Clinical trial NCT02420379
Conditions: Duchenne Muscular Dystrophy (DMD)
Keywords: DMD Duchenne muscular dystrophy eteplirsen Dystrophin exon 51
Sponsor: Sarepta Therapeutics, Inc.
Start date: 2015-06-30; Completion date: 2018-12-17
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:
Safety, including adverse event monitoring and routine laboratory assessments, will be followed on an ongoing basis for all patients.

Clinical efficacy, including functional tests and MRI, will be assessed at regularly scheduled study visits. Patients will undergo one baseline and one follow-up muscle biopsy.

Population and serial PK will be collected.

Arms: arm 1: Approximately 20 patients will receive weekly infusions of eteplirsen 30 mg/kg . arm 2: Approximately 20 patients with DMD not amenable to exon 51 skipping will be observed for 96 weeks.
Interventions: intervention 1: eteplirsen
Intervention descriptions: intervention 1: Eteplirsen 30 mg/kg will be administered as an IV infusion once a week for 96 weeks.

Protocol documents:
Prot_001.pdf: 
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Sarepta Therapeutics, Inc. 
Study 4658-203 Version 3. Amendment 2 
Page 2 
SIGNATURE PAGE FOR SPONSOR 
Protocol Title: 
An Open-Label, Multi-Center Study to Evaluate the Safety, 
Efficacy and Tolerability of Eteplirsen in Early-Stage Duchenne 
Muscular Dystrophy 
Study No: 
4658-203. Amendment 2 
Current Version Date: 08 June 2017 
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the Sponsor. The information contained in this protocol is 
consistent with: 
• 
The current risk-benefit evaluation of the investigational product (IP). 
• 
The ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of Good Clinical Practice (GCP) as described 
in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and the European 
Clinical Trial Directive 2001 /20/EC. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events (AEs). relating to treatment with the IP. 
  
 
 
 
 
 
 
08 June 2017 
 
Date 
 
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Study 4658-203 Version 3, Amendment 2 
 
 
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08 June 2017 
 
  
INVESTIGATOR’S AGREEMENT 
 
I have read Study No. 4658-203 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 
 


Sarepta Therapeutics, Inc. 
Study 4658-203 Version 3, Amendment 2 
 
 
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08 June 2017 
 
  
PROCEDURES IN CASE OF EMERGENCY 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Responsible Physician 
, MD 
 
 
 
Telephone: 
 
Mobile: 
 
 
 
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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, Multi-Center Study to Evaluate the Safety, Efficacy and Tolerability of 
Eteplirsen in Early-Stage Duchenne Muscular Dystrophy 
PROTOCOL NUMBER:  4658-203 
PHASE OF STUDY:  Phase 2 
INVESTIGATOR STUDY SITES:  This study will be conducted at approximately 15 study sites in 
the United States. 
OBJECTIVES: 
The primary objective of this study is to evaluate the safety and tolerability of eteplirsen in patients with 
Duchenne muscular dystrophy (DMD) between 4 and 6 years of age who are amenable to exon 51 
skipping 
The secondary objective is to evaluate the effect of eteplirsen on dystrophin expression as measured by 
dystrophin quantification by Western blot and dystrophin intensity levels determined by 
immunofluorescence on-treatment as compared to pre-treatment biopsied skeletal muscle tissue. 
 
 
 
The pharmacokinetic (PK) objective is to evaluate the pharmacokinetic profile of eteplirsen in this age 
group. 
METHODOLOGY: 
This is an open-label, multi-center study to evaluate the safety and tolerability of eteplirsen in patients 
4 to 6 years of age with genotypically confirmed DMD with genetic mutations amenable to treatment by 
exon 51 skipping.  An untreated control group (DMD patients not amenable to exon 51 skipping) will be 
enrolled to further evaluate the natural history of DMD in this patient population. 
Patients will be evaluated for inclusion during a Screening/Baseline period of up to 5 weeks.  Eligible 
patients for the eteplirsen-treated group will receive once weekly intravenous (IV) infusions of 30 mg/kg 
eteplirsen for up to 96 weeks.  An extension to the dosing period may be considered prior to the end of 
the 96-week planned dosing period.  Eligible patients for the untreated group (eg, deletions of exons 44, 
45, or 53) will not receive treatment with eteplirsen.  Untreated patients will undergo select safety, 
functional, and laboratory assessments but will not provide blood samples for PK determination and will 
not undergo muscle biopsy procedures. 
Safety will be assessed through the collection of adverse events (AEs)/serious AEs (SAEs), laboratory 
tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations 
throughout the study. 
Upon qualification for the study, patients enrolled into the eteplirsen-treated group will undergo the 
baseline assessments including a muscle biopsy, which may occur at a different study site (denoted as 
the surgical unit) than where patients will undergo infusions and study assessments (denoted as the 
infusion site).  Eteplirsen-treated patients will be randomized to a second muscle biopsy scheduled at 
Week 48 or Week 96.  
 
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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 
 
 
Blood samples for population PK estimation will be collected from all eteplirsen-treated patients.  Blood 
samples for serial PK estimation will be collected at select sites. 
Following the end of the weekly infusions, patients will be required to return to the study site for End of 
Study safety evaluations. 
DURATION OF STUDY: 
Screening/Baseline Period:  Up to 5 weeks 
Treatment Period:  Up to 96 weeks 
Safety Follow-up period:  Four weeks following Week 96 or early discontinuation 
Total duration of patient participation:  Approximately 105 weeks 
NUMBER OF PATIENTS:  Up to 40 patients will be included in this study:  approximately 
20 patients in the eteplirsen-treated group (those amenable to exon 51 skipping) and up to 20 in the 
untreated control group (those not amenable to exon 51 skipping). 
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 and meet one of the following criteria:   
 
Have an out-of-frame deletion amenable to exon 51 skipping (eg, 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 deletion endpoints by multiplex ligation-dependent probe amplification 
(MLPA) or sequencing.  These patients will be enrolled into the eteplirsen-treated group. 
 
Have a deletion mutation that is not amenable to correction by exon 51 skipping as documented 
by a genetic report from an accredited laboratory confirming deletion endpoints by MLPA or 
sequencing.  These patients will be enrolled into the untreated group. 
2. Be 4 to 6 years of age, inclusive, at the Screening visit. 
3. Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug 
administration and the dose is expected to remain constant (except for modifications to 
accommodate changes in weight) for at least the first 12 weeks of the study OR has not received 
corticosteroids for at least 12 weeks prior to study drug administration and does not expect to start 
corticosteroids within the first 12 weeks of eteplirsen dosing.  
4. Have intact right and left biceps muscles or 2 alternative upper arm muscle groups (eteplirsen-
treated patients only). 
5. Have a parent(s) or legal guardian(s) who is able to understand and comply with all the study 
requirements. 
6. 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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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 
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 for DMD) within 12 weeks of study 
drug administration that might affect muscle strength or function (eg, growth hormone, anabolic 
steroids). 
2. Previous or current treatment with any other experimental treatments within 12 weeks prior to study 
entry or participation in any other clinical trial within 6 months prior to study entry.  (A patient may 
be enrolled in a concurrent non-interventional or observational study provided his participation does 
not interfere with this study.) 
3. Major surgery within 3 months of study drug administration or planned major surgery for any time 
during this study.  
4. Presence of other clinically significant (CS) illness including significant cardiac, pulmonary, 
hepatic, renal, hematologic, immunologic, behavioral disease or malignancy. 
5. Use of any systemic aminoglycoside antibiotic within 12 weeks of study drug administration or need 
for use of systemic aminoglycoside antibiotics or statins during the study. 
6. Have a left ventricular ejection fraction (LVEF) of <50% based on the screening ECHO or QT 
interval corrected by Fridericia’s formula (QTcF) ≥450 msec based on the screening ECG. 
7. 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. Patients who seem unwilling or unable to comply with the study procedures, in the Investigator’s 
opinion, are to be excluded. 
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. 
REFERENCE TREATMENT:  None 
CRITERIA FOR EVALUATION: 
Safety Endpoints: 
Incidence of the following for all patients in the study: 
 
Adverse events  
 
Clinical laboratory abnormalities  
 
Abnormalities in vital signs and physical examinations 
 
Abnormalities on ECGs and ECHOs 
Secondary Endpoints: 
Change from Baseline to Weeks 48 and 96 for the following: 
 
Dystrophin protein levels quantified by Western blot (eteplirsen-treated patients only) 
 
Dystrophin intensity as determined by immunofluorescence histochemistry (IHC) (eteplirsen-
treated patients only) 


Sarepta Therapeutics, Inc. 
Study 4658-203 Version 3, Amendment 2 
 
 
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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 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
Pharmacokinetic Endpoints: 
 
The PK of eteplirsen (eteplirsen-treated patients only) will be determined, as described below 
Pharmacokinetics:  
From the population PK samples, standard population PK parameters will be estimated.  The effects of 
demographic characteristics, concomitant medications, laboratory values, and other covariates on 
eteplirsen PK will be evaluated. 
From the serial PK samples, the following pharmacokinetic parameters will be determined, as 
appropriate: 
 
Maximum plasma concentration (Cmax) 
 
Time to maximum plasma concentration (Tmax) 
 
Area under the plasma concentration-curve (AUC) 
 
Apparent volume of distribution at steady state (Vss) 
 
Elimination half-life (t½) 
 
Total clearance (CL) 
 
Mean residence time (MRT) 
SAMPLE SIZE: 
Sample size for this study is based upon qualitative considerations.  No formal sample size calculation 
has been made.  The selected sample size is considered sufficient to provide initial safety evaluation of 
eteplirsen in the studied population; to provide adequate data to allow for estimation of PK parameters; 
and to provide biological proof-of -concept of exon skipping by eteplirsen in this age group. 
STATISTICAL METHODS: 
Safety Analyses 
Treatment-emergent adverse events (TEAEs) will be summarized by system organ class (SOC) and 
preferred term (PT) for the eteplirsen-treated group.  Adverse events since study enrollment will be 
summarized in the same fashion for the untreated group.  For all AE tables, the number and percentage 
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Study 4658-203 Version 3, Amendment 2 
 
 
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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 
of patients reporting AEs will be grouped by the most current version of 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 specific visit, as well as the change from Baseline to that visit, 
will also be displayed.  All safety data will be presented in data listings. 
Efficacy Analyses 
Analyses of Secondary Endpoints:  The analysis of change from Baseline to Weeks 48 and 96 in the 
dystrophin protein levels quantified by Western blot (eteplirsen-treated patients only) will be based on a 
1-sample permutation t-test for each time point.  Change from Baseline to Weeks 48 and 96 in 
dystrophin intensity as determined by IHC will be analyzed similarly. 
 
