
administration or anticipated need for use of an aminoglycoside antibiotic or statin during 
the study.
8.
.
9. Must not require antiarrhythmic and/or antidiuretic therapy for heart failure. Patients are 
allowed to take other medication including angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin receptor blocking agents (ARBs), β blockers or potassium, 
provided they have been on a stable dose for 24 weeks prior to study drug administration 
and the dose is expected to remain constant throughout the study.
10.
.
11. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely 
affect the safety of the patient, make it unlikely that the course of treatment would be 
completed, or impair the assessment of study results.
8.4.
Completion of a Patient’s Participation in the Study
The length of a patient’s participation may be from the time the informed consent form is signed 
up to Week 148 or up until the product is commercially available or until the patient transitions 
into a separate eteplirsen study.
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8.5.
Patient Withdrawal Criteria
Any patient can decide to withdraw from study participation at any time for any reason. In
addition, the study Sponsor may decide to stop the study participation of any patient as deemed 
necessary. The Investigator may also stop the study participation of any patient at any time.
Reasons for study withdrawal include but are not limited to:
x
The patient was erroneously included in the study (i.e., was found to have not met the 
eligibility criteria).
x
The patient experiences an intolerable or unacceptable AE.
x
The patient is unable to comply with the requirements of the protocol.
x
The patient participates in another investigational study without the prior written 
authorization of the Sponsor.
The Investigator or study staff will document the reason(s) for treatment discontinuation on the 
case report form (CRF).
Patients who received at least 1 dose of IP who discontinue from treatment within 4 weeks after 
a functional assessment visit will be asked to return for an End of Study visit within 4 weeks of 
their last visit. Patients who received at least one (1) dose of IP who discontinue treatment more 
than 4 weeks after a functional assessment visit will be asked to complete all Early Termination 
(Week 96) assessments within 30 days of discontinuation and a subsequent End of Study visit 
within 4 weeks of the Early Termination (ET) visit.
Following Week 96, patients may continue to receive eteplirsen for up to an additional 48 weeks
and be followed as described in the Safety Extension portion of Section 2, Table 3 (Safety 
Extension Schedule of Events). They may receive weekly infusions of eteplirsen at the same 
dose, with continuous monitoring of adverse events and concomitant medications, while 
undergoing physical examination and safety laboratory assessments every 24 weeks. If patients 
discontinue eteplirsen during the Safety Extension, they will be asked to return for an End of 
Study visit 4 weeks after their final dose. 
Patients who discontinue eteplirsen dosing in the Safety Extension Period in order to transition 
onto commercial drug or into a separate eteplirsen study do not require an End of Study visit.
8.6.
Study Discontinuation
If the Sponsor, the Investigator, the medical monitor, the study monitor, institutional review 
board/independent ethics committee(s) (IRB/IEC), or appropriate regulatory officials discover 
conditions arising during the study that indicate the study should be halted or that the study 
center should be terminated, appropriate action may be taken after consultation among (at a 
minimum) the Sponsor, the Investigator, IRB/IEC and the medical monitor.
Conditions that may warrant termination of the study or an individual site include, but are not 
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x
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study
x
A decision by the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product
x
Failure of the Investigator to enroll patients into the study at an acceptable rate
x
Failure of the Investigator to comply with pertinent regulations of IRB/IEC or 
appropriate regulatory authorities
x
Failure of the Investigator to comply with the protocol
x
Submission of knowingly false information from the research facility to the Sponsor, 
the study monitor, IRB/IEC or regulatory authority
x
Insufficient adherence to protocol requirements consistent with 21 CFR 312 or the 
European Clinical Trial Directive 2001/20/EC
Study termination and follow-up will be performed in compliance with the conditions set forth in 
International Conference on Harmonisation (ICH) E6 on Good Clinical Practice (GCP) as well 
as 21 CFR 312.56b and the European Clinical Trial Directive 2001/20/EC which require a 
Sponsor to ensure an Investigator’s compliance with these requirements and to promptly secure a 
plan for compliance or discontinue shipments of the IP to the Investigator and end the 
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9.
TREATMENT OF PATIENTS
9.1.
Investigational Product
Eteplirsen Injection
9.1.1.
Packaging and Labeling
Please refer to the study-specific Pharmacy Manual for information on packaging and labeling.
The label text for the IP will at a minimum include the following information:  product 
name/identifier, cautionary statement per 21 CFR 312.6, lot number (or alternative code), storage 
conditions, and the name of the Sponsor.
9.1.2.
Storage
Vials of IP must be stored in a secured, limited-access area with appropriate temperature 
recording, controls, and monitoring. Details for IP handling, storage and for preparation of the 
diluted IP for administration can be found in the study specific Pharmacy Manual. 
9.2.
Treatments Administered
Eligible patients will receive a weekly IV infusion of 30-mg/kg dose of eteplirsen for 96 weeks,
followed by a safety extension (not to exceed 48 weeks), until the product is commercially 
available or until patients can transition into a separate eteplirsen study.
The dose of eteplirsen will be calculated based on the most recent patient weight obtained at the 
site prior to the current visit. Eteplirsen should be prepared for dosing by following the steps 
detailed in the study-specific Pharmacy Manual.
Eteplirsen will be administered as an IV infusion over a period of approximately 35 to
60 minutes, or approximately 5 mL/min. It is recommended that a topical anesthetic cream 
(e.g., lidocaine 2.5%, prilocaine 2.5%, or LMX4 cream) be applied to the infusion site prior to 
each administration of eteplirsen. Additional administration and IP details are available in the 
study-specific Pharmacy Manual.
An implanted venous access port may be inserted for eteplirsen administration at the discretion 
of the Investigator. If eteplirsen is administered into an existing IV line, the line should be
flushed with normal saline before and after administration of eteplirsen. After eteplirsen 
administration and the saline flush, the port may be flushed with heparin to heplock the port prior 
to removal of the infusion line.
No other medications may be administered concomitantly during the eteplirsen infusion.
All treated patients will be observed for at least 1 hour following the end of each eteplirsen 
infusion.
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The following guidelines for the timing of dosing should be followed throughout the study:
1. Patients should receive eteplirsen once every 7 days starting on Study Day 1. A window 
of ±3 days from the scheduled dose is acceptable after the first infusion. 
2. Patients may not receive 2 separate doses of eteplirsen within the same 60-hour period. 
3. The medical monitor should be contacted in the event of ≥2 consecutive missed doses. 
9.2.1.
Dose Modification, Reduction, or Delay
There is no provision for dose alteration in this study. If a patient experiences an AE that requires 
interruption of administration of eteplirsen for ≥2 consecutive doses, the Investigator will consult 
with the Medical Monitor to determine whether the patient may resume treatment.
9.3.
Randomization and Blinding
This is an open-label study, and therefore all patients will receive eteplirsen. 
9.4.
Prior and Concomitant Medications
The dosing regimen for oral corticosteroids for treatment of DMD including, but not limited to, 
prednisolone and prednisone, should be kept the same throughout the study.
The following therapies may be used before enrollment and throughout the study; however, the 
dosage should be constant throughout the treatment period, unless clinically indicated:
x
Oral ACE inhibitors, including but not limited to perindopril and lisinopril
x
Oral β-blockers, including but not limited to carvedilol and atenolol
x
Angiotensin-receptor blockers, including but not limited to losartan, irbesartan, 
valsartan, and candesartan
x
Oral laxatives, including but not limited to lactulose, Senokot, and Movicol
x
Vitamin D and calcium supplements
x
Alendronate (Fosamax) or other bisphosphonates used to treat 
osteoporosis/osteopenia by inhibiting osteoclasts
x
Over-the-counter herbal preparations, including herbal supplements, vitamins, 
minerals, and homeopathic preparations, provided the patient had been on stable 
doses for 24 weeks before enrollment in this study
Other concomitant medications (e.g., vitamins or other non-RNA antisense medications) may 
also be taken if, in the opinion of the Investigator, they do not interfere with study assessments 
and outcomes. The Investigator should contact the Medical Monitor if he/she is unsure of the 
impact of a concomitant medication on study assessments and outcomes. Every attempt should 
be made to keep the dosage constant throughout the study period (i.e., through Week 96); 
although modifications to accommodate changes in weight are permitted.
Introduction of new physiotherapy interventions during the course of the study must be avoided 
unless the best interests of the patient are at risk. Should a contracture develop during the course 


