Clinical trial NCT03218995
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD Duchenne Eteplirsen dystrophy dystrophin exon 51
Sponsor: Sarepta Therapeutics, Inc.
Start date: 2017-08-16; Completion date: 2021-03-10
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, and PK of once-weekly IV infusions of eteplirsen in approximately 12 male participants, ages 6 months to 48 months (inclusive), who have genotypically confirmed DMD with a deletion mutation amenable to exon 51 skipping.

Detailed description:

Arms: arm 1: Eteplirsen will be administered once every 7 days by intravenous (IV) infusion starting on Day 1 for up to 96 weeks. The starting dose will be 2 milligrams/kilogram (mg/kg) eteplirsen, with escalation to 4, 10, 20, and 30 mg/kg for 10 weeks, and then participants will continue to receive eteplirsen at 30 mg/kg for the duration of the study.
Interventions: intervention 1: Eteplirsen
Intervention descriptions: intervention 1: Infusion for intravenous use.

Protocol documents:
Prot_000.pdf: 
Sa repta Therapeutics, Inc.
Protocol 4658-102, Version 4
Page 1 of 70
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CLINICAL STUDY PROTOCOL
DRUG:
Eteplirsen (Eteplirsen Injection)
STUDY NUMBER:
4658-102 
STUDY TITLE:
An Open-Label Safety, Tolerability, and 
Pharmacokinetics Study of Eteplirsen in Young 
Patients with Duchenne Muscular Dystrophy 
Amenable to Exon 51 Skipping 
EUDRACT Number:
2016-000951-29 
SPONSOR:
Sarepta Therapeutics, Inc.
215 First Street
Cambridge, MA 02142 USA
Phone: +1-617-274-4000 
CURRENT VERSION DATE:
Version 4, 07 February 2020 
PRIOR VERSION DATE:
Version 1 (Original; 30 June 2016) 
Version 2, 09 January 2017 
Version 3, 06 March 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, is the property of theSponsor and is confidential. This
information may not be disclosed, reproduced or distributed to anyone other than personnel directly involved
in the conduct of the study and in response to a relevant Institutional Review Board/Independent Ethics
Committee and review by a regulatory authority as required by theapplicable laws and regulations, without
NCT # NCT03985878


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the written authorization of the Sponsor, except to the extent necessary to obtain written informed consent 
from those individuals to whom the drug may be administered. These restrictions will continue to apply after 
the study has closed. 


 
Protocol Title: 
An Open-Label Safety, Tolerability, and Pharmacokinetics Study of 
Eteplirsen in Young Patients with Duchenne Muscular Dystrophy 
Amenable to Exon 51 Skipping 
Study No: 
4658-102 
Current Version Date: 
07 February 2020 
 
 
 
 
Sarepta Therapeutics , Inc. 
Protocol 4658-102, Ver s io n 4 
Page 3 of 70 
 
SIGNATURE PAGE FOR SPONSOR 
 
 
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) described in 
21 Code of Federal Regulations (CFR) parts 50, 54, 56, and 312; and the European 
Clinical Trial Directive 2001/20/EC and European Union (EU) Clinical Practice 
Directive 2005/28/EC; ICH E6 (R2) Good Clinical Practice Guideline. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events (AEs), relating to treatment with the IP. 
 
 
 
 
Sarepta Therapeutics Inc. 
215 First Street 
Cambridge, MA 02142 USA 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 


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INVESTIGATOR’S AGREEMENT 
I have read the Study Protocol 4658-102 and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone Number 
Responsible Physician 
 
 
 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
Mobile Phone : 
 
Email: 
 


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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 Safety, Tolerability, and Pharmacokinetics Study of Eteplirsen in Young 
Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping 
Study Number: 4658-102 
Phase of Study: Phase 2 
INVESTIGATOR STUDY SITES: This multicenter study will be conducted at approximately 5 sites 
in the European Union. 
OBJECTIVES: 
Primary Objective 
• 
To evaluate the safety and tolerability of eteplirsen administered once weekly by intravenous 
(IV) infusion in male Duchenne muscular dystrophy (DMD) patients ages 6 months to 
48 months, inclusive. 
Secondary Objective 
• 
To determine the pharmacokinetics (PK) of eteplirsen at the 2-, 10-, 20-, and 30-mg/kg dose 
levels, administered once weekly by IV infusion in male DMD patients ages 6 months to 
48 months, inclusive. 
 
• 
 
METHODOLOGY: 
This is a multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, and 
efficacy of once-weekly IV infusions of eteplirsen in approximately 12 male patients ages 6 months to 
48 months (inclusive) who have genotypically confirmed DMD with a deletion mutation amenable to 
exon 51 skipping. 
Screening 
Patients will be evaluated for inclusion during the Screening Period of up to 2 weeks to ensure eligibility 
prior to dosing with eteplirsen. After obtaining informed consent, screening assessments will include a 
review of inclusion/exclusion eligibility criteria, demographics and medical history, previous and 
current medications, clinical safety laboratory testing (blood and urine samples), vital signs, physical 
examination (including height/length and weight), 12-lead electrocardiogram (ECG), and 
echocardiogram (ECHO). Blood samples for the screening clinical safety laboratory assessments must 
be obtained within 2 weeks prior to the Baseline/Week 1 visit, and results must be available prior to 
dosing at Baseline/Week 1. A blood sample to confirm DMD genotype will also be obtained. Patients 
not previously genotyped may be consented and have genotype performed as part of the study. Once the 
genotype is confirmed, all additional screening procedures will be performed 2 weeks from 
Week 1/Baseline. The sample for genotyping can be drawn at Screening or any time prior to the Week 2 
visit so that total blood volume taken for the Screening visit does not exceed recommendations. A 
separate blood sample will be obtained for genotyping of latent transforming growth factor beta (TGF) 
binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP-1); this may be drawn at any time 
during the dose-titration period. 
 