 
Pharmacokinetic Analyses 
Individual plasma levels of eteplirsen will be listed with the corresponding time related to eteplirsen 
administration, and summary statistics will be generated by per-protocol time of collection. 
Pharmacokinetic parameters for eteplirsen will be calculated using non-compartmental analysis.  Actual 
sampling times will be used in all final PK analyses; per protocol times will be used to calculate mean 
plasma concentrations for graphical displays.  
Plasma concentration-time data of eteplirsen will be used to perform a future population PK analysis 
using nonlinear mixed-effects modeling.  Data may be combined with those of completed studies to 
support a relevant structural model.   
 
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2. 
SCHEDULE OF EVENTS FOR ETEPLIRSEN-TREATED PATIENTS 
Study Period 
Screening 
Baselinea 
Treatment Period 
Week  
Up to 5 weeks 
prior to Week 1 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Informed Consent 
X 
 
Inclusion/Exclusionb 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationc 
X 
X 
Medical History 
X 
 
Full Physical Exam 
X 
 
X 
X 
X 
X 
X 
Brief Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
Weeklyd 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Assessments 
X 
Xe 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Whole Blood (DMD 
Genotyping and 
 
) 
X 
 
Height and Ulnar Length 
X 
 
 
X 
 
X 
Population PKh 
 
 
X 
 
 
Xi 
 
 
X 
 
 
Xi 
 
 
X 
Serial PKj 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Study Period 
Screening 
Baselinea 
Treatment Period 
Week  
Up to 5 weeks 
prior to Week 1 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
ECG 
Xk 
 
 
Xl 
 
Xl 
ECHO 
Xk 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
Xl 
Muscle Biopsyn 
X 
X 
Study Drug Infusion 
 
Weekly (Infusion Site) 
Conmed/Therapy 
Continuous 
AE Assessment 
Continuous 
a For patients whose infusion site is the same as their surgical unit, Baseline visit may be performed on the same day as the Week 1 visit. 
b Eligibility will be assessed during Screening and confirmed by the Infusion Site at the Baseline visit.  Eligibility will be reconfirmed at Week 1 based on all 
available data including safety laboratory assessments.   
c Upon qualification for the study during the Baseline visit, patients will be randomized to a muscle biopsy schedule. 
d Patients will have vital signs measured on infusion days 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 reduced to pre-infusion and 
30 minutes after the end of the infusion.  
e Blood samples for the safety laboratory assessments must be obtained within 3 weeks prior to Week 1, and results must be available prior to dosing at Week 1. 
If more than 3 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, it must be repeated.  If less than 
3 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. 
f  Blood samples for safety laboratory assessments must be obtained prior to infusion. 
h  Population PK blood samples will be taken prior to the beginning of the infusion and approximately 5 to 10 minutes after the completion of the infusion.   
i  Additional population PK blood samples collected approximately 1 to 2 hours after the completion of the infusion.   
j  Blood samples for serial PK sampling will be collected from some patients at select sites as follows:  pre-dose (within 30 minutes prior to the start of infusion), 
and post-infusion at 5, 15, 30, 60, and 90 minutes, and 2, 5, 8, 12, 16, and 24 hours after the completion of study drug infusion. 
k  Screening ECG and ECHO may be performed at any time during the Screening period and results must be available on Day 1, prior to dosing. 
l  ECG and ECHO may be performed within ±2 weeks and should be performed at the same time of day for each visit during the course of the study. 
n Procedure will occur at the surgical unit.  The biopsies at Weeks 48 and 96 must occur within 2 to 14 days of the visit.  The muscle biopsy must occur after the 
clinical evaluation. 
(table continued) 
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Study Period 
Treatment Period (Continued) 
End of Study 
Week  
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
Informed Consent 
 
Inclusion/Exclusionb 
 
Randomizationc 
 
Medical History 
 
 
 
Full Physical Exam 
 
 
 
 
X 
X 
Brief Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Weeklyd 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Assessments 
 
Xf 
Xf 
X 
Whole Blood (DMD Genotyping 
and 
) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Ulnar Length 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Population PKh 
 
Xi 
X 
Xi 
X 
Serial PKj 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ECG 
 
Xl 
Xl 
ECHO 
 
 
 
 
 
Xl 
 
 
 
 
 
Xl 
 
Muscle Biopsyn 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Study Period 
Treatment Period (Continued) 
End of Study 
Week  
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
Study Drug Infusion 
Once Weekly 
Conmed/Therapy 
Continuous 
AE Assessment 
Continuous 
a For patients whose infusion site is the same as their surgical unit, Baseline visit may be performed on the same day as the Week 1 visit. 
b Eligibility will be assessed during Screening and confirmed by the Infusion Site at the Baseline visit.  Eligibility will be reconfirmed at Week 1 based on all 
available data including safety laboratory assessments.   
c Upon qualification for the study during the Baseline visit, patients will be randomized to a muscle biopsy schedule. 
d Patients will have vital signs measured on infusion days 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 reduced to pre-infusion and 
30 minutes after the end of the infusion. 
e Blood samples for the safety laboratory assessments must be obtained within 3 weeks prior to Week 1, and results must be available prior to dosing at 
Week 1. If more than 3 weeks have elapsed since the collection of blood samples for the Screening safety laboratory assessments, it must be repeated.  If less 
than 3 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. 
f Blood samples for safety laboratory assessments must be obtained prior to infusion. 
 
h Population PK blood samples will be taken prior to the beginning of the infusion and approximately 5 to 10 minutes after the completion of the infusion.   
i Additional population PK blood samples collected approximately 1 to 2 hours after the completion of the infusion.   
j Blood samples for serial PK sampling will be collected from some patients at select sites as follows:  pre-dose (within 30 minutes prior to the start of 
infusion), and post-infusion at 5, 15, 30, 60, and 90 minutes, and 2, 5, 8, 12, 16, and 24 hours after the completion of study drug infusion. 
k Screening ECG and ECHO may be performed at any time during the Screening period and results must be available on Day 1, prior to dosing. 
l The ECG and ECHO may be performed within ±2 weeks.  The ECG and ECHO should be performed at the same time of day for each visit during the course 
of the study. 
n Procedure will occur at the surgical unit.  The biopsies at Weeks 48 and 96 must occur within 2 to 14 days of the visit.  The muscle biopsy must occur after 
the clinical evaluation. 
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3. 
SCHEDULE OF EVENTS FOR UNTREATED CONTROL PATIENTS 
Study Period 
Screening/Week 1a 
Observation Period 
Week  
12 
24 
36 
48 
72 
96/EOS 
Informed Consent 
X 
Inclusion/Exclusionb 
X 
 
 
 
 
 
 
Medical History 
X 
Full Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Assessments 
X 
X 
X 
X 
X 
X 
X 
Whole Blood (DMD 
Genotyping and 
) 
X 
Height and Ulnar Length 
X 
X 
X 
ECGc 
X 
X 
X 
X 
X 
ECHOc  
X 
 
X 
 
X 
X 
X 
Conmed/Therapy 
Continuous 
AE Assessment 
Continuous 
a All assessments should be completed within a 5-week window for this visit with 
 occurring last within this window. 
b For patients in the untreated control group, the date of the last Screening/Week 1 assessment (ie, 
) will be used and recorded as the study start date.  
c ECG and ECHO may be performed within ±2 weeks and should be performed at the same time of day for each visit during the course of the study. 
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4. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE FOR SPONSOR ............................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
SCHEDULE OF EVENTS FOR ETEPLIRSEN-TREATED PATIENTS ................10 
3. 
SCHEDULE OF EVENTS FOR UNTREATED CONTROL PATIENTS ...............14 
4. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................15 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
6. 
INTRODUCTION ......................................................................................................23 
6.1. 
Background of Duchenne Muscular Dystrophy .........................................................23 
6.2. 
Phosphorodiamidate Morpholino Oligomers (PMOs) for the Treatment of 
Duchenne Muscular Dystrophy ..................................................................................23 
6.3. 
Clinical Experience with Eteplirsen ...........................................................................24 
6.4. 
Rationale for the Current Study ..................................................................................25 
7. 
STUDY OBJECTIVES ..............................................................................................26 
7.1. 
Primary Objective .......................................................................................................26 
7.2. 
Secondary Objective ...................................................................................................26 
7.4. 
Pharmacokinetic Objective .........................................................................................26 
8. 
INVESTIGATIONAL PLAN .....................................................................................27 
8.1. 
Overall Study Design ..................................................................................................27 
8.2. 
Dose Selection Rationale ............................................................................................28 
8.3. 
Study Endpoints ..........................................................................................................28 
8.3.1. 
Safety Endpoints .........................................................................................................28 
8.3.2. 
Secondary Endpoints ..................................................................................................28 
8.3.4. 
Pharmacokinetic Endpoints ........................................................................................29 
8.4. 
Discussion of Study Design ........................................................................................29 
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9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................31 
9.1. 
Number of Subjects ....................................................................................................31 
9.2. 
Patient Inclusion Criteria ............................................................................................31 
9.3. 
Patient Exclusion Criteria ...........................................................................................31 
9.4. 
Completion of a Subject’s Participation in the Study .................................................32 
9.5. 
Patient Withdrawal Criteria ........................................................................................32 
9.6. 
Study Discontinuation ................................................................................................33 
10. 
TREATMENT OF SUBJECTS ..................................................................................34 
10.1. 
Investigational Drug Product – Eteplirsen Injection ..................................................34 
10.1.1. 
Packaging and Labeling ..............................................................................................34 
10.1.2. 
Storage ........................................................................................................................34 
10.2. 
Treatments Administered ............................................................................................34 
10.2.1. 
Dose Modification, Reduction, or Delay ....................................................................35 
10.3. 
Randomization and Blinding ......................................................................................35 
10.4. 
Prior and Concomitant Medications ...........................................................................35 
10.5. 
Treatment Compliance ................................................................................................37 
11. 
STUDY ASSESSMENTS ..........................................................................................38 
11.1. 
Study Schedule of Events ...........................................................................................38 
11.2. 
Assessments at the Screening/Baseline Visits ............................................................38 
11.2.1. 
Informed Consent .......................................................................................................38 
11.2.2. 
Medical History ..........................................................................................................38 
11.2.3. 
Blood samples for DMD Genotyping 
 ...........................................38 
11.3. 
Safety Assessments .....................................................................................................38 
11.3.1. 
Physical Examination .................................................................................................38 
11.3.2. 
Vital Signs and Weight ...............................................................................................39 
11.3.3. 
Clinical Laboratory Evaluations .................................................................................39 
11.3.4. 
Height and Ulnar Length ............................................................................................40 
11.3.5. 
Electrocardiogram .......................................................................................................40 
11.3.6. 
Echocardiogram ..........................................................................................................40 
11.3.7. 
Concomitant Medications and Therapies ...................................................................40 
11.3.8. 
Adverse Events ...........................................................................................................40 
11.4. 
Efficacy Assessments .................................................................................................41 
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11.4.1. 
Secondary Efficacy Assessment .................................................................................41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.5. 
Pharmacokinetic Assessments ....................................................................................42 
11.5.1. 
Population PK Sampling.............................................................................................43 
11.5.2. 
Serial PK Sampling .....................................................................................................43 
12. 
ADVERSE EVENTS..................................................................................................44 
12.1. 
Collection of Adverse Events .....................................................................................44 
12.2. 
Definition of Adverse Events .....................................................................................44 
12.2.1. 
Adverse Event (AE) ....................................................................................................44 
12.2.2. 
Serious Adverse Event (SAE) ....................................................................................44 
12.3. 
Classification of Adverse Events ................................................................................45 
12.3.1. 
Relationship to Investigational Product ......................................................................45 
12.3.2. 
Relationship to Study Procedures ...............................................................................45 
12.3.3. 
Relationship to Underlying Disease ...........................................................................46 
12.3.4. 
Severity of Adverse Events ........................................................................................46 
12.3.5. 
Outcome ......................................................................................................................46 
12.3.6. 
Action Taken Regarding the Investigational Drug Product .......................................46 
12.3.7. 
Expectedness of an Adverse Event .............................................................................46 
12.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ...................................47 
12.4. 
Recording Adverse Events .........................................................................................47 
12.5. 
Reporting Serious Adverse Events .............................................................................47 
12.6. 
Special Situations ........................................................................................................47 
12.6.1. 
Overdose .....................................................................................................................47 
12.6.2. 
Death ...........................................................................................................................47 
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12.6.3. 
Responsibilities of the Investigator ............................................................................48 
12.6.4. 
Responsibilities of the Sponsor ..................................................................................48 
13. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ..........49 
13.1. 
Recording of Data .......................................................................................................49 
13.2. 
Quality Assurance .......................................................................................................49 
13.3. 
Retention of Study Documents ...................................................................................49 
14. 
STATISTICS ..............................................................................................................51 
14.1. 
General Considerations ...............................................................................................51 
14.2. 
Determination of Sample Size ....................................................................................51 
14.3. 
Analysis Sets ...............................................................................................................51 
14.4. 
Protocol Deviations ....................................................................................................51 
14.5. 
Disposition, Demographics, and Baseline Characteristics .........................................52 
14.6. 
Medical History ..........................................................................................................52 
14.7. 
Dosing and Compliance ..............................................................................................52 
14.8. 
Safety Analyses ..........................................................................................................52 
14.8.1. 
Safety Variables ..........................................................................................................52 
14.8.2. 
Safety Analysis ...........................................................................................................52 
14.8.2.1. 
Adverse Events ...........................................................................................................52 
14.8.2.2. 
Physical Examination, Vital Signs, Weight, and Height/Ulnar Length .....................53 
14.8.2.3. 
Clinical Laboratory Tests ...........................................................................................53 
14.8.2.4. 
Electrocardiograms .....................................................................................................53 
14.8.2.5. 
Echocardiograms ........................................................................................................54 
14.8.2.6. 
Prior and Concomitant Medications and Physiotherapeutic Interventions .................54 
14.9. 
Efficacy Analysis ........................................................................................................54 
14.9.1. 
Efficacy Variables ......................................................................................................54 
14.9.1.1. 
Secondary Efficacy Endpoints ....................................................................................54 
 