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of the study, and it is considered in the best interest of the patient to treat the contracture, then 
any of the following interventions may be used to reduce the contracture, but they must be 
clearly documented:
x
Contracture control devices
x
Night splints
x
Stretching exercises (passive, active, self)
x
Serial casting
The following therapies are not permitted during the conduct of this study:
x
Systemic or oral steroids for non-DMD conditions
x
Investigational agents for the treatment of DMD 
x
Any medication with the potential to affect muscle mass, strength, and/or function, 
such as, but not limited to, growth hormone and PDE-5 inhibitors 
x
Immunosuppressants (other than oral or systemic corticosteroids, as outlined) 
x
Systemic aminoglycoside antibiotics (unless discussed and agreed upon with the 
Investigator and the Medical Monitor)
x
Statins (unless discussed and agreed upon with the Investigator and Medical Monitor)
9.5.
Treatment Compliance
Treatment compliance will be assessed via compliance with scheduled weekly infusions.


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10.
STUDY ASSESSMENTS
10.1.
Study Schedule of Events
A detailed schedule of the study assessments and times is shown in Section 2.
10.2.
Assessments at the Screening/Baseline Visits
10.2.1.
Informed Consent
Written informed consent from the patient or parent/legal guardian(s) and assent from the patient 
(if applicable) to participate in this study must be obtained prior to beginning any of the 
procedures for this study.
10.2.2.
Medical History
Medical history will be obtained for all patients.
10.2.3.
Blood samples for DMD Genotyping and 
Blood samples will be obtained at Screening for confirmation of DMD genotyping. Patients may 
start dosing based on local genotyping results provided that these results fulfill the required 
criteria described in Section 8.2; however, all patients must undergo genetic testing to confirm 
the exon 51 skippable mutation. Patients whose genotype is not confirmed to be exon 51
skippable will be excluded from continuing in this trial.
10.3.
Safety Assessments
10.3.1.
Physical Examination
Physical examinations, full and brief, will be conducted at the time points specified in Section 2.
Physical examinations will be 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 will include examination of general appearance; head, ears, eyes nose, and 
throat (HEENT); heart; lungs; chest; abdomen; skin; lymph nodes; musculoskeletal; and 
neurological systems. Brief physical examinations will include examination of general 
appearance, HEENT, heart, lungs, chest, abdomen, and skin.
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10.3.2.
Vital Signs and Weight
Vital signs (blood pressure, heart rate, respiration, and oral temperature) and weight will be 
measured at the time points specified in Section 2.
For infusion visits, vital signs are to be collected within approximately 30 minutes prior to 
infusion and approximately 5, 30, and 60 minutes after the end of the infusion. If the patient has 
not experienced an infusion reaction after the first year of treatment, vital signs may be collected 
only 30 minutes after the end of the infusion. All assessments will be performed after patients 
have remained seated for 5 minutes. Pulse rate and respiratory rate should be measured over 1 
minute.
Details about how weight measurements are obtained are provided in the Clinical Evaluator 
Manual. If a patient’s weight varies by more than 10% from the prior visit, the patient should be 
re-weighed to confirm the result, and an explanation of the change should be documented.
10.3.3.
Clinical Laboratory Evaluations
The following routine clinical laboratory tests will be collected at the time points specified in 
Section 2 and analyzed by an accredited central laboratory selected by the Sponsor and prepared 
according to the Laboratory Manual provided for the study:
Chemistry:
Sodium, chloride, potassium, calcium, glucose, creatinine, blood urea 
nitrogen (BUN), albumin, uric acid, total bilirubin, alkaline 
phosphatase, amylase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (GGT), lactase 
dehydrogenase (LDH), C-reactive protein (CRP), creatine kinase 
(CK), and serum cystatin C
Hematology:
Red blood cells (RBCs), total white blood cells (WBCs), hemoglobin, 
hematocrit, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, platelets, and abnormal cells
Coagulation Screen:
Prothrombin time, International Normalized Ratio (INR), and 
activated partial thromboplastin time (aPTT)
Urinalysis:
pH, specific gravity, protein, glucose, ketones, cytology, hemoglobin, 
and kidney injury molecule-1 (KIM-1)
Any value outside of the current reference ranges for the laboratory performing the test will be 
flagged on the laboratory results. The Investigator will determine whether abnormal assessment 
results are clinically significant (CS) or not clinically significant (NCS). Clinical significance is 
defined as any variation in assessment results that has medical relevance resulting in an alteration 
in medical care. If clinically significant deterioration from baseline levels is noted, the 
Investigator will continue to monitor the patient with additional assessments until:
x
Values have reached normal range and/or baseline levels; or
x
In the judgment of the Investigator together with the Sponsor’s Medical Monitor, 
abnormal values assessed to be not related to the administration of investigational 