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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 
 
 
Treatment Period 
Patients will be enrolled into 1 of 2 age cohorts. Cohort 1 will include approximately 6 patients ages 
24 to 48 months old and Cohort 2 will include approximately 6 patients ages 6 to <24 months old. 
Cohort 1 will be enrolled first, and only after the first 3 patients in Cohort 1 have completed at least 
12 infusions of eteplirsen and all available safety data have been reviewed will enrollment begin for 
patients in Cohort 2. An external Data Monitoring Committee (DMC) will review safety data at least 
weekly through the first 12 weeks of dosing for the first 3 patients of each age cohort. Reviews will be 
at least quarterly thereafter. 
The dose-titration period will last 10 weeks overall (1 infusion/week) to slowly achieve the target dose 
of 30 mg/kg. Eteplirsen dosing will begin at 2 mg/kg for 2 weeks (Weeks 1 and 2) and will escalate to 
4 mg/kg (Weeks 3 and 4), 10 mg/kg (Weeks 5 and 6), 20 mg/kg (Weeks 7 and 8), and 30 mg/kg 
(Weeks 9 and 10). Patients will continue to receive 30 mg/kg eteplirsen for the duration of the study. 
The duration of each patient’s treatment in the study is expected to be at least 48 weeks (including the 
titration period), and patients may continue to receive treatment in the study for up to 96 weeksbased on 
the judgement of the Investigator. In addition, study drug may be interrupted or discontinued for specific 
safety reasons. 
Safety will be regularly assessed throughout the study via the collection of adverse events (AEs), 
clinical safety laboratory tests (blood chemistry, hematology, renal function, coagulation, and 
urinalysis), ECGs, ECHOs, vital signs, and physical examinations. Specific laboratory assessments of 
interest include: 
• 
Any ≥Grade 2 (moderate) or serious event without an alternative etiology that the Investigator 
deems is related to study drug 
• 
Two consecutive drug-related serum creatinine levels ≥2 × upper limit of normal (ULN) without 
an alternative etiology 
• 
A confirmed, unexplained, increase in gamma-glutamyl transferase (GGT) >3 × ULN and either 
an increase in bilirubin >2 × ULN or nascent prothrombin time >2 × ULN concurrently, without 
an alternative etiology 
Plasma and urine samples for PK determination will be collected at Week 2 (2-mg/kg dose level), 
Week 6 (10-mg/kg dose level), Week 8 (20-mg/kg dose level) and at Weeks 10 and 24 (30-mg/kg dose 
level). Plasma samples will be collected pre-dose, immediately prior to the end of infusion (prior to 
flush) and approximately 1 to 3 hours and 6-8 hours after completion of study drug infusion. Urine PK 
samples will be collected over the first 4 hours after start of infusion. 
 
 
 
 
 


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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 
 
End-of-Study Follow-up Visit 
Approximately 4 weeks after the last eteplirsen infusion (regardless of the duration of the patient’s 
participation in the study), patients will be required to return to the study site for safety evaluations. The 
safety follow-up visit will include clinical safety laboratory testing, vital signs, physical examination, 
and assessment of AEs and concomitant medications. 
DURATION OF STUDY: 
Screening Period: Up to 2 weeks 
Treatment Period: At least 48 weeks (including the 10-week titration period) and continuing for up to 
96 weeks 
Safety Follow-up Period: Up to 4 weeks after the last infusion 
Total Patient Participation: The duration of each patient's treatment in the study is expected to be at least 
48 weeks, and patients may continue to receive treatment in the study for up to 96 weeks. Therefore, the 
overall duration of a patient’s participation in the study, inclusive of the 2-week Screening Period and 
4-week Follow-up Period, may be up to 101 weeks. 
NUMBER OF PATIENTS: Approximately 12 patients will be enrolled in this study (approximately 
6 patients in Cohort 1 and approximately 6 patients in Cohort 2). 
INCLUSION/EXCLUSION CRITERIA: 
Inclusion Criteria: 
A patient must meet all of the following criteria to be eligible to participate in this study: 
1. Be a male between 6 months to 48 months of age, inclusive. 
2. Have an established clinical diagnosis of DMD with a deletion mutation amenable to exon 51 
skipping (eg, deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63). 
3. Have a parent(s) or legal guardian(s) who is able to understand and comply with the study 
requirements and is willing to provide written informed consent for the patient to participate in 
the study. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study: 
1. Has received any pharmacologic treatment that might have an effect on muscle strength or 
function within 12 weeks prior to dosing at Week 1 (eg, growth hormone, anabolic steroids). 
2. Has received previous or current treatment with any experimental treatment. Prior drisapersen 
therapy is permitted if a patient has not received drisapersen for 6 months prior to the Week 1 
dose. 
3. Has a clinically significant illness other than DMD, including cardiac, pulmonary, hepatic, 
renal, hematologic, immunologic, behavioral disease, or malignancy likely to impair the 
patient’s ability to participate in this study. 
4. Has a clinically significant laboratory abnormality that is either not expected or is of a greater 
severity than what is expected in DMD patients. 
5. Has any other condition that, in the Investigator’s opinion, could interfere with the patient’s 
participation 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 
DOSE/ROUTE/REGIMEN (TEST ARTICLE): 
Eteplirsen drug product is supplied as a sterile, clear, colorless, phosphate-buffered saline solution in 
single-use, 2-mL vials each containing 2 mL of eteplirsen at 50 mg/mL. Eteplirsen will be administered 
once a week by IV infusion. 
The starting dose is 2 mg/kg eteplirsen, with escalation to 4, 10, 20, and 30 mg/kg over the course of the 
dose-titration period. 
REFERENCE TREATMENT: None 
CRITERIA FOR EVALUATION: 
Primary Endpoint 
The primary endpoint is safety and tolerability of eteplirsen in this study population, as measured by: 
• 
Incidence of AEs 
• 
Abnormal changes from Baseline or clinically significant worsening of clinical safety laboratory 
abnormalities (hematology, chemistry, coagulation, and urinalysis) 
• 
Abnormal changes from Baseline or worsening of vital signs 
• 
Abnormal changes from Baseline or worsening of physical examination findings 
• 
Abnormal changes from Baseline or clinically significant worsening of ECGs and ECHOs 
Secondary Endpoint 
The secondary endpoint is to determine the PK of eteplirsen by population PK methods, including 
assessment of the following PK parameters (if evaluable): 
• 
Maximum plasma concentration (Cmax) 
• 
Time of Cmax (Tmax) 
• 
Area under the concentration-time curve (AUC) 
• 
Apparent volume of distribution at steady state (Vss) 
• 
Clearance (CL) 
• 
Elimination half-life (t½) 
• 
Amount of drug eliminated in urine (Ae%) 
 
 
 
 
 
 
 
 