 
14.9.2. 
Efficacy Analyses .......................................................................................................54 
14.9.2.1. 
Analyses of Secondary Efficacy Endpoints ................................................................54 
 
 
14.10. 
PK Analysis ................................................................................................................55 
14.11. 
Interim Analysis ..........................................................................................................55 
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14.12. 
Other Statistical Issues ................................................................................................55 
15. 
SPECIAL REQUIREMENTS AND PROCEDURES................................................56 
15.1. 
Compliance with Ethical and Regulatory Guidelines .................................................56 
15.2. 
Institutional and Ethics Review ..................................................................................56 
15.3. 
Informed Consent and Authorization for Use and Disclosure of Protected 
Health Information ......................................................................................................56 
15.4. 
Compliance with the Protocol ....................................................................................56 
15.5. 
Confidentiality ............................................................................................................57 
15.5.1. 
Data .............................................................................................................................57 
15.5.2. 
Patient Anonymity ......................................................................................................57 
16. 
STUDY DOCUMENTATION AND GENERAL INFORMATION .........................58 
16.1. 
Essential Study Documents ........................................................................................58 
16.2. 
General Information ....................................................................................................58 
16.3. 
Dissemination of Study Results ..................................................................................58 
16.4. 
Product Handling and Complaints Reporting .............................................................58 
17. 
LIST OF REFERENCES ............................................................................................59 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
 


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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
2D 
2 dimensional 
6MWT 
6-Minute Walk Test 
AAOS 
American Academy of Orthopaedic Surgeons 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMD 
Becker muscular dystrophy 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CD 
compact disc 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CL 
total clearance 
Cmax  
maximum plasma concentration 
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 
EOS 
End of Study 
GCP 
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Abbreviation  
Definition 
GGT 
gamma-glutamyl transferase 
HEENT 
head, ears, eyes, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunofluorescence histochemistry 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IRT 
Interactive response technology 
IV 
intravenous, intravenously 
KIM-1 
kidney injury molecule-1 
LDH 
lactate dehydrogenase 
 
  
LVEF 
left ventricular ejection fraction 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
 
 
mITT 
modified Intent-to-Treat 
 
 
MPLA 
multiplex ligation-dependent probe amplification 
 
 
mRNA 
messenger ribonucleic acid 
 
 
MRT 
Mean residence time 
NCS 
not clinically significant 
 
 
PDE-5 
phosphodiesterase type 5 
PK 
pharmacokinetic 
PMO 
phosphorodiamidate morpholino oligomer 
 
 
PT 
Preferred Term 
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Abbreviation  
Definition 
QTcF 
QT interval corrected by Fridericia’s correction 
RBC 
red blood cells 
RNA 
ribonucleic acid 
 
 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC  
System Organ Class 
 
 
SUSARs 
Suspected unexpected serious adverse reactions 
t½  
elimination half-life 
TEAE 
treatment-emergent adverse event 
Tmax  
time to maximum plasma concentration 
US FDA 
United States Food and Drug Administration 
Vss  
apparent volume of distribution at steady state 
WBC 
white blood cell 
 
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6. 
INTRODUCTION 
6.1. 
Background of Duchenne Muscular Dystrophy 
Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease with an X-linked 
recessive inheritance caused by mutations in the dystrophin gene, with a worldwide incidence of 
1 in 5000 newborn boys, irrespective of geographical region, race, or population density 
(Zaharieva 2013; Mendell 2012; Moat 2013).  The mutations that cause DMD typically disrupt 
the messenger ribonucleic acid (mRNA) reading frame and prevent production of dystrophin, a 
critically important part of the protein complex that connects the cytoskeleton of a muscle fiber 
to the cell membrane and extracellular matrix.  In the absence of dystrophin, the stress of muscle 
contraction causes progressive muscle damage that ultimately involves all muscles, including 
skeletal, smooth, and cardiac.  The clinical effect of this disrupted dystrophin reading frame is 
progressive worsening of muscle function and ultimately death. 
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 (eg, 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). 
6.2. 
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 6-membered morpholinyl ring which 
replaces the 5-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 a result of the combination of the 
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morpholinyl rings and the uncharged linkages, PMOs have increased exon skipping activity and 
have decreased non-specific 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-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). 
6.3. 
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 these early clinical studies, a double-blind, placebo-controlled Phase 2 study 
(Study 4658-us-201) was initiated.  This study randomized 12 patients aged 7 to 13 years to 
receive once weekly infusions of eteplirsen or placebo as follows:  Group 1 received 50 mg/kg 
eteplirsen for 28 weeks (n=4); Group 2 received 30 mg/kg eteplirsen for 28 weeks (n=4); 
Group 3a received placebo for 24 weeks followed by 50 mg/kg eteplirsen for 4 weeks (n=2); and 
Group 3b received placebo for 24 weeks followed by 30 mg/kg eteplirsen for 4 weeks (n=2).  
All 12 patients successfully completed Study 4658-us-201 and transitioned to an open-label 
extension study (Study 4658-us-202) where they continue to receive the same dose of eteplirsen 
(30 mg/kg or 50 mg/kg via weekly intravenous [IV] infusion) they were receiving at the end of 
Study 4658-us-201. 
Study 4658-us-202 met its primary biological efficacy endpoint of increased novel dystrophin as 
assessed by immunofluorescence histochemistry (IHC) in muscle (biopsies at Week 48).  Results 
through more than 2 years in Studies 4658-us-201 and 4658-us-202 have shown a continued 
stabilization of walking ability in continuously eteplirsen-treated patients evaluable on the 
6-minute walk test (6MWT).  At 120 weeks, patients in the 30 mg/kg and 50 mg/kg continuous-
eteplirsen cohorts who were able to perform the 6MWT (n=6, modified Intent-to-Treat [mITT]) 
experienced a decline of 13.9 meters (<5%) from baseline in walking ability.  (Note that 2 DMD 
boys lost their ambulation within the first month in Study 4658-us-201 due to disease 
progression.  These boys were identical twins close to 10 years old who were excluded from the 
mITT population.)  A statistically significant treatment benefit of 64.9 meters (p≤0.006) was 
observed for this group as compared to the placebo/delayed-treatment cohort (n=4), which 
initiated treatment at Week 25 following 24 weeks of placebo.  After experiencing a substantial 
decline earlier in the study, this placebo/delayed-treatment cohort also demonstrated stabilization 
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in walking ability for more than 1.5 years (from Week 36 through Week 120), the period from 
which meaningful levels of dystrophin were likely produced, with a decline of 9.5 meters over 
this timeframe.  These analyses were based on the maximum 6MWT score when the test was 
performed on 2 consecutive days.  
No patient has withdrawn from Study 4658-us-202 due to an adverse event (AE).  Through 
120 weeks, eteplirsen has continued to be well tolerated, and there have been no reported 
clinically significant treatment-related AEs and no treatment-related serious adverse events 
(SAEs).  In addition, there have been no treatment-related hospitalizations or discontinuations.  
Refer to the Investigator’s Brochure for further details on the nonclinical and additional clinical 
data for eteplirsen. 
6.4. 
Rationale for the Current Study 
The purpose of this study is to evaluate the safety of eteplirsen over 2 years of dosing in patients 
between 4 to 6 years of age, inclusive, with genetic mutations amenable to treatment by exon 51 
skipping In addition, this study will enroll an untreated control group (DMD patients not 
amenable to exon 51 skipping) to further evaluate the natural history of DMD in this patient 
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7. 
STUDY OBJECTIVES  
7.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of eteplirsen in 
patients with DMD between 4 and 6 years of age who are amenable to exon 51 skipping.  
7.2. 
Secondary Objective 
The secondary objective is to evaluate the effect of eteplirsen on dystrophin expression as 
measured by dystrophin quantification by Western blot and dystrophin intensity levels 
determined by immunofluorescence on-treatment as compared to pre-treatment biopsied skeletal 
muscle tissue. 
 