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product or other protocol-specific procedures, and additional assessments are not 
medically indicated.
10.3.4.
Height and Ulnar Length
Height and ulnar length will be measured at the time points specified in Section 2.
Height should be measured with shoes off. If standing height cannot be obtained, height should
be calculated using the following equation (Gauld 2004):
Height (cm) = 4.605U + 1.308A + 28.003
where U is length of the ulna measured using an anthropometer or callipers, and A is patient’s 
age (years).
10.3.5.
Electrocardiogram
Twelve-lead ECGs and Holter ECGs will be obtained at the time points specified in Section 2.
ECGs will be performed at a consistent time of day throughout the study. ECGs will be 
performed only after the patient is in the supine position, resting, and quiet for a minimum of 
15 minutes. The ECG will be manually reviewed and interpreted by medically qualified 
personnel using a central vendor according to pre-specified criteria. The Investigator will review 
the results of the centrally read ECG report and determine if the findings are clinically 
significant.
10.3.6.
Echocardiogram
A standard 2-dimensional (2D) ECHO will be obtained at the time points specified in Section 2.
ECHOs will be performed at a consistent time of day throughout the study. The ECHO will be 
reviewed and interpreted by medically qualified personnel using a central vendor according to 
pre-specified criteria. Ejection fraction (EF) will be noted. The Investigator will review the 
results of the ECHO report and determine if the findings are clinically significant.
10.3.7.
Concomitant Medications and Therapies
Concomitant medications, changes in dosage of concomitant medications, and concomitant 
therapies will be reviewed and recorded at each visit from the time the patient signs informed 
consent, or parent/legal guardian signs informed consent and the patient signs the assent form (if 
applicable). Information on any physiotherapeutic intervention must be collected in detail for this 
study.
10.3.8.
Adverse Events
The collection of adverse events is described in Section 11.
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11.
ADVERSE EVENTS
11.1.
Collection of Adverse Events
Over the entire duration of the study, site personnel will ensure that all AEs are recorded 
appropriately. If an AE occurs, the primary concern is for patient safety, and the Investigator will 
use their judgment and expertise to determine the appropriate course of action.
All AEs from the time of informed consent through study completion or study discontinuation 
will be recorded in each individual patient’s CRF. For patients who prematurely discontinue the 
study (see Section 8.5), AEs will continue to be recorded until 4 weeks after the last eteplirsen 
infusion.
If, at any time after the patient has completed participation in the study (see Section 8.5), the 
Investigator or study staff becomes aware of a serious adverse event (SAE) that the Investigator 
believes is possibly/probably or definitely related to the IP (Section 11.3.1) or is 
possibly/probably or definitely related to a study procedure (Section 11.3.2), then the event and 
any known details must be reported promptly to the Sponsor.
11.2.
Definition of Adverse Events
11.2.1.
Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical trial participant, which does not 
necessarily have a causal relationship with the investigational drug. An AE can, therefore, be any 
unfavorable and unintended symptom, sign, disease, condition, or test abnormality that occurs 
during or after administration of an IP whether or not considered related to the IP. Adverse 
events include:
x
Symptoms described by the patient or signs observed by the Investigator or medical 
staff.
x
Test abnormalities (laboratory tests, ECG, X-rays, etc.) that result in an alteration in 
medical care (diagnostic or therapeutic).
Abnormalities present at baseline are considered AEs only if they reoccur after resolution or 
worsen during the AE collection period.
11.2.2.
Serious Adverse Event (SAE)
An SAE is defined as any AE that results in any of the following:
x
Death:  The patient died as the result of the event.
x
Life-threatening event:  Any AE that places the patient, in the view of the 
Investigator or Sponsor, at immediate risk of death from the AE as it occurred, 
i.e., does not include an AE that had it occurred in a more severe form, might have 
caused death.


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x
Required or prolonged inpatient hospitalization:  The AE resulted in 
hospitalization or prolonged an existing hospitalization. Since hospitalization may be 
part of the study, only hospitalizations that are longer than expected based on 
Investigator judgment, will be considered prolonged hospitalizations.
x
Persistent or significant disability/incapacity:  An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions.
x
Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in 
the offspring of a patient exposed to the IP.
x
Important medical events:  An AE that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
11.3.
Classification of Adverse Events
Each AE whether serious or nonserious will be classified by the Investigator according to the 
following rules and definitions.
11.3.1.
Relationship to Investigational Product
For each AE, the Investigator determines whether there is a reasonable likelihood that the AE 
may have been caused by the study treatment according to the categories below:
Unrelated:
The event is clearly not related to the IP
Possibly/probably related:
The event could be related/is likely to be related to the IP 
Definitely related:
The event is clearly related to the IP 
AEs that the Investigator or Sponsor considers to be possibly, probably, or definitely related to 
the IP will be considered adverse drug reactions.
11.3.2.
Relationship to Study Procedures
For each AE the Investigator determines whether there is a reasonable possibility that the AE 
may have been caused by the study procedures according to the categories below:
Unrelated:
The event is clearly not related to the study procedures
Possibly/probably related:
The event could be related/is likely to be related to study 
procedures
Definitely related:
The event is clearly related to the study procedures


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11.3.3.
Relationship to Underlying Disease
For each AE the Investigator determines whether there is a reasonable possibility that the AE 
may be related to the underlying disease according to the categories below:
Unrelated:
The event is clearly not related to the underlying disease
Possibly/probably related:
The event could be related/is likely to be related to the 
underlying disease
Definitely related:
The event is clearly related to the underlying disease
Events of disease progression may be considered AEs, based on the investigator’s discretion.
11.3.4.
Severity of Adverse Events
Note that severity is not the same as “seriousness,” which is defined in Section 11.2.2 and which 
serves as a guide for defining regulatory reporting obligations.
The Investigator will assess the severity of all AEs as Mild, Moderate, or Severe, based on the 
following definitions:
Mild:
The event does not interfere with the patient’s usual activities.
Moderate:
The event interferes with the patient’s usual activities.
Severe:
The event prevents the patient from undertaking their usual activities and 
requires therapeutic intervention or cessation of the IP.
11.3.5.
Outcome
Outcome describes the status of the AE. The Investigator will provide information regarding the 
patient outcome of each AE.
11.3.6.
Action Taken Regarding the Investigational Drug Product
The Investigator will provide information regarding the action taken with respect to the IP in 
response to the AE.
11.3.7.
Expectedness of an Adverse Event
The expectedness of all AEs will be determined according to the most recent version of the 
Investigator’s Brochure for eteplirsen.
11.3.8.
Suspected Unexpected Serious Adverse Reactions (SUSAR)
Suspected unexpected serious adverse reactions (SUSARs) will be handled by appropriate 
personnel at the Sponsor or designee and reported within the required timelines in an unblinded 
fashion to regulatory authorities and IRB/IEC per the requirements of the concerned competent
bodies. SUSARs will also be reported to study Investigators.


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11.4.
Recording Adverse Events
All AEs/SAEs experienced from the time of informed consent/assent to the last follow-up will be 
recorded within each patient’s CRF. Information should include: a concise description of the 
event; date and time of event onset and resolution; determination of seriousness, severity, 
corrective treatment, outcome, and relationship to IP or study procedure or underlying disease; 
and any action taken will be recorded. Resolution occurs when the patient has returned to his
baseline state of health or further improvement or worsening of the event is not expected. 
Whenever possible, a diagnosis will be recorded as an AE, rather than symptoms or isolated 
laboratory abnormalities related to that diagnosis. Several symptoms or laboratory results that are 
related to the same diagnosis can thus be part of the same AE. A medical or surgical procedure is 
not an AE; rather the condition leading to the procedure should be recorded as the AE. Similarly, 
death is not an AE, but is rather the outcome of the AE(s) that resulted in death. If the AE(s) 
leading to death are not known, then death must be reported as an AE. All AEs will be followed 
until the resolution of AE, completion of the patient’s study participation, or study termination, 
whichever occurs first. SAEs will be followed until resolution or until the condition stabilizes or 
returns to baseline status.
11.5.
Reporting Serious Adverse Events
It is the responsibility of the Investigator that reporting is done adequately. In order to meet 
Regulatory reporting timelines, the study site is obligated to report any SAE(s) to the Sponsor or 
designee immediately and no later than 24 hours after receiving information of an event that 
meets at least one of the criteria for seriousness as defined in Section 11.2.2. Refer to the SAE 
Reporting Plan for further details on the submission of SAE Reports.
11.6.
Special Situations
11.6.1.
Overdose
An overdose is defined as administration of a dose that is over 50 mg/kg. An overdose is not an 
AE. An overdose will be reported even if it does not result in an AE. An overdose will be 
recorded in the source documents and reported to the Sponsor or designee within 24 hours.
11.6.2.
Death
Death is an outcome of an event. All causes of death are SAEs. In the event of death, every effort 
should be made to obtain a death certificate and if possible, an autopsy report. If the cause of 
death is unknown, death will be recorded as the event.
11.6.3.
Responsibilities of the Investigator
The responsibilities of the Investigator include but are not limited to the following:
x
Monitor and record all AEs
x
Determine seriousness, severity, and relationship to IP and/or study procedure and/or 
underlying disease