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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 
STATISTICAL METHODS: 
Safety Analyses 
Treatment-emergent adverse events (TEAEs) will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term. 
Non-treatment-emergent events will be recorded in the data listings. For all AE tables, the number and 
percentage of patients reporting AEs will be grouped by SOC and preferred term for each age cohort 
and overall. Multiple occurrences of the same AE (at the preferred term level) in the same patient will 
be counted only once in the frequency tables. If a patient experiences multiple episodes of the same 
event with different severity, the event with the maximum severity will be used to summarize AEs by 
severity (likewise for relationship). Treatment related TEAEs will be defined as those that the 
Investigator considers related to the investigational product. 
Descriptive statistics for ECG, ECHO, vital signs, height/length, weight, and safety laboratory 
parameters will be displayed by visit for each age cohort and overall. Summary statistics for each 
parameter at specific time points, as well as the change from baseline to that time point, will also be 
displayed. All data will be presented in data listings. Clinically significant physical examination findings 
will be recorded as AEs. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters of eteplirsen will be determined from plasma and urine concentration data 
obtained at the 2-, 10-, 20-, and 30-mg/kg dose levels. Individual plasma and urine levels of eteplirsen 
will be listed with the corresponding time relative to eteplirsen administration, and summary statistics 
will be generated by per-protocol time of collection. PK parameters for eteplirsen will be calculated 
using non-compartmental analysis and/or using population PK methodology, as appropriate. 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. 
 
 
 
Interim Analysis 
An interim analysis of the PK and safety data following completion of dose escalation for one or both 
age cohorts may be done. 


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2. 
SCHEDULE OF EVENTS 
The schedule of study events is presented in Table 2. 


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Table 2: 
Schedule of Events: Screening through Week 48 
 
Study Period 
Screening
Treatment Period: Dose Titration 
Stable Dose Treatment Period 
Visit/Week 
Up to 
-2 wks 
1 
BL 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
18 
20 
24 
28 
32 
36 
40 
44 48a 
Informed consentb 
X 
Inclusion/Exclusion 
eligibility 
X 
X 
Demographics and 
medical history 
X 
Blood samples 
genotypingb 
X 
Clinical safety 
laboratory samplec 
X 
X 
X 
X 
X 
X 
X 
X 
PK plasma and urine 
samplingd 
X 
X 
X 
X 
X 
Vital signse 
X 
X 
On weekly infusion days 
Weightf 
X 
X 
Weekly 
Urine dipstick 
testing 
Weekly 
Renal function blood 
testsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative urine 
analysisn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
(including 
height/length)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGi,k 
X 
X 
X 
X 
X 
X 
ECHOi,k 
X 
X 
X 
X 
X 
X 
Eteplirsen dosingl 
Weekly IV infusion 
Weekly IV infusion 


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2 mg/kg 
4 mg/kg 
10 mg/kg 20 mg/kg 
30 mg/kg 
30 mg/kgl 
Concomitant 
medications 
Continuous 
AE monitoring 
Continuous 


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Footnotes for Table 2 Scheduleof Events: Screening through Week 48 
Abbreviations: AE = adverse event; 
; BL = baseline; DMB = Duchenne muscular 
dystrophy; DNA = Deoxyribonucleic acid; ECG= electrocardiogram; ECHO = echocardiogram;
 
IV= intravenous; LTBP4 = latent transforming growth factor beta binding protein 4;
 
 PK = pharmacokinetic; SPP-1 = secreted phosphoprotein 1. 
a Patients are considered completers for thepurpose of analysis once the Week 48 assessments havebeen completed. Patients may continue in the study up to 
and including 96 weeks; however, a Safety Follow-up visit will occur approximately 4 weeks after the last doseadministered rega rdless of the patient’s 
duration in the study (see Table 3). 
b Patients not previously genotyped may beconsented and havegenotypeperformed as part of the study. Oncethe genotype is con firmed, all additional 
screening procedures will be performed -2 weeks from Week 1/Baseline. Patients may be enrolled in the study based on historical DNA test results; however, a 
blood sample for DNA testing will be obtained on all patients to confirm DMD mutation(s). In addition, a second blood sample will be obtained for genotyping 
of LTBP4 and SPP-1. So that total blood volume taken for the Screening visit does not exceed recommendations, theblood sample for DMD genotyping may 
be drawn at any time prior to the Week 2 visit and theblood sample for LTBP4 and SPP-1 may be drawn at any timeduring the dose-titration period. If the 
confirmatory DNA sample is negative for DMD on any enrolled patient, that patient will be withdrawn from the study. 
c Clinical safety laboratory assessments (blood chemistry [including liver function], renal function, hematology [including pla telets], and coagulation) must be 
obtained with results available within 2 weeks prior to dosing. (See Section 10.3.5 for the list of tests to be completed.) 
d Pla sma PK samples will be collected pre-dose, immediately prior to the end of infusion (prior to flush) and approximately 1 -3 hours and 6-8 hours after 
completion of study drug infusion. Urine PK will be collected over the first 4 hours after start of infusion. 
e Vital signs include blood pressure, heart rate, respiration, and temperature. On infusion days, vital signs will be measured within 60 minutes prior to infusion, 
within 5 minutes (±2) after the end of infusion, and at 30 minutes (±5), and 60 minutes (±10) after the end of the infusion. All assessments will be performed 
after patients have remained calm for 5 minutes. Pulse rate and respiratory rate should bemeasured over 1 minute. 
f Weight will be measured prior to study drug infusions at thespecified visits. 
g Height/length will be measured as part of every physical examination. The examination will include general appearance; head, ears, eyes, nose, and throat; 
heart; lungs; chest; abdomen; skin; lymph nodes; musculoskeletal; and neurological systems. 
h 
 
i A 2-week window is allowed in the event thechild is unable to completethis assessment at a given visit. 
j Only performed in patients 36 months of age and older 
k 
 
l Patients should receiveeteplirsen once every 7 days starting on Study Week 1. A window of ±3 days from the scheduled dose is acceptable after thefirst 
infusion. Patients may not receive 2 separatedoses of eteplirsen within the same 60-hour period. The Medical Monitor should be contacted in the event of 
≥2 consecutivemissed doses. 
m. Renal function blood tests includecreatinine, blood urea nitrogen, and serum cystatin C. 
n. Quantitativeurine analysis includes KIM-1 and urinalysis (pH, specific gravity, protein, glucose, ketones, cytology, and hemoglobin). 
 