 
 
 
 
7.4. 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective is to evaluate the pharmacokinetic profile of eteplirsen in 
this age group. 
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8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design 
This is an open-label, multi-center study to evaluate the safety and tolerability of eteplirsen in 
patients 4 to 6 years of age with genotypically confirmed DMD with genetic mutations amenable 
to treatment by exon 51 skipping. In addition, this study will enroll an untreated control group 
(DMD patients not amenable to exon 51 skipping) to further evaluate the natural history of DMD 
in this patient population. 
All patients will be evaluated for inclusion during a Screening/Baseline period.  Written 
informed consent from the parent/legal guardian to participate in the study must be obtained 
prior to beginning any study-related procedures.  Once eligibility is confirmed, all patients will 
undergo Screening Assessments as indicated in Sections 2 and 3 (Schedule of Events).   
For patients in the eteplirsen group, blood samples collected at the Screening Visit for the safety 
lab assessments must be obtained within 3 weeks prior to the Week 1 visit, and results must be 
available prior to dosing at Week 1.  
 However, if more than 3 weeks have elapsed since the collection of blood samples for 
the Screening safety lab assessments, it must be repeated.   
 If less than 3 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 Week 1 assessments as indicated in 
Section 2. 
Starting at Week 1, patients amenable to exon 51 skipping (treated patients) will receive once 
weekly IV infusions of 30 mg/kg eteplirsen for up to 96 weeks.  An extension to the dosing 
period may be considered prior to the end of the 96-week planned dosing period.  
Safety will be assessed through the collection of AEs, laboratory tests, electrocardiograms 
(ECGs), echocardiograms (ECHOs), vital signs, and physical examinations throughout the study. 
Upon qualification for the study, patients enrolled into the eteplirsen group will undergo the 
baseline assessments including a muscle biopsy, which may occur at a different study site 
(denoted as the surgical unit) than where patients will undergo infusions and study assessments 
(denoted as the infusion site).  Eteplirsen-treated patients will be randomized to a second muscle 
biopsy scheduled at Week 48 or Week 96.  
 
 
 
 
 
 
Blood samples for population PK estimation will be collected from all eteplirsen-treated patients.  
Blood samples for serial PK estimation will be collected at select sites. 
Following the end of the weekly infusions, patients will be required to return to the study site for 
End of Study safety evaluations.  The total duration including Screening, Treatment, and Follow-
up periods is approximately 105 weeks. 
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Patients in the untreated control group will undergo select safety, functional, and laboratory 
assessments over the course of the study but will not provide blood samples for PK 
determination and will not undergo muscle biopsy procedures.  See Section 3 for the timing of 
applicable assessments for the untreated control group. 
Refer to Section 11 for the detailed list of study assessments. 
8.2. 
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 6.3, these studies assessed 
the efficacy, safety, tolerability, and PK of 2 eteplirsen doses (50 mg/kg 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 
2 doses tested in this study.  Therefore, the lower dose was selected as the more conservative 
choice, because patients would presumably receive this drug as a life-long treatment. 
8.3. 
Study Endpoints 
8.3.1. 
Safety Endpoints 
Incidence of the following (all patients in the study): 
 AEs 
 Clinical laboratory abnormalities  
 Abnormalities in vital signs and physical examinations 
 Abnormalities on ECGs and ECHOs 
8.3.2. 
Secondary Endpoints 
Change from Baseline to Weeks 48 and 96 for the following: 
 Dystrophin protein levels quantified by Western blot (eteplirsen-treated patients only) 
 Dystrophin intensity as determined by IHC (eteplirsen-treated patients only) 


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8.3.4. 
Pharmacokinetic Endpoints 
From the population PK samples (eteplirsen-treated patients only), standard population PK 
parameters will be estimated.  The effects of demographic characteristics, concomitant 
medications, laboratory values, and other covariates on eteplirsen PK will be evaluated. 
From the serial PK samples, the following pharmacokinetic parameters will be determined, as 
appropriate: 
 Maximum plasma concentration (Cmax) 
 Time to maximum plasma concentration (Tmax) 
 Area under the plasma concentration-curve (AUC) 
 Apparent volume of distribution at steady state (Vss) 
 Elimination half-life (t½) 
 Total clearance (CL) 
 Mean residence time (MRT) 
8.4. 
Discussion of Study Design 
This is an open-label study to provide safety data on eteplirsen in patients with DMD who are 
between 4-6 years of age.  The primary focus of the study is safety; however, muscle biopsies are 
being performed and analyzed from all subjects to provide data about the effect of eteplirsen on 
dystrophin levels in this young patient population.  
 
 
 
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  Additionally, pharmacokinetic samples are being collected to 
provide information about the standard PK parameters for eteplirsen in this age group as well as 
to provide additional data for the population PK model. 
The 96-week treatment duration of the study provides sufficient follow-up time to obtain safety 
data in this population. 
An untreated group of DMD patients not amenable to exon 51 skipping (eg, those with 
confirmed deletions of exons 44, 45, or 53) have been included as a control group.  These 
patients will not receive eteplirsen and will not undergo muscle biopsy procedures nor will they 
provide blood samples for PK determination.  Patients in this untreated group will be followed 
for the entire study duration and will undergo select safety, functional, and laboratory 
assessments.  These untreated patients are being enrolled to further evaluate the natural history of 
DMD in this patient population. 
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9. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1. 
Number of Subjects 
Up to 40 patients will be enrolled in this study:  approximately 20 patients in the eteplirsen-
treated group (those amenable to exon 51 skipping) and up to 20 in the untreated control group 
(those not amenable to exon 51 skipping). 
9.2. 
Patient Inclusion Criteria 
A patient must meet all of the following criteria to be eligible for this study. 
1. Be a male with DMD and meet one of the following criteria:   
 Have an out-of-frame deletion amenable to exon 51 skipping (eg, 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 deletion endpoints by multiplex ligation-dependent 
probe amplification (MLPA) or sequencing.  These patients will be enrolled into the 
eteplirsen-treated group. 
 Have a deletion mutation that is not amenable to correction by exon 51 skipping as 
documented by a genetic report from an accredited laboratory confirming deletion 
endpoints by multiplex ligation-dependent probe amplification (MLPA) or 
sequencing.  These patients will be enrolled into the untreated group. 
2. Be 4 to 6 years of age, inclusive, at the Screening visit. 
3. Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug 
administration and the dose is expected to remain constant (except for modifications to 
accommodate changes in weight) for at least the first 12 weeks of the study OR has not 
received corticosteroids for at least 12 weeks prior to study drug administration and does 
not expect to start corticosteroids within the first 12 weeks of eteplirsen dosing.  
4. Have intact right and left biceps muscles or 2 alternative upper arm muscle groups. 
5. Have a parent(s) or legal guardian(s) who is able to understand and comply with all the 
study requirements. 
6. Have a parent(s) or legal guardian(s) who is willing to provide written informed consent 
for the patient to participate in the study. 
9.3. 
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 for DMD) within 
12 weeks of study drug administration that might affect muscle strength or function (eg, 
growth hormone, anabolic steroids). 
2. Previous or current treatment with any other experimental treatments within 12 weeks 
prior to study entry or participation in any other clinical trial within 6 months prior to 


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study entry.  (A patient may be enrolled in a concurrent non-interventional or 
observational study provided his participation does not interfere with this study.) 
3. Major surgery within 3 months of study drug administration or planned major surgery for 
any time during this study. 
4. Presence of other clinically significant illness including significant cardiac, pulmonary, 
hepatic, renal, hematologic, immunologic, behavioral disease or malignancy. 
5. Use of any systemic aminoglycoside antibiotic within 12 weeks of study drug 
administration or need for use of systemic aminoglycoside antibiotics or statins during 
the study. 
6. Have a left ventricular ejection fraction (LVEF) of <50% based on the screening ECHO 
or QT interval corrected by Fridericia’s formula (QTcF) ≥450 msec based on the 
screening ECG. 
7. 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. Patients who seem unwilling or unable to comply with the study procedures, in the 
Investigator’s opinion, are to be excluded. 
9.4. 
Completion of a Subject’s Participation in the Study 
The length of a patient’s participation will be from the time the informed consent form is signed 
until completion of the End of Study (Week 100) assessments for eteplirsen-treated patients or 
until Week 96 for untreated control patients.  
9.5. 
Patient Withdrawal Criteria 
Any patient can decide to withdraw from study participation at any time for any reason.  In 
addition, the 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, in 
consultation with the Sponsor’s medical monitor.  Reasons for study withdrawal include but are 
not limited to: 
 The patient was erroneously included in the study (ie, was found to not have met the 
eligibility criteria). 
 The patient experiences an intolerable or unacceptable AE. 
 The patient is unable to comply with the requirements of the protocol. 
 The patient participates in another investigational study. 
The Investigator or study staff will document the reason(s) for treatment (or study) 
discontinuation for all patients on the case report form (CRF).   
Patients who receive at least 1 dose of eteplirsen who withdraw from the study within 4 weeks 
from their last functional assessment visit will be asked to return to the study site to complete an 
End of Study (EOS) visit (Week 100, Section 2) within 4 weeks after their last dose. 