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x
Determination of the onset and end date of each event
x
Provide initial report on all SAEs within 24 hours of knowledge to the Sponsor or 
designee
x
Provide follow-up information on SAEs in a timely and proactive manner
x
Respond to queries regarding AEs and SAEs in a timely manner
x
Ensure source documentation for all AEs are accurate and complete
x
Ensure that the study is conducted as defined in this document
11.6.4.
Responsibilities of the Sponsor
The responsibilities of the study Sponsor (Sarepta Therapeutics, Inc.) include but are not limited 
to the following:
x
Training of Investigator and site staff on AE/SAE definitions, safety assessments, and 
site obligations related to safety monitoring and reporting of AE/SAEs
x
Training with regard to the accurate and legal reporting of SAEs to all applicable 
regulatory bodies, IRBs/IECs, clinical trial sites, and other parties as appropriate and 
required within the regulated timing
x
Recording of AEs
x
Notification of expedited SAEs to sites
x
Annual safety reporting to regulatory authorities and IRBs/IECs according to regional 
requirements


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12.
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT
12.1.
Recording of Data
Clinical data for this study will be captured in an electronic format. Electronic data capture 
(EDC) will be provided by a contract research organization. The Investigator, or personnel 
delegated by the Investigator, will perform primary data collection/perform assessments based on 
the protocol design and captured in source documentation. All required study information must 
be recorded on the appropriate CRF screens/forms using the CRF Completion Guidelines for the 
study. A CRF must be completed for each patient that is enrolled. The study monitor will 
conduct 100% source data verification to ensure maximum data integrity. All data must be 
carefully entered in a timely fashion to permit meaningful interpretation and study oversight.
12.2.
Quality Assurance
The CRFs will be reviewed at regular intervals by a clinical monitor from the Sponsor or a 
representative of the Sponsor per the agreed upon Monitoring Plan against the source 
documentation for identification and clarification of any discrepancies. Automated and manual 
quality checks will be in place to identify discrepancies, such as missing data, protocol 
deviations, out-of-range data, other data inconsistencies and compliance. Requests for data 
clarification or correction will be documented as electronic queries within the CRF and for the 
Investigator or study coordinator to resolve. All changes to the CRFs will be tracked in an 
electronic audit trail. Site Study Files will be reviewed for compliance throughout the study.
Audits may be carried out by the Sponsor’s representatives, and inspections may be performed 
by IRBs/IECs or regulatory authorities before, during, or after the study. The Investigator will 
allow and assist the Sponsor’s representatives and any regulatory agency to have direct access to 
all study records, CRFs, patient medical records and other source documentation, IP dispensing 
records and IP storage area, study facilities, and any other source documentation. 
The Investigator must make study files and data accessible to the study monitor, to other 
authorized representatives of the Sponsor, and to the appropriate regulatory authority inspectors 
such as the United States Food and Drug Administration (US FDA).
12.3.
Retention of Study Documents
At study completion, all CRF data for an individual site will be copied onto a compact disc (CD) 
and provided to the Investigator for retention in the Study Files. The supporting Site Study Files 
must be retained by the Investigator for a period of 3 years after the investigation is discontinued 
and regulatory authorities are notified.
However, these documents should be retained for a longer period, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. No study documents will be 
destroyed or moved to a new location without prior written approval from the Sponsor. If the 


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Investigator relocates, retires, or withdraws from the clinical study for any reason, all records 
that are required to be maintained for the study should be transferred to an agreed upon designee.
Patient records or other source data must be kept for the maximum period of time mandated by 
the hospital, institution, or private practice, but not less than 15 years.
If off-site archiving is used, all records should be retrieved and made available for review at the 
time of an audit or regulatory authority inspection.


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13.
STATISTICS
13.1.
General Considerations
This section describes the rules, conventions, statistical analysis, and presentation of data for this 
study. Full details will be provided in the Statistical Analysis Plan (SAP) for this study.
Revisions during the study may be made to accommodate protocol amendments and to make 
changes to adapt to unexpected issues in study execution that could affect planned analyses. Any
revisions will be based on blinded review of the data. A formal SAP for the analysis and 
presentation of data from this study will be prepared and issued before database lock. The SAP 
will provide a more technical and detailed description of the proposed data analysis methods and 
procedures. Deviations from the statistical analyses outlined in this protocol will be included in 
this plan; any further modifications will be noted in the clinical study report (CSR). All statistical 
analyses will be performed by or under supervision of the Sponsor.
All available data will be included in data listings and tabulations. No imputation of values for 
missing data will be performed. Percentages of patients with AEs or laboratory abnormalities 
will be based on nonmissing values.
All data collected in this study will be presented using summary tables and patient data listings.
Summary statistics for raw and change from Baseline data of continuous variables will 
minimally include n, mean, standard deviation (SD), minimum, median, and maximum. For
categorical variables, frequencies and percentages will be presented. Graphical displays will be 
provided as appropriate.
Endpoints will be assessed primarily using simple descriptive statistics and/or inferential 
statistics. Baseline will generally be defined as the last available value before dosing. 
13.2.
Determination of Sample Size
There is no formal sample size calculation. The sample size is based on qualitative
considerations and is sufficient to provide safety evaluation of eteplirsen in the studied 
population.
13.3.
Analysis Sets
There will be one analysis population, the Safety set, which includes all patients who are 
enrolled in the study and receive at least 1 dose of eteplirsen.
13.4.
Protocol Deviations
A listing of protocol deviations will be provided. This deviation listing will be based on the 
review of study data prior to locking the database and will include the nature of the deviation 
(e.g., inclusion/exclusion, prohibited therapies).