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Table 3: 
Schedule of Events: Week 49 through Week 96 and End-of-Study Follow-up 
 
Study Period 
Stable Dose Treatment Period 
Visit/Week 
49 
60 
72 
84 
96/ETa 
Safety F/Ub 
Clinical safety laboratory samplec 
X 
X 
X 
X 
X 
Vital signsd 
On weekly infusion days 
X 
X 
Weighte 
Weekly 
X 
X 
Urine dipstick testing 
Weekly 
Renal function blood testsl 
X 
X 
X 
X 
X 
Quantitative urine analysism 
X 
X 
X 
X 
X 
Physical examination (including height/length)f 
X 
X 
X 
X 
X 
12-lead ECGh,j 
X 
X 
X 
X 
ECHOh,j 
X 
X 
X 
X 
Eteplirsen dosingk 
Weekly IV infusionsk 
Concomitant medications 
Continuous 
X 
AE monitoring 
Continuous 
X 


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Abbreviations: AE = adverse event; 
; ECG= electrocardiogram; 
ECHO = echocardiogram; ET = early termination; F/U = follow up; 
; IV = intravenous; 
 
a Early termination assessments are thesame as Week 96 assessments. 
b A Safety Follow-up visit will occur approximately 4 weeks after the last infusion regardless of thepatient’s duration in the study. 
c Clinical safety laboratory assessments (blood chemistry [including liver function], hematology [including platelets], and coa gulation) will be obtained every 
12 weeks after Week 48. (See Section 10.3.5 for the list of tests to be completed.) 
d Vital signs include blood pressure, heart rate, respiration, and temperature. On infusion days, vital signs will be measured approximately 60 minutes prior to 
infusion and at 5 minutes(±2), 30 minutes (±5), and 60 minutes (±10) after the end of the infusion. If the patient has not experienced an infusion reaction after 
the first 48 weeks of treatment, vital signs may be limited to approximately 30 minutes prior to infusion and 30 minutes (±5) after theend of the infusion. All 
assessments will be performed after patients have remained calm for 5 minutes. Pulse rate and respiratory rate should be measured over 1 minute. 
e Weight measured will be measured prior to study drug infusions at thespecified visits. 
f Height/length will be measured as part of every physical examination. The examination will include general appearance; head, ears, eyes, nose, throat; heart; 
lungs; chest; abdomen; skin; lymph nodes; musculoskeletal; and neurological systems. 
g 
 
h A 2-week window is allowed in the event thechild is unable to completethis assessment at a given visit. 
I Only performed in patients 36 months of age and older. 
j 
 
k Patients should receiveeteplirsen once every 7 days relative to the Study Week 1 date. A window of ±3 days from the scheduled doseis acceptable after the 
first infusion. Patients may not receive 2 separate doses of eteplirsen within thesame 60-hour period. The Medical Monitor should be contacted in the event of 
≥2 consecutivemissed doses. 
l. Renal function blood tests includecreatinine, blood urea nitrogen, and serum cystatin C. 
m. Quantitative urine analysis includes KIM-1 and urinalysis (pH, specific gravity, protein, glucose, ketones, cytology, and hemoglobin). 
 


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3. 
TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................... 1 
SIGNATURE PAGE FOR SPONSOR ............................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................... 4 
PROCEDURES IN CASE OF EMERGENCY ............................................................................... 5 
1. 
SYNOPSIS ................................................................................................................... 6 
2. 
SCHEDULE OF EVENTS ........................................................................................ 11 
3. 
TABLE OF CONTENTS .......................................................................................... 17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 22 
5. 
INTRODUCTION ..................................................................................................... 24 
5.1. 
Background of Duchenne Muscular Dystrophy ........................................................ 24 
5.2. 
Phosphorodiamidate Morpholino Oligomers for the Treatment of Duchenne 
Muscular Dystrophy .................................................................................................. 24 
5.3. 
Clinical Experience with Eteplirsen .......................................................................... 25 
5.4. 
Rationale for the Current Study ................................................................................. 26 
5.5. 
Benefit and Risk Assessment..................................................................................... 26 
6. 
STUDY OBJECTIVES AND PURPOSE ................................................................. 28 
6.1. 
Primary Objective ...................................................................................................... 28 
6.2. 
Secondary Objective .................................................................................................. 28 
6.3. 
 ................................................................................................ 28 
7. 
INVESTIGATIONAL PLAN .................................................................................... 29 
7.1. 
Overall Study Design ................................................................................................. 29 
7.2. 
Dose Selection Rationale ........................................................................................... 30 
7.3. 
Study Endpoints ........................................................................................................ 31 
7.3.1. 
Primary Endpoint....................................................................................................... 31 
7.3.2. 
Secondary Endpoint................................................................................................... 31 
7.3.3. 
................................................................................................. 32 
7.4. 
Discussion of Study Design ....................................................................................... 32 
7.5. 
Data Monitoring Committee ...................................................................................... 33 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 34 
8.1. 
Number of Patients .................................................................................................... 34 
8.2. 
Patient Inclusion Criteria ........................................................................................... 34 