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Patients who discontinue eteplirsen dosing at Week 96, and transition to commercial drug, do not 
need to complete the End of Study visit assessments. 
9.6. 
Study Discontinuation 
If the Sponsor, the Investigator, the medical monitor, the study monitor, institutional review 
board/independent ethics committee (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 
limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study 
 A decision by the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
 A decision by the Sponsor to suspend or discontinue the study 
 Failure of the Investigator to enroll patients into the study at an acceptable rate 
 Failure of the Investigator to comply with pertinent regulations of IRB/IEC or 
appropriate regulatory authorities 
 Failure of the Investigator to comply with the protocol 
 Submission of knowingly false information from the research facility to the Sponsor, 
the study monitor, IRB/IEC or regulatory authority 
 Insufficient adherence to protocol requirements consistent with 21 Code of Federal 
Regulations (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 eteplirsen drug product to the Investigator and 
end the Investigator’s participation in the study. 
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10. 
TREATMENT OF SUBJECTS 
10.1. 
Investigational Drug Product – Eteplirsen Injection 
10.1.1. 
Packaging and Labeling 
Please refer to the study-specific Pharmacy Manual for information on packaging and labeling. 
The label text for the eteplirsen drug product 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. 
10.1.2. 
Storage 
Vials of eteplirsen drug product must be stored in a secured, limited-access area with appropriate 
temperature recording, controls, and monitoring.  Details for eteplirsen drug product handling, 
storage and for preparation of the diluted eteplirsen drug product for administration can be found 
in the study specific Pharmacy Manual.  
10.2. 
Treatments Administered 
Eligible patients in the eteplirsen-treated group will receive a weekly 30-mg/kg dose of 
eteplirsen as an IV infusion for up to 96 weeks. 
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.  It is recommended that a topical anesthetic cream (eg, 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 for the first year of treatment. If the patient has not experienced an infusion reaction 
after the first year of treatment, patients may be observed for at least 30 minutes following the 
end of each eteplirsen injection. 
In-home study treatment administration by a visiting nurse may be available after Week 48. 
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.  


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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.  
10.2.1. 
Dose Modification, Reduction, or Delay 
There is no provision for dose alteration in this study.  If an eteplirsen-treated 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. 
Patients who discontinue eteplirsen dosing at Week 96, and transition to commercial drug, do not 
need to complete the End of Study visit assessments. 
10.3. 
Randomization and Blinding 
This is an open-label study. DMD patients enrolled who are amenable to exon 51 skipping will 
receive weekly infusions of eteplirsen.  DMD patients enrolled who are not amenable to exon 51 
skipping will be included in the untreated control group. 
Eteplirsen-treated patients will have a muscle biopsy performed at Baseline. Additionally, 
eteplirsen-treated patients will be randomly assigned through interactive response technology 
(IRT) to a second muscle biopsy to be performed at Week 48 or Week 96.  The evaluation of the 
quantification of the dystrophin protein will be performed by personnel blinded to the time point 
of the patient’s muscle biopsy (ie, pre- and on-treatment).  For further details about this 
assessment refer to Section 11.4.1. 
Evaluation of 
 
 
 
assessors will be blinded to patient identity and study treatment.   
10.4. 
Prior and Concomitant Medications 
Oral corticosteroids, including, but not limited to, prednisolone and prednisone, for treatment of 
DMD may be required during the course of this study.  Patients entering the study must have 
been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug 
administration with the expectation the dose is expected to remain constant (except for 
modifications to accommodate changes in weight) for at least the first 12 weeks of the study and 
to the completion of study to the degree that is clinically feasible. 
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: 
 Oral angiotensin-converting enzyme (ACE) inhibitors, including but not limited to 
perindopril and lisinopril 
 Oral β-blockers, including but not limited to carvedilol and atenolol 
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 Angiotensin-receptor blockers, including but not limited to losartan, irbesartan, 
valsartan, and candesartan 
 Oral laxatives, including but not limited to lactulose, Senokot, and Movicol 
 Vitamin D and calcium supplements 
 Alendronate (Fosamax) or other bisphosphonates used to treat 
osteoporosis/osteopenia by inhibiting osteoclasts 
 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 (eg, 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 (ie, 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 
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: 
 Contracture control devices 
 Night splints 
 Stretching exercises (passive, active, self) 
 Serial casting 
The following therapies are not permitted during the conduct of this study: 
 Systemic or oral steroids for non-DMD conditions, except for treatment of an acute 
condition, eg, poison ivy 
 Investigational agents for the treatment of DMD  
 Any medication with the potential to affect muscle mass, strength, and/or function, 
such as, but not limited to, growth hormone and phosphodiesterase type 5 (PDE-5) 
inhibitors  
 Immunosuppressants (other than oral or systemic corticosteroids, as outlined)  
 Systemic aminoglycoside antibiotics (unless discussed and agreed upon with the 
Investigator and the Medical Monitor). (The use of topical aminoglycosides is 
allowed.) 
 Statins (unless discussed and agreed upon with the Investigator and Medical Monitor) 


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10.5. 
Treatment Compliance 
Treatment compliance (eteplirsen-treated patients) will be assessed via compliance with 
scheduled weekly infusions. 


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11. 
STUDY ASSESSMENTS 
Unless otherwise noted below, assessments described in this section apply to all patients in the 
study, eteplirsen-treated and untreated. 
11.1. 
Study Schedule of Events 
A detailed schedule of the study assessments and times for eteplirsen-treated patients is shown in 
Section 2. A schedule of assessments for the untreated control group is provided in Section 3. 
11.2. 
Assessments at the Screening/Baseline Visits 
11.2.1. 
Informed Consent 
Written informed consent from parent/legal guardian(s) for all patients’ participation in this 
study must be obtained prior to beginning any of the procedures for this study. 
11.2.2. 
Medical History 
Medical history will be obtained for all patients. 
11.2.3. 
Blood samples for DMD Genotyping 
 
Blood samples for all patients will be obtained at Screening for confirmation of DMD 
genotyping.  Eteplirsen-treated patients may start dosing based on local genotyping results 
provided that these results fulfill the required criteria described in Section 9.2; these 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.  
 
 
  
Patients in the untreated control group will also undergo genetic testing to confirm their DMD 
mutation (eg, deletions of exons 44, 45, or 53).  Patients whose genotype is not verifiable will be 
excluded from continuing in this trial.  
 
  
11.3. 
Safety Assessments 
11.3.1. 
Physical Examination 
Physical examinations, full and brief, will be conducted at the time points specified in Section 2 
for eteplirsen-treated patients.  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 
(eteplirsen-treated patients only) will include examination of general appearance, HEENT, heart, 
lungs, chest, abdomen, and skin. 
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Untreated patients will have a full physical examination performed at time points specified in 
Section 3. 
11.3.2. 
Vital Signs and Weight 
For eteplirsen-treated patients, vital signs (blood pressure, heart rate, respiration, and 
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 reduced 
to pre-infusion and 30 minutes after the end of 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. 
Patients in the untreated control group will have their vital signs and weight recorded at the time 
points specified in Section 3. 
11.3.3. 
Clinical Laboratory Evaluations 
The following routine clinical laboratory tests will be collected for eteplirsen-treated patients 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), lactate 
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 


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in medical care.  If clinically significant deterioration from baseline levels is noted, the 
Investigator will continue to monitor the patient with additional assessments until: 
 Values have reached normal range and/or baseline levels; or 
 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 
product or other protocol-specific procedures, and additional assessments are not 
medically indicated. 
Patients in the untreated control group will also undergo laboratory testing at the time points 
specified in Section 3. 
11.3.4. 
Height and Ulnar Length 
Height and ulnar length will be measured at the time points specified in Sections 2 and 3. 
Height should be measured with shoes off.  
For ulnar length, 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). 
11.3.5. 
Electrocardiogram 
Twelve-lead ECGs will be obtained at the time points specified in Sections 2 and 3.  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. 
11.3.6. 
Echocardiogram 
A standard 2-dimensional (2D) ECHO will be obtained at the time points specified in Sections 2 
and 3.  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. 
11.3.7. 
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 parent or legal guardian 
signs the informed consent form.  Information on any physiotherapeutic intervention must be 
collected in detail for this study. 
11.3.8. 
Adverse Events 
The collection of AEs is described in Section 12. 


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11.4. 
Efficacy Assessments 
11.4.1. 
Secondary Efficacy Assessment 
Upon qualification for the study during the Baseline visit, patients in the eteplirsen group will 
undergo a muscle biopsy at Baseline and will be randomized to a second muscle biopsy schedule 
at either Week 48 (50%) or Week 96 (50%).  The biopsies at Weeks 48 and 96 must occur within 
2 to 14 days of the visit.  The muscle biopsy must occur after the clinical evaluation. 
The Baseline muscle biopsy will be obtained from 1 biceps brachii muscle and the subsequent 
muscle biopsy will be obtained from the contralateral muscle.  A previously unbiopsied 
alternative upper arm muscle, such as the deltoid, may be used if the biceps brachii has been 
biopsied previously.  If an alternative muscle group is used, the same contralateral muscle will be 
biopsied at the subsequent muscle biopsy as well. 
Muscle biopsy samples will be collected at the Surgical Units and will be sent to a designated 
laboratory for analysis.  All analyses related to quantification of the dystrophin protein as 
measured by dystrophin quantification by Western blot and dystrophin intensity levels 
determined by immunofluorescence will be performed by personnel blinded to the time point of 
the patient’s muscle biopsy (ie, pre- and on-treatment).  Details are provided in the Laboratory 
Manual. 
Additional assessments completed on the muscle biopsy samples are presented in 
Section 11.4.2.5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 
 
 
 
 
  
 
 
 
 
   
11.5. 
Pharmacokinetic Assessments 
Blood samples for assessing plasma drug concentrations will be obtained from eteplirsen-treated 
patients, as specified in Section 2.  Refer to the Study Laboratory Manual for sample processing.  
Plasma samples will be analyzed to determine concentrations of eteplirsen. 
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11.5.1. 
Population PK Sampling 
Population PK blood samples will be obtained from eteplirsen-treated patients at the time points 
specified in Section 2 prior to the beginning of the infusion and approximately 5 to 10 minutes 
after the completion of the infusion.  Additional population PK blood samples will be collected 
at the time points specified in Section 2 approximately 1 to 2 hours after the completion of the 
infusion. 
11.5.2. 
Serial PK Sampling 
Blood samples for serial PK sampling will be collected from some eteplirsen-treated patients at 
select sites at the time points specified in Section 2 as follows:  pre-dose (within 30 minutes prior 
to the start of infusion), and post-infusion at 5, 15, 30, 60, and 90 minutes, and 2, 5, 8, 12, 16, 
and 24 hours after the completion of study drug infusion. 