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13.5.
Disposition, Demographics, and Baseline Characteristics
The number and percentage of patients completing or prematurely discontinuing the study will 
be summarized. Reasons for premature discontinuation will also be summarized.
Demographic characteristics including age (years), race, ethnicity, and baseline characteristics 
including height (cm), weight (kg), body mass index (BMI; kg/m2),
 will be 
summarized. Demographic data and baseline characteristics will be presented in data listings.
13.6.
Medical History
Medical history will be presented in data listings.
13.7.
Dosing and Compliance
The cumulative exposure to eteplirsen, total volume of drug administered (mL), total number of 
infusions received, and the cumulative amount of drug received will be summarized by dose 
group for all treated patients. Dosing information will be provided in a data listing.
13.8.
Safety Analysis
13.8.1.
Safety Variables
Incidence of:
x
AEs
x
Clinical laboratory abnormalities
x
Abnormalities in vital signs and physical examinations
x
Abnormalities on ECGs and ECHO
13.8.2.
Safety Analyses
Safety analyses will be descriptive in nature. Summary statistics for each parameter at a specific 
visit, as well as the change from Baseline to that visit, will also be displayed. All safety data will 
be presented in the data listings.
13.8.2.1.
Adverse Events
Only treatment-emergent adverse events (TEAEs) will be summarized. Non-emergent events 
will be recorded in data listings. For all AE tables, the number and percent of patients reporting 
AEs (grouped by the Medical Dictionary for Regulatory Activities [MedDRA] System Organ 
Class [SOC] and Preferred Term [PT]) will be summarized by treatment condition. In general, 
tables will have events categorized into all TEAEs and treatment-related TEAEs.
Multiple occurrences of the same AE (at the PT level) in the same patient will be counted only 
once in frequency tables. If a patient experiences multiple episodes of the same event with 
different relationship/severity, the event with the strongest relationship and maximum severity to 
CCI


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IP will be used to summarize AEs by relationship and severity. Treatment-related TEAEs will be 
defined as those that the Investigator considers possibly/probably or definitely related to the IP.
The following summary tables will be produced:
x
TEAEs
x
TEAEs by severity
x
Treatment-related TEAEs
x
Treatment-related TEAEs by severity
x
SAEs
In addition, all SAEs, regardless of their treatment-emergent status will be summarized by SOC 
and PT. 
The following listings will be produced:
x
Non-treatment emergent AEs
x
All TEAEs
x
AEs leading to discontinuation 
x
SAEs
13.8.2.2.
Physical Examination, Vital Signs, Weight, and Height/Ulnar Length
Vital signs, weight, and height/ulnar length will be presented by treatment condition and visit, 
summarizing the actual values and change from Baseline to each visit for each parameter using 
descriptive statistics. Frequency tables of predefined change abnormal in vital sign values will be 
generated.
Results from physical examinations will be presented in patient data listings.
13.8.2.3.
Clinical Laboratory Tests
Clinical chemistry, hematology, coagulation, and urinalysis will be presented by treatment 
condition and visit, summarizing the actual values and change from Baseline to each visit for 
each parameter using descriptive statistics for each continuous, and frequency tables for each 
discrete parameter. Frequency tables of predefined change abnormal of select laboratory 
parameter values will be generated.
13.8.2.4.
Electrocardiograms and Holter Electrocardiograms
The actual value and change from Baseline to each visit will be presented by treatment condition 
and visit, summarizing the actual values and change from Baseline to each visit for each 
parameter using descriptive statistics. Shift and frequency tables of predefined change abnormal 
of select ECG parameter values will be generated.


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13.8.2.5.
Echocardiograms
The actual value and change from Baseline to each visit will be summarized by treatment 
condition for each ECHO for EF.
13.8.2.6.
Prior and Concomitant Medications and Physiotherapeutic Interventions
All prior and concomitant medications, as well as physiotherapeutic interventions, will be 
presented in data listings.
13.10.
Interim Analysis
No interim analysis is planned for this study.
CCI
CCI
CCI
CCI
CCI


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13.11.
Other Statistical Issues
Additional analyses may be conducted. Any such analyses will be detailed in the SAP.


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14.
SPECIAL REQUIREMENTS AND PROCEDURES
14.1.
Compliance with Ethical and Regulatory Guidelines
This study will comply with the requirements that are enunciated in the European Clinical Trial 
Directive 2001/20/EC and in the US CFR.
14.2.
Institutional and Ethics Review
This study will be conducted in full compliance with the IRB regulations in 21 CFR 56 and/or 
the European Clinical Trial Directive 2001/20/EC. Before enrollment of patients into the study, 
the protocol and informed assent (for patients, if applicable) and informed consent (for 
parents/legal guardians) documents will be reviewed and approved by the appropriate IRB/IEC 
and regulatory authority. Amendments to the protocol will be subjected to the same IRB/IEC and 
regulatory authority review requirements as the original protocol. The Investigator will promptly 
notify the IRB/IEC and Sponsor of any SAEs or of any other information that might affect the 
safe use of the IP during the study. IRB approvals/IEC positive opinions and regulatory 
authorities’ approvals must be sent to the Sponsor, or its designee, before initiation of the study 
or before an amendment is instituted. All correspondence with the IRB/IEC and the regulatory 
authority should be retained in the study regulatory files.
14.3.
Informed Consent/Assent and Authorization for Use and Disclosure 
of Protected Health Information 
Written informed consent from each patient, or patient’s parent(s) or legal guardian(s), if 
applicable, and written assent from each patient, if applicable, must be obtained before any 
study-specific screening or baseline period evaluations are performed. One copy of the signed 
informed consent/assent documents will be given to the patient; the Investigator will retain the 
original copies of these documents.
The informed consent/assent documents, as prepared by the Sponsor or designee, must be 
reviewed and approved by the IRB/IEC and regulatory authorities, as applicable, before initiation 
of the study. The informed consent document must contain the basic required elements of 
consent and additional elements, as applicable, as specified in the 21 CFR 50.25.
14.4.
Compliance with the Protocol
All processes and procedures defined in this protocol will be adhered to. Emergency departures 
from the protocol that eliminate an apparent immediate hazard to a particular patient and that are 
deemed by the Investigator as crucial for the safety and wellbeing of that patient may be 
instituted for that patient only and documented as deviations. The Investigator will contact the 
medical monitor as soon as possible regarding such a deviation. These departures do not require 
preapproval by the IRB/IEC; however, the IRB/IEC and Medical Monitor must be notified in 
writing as soon as possible in accordance with the IRB/IEC policies after the departure has been 
made.


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14.5.
Confidentiality
14.5.1.
Data
All information regarding the nature of the proposed investigation that is provided to the 
Investigator by the Sponsor, the Sponsor’s designee, or the study monitor, with the exception of 
information that is required by law or regulations to be disclosed to the IRB/IEC, the patient’s 
parent(s) or legal guardian(s) or the appropriate regulatory authority, must be kept in confidence 
by the Investigator in accordance with current Health Insurance Portability and Accountability 
Act (HIPAA) standards and/or European standards.
14.5.2.
Patient Confidentiality
The anonymity of participating patients will be maintained to the extent required by applicable 
laws and in accordance with current HIPAA standards. Patients may be referenced by their 
initials and an assigned patient identification number on the CRFs and other data collected by the 
Sponsor. The Investigator must maintain all documents related to the study that identify the 
patient (e.g. the signed informed consent document) in strict confidence, except to the extent 
necessary to allow auditing by the appropriate regulatory authorities, the IRB/IEC, the study 
monitor, or the Sponsor or its representatives.