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8.3. 
Patient Exclusion Criteria ........................................................................................... 34 
8.4. 
Completion of a Patient’s Participation in the Study .................................................. 34 
8.5. 
Completion of the Trial .............................................................................................. 35 
8.6. 
Patient Withdrawal Criteria ........................................................................................ 35 
8.7. 
Study Discontinuation ................................................................................................ 35 
9. 
TREATMENT OF PATIENTS .................................................................................. 37 
9.1. 
Investigational Product ............................................................................................... 37 
9.1.1. 
Packaging and Labeling ............................................................................................. 37 
9.1.2. 
Storage ........................................................................................................................ 37 
9.2. 
Treatments Administered ........................................................................................... 37 
9.2.1. 
Dose Modification, Reduction, or Delay .................................................................... 38 
9.2.1.1. 
Dose Interruption ........................................................................................................ 38 
9.2.1.2. 
Dose Escalation .......................................................................................................... 39 
9.3. 
Randomization and Blinding ...................................................................................... 39 
9.4. 
Prior and Concomitant Medications ........................................................................... 39 
9.5. 
Treatment Compliance ............................................................................................... 40 
10. 
STUDY ASSESSMENTS .......................................................................................... 41 
10.1. 
Study Schedule of Events ........................................................................................... 41 
10.2. 
Screening/Baseline Assessments ................................................................................ 41 
10.2.1. 
Informed Consent ....................................................................................................... 41 
10.2.2. 
Demographics and Medical History ........................................................................... 41 
10.2.3. 
Genotyping ................................................................................................................. 41 
10.2.3.1. 
DMD ........................................................................................................................... 41 
10.2.3.2. 
LTBP4 and SPP-1 ....................................................................................................... 41 
10.2.4. 
Other Assessments ...................................................................................................... 41 
10.3. 
Safety Assessments .................................................................................................... 42 
10.3.1. 
Physical Examination ................................................................................................. 42 
10.3.2. 
Vital Signs .................................................................................................................. 42 
10.3.3. 
Height/Length and Weight ......................................................................................... 42 
10.3.4. 
Safety Monitoring, Additional Investigations and Stopping Rules ............................ 42 
10.3.4.1. 
Safety Monitoring for Liver Chemistry Tests ............................................................ 42 
10.3.4.2. 
Safety Monitoring for Renal Function ........................................................................ 43 
10.3.5. 
Clinical Safety Laboratory Evaluations ...................................................................... 46 


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10.3.5.1. 
Laboratory Assessments of Interest ............................................................................ 47 
10.3.6. 
Electrocardiogram ...................................................................................................... 47 
10.3.7. 
Echocardiogram .......................................................................................................... 47 
10.3.8. 
Concomitant Medications and Therapies ................................................................... 48 
10.3.9. 
Adverse Events ........................................................................................................... 48 
10.4. 
Pharmacokinetic Assessments .................................................................................... 48 
10.4.1. 
Blood Sample Collection ............................................................................................ 48 
10.4.2. 
Urine Sample Collection ............................................................................................ 48 
10.5. 
 ............................................................................................ 48 
10.5.1. 
 .............................................. 49 
10.5.2. 
 ..................................................... 49 
10.5.3. 
........................................................................ 49 
10.5.4. 
 .................................................................. 50 
11. 
ADVERSE EVENTS ................................................................................................. 51 
11.1. 
Collection of Adverse Events ..................................................................................... 51 
11.2. 
Definition of Adverse Events ..................................................................................... 51 
11.2.1. 
Adverse Event ............................................................................................................ 51 
11.2.2. 
Serious Adverse Event ................................................................................................ 51 
11.3. 
Classification of Adverse Events ............................................................................... 52 
11.3.1. 
Relationship to Investigational Product ..................................................................... 52 
11.3.2. 
Relationship to Study Procedures .............................................................................. 52 
11.3.3. 
Relationship to Underlying Disease ........................................................................... 53 
11.3.4. 
Severity of Adverse Events ........................................................................................ 53 
11.3.5. 
Outcome ...................................................................................................................... 53 
11.3.6. 
Action Taken Regarding the Investigational Drug Product ....................................... 53 
11.3.7. 
Expectedness of an Adverse Event ............................................................................. 53 
11.3.8. 
Suspected Unexpected Serious Adverse Reactions .................................................... 53 
11.3.9. 
Adverse Events of Special Interest ............................................................................. 54 
11.4. 
Recording Adverse Events ......................................................................................... 55 
11.5. 
Reporting Adverse Events .......................................................................................... 55 
11.6. 
Special Situations ....................................................................................................... 55 
11.6.1. 
Overdose ..................................................................................................................... 55 
11.6.2. 
Pregnancy ................................................................................................................... 55 


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11.6.3. 
Medication Error ........................................................................................................ 56 
11.6.4. 
Accidental/Occupational Exposure ............................................................................ 56 
11.6.5. 
Death ........................................................................................................................... 56 
11.6.6. 
Responsibilities of the Investigator ............................................................................ 56 
11.6.7. 
Responsibilities of the Sponsor .................................................................................. 57 
12. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT .......... 58 
12.1. 
Recording of Data ....................................................................................................... 58 
12.2. 
Quality Assurance ...................................................................................................... 58 
12.3. 
Retention of Study Documents .................................................................................. 58 
13. 
STATISTICS .............................................................................................................. 60 
13.1. 
General Considerations ............................................................................................... 60 
13.2. 
 .................................................................................... 60 
13.3. 
Analysis Sets .............................................................................................................. 60 
13.4. 
Protocol Deviations ..................................................................................................... 60 
13.5. 
Disposition, Demographics, and Baseline Characteristics ......................................... 61 
13.6. 
Medical History .......................................................................................................... 61 
13.7. 
Dosing and Compliance .............................................................................................. 61 
13.8. 
Safety Analysis ........................................................................................................... 61 
13.8.1. 
Safety Variables.......................................................................................................... 61 
13.8.2. 
Safety Analyses .......................................................................................................... 61 
13.8.2.1. 
Adverse Events ........................................................................................................... 61 
13.8.2.2. 
Physical Examinations, Vital Signs, Height, and Weight .......................................... 62 
13.8.2.3. 
Clinical Safety Laboratory Tests ................................................................................ 62 
13.8.2.4. 
Electrocardiograms ..................................................................................................... 62 
13.8.2.5. 
Echocardiograms ........................................................................................................ 63 
13.8.2.6. 
Prior and Concomitant Medications and Physiotherapeutic Interventions ................ 63 
13.9. 
 .................................................................................................. 63 
13.10. 
Pharmacokinetic Analysis .......................................................................................... 63 
13.11. 
Interim Analysis ......................................................................................................... 63 
13.12. 
Other Statistical Issues................................................................................................ 63 
14. 
SPECIAL REQUIREMENTS AND PROCEDURES ............................................... 64 
14.1. 
Compliance with Ethical and Regulatory Guidelines ................................................ 64 
14.2. 
Institutional and Ethics Review .................................................................................. 64 