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12. 
ADVERSE EVENTS 
12.1. 
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 the End of Study visit (or early termination 
from the study) will be recorded in each individual patient’s CRF.  For eteplirsen-treated patients 
who prematurely discontinue the study (see Section 9.5), 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 9.5), the 
Investigator or study staff becomes aware of an SAE that the Investigator believes is 
possibly/probably or definitely related to the IP (Section 12.3.1) or is possibly/probably or 
definitely related to a study procedure (Section 12.3.2), then the event and any known details 
must be reported promptly to the Sponsor. 
12.2. 
Definition of Adverse Events 
12.2.1. 
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.  AEs 
include: 
 Symptoms described by the patient or signs observed by the Investigator or medical 
staff. 
 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. 
12.2.2. 
Serious Adverse Event (SAE) 
An SAE is defined as any AE that results in any of the following: 
 Death:  The patient died as the result of the event. 
 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, 
ie, does not include an AE that had it occurred in a more severe form, might have 
caused death. 
 Required or prolonged inpatient hospitalization:  The AE resulted in 
hospitalization or prolonged an existing hospitalization.  Since hospitalization may be 


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part of the study, only hospitalizations that are longer than expected based on 
Investigator judgment, will be considered prolonged hospitalizations. 
 Persistent or significant disability/incapacity:  An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
 Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in 
the offspring of a patient exposed to the IP. 
 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.  
12.3. 
Classification of Adverse Events 
Each AE whether serious or non-serious will be classified by the Investigator according to the 
following rules and definitions. 
12.3.1. 
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. 
12.3.2. 
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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12.3.3. 
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 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. 
12.3.4. 
Severity of Adverse Events 
Note that severity is not the same as “seriousness,” which is defined in Section 12.2.2 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. 
12.3.5. 
Outcome 
For eteplirsen-treated patients, all AEs will be followed for 4 weeks after the last dose of 
investigational drug product.  Serious AEs will be followed until resolution or until the condition 
stabilizes or returns to baseline status or until no further follow-up is expected. The Investigator 
will record all information regarding to patient outcome for each AE or SAE. 
For untreated control patients, AE/SAEs will be followed until resolution to the extent possible. 
12.3.6. 
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. 
12.3.7. 
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. 


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12.3.8. 
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(s) per the requirements of the concerned 
competent bodies.  SUSARs will also be reported to study Investigators. 
12.4. 
Recording Adverse Events 
All AEs/SAEs experienced from the time of informed consent 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. 
12.5. 
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 12.2.2.  Refer to the SAE 
Reporting Plan for further details on the transmission of SAE Reports. 
12.6. 
Special Situations 
12.6.1. 
Overdose 
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.   
12.6.2. 
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. 


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12.6.3. 
Responsibilities of the Investigator 
The responsibilities of the Investigator include but are not limited to the following: 
 Monitor and record all AEs 
 Determine seriousness, severity, and relationship to IP and/or study procedure and/or 
underlying disease 
 Determination of the onset and end date of each event 
 Provide initial report on all SAEs within 24 hours of knowledge to the Sponsor or 
designee 
 Provide follow-up information on SAEs in a timely and proactive manner 
 Respond to queries regarding AEs and SAEs in a timely manner 
 Ensure source documentation for all AEs are accurate and complete 
 Ensure that the study is conducted as defined in this document 
12.6.4. 
Responsibilities of the Sponsor 
The responsibilities of the study Sponsor (Sarepta Therapeutics, Inc.) include but are not limited 
to the following: 
 Training of Investigator and site staff on AE/SAE definitions, safety assessments, and 
site obligations related to safety monitoring and reporting of AE/SAEs 
 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 
 Recording of AEs 
 Notification of expedited SAEs to sites 
 Annual safety reporting to regulatory authorities and IRBs/IECs according to regional 
requirements 


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13. 
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT 
13.1. 
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. 
13.2. 
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). 
13.3. 
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 
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. 


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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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14. 
STATISTICS 
14.1. 
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 non-missing values.  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.  Inferential statistics, if 
calculated, will be used for descriptive purposes only. 
14.2. 
Determination of Sample Size 
Sample size for this study is based upon qualitative considerations.  No formal sample size 
calculation has been made. The selected sample size is considered sufficient to provide initial 
safety evaluation of eteplirsen in the studied population; to provide adequate data to allow for 
estimation of pharmacokinetic parameters; and to provide biological proof-of -concept of exon 
skipping by eteplirsen in this age group. 
14.3. 
Analysis Sets 
The Safety set includes all patients who are enrolled in the eteplirsen group and receive at least 
1 dose of eteplirsen as well as all patients who are enrolled in the untreated group who have at 
least 1 safety assessment post-enrollment. 
Additional analysis sets will be defined in the SAP. 
14.4. 
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 (eg, 
inclusion/exclusion, prohibited therapies). 


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14.5. 
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. 
14.6. 
Medical History 
Medical history will be presented in data listings. 
14.7. 
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 for all 
eteplirsen-treated patients.  Dosing information will be provided in a data listing. 
14.8. 
Safety Analyses 
14.8.1. 
Safety Variables 
Incidence of: 
 AEs 
 Clinical laboratory abnormalities 
 Abnormalities in vital signs and physical examinations 
 Abnormalities on ECGs and ECHOs 
14.8.2. 
Safety Analysis 
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. 
14.8.2.1. Adverse Events 
For eteplirsen-treated patients, 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.  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 
IP will be used to summarize AEs by relationship and severity.   
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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: 
 TEAEs 
 TEAEs by severity 
 Treatment-related TEAEs 
 Treatment-related TEAEs by severity 
 Treatment-emergent SAEs 
 Death 
 Overdose 
In addition, all SAEs, regardless of their treatment-emergent status will be summarized by SOC 
and PT.  
For untreated patients, AEs and SAEs that first occur or worsen in severity after the study 
enrollment will be summarized in the same fashion as the TEAEs and treatment-emergent SAEs 
for the eteplirsen-treated group.  In addition, all SAEs, regardless of time of occurrence, will be 
summarized by SOC and PT. 
For all patients, the following listings will be produced: 
 All AEs, including non-treatment emergent AEs and TEAEs 
 AEs leading to discontinuation  
 SAEs 
14.8.2.2. Physical Examination, Vital Signs, Weight, and Height/Ulnar Length 
Vital signs, weight, and height/ulnar length will be presented by 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. 
14.8.2.3. Clinical Laboratory Tests 
Clinical chemistry, hematology, coagulation, and urinalysis will be presented by 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. 
14.8.2.4. Electrocardiograms 
The actual value and change from Baseline to each visit will be presented by visit, summarizing 
the actual values and change from Baseline to each visit for each parameter using descriptive 


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statistics.  Shift and frequency tables of predefined change abnormal of select ECG parameter 
values will be generated. 
14.8.2.5. Echocardiograms 
The actual value and change from Baseline to each visit will be summarized for each ECHO for 
EF. 
14.8.2.6. Prior and Concomitant Medications and Physiotherapeutic Interventions 
All prior and concomitant medications, as well as physiotherapeutic interventions, will be 
presented in data listings. 
14.9. 
Efficacy Analysis 
14.9.1. 
Efficacy Variables 
14.9.1.1. Secondary Efficacy Endpoints 
Change from Baseline to Weeks 48 and 96 for the following: 
 Dystrophin protein levels quantified by Western blot (eteplirsen-treated patients only) 
 Dystrophin intensity as determined by IHC (eteplirsen-treated patients only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.9.2. 
Efficacy Analyses 
14.9.2.1. Analyses of Secondary Efficacy Endpoints  
The analysis of change from Baseline to Weeks 48 and 96 in dystrophin protein level as 
quantified by Western blot (eteplirsen-treated patients only) will be based on a 1-sample 
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permutation t-test for each time point.  Change from Baseline to Weeks 48 and 96 in dystrophin 
intensity as determined by IHC will be analyzed similarly. 
 
 
  
 
 
14.10. 
PK Analysis 
For eteplirsen-treated patients, individual plasma levels of eteplirsen will be listed with the 
corresponding time related to eteplirsen administration and summary statistics will be generated 
by per-protocol time of collection. 
Pharmacokinetic parameters for eteplirsen will be calculated using non-compartmental analysis. 
Actual sampling times will be used in all final PK analyses; per protocol times will be used to 
calculate mean plasma concentrations for graphical displays.  
Plasma concentration-time data of eteplirsen will be used to perform a future population PK 
analysis using nonlinear mixed-effects modeling.  Data may be combined with those of 
completed studies to support a relevant structural model.   
14.11. 
Interim Analysis 
No interim analysis is planned for this study. 
14.12. 
Other Statistical Issues 
Additional analyses may be conducted.  Any such analyses will be detailed in the SAP. 
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15. 
SPECIAL REQUIREMENTS AND PROCEDURES 
15.1. 
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. 
15.2. 
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 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. 
15.3. 
Informed Consent and Authorization for Use and Disclosure of 
Protected Health Information  
Written informed consent from each patient’s parent(s) or legal guardian(s) must be obtained 
before any study-specific screening or baseline period evaluations are performed.  One copy of 
the signed informed consent documents will be given to the patient; the Investigator will retain 
the original copies of these documents. 
The informed consent 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.  
15.4. 
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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15.5. 
Confidentiality 
15.5.1. 
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. 
15.5.2. 
Patient Anonymity 
The anonymity of participating patients will be maintained to the extent required by applicable 
laws and in accordance with current HIPAA standards.  Patients will 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 (eg, 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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16. 
STUDY DOCUMENTATION AND GENERAL INFORMATION 
16.1. 
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 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 IND safety reports / Safety 
Alert Letters. 
16.2. 
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. 
16.3. 
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. 
16.4. 
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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17. 
LIST OF REFERENCES 
American Academy of Orthopaedic Surgeons (AAOS). 
http://www.aaos.org/research/outcomes.outcomes_peds.asp. Website accessed on: 26 Jul 2013. 
AAOS. http://www.aaos/org/ Website accessed on: February 2014. 
Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, et al. 
Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy 
mutations. Hum Mutat. 2009 Mar;30(3):293-9. 
Beenakker, EA, Fock JM, et al. Intermittent prednisone therapy in Duchenne muscular 
dystrophy: a randomized controlled trial. Arch 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, Florence J, et al. Duchenne 
muscular dystrophy: patterns of clinical progression and effects of supportive therapy. Neurol. 
1989 Apr;39(4):475-81. 
Bushby, KM and Gardner-Medwin D. The clinical, genetic and dystrophin characteristics of 
Becker muscular dystrophy. I. Natural history. J Neurol. 1993;240(2):98-104. 
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. 
Gauld LM, Kappers J, Carlin JB, Robertson CF. Height prediction from ulna length. Dev Med 
Child Neurol. 2004 Jul;46(7):475-80. 
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.  
Manzur AY, Kuntzer T, Pike M, Swan A.  Glucocorticoid corticosteroids for Duchenne 
muscular dystrophy. Cochrane Database Syst Rev. 2004;(2):CD003725. 
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Mazzone E, Vasco G, Sormani MP, Torrente Y, Berardinelli A, Messina S, et al. Functional 
changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurol. 
2011;77(3):250-6. 
Mendell JR, Shilling C, Leslie ND, Flanigan KM, Al-Dahhak R, et al. Evidence-Based Path to 
Newborn Screening for Duchenne Muscular Dystrophy. Ann Neurol. 2012;71:304–13. 
Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn Bloodspot Screening for 
Duchenne Muscular Dystrophy: 21 Years Experience in Wales (UK). Eur J Hum Genet. 
2013;Doi:10.1038/Ejhg.2012.301. 
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. 
Uzark K, Cripe L, Spicer R, Spicer R, Sage J, Kinnett K, et al. Health-related quality of life in 
children and adolescents with Duchenne muscular dystrophy. Pediatrics. 2012;130:e1559-66. 
Zaharieva I, Calissano M, Scoto M, Preston M, Cirak S, Feng L, et al. Dystromirs as Serum 
Biomarkers for Monitoring the Disease Severity in Duchenne Muscular Dystrophy. PLoS One. 
2013;8(11):e80263. doi:10.1371/journal.pone.0080263 
 