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15.
STUDY DOCUMENTATION AND GENERAL INFORMATION
15.1.
Essential Study Documents
Essential study documents are among the critical documents required before study enrollment is 
to occur. Essential documents, as well as supplemental information such as the Investigator’s 
Brochure, Pharmacy Manual, CRF Completion Guidelines, final protocol, as specified in the 
Clinical Operations Manual and/or Regulatory Binder, must be kept on-site in a designated study 
site file. 
The study site files will also contain, including but not limited to, patient accountability records, 
drug accountability (receipt/dispensing) records, Sponsor/Investigator correspondence, IRB/IEC 
correspondence, deviations, biological sample records, and SAE and Investigational New Drug 
(IND) safety reports/Safety Alert Letters.
15.2.
General Information
The Investigator should refer to the current Investigator’s Brochure along with subsequent Safety 
Alert Letters, the Clinical Study Operations Manual, Pharmacy Manual, Laboratory Manual, 
CRF Completion Guidelines, and all other study-specific information that is provided during the 
study initiation visit or by the study monitor.
15.3.
Dissemination of Study Results
The information that is developed during the conduct of this clinical study is considered to be 
strictly confidential. This information may be disclosed only as deemed necessary by Sarepta 
Therapeutics, Inc. However, at the conclusion of this clinical study, a clinical study report will be 
prepared. In addition, a manuscript will be prepared for publication in a reputable scientific 
journal under the direction of the Sponsor. Sarepta Therapeutics, Inc. will publish and 
communicate the clinical study results, irrespective of positive or negative findings. Data 
generated for this study will be exclusively owned by Sarepta Therapeutics, Inc., as detailed in 
the Clinical Trial Agreement. The study will be registered on ClinicalTrials.gov. After 
completion of the study, results will be disseminated through ClinicalTrials.gov.
15.4.
Product Handling and Complaints Reporting
If there are any issues during the course of the study related to the quality of the IP, the 
Investigator, clinical site pharmacist or pharmacy designee should contact the Sponsor or 
designated contract research organization (CRO).


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16.
LIST OF REFERENCES
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Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy 
mutations. Hum Mutat. 2009 Mar;30(3):293-9.
Bushby KM and Gardner-Medwin D. The clinical, genetic and dystrophin characteristics of 
Becker muscular dystrophy. I. Natural history." J of Neurol. 1993;240(2):98-104.
Beenakker, EA, Fock JM, et al. Intermittent prednisone therapy in Duchenne muscular 
dystrophy: a randomized controlled trial. Archives of Neurol. 2005;62(1):128-32.
Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for 
boys with Duchenne muscular dystrophy in their second decade. Neuromuscular Dis. 2006 
Apr;16(4):249-55.
Brooke MH, Fenichel, GM, Griggs RC, Mendell JR, Moxley R, Miller JP, et al. Clinical 
Investigation in Duchenne dystrophy: 2. Determination of the “power” on therapeutic trials 
based on the natural history. Muscle and Nerve. 1983;6:91-103.
Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Florence J, et al. Duchenne 
muscular dystrophy: patterns of clinical progression and effects of supportive therapy. Neurol. 
1989 Apr;39(4):475-81.
Cacchiarelli D, Legnini I, Martone J, Cazzella V, D’Amico A, Bertini E, Bozzoni. miRNAs as 
serum biomarkers for Duchenne muscular dystrophy. EMBO Mol Med. 2011;3(5):258-65.
CDC-MMWR. Prevalence of Duchenne/Becker Muscular Dystrophy Among Males Aged 5-24
Years – Four States, 2007. 2009;1119.
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne 
muscular dystrophy: improvements in life expectancy since 1967 and the impact of home 
nocturnal ventilation. Neuromuscular Dis. 2002 Dec;12(10):926-9.
Emery, AE. Population frequencies of inherited neuromuscular diseases--a world survey. 
Neuromuscular Dis. 1991;1(1):19-29.
Gauld LM, Kappers J, Carlin JB, Robertson CF. Height prediction from ulna length. Dev Med 
Child Neurol. 2004;46:475-480.
Kohler M, Clarenbach CF, Bahler C, Brack T, Russi EW, Bloch KE. Disability and survival in 
Duchenne muscular dystrophy. J Neurol Neurosurg Psychiatry. 2009 Mar;80(3):320-5.
Lowes LP, Alfano LN, Yetter BA, Worthen-Chaudhari L, Hinchman W, Savage J, et al. Proof of 
concept of the ability of the kinect to quantify upper extremity function in dystrophinopathy. 
PLoS Curr. 2013 Mar 14
Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular 
dystrophy. Cochrane Database Syst Rev. 2004;(2):CD003725.
Mayhew A, Mazzone ES, Eagle M, Duong T, Ash M, Decostre V, et al. Development of the 
Performance of the Upper Limb module for Duchenne muscular dystrophy. Dev Med Child 
Neurol. 2013;55(11):1038-45.


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Nadarajah VD, van Putten M, Chaouch A, Garrood P, Straub V, Lochmüller H, et al. Serum 
matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in 
Duchenne muscular dystrophy (DMD). Neuromuscul Disord. 2011 Aug;21(8):569-78.
Pradhan, SD, Ghosh D, Srivastava NK, Kumar A, Mittal B, Pandey CM, et al. Prednisolone in 
Duchenne muscular dystrophy with imminent loss of ambulation. J Neurol. 
2006;253(10):1309-16.

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Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 3 of 40 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................... 2 
1. 
Introduction ............................................................................................................ 5 
2. 
Study Objectives ..................................................................................................... 6 
3. 
List of Abbreviations and Definitions of Terms .................................................... 7 
4. 
Study Overview ....................................................................................................... 9 
4.1. 
Study Design .......................................................................................................... 9 
4.2. 
Number of Study Sites .......................................................................................... 9 
4.3. 
Overall Time and Events Schedule ................................................................... 10 
4.4. 
Analysis Variables ............................................................................................... 15 
4.4.1 Subject Disposition ............................................................................................... 15 
4.4.2 Demographics and Baseline Characteristics ......................................................... 15 
4.4.3 Prior and Concomitant Medication ....................................................................... 15 
4.4.4 Efficacy Variables ................................................................................................. 15 
4.4.5 Safety Variables .................................................................................................... 16 
4.5. 
Randomization and Blinding ............................................................................. 16 
5. 
Statistical Methods ............................................................................................... 17 
5.1. 
Sample Size .......................................................................................................... 17 
5.2. 
Analysis Population ............................................................................................ 17 
5.2.1 Safety Population .................................................................................................. 17 
5.3. 
Handling of Missing Data ................................................................................... 17 
5.4. 
Conventions ......................................................................................................... 17 
5.4.1 Covariates ............................................................................................................. 17 
5.4.2 Multiple Testing .................................................................................................... 17 
5.4.3 
Imputation of Missing Data for 10 Meter Walk/Run Test .................................... 17 
5.4.4 
Imputation of Incomplete Dates for Concomitant Medications and Adverse 
Events .................................................................................................................... 17 
5.4.5 Presentations Over Time ....................................................................................... 18 
5.4.6 Definitions and Terminology ................................................................................ 18 
5.4.7 Timing of Analyses ............................................................................................... 20 
5.4.8 Programming Conventions ................................................................................... 20 
5.5. 
Statistical Analyses.............................................................................................. 21 
5.5.1 Subject Disposition ............................................................................................... 21 
5.5.1 Demographics and Baseline Characteristics ......................................................... 21 
5.5.2 Prior and Concomitant Medications ..................................................................... 21 
5.5.3 Medical History .................................................................................................... 21 
5.5.4 Protocol Deviations ............................................................................................... 22 
5.5.5 Dosing ................................................................................................................... 22 
5.5.6 Efficacy ................................................................................................................. 22 
5.5.7 Safety .................................................................................................................... 24 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 4 of 40 
6. 
Changes from Planned Analyses ......................................................................... 31 
7. 
References ............................................................................................................ 32 
8. 
Proposed Tables, Figures, and Listings .............................................................. 33 
 