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14.3. 
Informed Consent and Authorization for Use and Disclosure of Protected 
Health Information .................................................................................................... 64 
14.4. 
Compliance with the Protocol ................................................................................... 64 
14.5. 
Confidentiality ........................................................................................................... 64 
14.5.1. 
Data ............................................................................................................................ 64 
14.5.2. 
Patient Confidentiality ............................................................................................... 65 
15. 
STUDY DOCUMENTATION AND GENERAL INFORMATION ....................... 66 
15.1. 
Essential Study Documents ....................................................................................... 66 
15.2. 
General Information .................................................................................................. 66 
15.3. 
Dissemination of Study Results ................................................................................. 66 
15.4. 
Product Handling and Complaints Reporting ............................................................ 66 
16. 
LIST OF REFERENCES ........................................................................................... 67 
17. 
APPENDICES ........................................................................................................... 69 
17.1. 
Estimated Blood Volumes to be Drawn .................................................................... 69 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information................................................................................... 5 
Table 2: 
Schedule of Events: Screening through Week 48 ..................................................... 12 
Table 3: 
Schedule of Events: Week 49 through Week 96 and End-of-Study Follow-up ......... 15 
Table 4: 
Study Cohorts and Enrollment Criteria ...................................................................... 29 
Table 5: 
Example Eteplirsen Dilution Scheme ......................................................................... 38 
Table 6: 
Mean Blood Volume per Body Weight ...................................................................... 69 
Table 7: 
Blood Volume Requirements per Test ........................................................................ 69 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
Abbreviation 
Definition 
6MWT 
6-minute walk test 
AE 
adverse event 
Ae% 
amount of drug eliminated in urine (expressed as % of dose administered) 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from Hour 0 to 24 hours postdose 
 
 
BMD 
Becker muscular dystrophy 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CK 
creatine kinase 
CL 
clearance 
CNS 
central nervous system 
Cmax 
maximum plasma concentration 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
CT 
Computed tomography 
DMC 
Data Monitoring Committee 
DMD 
Duchenne muscular dystrophy 
DNA 
Deoxyribonucleic acid 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
eGFR 
Estimated glomerular filtration rate 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
HEENT 
head, ears, eyes, nose, throat 
 
 


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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous, intravenously 
KIM-1 
kidney injury molecule 1 
LTBP4 
latent transforming growth factor beta binding protein 4 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
 
 
 
 
PK 
Pharmacokinetic(s) 
PMO 
phosphorodiamidate morpholino oligomers 
 
 
RBC 
Red blood cell(s) 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SMA 
spinal muscular atrophy 
SPP-1 
secreted phosphoprotein 1 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
elimination half life 
TEAE 
treatment-emergent adverse event 
TGF 
transforming growth factor beta 
Tmax 
time of occurrence of Cmax 
UACR 
Urine Albumin to Creatinine Ratio 
ULN 
upper limit of normal 
UPCR 
Urine Protein to Creatinine Ratio 
Vss 
apparent volume of distribution at steady state 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
5.1. 
Background of Duchenne Muscular Dystrophy 
Duchenne muscular dystrophy (DMD) is a rare (estimated incidence of 1 in 3,500 to 5,000 live 
male births; CDC 2009; Emery 1991), degenerative, X-linked recessive genetic disorder caused 
by mutations in the dystrophin gene. In DMD, mutations in the dystrophin gene disrupt the open 
reading frame, resulting in an absence of functional dystrophin, a critically important part of the 
protein complex that connects the cytoskeletal actin of a muscle fiber to the extracellular matrix. 
In the absence of dystrophin, the stress of repeated muscle contraction causes cellular 
degeneration, regeneration, and inflammation, and, over time, myonecrosis. 
The progression of DMD follows a highly predictable course. Significant motor deficits may be 
present during the first year of life, but diagnosis is usually made between the ages of 3 to 
5 years when toddlers begin to show functional symptoms (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). 
Existing interventions for DMD patients with mutations amenable to exon skipping are largely 
supportive in nature and include bracing, muscle-stretching exercises to avoid onset of 
contractures, tendon-release surgery, and eventual wheelchair use and assisted ventilation. 
Current pharmacologic treatments, such as corticosteroids, focus on alleviation of symptoms, but 
do not address the underlying cause of the disease. Corticosteroids may prolong ambulation, 
delay the onset of scoliosis, and improve performance on some measures of clinical function 
(Beenakker 2005; Biggar 2006; Pradhan 2006). However, their benefits are only temporary, and 
their use is often limited by numerous side effects, including growth inhibition, effects on 
pubertal changes, weight gain, behavioral changes, osteoporosis, Cushingoid facies and habitus, 
and cataracts (Biggar 2006; Manzur 2004). 
5.2. 
Phosphorodiamidate Morpholino Oligomers for the Treatment of 
Duchenne Muscular Dystrophy 
Ribonucleic acid (RNA) therapeutics are compounds composed of heterocyclic nucleobases 
(adenine, cytosine, guanine, and thymine, or analogues) linked together on an oligomer backbone 
that supports hybridization via Watson-Crick base pairing with specific complementary RNA 
targets. RNA therapeutics can be synthesized to bind targeted RNA sequences in a pathogen or 
pathogenic process to treat a wide range of diseases through positively or negatively modulating 
gene expression. A relatively new use of RNA therapeutics is to target a pre-messenger RNA 
(mRNA) in the nucleus of a cell to influence the splicing process that creates a mature mRNA. 
Referred to as “exon skipping,” this approach allows determination of which exons will be 
incorporated into the mature mRNA to be translated into the protein product. 