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SAP_000.pdf: 
Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 1 of 39 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol 4658-203 
 
An Open-Label, Multi-Center Study to Evaluate the Safety, Efficacy and 
Tolerability of Eteplirsen in Early-Stage Duchenne Muscular Dystrophy 
 
 
 
 
 
 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
 
 
 
 
 
 
 
 
 
 
(Protocol version: Amendment 2, 08 June 2017) 
 
 
 
 
Version: 1.0 
 
 
Date: 11 February 2019 
 
 
 
 


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Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 6 of 39 
Tmax  
 
 
Time to maximum plasma concentration 
Vss 
 
 
 
Apparent volume of distribution at steady state 
WHO Drug 
 
 
World Health Organization Drug Dictionary 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 7 of 39 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a detailed description of 
the statistical methods and procedures that will be used to analyze and report results for   
Study 4658-203, titled “An Open-Label, Multi-Center Study to Evaluate the Safety, 
Efficacy and Tolerability of Eteplirsen in Early-Stage Duchenne Muscular Dystrophy”. 
 
This SAP has been prepared based on Protocol Amendment 2, dated 08 June 2017.   
 


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Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 11 of 39 
3.2.4 
Pharmacokinetic Endpoints 
The following PK parameters will be determined, as appropriate for eteplirsen-treated 
patients only: 
• Maximum plasma concentration (Cmax) 
• Time to maximum plasma concentration (tmax) 
• Area under the plasma concentration-curve (AUC) 
• Apparent volume of distribution at steady state (Vss) 
• Elimination half-life (t½) 
• Total clearance (CL) 
• Mean residence time (MRT) 
• Renal clearance (CLR) 
3.3. 
Sample Size and Power 
 
Sample size for this study is based upon qualitative considerations; no formal sample size 
calculations will be performed. Up to 40 patients will be included in this study: 
approximately 20 patients in the eteplirsen-treated group (those amenable to exon 51 
skipping) and up to 20 in the untreated control group (those not amenable to exon 51 
skipping). 
3.4. 
Planned Analyses 
3.4.1 
 Periodic Safety Data Reviews 
Periodic safety analyses will be performed for Investigator's Brochure (IB) update, and 
regulatory submissions (Development Safety Update Report [DSURs]) as necessary. 
These periodic safety analyses will continue to be performed approximately every 12 
months during this study.   
3.4.2 
Final Analysis  
A final analysis of safety and efficacy will be conducted once the last patient completes 
or discontinues the entire study and the resulting database is cleaned, quality assured, and 
locked. All statistical analyses will be performed by or under the supervision of the 
Sponsor. 
All available data will be included in data listings and tabulations. 
Because the untreated control group had not been able to enroll the planned number (20) 
of patients, had a high dropout rate, and resulted in a very small sample size, an external 
control dataset may be identified and used to evaluate the effect of eteplirsen treatment. 
The statistical methods for the identification and use of the external control dataset may 
be presented in a separate SAP if deemed appropriate. The results from analysis of 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 12 of 39 
eteplirsen treated patients as compared to an external control if performed will not be 
included in the Clinical Study Report (CSR), but may be reported in a standalone report. 


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CCI


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 14 of 39 
stop date is available and the year is prior to the year of dosing, the medication 
will be classified as a prior medication.  
• For a partial AE onset date, the event will be classified as treatment emergent if 
the month and/or year of the onset date are on or after the initiation of eteplirsen 
for eteplirsen treated patients or after Day 1 for untreated patients and within 28 
days of the last dose of eteplirsen for eteplirsen treated patients or within a day  
after last visit for untreated patients, or if the month and/or year of the onset date 
are on or after the date of the qualifying visit for untreated patients. All AEs with 
a missing AE onset date will be classified as treatment emergent.  
• For the purpose of calculating the time since DMD diagnosis or duration of prior 
corticosteroid use, if the date of DMD diagnosis or the start date of corticosteroid 
use has a missing day but known month and year, then the 15th of the month will 
be used in the calculation. If the date has a missing day and month and only the 
year is known, December 31st of the recorded year will be used in the calculation. 
 
In all cases, the original missing or incomplete dates will be presented in the data listings. 
4.3. 
Analysis Populations 
There will be 3 analysis populations with the definitions below for analyzing safety data, 
efficacy data, biopsy data and pharmacokinetics, as appropriate. 
• Full Set: Full set includes all patients who are enrolled in the eteplirsen group and 
receive at least 1 dose of eteplirsen as well as all patients who are enrolled in the 
untreated group who have at least 1 assessment post-enrollment assessment. Full 
Set will be used for summarizing safety and efficacy data. 
• Muscle Biopsy Set: This set includes all patients who receive at least one dose of 
eteplirsen and who have data from both Baseline (pre-treatment) and Week 48 or 
Week 96 (on-treatment) muscle biopsy samples.   
• Pharmacokinetic Set: All patients who receive at least one dose of eteplirsen and 
for whom there are adequate PK samples with which to estimate PK parameters. 
The PK Set will be further described in a separate PK SAP. 
4.4. 
Multiple Testing and Comparisons 
No adjustment will be made for the testing of multiple endpoints. 
4.5. 
Adjustment for Covariates 
Not applicable.  
4.6. 
Subgroups 
Due to small sample size, no subgroups will be identified for this study. 


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Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 19 of 39 
5. 
STATISTICAL ANALYSES 
5.1. 
Patient Disposition 
 
The number of patients enrolled, the number in the safety population, the number 
randomized to muscle biopsy, the duration of the study (weeks) [both continuous and 
categorical interval summaries], the number and percentage of patients completing the 
study through Week 96 (i.e., completers), and the number and percentage of patients 
prematurely discontinuing before Week 96 will be summarized. Reasons for premature 
discontinuation will also be summarized. All analyses will be performed by treatment 
group. 
 