LIST OF TABLES 
Table 1  
Schedule of Events - Screening to End of Study ............................................10 
Table 2  
Schedule of Events - Safety Extension Period ...............................................14 
Table 3-1  Predefined Markedly Abnormal Hematology Laboratory Values ..................26 
Table 3-2  Predefined Markedly Abnormal Chemistry Laboratory Values .....................27 
Table 3-3  Predefined Markedly Abnormal Urinalysis Laboratory Values ....................28 
Table 4  
Predefined Markedly Abnormal Vital Sign Values ........................................28 
Table 5  
Predefined Markedly Abnormal Electrocardiogram Values ..........................29 
Table 6  
Predefined Markedly Abnormal Echocardiography Values ...........................30 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 5 of 40 
1. 
INTRODUCTION 
This analysis plan summarizes the planned analyses and presentation of the safety and 
efficacy data from the Sarepta Therapeutics, Inc. Protocol 4658-204: “An Open-Label, 
Multi-Center Study to Evaluate the Safety and Tolerability of eteplirsen in Patients with 
Advanced Stage Duchenne Muscular Dystrophy”. 
The investigational product is eteplirsen injection. Eteplirsen 30 mg/kg will be 
administered as an intravenous (IV) infusion over approximately 35 to 60 minutes, or 
approximately 5 mL/min, once a week for up to 96 weeks, followed by a safety extension 
(not to exceed 48 weeks), until the product is commercially available or until patients can 
transition into another eteplirsen trial. 
 
 
 
 
 


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Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 18 of 40 
• For partial or missing medication dates, the medication will be classified as a 
concomitant medication unless the available part of the date indicates it is not 
possible for the drug to be concomitant. For example, if only the year for the stop 
date is available and the year is prior to the year of dosing, the medication would 
be classified as a prior medication. 
For partial or missing adverse event dates, the event will be classified as 
treatment-emergent if the month and/or year are on or after the initiation of 
eteplirsen and within 28 days of the last dose of eteplirsen, or if it is not possible 
to determine whether the adverse event date is on or after the initiation of 
eteplirsen and within 28 days of the last dose of eteplirsen. 
• For the purpose of calculating the duration of an adverse event with a missing day 
but known month and year, the first of the month will be used for all start dates 
and the end of the month will be used for all end dates (where applicable). For 
example 01MMMYYYY will be used for UNMMYYYY for start date and 
31JANYYYY for UNJANYYYY (actual value will be based on the month 
recorded). 
5.4.5 
Presentations Over Time 
For endpoints that are collected serially over time (i.e. laboratory tests, efficacy 
assessments), events will be assigned to a time-point based upon the eCRF page the event 
was reported on (nominal time).  
5.4.6 
Definitions and Terminology 
Study Day 
Study day will be defined as Event Date – Study Day 1 + 1 
 
Study Day 1 
Day 1 is defined as the date of first dose of eteplirsen at the Week 1 visit during the 4658-
204 Study. 
 
Days on Study 
Days on Study is the number of days from Study Day 1 to the date of study completion or 
early termination as recorded on the END OF STUDY VISIT CRF. 
 
Days on Study Drug 
Days on Study Drug is the number of days from the date of first dose to the date of the 
last dose of the specific study medication as recorded on the STUDY DRUG 
ADMINISTRATION CRF. 
 
Planned Number of Infusions 
The planned number of infusions will be based on the subject’s last local site visit. The 
subject will be expected to receive an infusion once weekly up until their last local site 


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Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 25 of 40 
     5)  AEs leading to discontinuation 
5.5.7.1.1. Adverse Events of Special Interest 
Summaries of TEAEs of special interest (AESIs) and other AEs of Interest will be 
summarized by SOC and PT. All SMQs listed below will include broad and narrow 
terms. The AESIs are: 
• Hypersensitivity (Anaphylactic Reaction SMQ and Anaphylactic/Anaphylactoid 
Shock Conditions SMQ) 
• Renal Toxicity (Acute Renal Failure SMQ) 
• Leukopenia and Neutropenia (Haematopoietic SMQ) 
• Infusion Site Reactions (Extravasation Events SMQ and the following PTs: 
Application Site Erythema, Application Site Rash, Catheter Site Haematoma, 
Catheter Site Haemorrhage, Catheter Site Related Reaction, Infusion Site Rash, 
Infusion Site Swelling) 
• Severe Cutaneous Adverse Reactions (Severe Cutaneous Adverse Reactions 
SMQ) 
• Infusion Related Reactions (PTs of Nausea, Vomiting, Pyrexia, Body 
Temperature Increased, Erythema, Flushing Infusion Related Reaction, 
Hypotension, Blood Pressure Decreased, Diastolic Hypotension, Orthostatic 
Hypotension, Procedural Hypotension, Blood Pressure Ambulatory Decreased, 
Blood Pressure Diastolic Decreased, Blood Pressure Orthostatic Decreased, Blood 
Pressure Systolic Decreased, Blood Pressure Systolic Inspiratory Decreased) 
• Drug Induced Hepatotoxicities (Cholestasis and Jaundice of Hepatic Origin SMQ, 
Hepatic Failure, Fibrosis and Cirrhosis and Other Liver Damage-Related 
Conditions SMQ, Hepatitis, Non-infectious SMQ, Liver Neoplasms, Benign (incl 
Cysts and Polyps) SMQ, Liver Malignant Tumours SMQ, Liver Tumours of 
Unspecified Malignancy SMQ, Liver Related Investigations, Signs and 
Symptoms SMQ, Liver-Related Coagulation and Bleeding Disturbances SMQ) 
• Cardiac Events (Cardiomyopathy SMQ, Cardiac Failure SMQ, and Arrhythmia 
Related Investigations, Signs and Symptoms SMQ) 
• Coagulopathy (Haemorrhage Terms (excluding lab terms) SMQ, Haemotopoietic 
Thrombocytopenia SMQ, PTs in the Embolism and Thrombosis High Level 
Group Terms (HLGT) 
The Other AEs of Interest are: 
• Port-Related Events+ (Embolic and Thrombotic Events, Venous SMQ, 
Extravasation Events (Injections, Infusions and Implants) SMQ, PTs in the 
following High Level Terms (HLTs): Sepsis, Viraemia and Fungaemia NEC, 
Implant and Catheter Site Reactions, PTs in the following HLGTs: Endocardial 
Disorders and Device Issues. In addition, a search will be performed on the 
verbatim terms for “port”, “central venous” and “central line”) 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 26 of 40 
• Fractures (PTs in the following HLGTs: Fractures and Bone and Joint Injuries) 
• Falls (search of verbatim terms for “fall”) 
+ For subjects who have a port, Port-Related Events will only be identified after the port 
insertion occurred. 
A corresponding listing will be generated for each table. 
5.5.7.2. 
Laboratory Measurements 
Descriptive statistics for continuous hematology, clinical chemistry, urinalysis, and 
coagulation laboratory measurements will be presented by time point. Summary statistics 
for each lab parameter and time point as well as the change from Baseline to the time 
point will be displayed. For each numeric laboratory parameter, box plots of values over 
time will be generated. A shift table will compare N (%) of low, normal, and high status 
of the lab values at Baseline to their worst value post-Baseline through Week 96. A table 
summarizing the frequency and percent of subjects meeting the predefined markedly 
abnormal criteria at each visit will be presented. The predefined markedly abnormal 
criteria are defined below in Tables 3-1, 3-2, and 3-3. All laboratory values will be 
displayed in a data listing. 
 