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Phosphorodiamidate morpholino oligomers (PMOs) are a class of synthetic molecules based on a 
redesign of the natural nucleic acid structure. Phosphorodiamidate morpholino oligomers are 
distinguished from natural nucleic acids and other oligonucleotide therapeutic platforms by the 
attachment of nucleobases to a 6-membered morpholine ring as opposed to the 5-membered 
ribose ring found in RNA and deoxyribonucleic acid (DNA). Moreover, the morpholine rings are 
linked through neutrally charged phosphorodiamidate moieties as opposed to negatively charged 
phosphodiester linkages in RNA and DNA. These differences were designed to increase stability 
and address safety issues seen with some earlier oligonucleotide backbone chemistries. 
Phosphorodiamidate morpholino oligomers are capable of avid, sequence-specific binding 
in vivo to regulatory sites in pre-mRNA and thus alter the splicing of a pre-mRNA transcript, 
such as that of dystrophin, causing the skipping (omission) of specific exons in the final mRNA. 
Approximately 80% of boys with DMD have out-of-frame deletions that could be amenable to 
exon-skipping therapies (Aartsma-Rus 2009). Several PMOs are being evaluated by Sarepta for 
the potential treatment of DMD, as exon skipping may enable the production of an internally 
deleted, functional dystrophin protein. 
The active pharmaceutical ingredient of the investigational product (IP) eteplirsen injection is a 
charge-neutral PMO that selectively binds to exon 51 of the dystrophin pre-mRNA. In doing so, 
it causes the exon to be skipped during processing and restores the mRNA open reading frame in 
patients with mutations amenable to skipping exon 51 of the dystrophin gene, which is 
approximately 13% of all DMD patients (Aartsma-Rus 2009). This is expected to enable the 
production of an internally deleted, yet partially functional, dystrophin protein, similar to that 
observed in Becker muscular dystrophy (BMD), a much less severe form of dystrophinopathy. In 
contrast to DMD, most BMD patients remain ambulatory and have a near-normal life expectancy 
(Bushby 1993). 
5.3. 
Clinical Experience with Eteplirsen 
As of 24 June 2019, the eteplirsen clinical development program consists of 7 completed studies 
(Studies 4658-33, 4658-28, 4658-us-201, 4658-us-202, 4658-203, 4658-301 and 4658-204) and 
2 ongoing studies (Studies 4658-102/
) in patients with DMD who were amenable to 
Exon 51 skipping. In addition, 2 Phase 1 studies (Studies 4658-101 and 4658-103) have been 
completed and 1 Phase 1 study (Study 4658-104) is ongoing in volunteers who do not have 
DMD. 
Seven completed studies (Studies 4658-28, 4658-us-201, 4658-us-202, 4658-203, 4658-101, 
4658-301 and 4658-103) have contributed to the pharmacokinetic profile of eteplirsen. There 
was little or no accumulation in plasma following weekly administration. Maximum plasma 
concentration (Cmax) and area under the concentration-time curve (AUC) increased in an 
approximately dose-proportional or slightly less than proportional manner. Urinary elimination 
of the active ingredient without metabolites was the predominant route of excretion. Based on 
the results of Study 103, an increase in eteplirsen exposure was observed in non-DMD adults 
with mild to moderate renal impairment. 
Clinical efficacy results that include ambulatory and pulmonary function have been evaluated in 
completed Studies 4658-us-201/202, 4658-203, 4658-204 as well as Study 4658-301. Study 
4658-us-201/202 provides long-term results across multiple ambulatory and respiratory 
endpoints over the course of 4 years. Studies 4658-301 (interim analysis) and 4658-204 provide 


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additional supportive evidence of ambulatory and pulmonary function over the course of 2 years. 
Pooled results from these 3 studies (Studies 4658-us-201/202, 4658-203, and 4658-204) were 
compared with data from comparable external control cohorts and a comprehensive review of 
literature describing the natural history of DMD. Results from these analyses demonstrated a 
divergence, starting at Year 2, favoring eteplirsen-treated patients. Study 4658-301 confirmed 
mechanism of action showing increasing exon skipping leading to 0.52 % dystrophin levels by 
Western Blot which significantly & consistently increased over Baseline starting at Week 24 and 
continuing to Week 96 (n=77). Overall, the long-term safety profile of eteplirsen for treatment of 
patients with DMD was consistent with previous study data. 
Study 4658-203 was a Phase 2, multicenter, open-label trial to evaluate the safety and tolerability 
of eteplirsen in patients aged 4 to 6 years with genotypically-confirmed DMD with genetic 
mutations amenable to treatment by exon 51 skipping. The study enrolled 26 patients who 
received once-weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for up to 96 weeks. 
Treatment with eteplirsen was well tolerated and safety results were consistent with a favorable 
safety profile for eteplirsen. 
 
 
 
As of 24 June 2019, 182 patients with DMD and 59 non-DMD subjects have been treated with 
eteplirsen in clinical studies, including 175 who received IV eteplirsen and 155 who received 30 
mg/kg or higher. Of the 182 patients, 17 and 135 patients received at least 48 and 96 weeks of 
eteplirsen treatment, respectively. This includes 12 patients from Study 201/202 who have been 
treated for over 5 years. These studies demonstrated that treatment with eteplirsen was generally 
well-tolerated at doses of 30 mg/kg (N=149) and 50 mg/kg (N=6) and there were no observed 
difference in safety between these 2 doses. 
Based on the cumulative available safety data from these studies, eteplirsen has been shown to be 
well tolerated, with low rates of serious or severe adverse events (AEs). 
Refer to the Investigator’s Brochure for further details. 
 
5.4. 
Rationale for the Current Study 
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of 
eteplirsen over at least 48 weeks of dosing, and up to 96 weeks of dosing, in male patients with 
DMD with a deletion mutation amenable to exon 51 skipping between 6 months to 48 months of 
age (inclusive). Eteplirsen has not previously been studied in this age group. 
5.5. 
Benefit and Risk Assessment 
Details about the known and expected benefits and risks of, and expected AEs associated with, 
eteplirsen treatment are provided in the eteplirsen Investigator’s Brochure. 
Eteplirsen has been granted accelerated approval in the United States (US) by the Food and Drug 
Administration. This was based on the observation of dystrophin production in some patients and 
the safety experience in patients with DMD participating in clinical trials, who were 4 years of 
age or older, which includes the age range specified for this study. Patients have also used 
commercially available eteplirsen since the approval in September 2016. 


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To date, eteplirsen has been well tolerated, with low rates of serious or severe AEs. No major 
safety risk has been identified in patients dosed with eteplirsen, including patients dosed with up 
to 50 mg/kg once weekly for more than 4 years. 
Risks with eteplirsen include infusion-related reactions, hypersensitivity reactions, and potential 
renal toxicities including proteinuria or decreased renal function. These events have been seen in 
prior experience with eteplirsen with lower doses and are usually mild and resolve without 
clinical or pharmaceutical treatment. The use of higher doses of eteplirsen in this protocol could 
lead to more frequent or more severe reactions than seen with lower doses. Regularly scheduled 
review by a Safety Review Committee during the open-label period and a Data Monitoring 
Committee (DMC) during the double-blind period will look at aggregate unblinded data to 
determine the relative risk-benefit of continuing the dose or the study. Investigators are allowed 
to withhold dosing and must discuss such actions with the Medical Monitor. Further details on 
the safety of eteplirsen can be found in the Investigator’s Brochure. 
Based on the mechanism of action of eteplirsen and the benefit of eteplirsen treatment in DMD 
patients with mutations amenable to skipping exon 51, it is expected that patients in 
Study 4658-102 may derive a clinical benefit from treatment with a higher dose of eteplirsen. 
Taken together, these considerations support that patients participating in Study 4658-102 will 
not be exposed to undue risk and may potentially experience some clinical benefit. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
• 
To evaluate the safety and tolerability of eteplirsen administered once weekly by IV 
infusion in male DMD patients ages 6 months to 48 months, inclusive. 
 