Patient eligibility will be presented in a listing.  
5.2. 
Demographics and Baseline Characteristics 
Demographic characteristics including age (years), race, ethnicity, and baseline 
characteristics including height (cm), weight (kg), body mass index (BMI; kg/m2), time 
since DMD diagnosis (months) to Baseline, corticosteroid type (Deflazacort or 
Prednisone), corticosteroid frequency (continuous versus intermittent), mutation type(s), 
and duration of prior corticosteroid treatment (months) to Day 1 will be summarized by 
treatment group. Demographic data and baseline characteristics will also be presented in 
data listings.  
5.3. 
Prior and Concomitant Medications 
Concomitant medications will be coded by preferred term (PT) using the most recent 
World Health Organization (WHO) Drug Dictionary (WHODRUG, 01DEC2013). The 
number and percentage of patients in the safety population taking concomitant 
medications will be tabulated by Anatomical Therapeutic Chemical (ATC) classification, 
pharmacological subgroup, and WHO drug PT by treatment group. At each level of 
summarization, a patient is counted once if he/she reported 1 or more medications at that 
level. 
All prior medications and concomitant medication will be presented in data listings. 
5.4. 
Medical History  
 Medical history data for the safety set will be presented in data listings. 
5.5. 
Physiotherapeutic Interventions 
A listing of all physiotherapeutic interventions will be provided. 
5.6. 
Protocol Deviations 
A listing of major protocol deviations will be provided. The protocol deviations will be 
identified based on a review of the study data prior to the database lock and will include 
the nature of the deviation (e.g., inclusion/exclusion, prohibited therapies). 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 20 of 39 
5.7. 
Exposure to Study Drug 
The total number of infusions received, cumulative amount of drug received (mg), total 
volume of drug administered (mL), duration on eteplirsen in 24-week intervals, and the 
continuous number of weeks on eteplirsen will be summarized for all eteplirsen-treated 
patients. Dosing information will be provided in a data listing. 
A listing of patients with overdose will be generated. 
5.8. 
 Safety Analyses  
 Safety analyses will be descriptive in nature. Safety analyses will include summaries of 
the following: 
• The type, frequency, severity, timing, and relationship to the investigational drug 
product of AEs, SAEs, and discontinuations due to AEs. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA 17.1 or 
higher) and will be reported by primary system organ class (SOC) and PT. 
• Safety laboratory testing including hematology, coagulation, serum chemistry, 
and urinalysis 
• Vital signs 
• Physical examinations  
• ECG and/or ECHO   
5.8.1 
Adverse Events 
In general, only TEAEs will be summarized (for untreated subjects, AEs that first occur 
or worsen in severity after the study enrollment are considered treatment-emergent).  
Non-treatment-emergent adverse events will be recorded in the data listings. Unless noted 
otherwise, for all AE tables, the number and percentage of patients reporting AEs will be 
grouped using the MedDRA, SOC, and PT and summarized for treated patients, untreated 
patients, and overall. 
An overall summary table of adverse events will be produced and will include the 
frequency count and percentage of patients with  
o   TEAE 
o   Treatment-related TEAE 
o   Severe TEAE 
o   Treatment-Emergent SAE 
o   Treatment-Emergent Related SAE 
o   TEAE leading to discontinuation of study drug 
o   TEAE leading to death 
The number of events at each severity level (mild, moderate, severe) will also be 
included. 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 21 of 39 
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 a different relationship/severity, the event with the strongest relationship or 
maximum severity to investigational drug product will be used to summarize AEs by 
relationship and severity. 
The following summary tables will be produced: 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT and severity 
• TEAE by PT in descending frequency  
• Treatment-related TEAEs by SOC and PT 
• Treatment-related TEAEs by SOC, PT, and severity 
• Treatment-related TEAEs by PT in descending frequency 
• Treatment-Emergent SAEs by SOC and PT 
• Treatment-related Treatment-Emergent SAEs by SOC and PT 
• TEAEs leading to treatment discontinuation by SOC and PT 
• TEAEs leading to death by SOC and PT 
• Non-serious TEAEs by SOC and PT, displaying both number of subjects and 
number of events 
The following listings will be produced: 
• All AEs 
• AEs leading to treatment discontinuation 
• SAEs 
5.8.2 
Adverse Events of Special Interest 
Summaries of TEAEs of special interest will be summarized by SOC and PT. All 
standard MedDRA queries (SMQs based on MedDRA version 17.1) listed below will 
include broad and narrow terms. The AEs of special interest (AESI) are: 
• Hypersensitivity (hypersensitivity SMQ)  
• Renal toxicity (acute renal failure SMQ) 
• Infusion-related reaction (IRR) (AEs occurring within 24 hours of the start of any 
infusion [including events that occurred on the same date as an infusion where 
infusion start time or AE onset time was not reported]) 
For all IRRs as defined above, adjudicated IRRs will be identified by a 
pharmacovigilance physician. All IRRs as defined above that are considered as related to 
study drug by investigators will be counted in the list of adjudicated IRRs. In addition, all 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 22 of 39 
IRRs as defined above that meet the following criteria will be excluded from the list of 
adjudicated IRRs: 
• AE was an infusion site, application site, or other local AE not associated with 
IRR  
• AE had a clear alternate etiology that could be ascertained based on the 
reported event (eg, reaction to plaster, assessed as related to procedure or 
underlying disease by investigator) 
• AE not associated with an IRR due to the nature of the event or biologically 
implausible (eg, fibula fracture, chalazion) 
 A summary table will be generated and include the following: 
• Number of patients with adjudicated IRRs 
• Number of adjudicated IRRs 
• Number of adjudicated IRRs with event start time reported 
• Number of events on any day for adjudicated IRRs  
A corresponding listing will be generated for each table. Additionally, a table and listing 
corresponding to the AESIs that were related to study drug or moderate or severe will be 
produced. 
An overall summary of AESI events will include the total number of events, number of 
serious events, number of related events, number of not related events, number of mild 
events, number of moderate events, number of severe events, and number of events 
occurring on the same day as an infusion.  
5.8.3 
Additional Adverse Events for Review 
Summaries of Additional TEAEs for review will be summarized by SOC and PT. All 
SMQs based on MedDRA Version 17.1 are listed below and will include broad and 
narrow terms.  
Additional AEs for review are: 
• Drug-induced hepatotoxicities (cholestasis and jaundice of hepatic origin SMQ, 
hepatic failure, fibrosis, cirrhosis, and other liver damage-related conditions SMQ, 
hepatitis, noninfectious SMQ, liver neoplasms, benign [including cysts and polyps] 
SMQ, liver malignant tumors SMQ, liver tumors 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, sign and symptoms SMQ) 
• Thrombocytopenia (hematopoietic thrombocytopenia SMQ) 
• 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, bacteremia, viremia and fungemia NEC (not elsewhere 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 23 of 39 
classified), 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”). Note: The port-
related events will only be identified for patients who have a port placed/inserted and 
for events that occur after the port insertion occurred. It is noted that port insertion 
may occur during treatment or prior to the start of treatment. Percentages will be 
calculated based on the total number of patients who have had a port inserted 
A corresponding listing will be generated for each table. Additionally, a table and listing 
corresponding to the additional AEs for review that were related to study drug or 
moderate or severe will be produced. 
An overall summary of additional AEs for review will include total number of events, 
number of serious events, number of related events, number of not related events, number 
of mild events, number of moderate events, number of severe events, and number of 
events occurring on the same day as an infusion.  
5.8.4 
Clinical Laboratory Evaluation 
Clinical chemistry, hematology, coagulation, and urinalysis results will descriptively be 
summarized by treatment group and by selected time point. Baseline value, 
highest/lowest postbaseline value, and final observation and the corresponding change 
from Baseline will be summarized for treated patients and untreated patients. Frequency 
tables of patients with potentially clinically significant laboratory parameter values at any 
time point will be generated. The total number of potentially clinically significant values 
will also be summarized. Potentially clinically significant values can be found in 
Appendix 1 tables 1-3. 
A shift table will present the number and percentage of patients in each cell resulting 
from cross-tabulating the status (low, normal, and high) of the highest/lowest 
postbaseline value versus that of the baseline for each laboratory test, if applicable, by 
treatment group. If a specific test can have both a significant low and high, then a shift 
table will be generated for each direction. The percentage will be based on the total 
number of patients in the Safety Set. 
All patient-level clinical laboratory values will be displayed in data listings.  In addition, 
values meeting the potentially clinically significant abnormalities criteria will be 
presented in data listings.  Treatment-emergent abnormalities will be indicated in the 
listing. 
5.8.5 
Vital Signs and Other Physical Findings 
Vital signs, height/length, and weight will be summarized by treatment group and by 
selected time point. Baseline value, highest/lowest postbaseline value, and final 
observation and the corresponding change from Baseline will be summarized for treated 
patients, untreated patients. Highest/lowest value is considered as the largest absolute 
change from Baseline for systolic blood pressure, diastolic blood pressure, and 
respiratory rate, and highest value for pulse rate and temperature. The highest/lowest 
value will not be summarized for height, weight, or ulnar length. Frequency tables of 
patients with potentially clinically significant vital sign values will be generated. The 


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Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 28 of 39 
Pharmacokinetic parameters for eteplirsen will be calculated using non-compartmental 
analysis. Actual sampling times will be used in all final PK analyses; per protocol times 
will be used to calculate mean plasma concentrations for graphical displays. The PK 
parameters that will be determined include: Cmax, tmax, AUC, Vss, t½, CL, MRT and 
CLR. 
Plasma concentration-time data of eteplirsen will be used to perform a future population 
PK analysis using nonlinear mixed-effects modeling. Data may be combined with those 
of completed studies to support a relevant structural model. 
The details of PK analyses will be described in a separate PK SAP. 


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Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 31 of 39 
7. 
APPENDEX 1: ABNORMALITIES OF INTEREST 
Appendix Table 1. Chemistry Laboratory Abnormalities of Interest 
 
 
Predefined Change 
 
Test 
Unit 
Decrease 
Increase 
Markedly Abnormal 
Criteria 
BUN 
mmol/L 
NA 
NA 
Value >1.5× Baseline and 
>ULN 
Creatinine 
µmol/L 
NA 
35 
Value > ULN 
Sodium 
mmol/L 
8 
8 
NA 
Potassium 
mmol/L 
1.1 
1.0 
Value >5.5 mmol/L or  
<3 mmol/L 
Chloride 
mmol/L 
9 
8 
NA 
Uric acid 
µmol/L 
NA 
NA 
>1×ULN 
Calcium 
mmol/L 
0.30 
0.30 
NA 
AST (SGOT) 
U/L 
NA 
NA 
Value ≥2× Baseline Value 
and >ULN 
ALT (SGPT) 
U/L 
NA 
NA 
Value ≥2× Baseline Value 
and >ULN 
Gamma glutamyltransferase 
U/L 
NA 
NA 
Value >3× Baseline Value  
and > ULN 
Alkaline phosphatase 
U/L 
NA 
NA 
Value >1.5 × ULN 
Albumin 
g/L 
10 
10 
< LLN or >ULN 
Total bilirubin 
µmol/L 
NA 
10 
Value >1.5× ULN 
Lactate dehydrogenase 
U/L 
NA 
NA 
Value ≥2× Baseline Value 
Creatine phosphokinase 
U/L 
NA 
NA 
Value ≥2× Baseline Value 
Cystatin C 
mg/L 
NA 
NA 
>ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; LLN = 
lower limit of normal; NA = Not Applicable; ULN = upper limit of normal 
 
 
 
 
 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 32 of 39 
 
Appendix Table 2.  Hematology Laboratory Abnormalities of Interest 
Test 
Unit 
Markedly Abnormal Criteria 
Hematocrit 
1 
<LLN 
Hemoglobin 
g/L (or mmol/L) 
<LLN 
Red blood cell count 
trillion/L 
<LLN 
White blood cell count 
10^p/L 
>1.5 × ULN or <LLN 
Platelet count 
10^9/L 
<150 or <200 with a decrease of 
at least 100 
Basophils (abs) 
10^9/L 
>ULN or <LLN 
Eosinophils (abs) 
10^9/L 
>1.5 × ULN or <LLN 
Lymphocytes (abs) 
10^9/L 
<LLN 
Monocytes (abs) 
10^9/L 
<LLN 
Neutrophils (abs) 
10^9/L 
>1.5 × ULN or <0.000001 
abs = absolute; LLN = lower limit of normal; ULN = upper limit of normal 
Appendix Table 3.  Urinalysis Laboratory Abnormalities of Interest 
 
 
Test 
Markedly Abnormal Criteria 
Protein in urine 
> 1+  
Blood in urine 
Positive (+)  
RBCs in urine 
>0 
Appendix Table 4. Vital Sign Abnormalities of Interest 
Variable 
Units 
Markedly Abnormal 
Criteria Lower limit 
Markedly Abnormal 
Criteria Upper limit 
Systolic blood pressure 
mmHg 
<90 
>140 
Diastolic blood pressure 
mmHg 
<40 
>90 
Pulse rate 
beats/minute 
<60 
>130 
Respiratory rate 
breaths/min 
<12 
>20 
Temperature 
oC 
<36.0 
>38.0 
Weight 
kg 
Decrease of 7% or 
more 
NA 
NA = not applicable 
 


Sarepta Therapeutics, Inc. 
Protocol 4658-203  
Statistical Analysis Plan  
Version 1.0  
 
Page 33 of 39 
 
Appendix Table 5. Electrocardiogram and Echocardiogram Abnormalities of  
                                Interest 
Variable 
Units 
LLN 
ULN 
Age Group 
(years) 
Markedly Abnormal 
Criteria 
Heart rate 
Beats 
per 
minute 
60 
130 
 
NA 
QTcF interval 
 
 
msec 
 
 
 
 
NA 
 
 
NA 
All 
Screening Visit >450 
<12 
>480 
≥12 
>500 
All 
<320 
Increase >60 
>450 
>480 
>500 
QRS interval 
 
msec 
 
NA 
NA 
<12 
IVCD or any QRS 
conduction disturbance with 
a QRS >110 msec 
≥12 
IVCD or any QRS 
conduction disturbance  
with a QRS >120msec 
PR interval 
 
msec 
 
NA 
NA 
<12 
>190 
≥12 
>220 
Left ventricular 
ejection 
fraction 
% 
NA 
NA 
All 
<55% 
Fractional 
shortening 
% 
NA 
NA 
All 
<29% 
IVCD = intraventricular conduction delay; LLN = lower limit of normal; NA = not 
applicable; QTcF= QT interval Fridericia corrected; ULN = upper limit of normal 


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