Table 3-1 Predefined Markedly Abnormal Hematology Laboratory Values 
 
 
 
Test 
Unit 
Markedly Abnormal Criteria 
Hematocrit 
1 
< LLN 
Hemoglobin 
g/L (or mmol/L) 
< LLN 
Red blood cell count 
T/L 
< LLN 
White blood cell count 
count/L 
>1.5 × ULN or < LLN 
Platelet count 
10^3/L 
< 150 or < 200 with a decrease of at 
least 100 
Basophils (abs) 
count/L 
> ULN or < LLN 
Eosinophils (abs) 
count/L 
> 1.5xULN or < LLN 
Lymphocytes (abs) 
count/L 
< LLN 
Monocytes (abs) 
count/L 
< LLN 
Neutrophils (abs) 
count/L 
>1.5 × ULN or < 1000 
ULN = upper limit of normal 
LLN = lower limit of normal  
abs = absolute 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 27 of 40 
 
Table 3-2 Predefined Markedly Abnormal Chemistry Laboratory Values 
 
 
Predefined Change 
 
Test 
Unit 
Decrease 
Increase 
Markedly Abnormal Criteria 
Fasting blood glucose* 
mmol/L 
3.1 
3.2 
 
Urea (BUN) 
mmol/L 
 
 
Value >1.5 × Baseline Value 
AND > ULN 
Creatinine 
µmol/L 
 
35 
Value >1.5 × ULN 
Sodium 
mmol/L 
8 
8 
 
Potassium 
mmol/L 
1.1 
1.0 
Value >5.5 mmol/L or < 3 
mmol/L 
Chloride 
mmol/L 
9 
8 
 
Uric acid 
µmol/L 
 
 
>1 × ULN 
Calcium# 
mmol/L 
0.30 
0.30 
 
Total cholesterol 
mmol/L 
 
1.73 
 
AST (SGOT) 
U/L 
 
 
Value ≥3 × Baseline Value 
ALT (SGPT) 
U/L 
 
 
Value ≥2 × Baseline Value 
Gamma GT (GGT) 
U/L 
 
 
Value >3 × Baseline Value OR  
> ULN 
Alkaline phosphatase 
U/L 
 
 
Value >1.5 × ULN 
Total protein@ 
g/L 
11 
10 
 
Albumin 
g/dL 
1 g/dL 
decrease 
or  
1 g/dL 
increase   
Value < LLN or > ULN 
Total bilirubin& 
µmol/L 
 
10 
Value >1.5 × ULN 
LDH 
U/L 
 
 
Value ≥2 × Baseline Value 
Creatine phosphokinase 
U/L 
 
 
Value ≥2 × Baseline Value 
Triglycerides 
mmol/L 
 
2.88 
 
Cystatin C 
mg/L 
 
 
> ULN 
*Convert to SI unit by multiplying mg/dL value by 0.0555; #multiply mg/dL value by 0.25; @multiply g/dL 
value by 10; &multiply mg/dL value by 17.1. 
TEMA = treatment-emergent markedly abnormal 
LLN = lower limit of normal 
ULN = upper limit of normal 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 28 of 40 
 
Table 3-3 Predefined Markedly Abnormal Urinalysis Laboratory Values 
 
Predefined Change 
 
Test 
Decrease 
Increase 
Markedly Abnormal Criteria 
Protein in urine 
 
 
>1+ 
KIM-1* 
 
 
> ULN 
* Adult normal ranges provided by the laboratory will be used for all subjects as no 
pediatric ranges are available. 
5.5.7.3. 
Vital Signs 
Vital sign parameters will be presented by time point, summarizing the actual values and 
change from Baseline to each on-treatment time point using descriptive statistics. A table 
summarizing the frequency and percent of subjects meeting the predefined markedly 
abnormal criteria at each visit will be presented. The predefined markedly abnormal 
criteria are defined below in Table 4. Vital signs data will be presented in the data 
listings.  
Table 4 Predefined Markedly Abnormal Vital Sign Values 
Variable 
Units 
Markedly Abnormal 
Criteria Lower limit 
Markedly Abnormal 
Criteria Upper limit 
Systolic blood pressure 
mm Hg 
<80 
>130 
Diastolic blood pressure 
mm Hg 
<40 
>90 
Pulse Rate 
beats/min 
<50 
>130 
Temperature 
oC 
 
≥40 
 
5.5.7.4. 
12-Lead ECGs 
Electrocardiogram (ECG) parameters will be presented by time point, summarizing the 
actual values and change from Baseline to each on-treatment time point using descriptive 
statistics. A shift table will compare N (%) of ECG status at Baseline to the worst 
reported value through Week 96. A table summarizing the frequency and percent of 
subjects meeting the predefined markedly abnormal criteria at each visit will be 
presented. The predefined markedly abnormal criteria are defined below in Table 5. ECG 
data will be provided in a data listing. 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 29 of 40 
Table 5 Predefined Markedly Abnormal Electrocardiogram Values 
Variable 
Units 
Lower limit 
of normal 
Upper limit 
of normal 
Age 
Group 
(yrs) 
Markedly Abnormal Criteria 
Heart Rate 
beats/min 
50 
120 
 
 
QTcF Interval 
 
 
msec 
 
 
 
 
 
 
 
 
All 
Screening Visit >450 
<12 
>480 
≥12 
>500 
All 
<320 
Increase >60 
QRS Interval 
 
msec 
 
 
 
<12 
IVCD or any QRS conduction 
disturbance 
with a QRS >110ms 
≥12 
IVCD or any QRS conduction 
disturbance 
with a QRS >120ms 
PR Interval 
 
msec 
 
 
 
<12 
>190 
≥12 
>220 
5.5.7.5. 
Echocardiograms 
The actual value and change from Baseline to each on-treatment time point will be 
summarized for each ECHO parameter. A table summarizing the frequency and percent 
of subjects meeting the predefined markedly abnormal criteria at each visit will be 
presented. The predefined markedly abnormal criteria are defined below in Table 6. 
ECHO parameters will be listed by subject in a data listing. 
 
 
 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 30 of 40 
Table 6 Predefined Markedly Abnormal Echocardiography Values 
Variable 
Units 
Markedly Abnormal Criteria 
LVEF 
% 
<55% 
Fractional Shortening 
% 
<44% 
 
5.5.7.6. 
Holter Monitoring 
Holter monitoring data will be provided in a data listing. A separate listing will be created 
for hourly values and summary values. 
5.5.7.7. 
Physical Examinations 
Physical examination results will be listed by subject in a data listing. 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 31 of 40 
6. 
CHANGES FROM PLANNED ANALYSES 
This SAP has made the following change to the planned analyses in the protocol 
(Amendment 1, 05 July 2016): 
• Holter monitoring was to be summarized. It will instead be listed only. 


Sarepta Therapeutics, Inc. 
Protocol 4658-204 
  
Statistical Analysis Plan 
Version 1.0 (20 April 2017) 
 
Page 32 of 40 
7. 
REFERENCES 
None. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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