6.2. 
Secondary Objective 
• 
To determine the PK of eteplirsen at the 2-, 10-, 20-, and 30-mg/kg dose levels, 
administered once weekly by IV infusion in male DMD patients ages 6 months to 
48 months, inclusive. 
 
6.3. 
 
• 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, 
and efficacy of once-weekly IV infusions of eteplirsen in approximately 12 male patients, ages 
6 months to 48 months (inclusive), who have genotypically confirmed DMD with a deletion 
mutation amenable to exon 51 skipping. 
Patients will be evaluated for inclusion during the Screening Period of up to 2 weeks to assess 
eligibility. 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, patients will undergo screening assessments as 
indicated in Table 2 (Schedule of Events). 
• 
Blood samples for the screening clinical safety laboratory assessments must be 
obtained within 2 weeks prior to the Baseline/Week 1 visit, and results must be 
available prior to dosing at Baseline/Week 1. 
Patients will be enrolled into 1 of 2 age cohorts, as presented in Table 4. 
Table 4:          Study Cohorts and Enrollment Criteria 
 
Cohort 
Age 
Criteria for Enrollment 
1: approximately 
6 patients 
24 to 48 months old 
Meet all screening and I/E criteria. 
2: approximately 
6 patients 
6 to <24 months old 
DMC approves initiation of cohort 
Meet all screening and I/E criteria. 
Abbreviations: I/E = inclusion/exclusion. 
After the first 3 patients in Cohort 1 have completed 12 weeks of eteplirsen therapy (ie, 
12 infusions, including 2 infusions each at 2, 4, 10, and 20 mg/kg, and 4 infusions at 30 mg/kg), 
the DMC will review the safety data and determine whether to begin enrollment of the younger 
patients (Cohort 2). 
A DMC will review safety data at least weekly through the first 12 weeks of dosing for the first 
3 patients of each age cohort. Reviews will be at least quarterly thereafter. 
The dose-titration period will last 10 weeks overall (1 infusion/week) to slowly achieve the target 
dose of 30 mg/kg. Eteplirsen dosing will begin at 2 mg/kg for 2 weeks (Weeks 1 and 2) and will 
escalate to 4 mg/kg (Weeks 3 and 4), 10 mg/kg (Weeks 5 and 6), 20 mg/kg (Weeks 7 and 8), and 
30 mg/kg (Weeks 9 and 10). Patients will continue to receive 30 mg/kg eteplirsen for the 
duration of the study. The duration of each patient’s treatment in the study is expected to be at 
least 48 weeks (including the 10-week titration period), and patients may continue to receive 
treatment in the study for up to 96 weeks determined by the Investigator based on the absence of 
any safety signal and an indication of clinical benefit.
 
 
 


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In addition, study drug may be interrupted or discontinued for specific safety reasons. 
Safety will be regularly assessed throughout the study via the collection of AEs, clinical safety 
laboratory tests (blood chemistry, hematology, renal function, coagulation, and urinalysis), 
electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations. 
Plasma and urine samples for PK assessments will be collected at Week 2 (2-mg/kg dose level), 
Week 6 (10-mg/kg dose level), Week 8 (20-mg/kg dose level), and at Weeks 10 and 24 
(30-mg/kg dose level). Serial PK samples will be collected pre-dose, immediately prior to the 
end of infusion (prior to flush), and approximately 1-3 hours and 6-8 hours after completion of 
study drug infusion. Urine PK samples will be collected over the first 4 hours after start of 
infusion. 
 
 
 
Approximately 4 weeks after the last eteplirsen infusion (regardless of the duration of the 
patient’s participation in the study), patients will be required to return to the study site for safety 
evaluations. The total duration of patient participation, including Screening, Titration/Treatment, 
and Safety Follow-up periods is up to 101 weeks. 
Refer to Section 10 for the detailed list of study assessments. 
 
7.2. 
Dose Selection Rationale 
As this is the first safety and tolerability study to be conducted in pediatric patients’ ages 
6 months through 48 months (inclusive), eteplirsen will be dosed weekly in a dose-titration 
fashion starting at 2 mg/kg to slowly achieve the target dose of 30 mg/kg over the course of 
10 weeks. 
The selection of a 2-mg/kg starting dose for this study is based on nonclinical data as well as 
clinical safety experience with eteplirsen. Based on mean maximum plasma concentration (Cmax; 
4.82 µg/mL) and area under the concentration-time curve from time 0 to 24 hours postdose 
(AUC0-24hr; 6.20 µg•hr/mL) determined at the 2.0-mg/kg dose level in Study 4658-28, safety 
margins to the no-observed-adverse effect levels in juvenile rats (300 mg/kg) and non-human 
primates (320 mg/kg) are expected to be at least 50× the 2.0-mg/kg starting dose proposed for 
Study 4658-102. 
Dose selection for the group aged 6 months to 4 years old is based on the assumption that 
efficacy relates to exposure, defined by the use of AUC. The 30-mg/kg dose was chosen as the 
target dose based on results from the Phase 2, double-blind, placebo-controlled, multiple-dose 
study, Study 4658-us-201, and its open-label extension, Study 4658-us-202. As described in 
Section 5.3, these studies assessed the efficacy, safety, tolerability, and PK of 2 eteplirsen doses 
(50 mg/kg and 30 mg/kg) administered as IV infusions in twelve 7- to 13-year-old pediatric 
patients diagnosed with DMD with a deletion mutation amenable to exon 51 skipping. Once- 
weekly treatment with 30 mg/kg eteplirsen for 24 weeks significantly increased the mean 


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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 doses from Week 1 
(52% and 42% of normal, respectively, or 47% for the combined groups; data on file). 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, 30-mg/kg dose was 
selected as the more conservative choice, because patients presumably would receive this drug as 
a life-long treatment. To date, there is no evidence that the response differs across age groups. 
At the time that this trial was designed, 150 patients have been dosed with eteplirsen, 124 of 
which received 30 or 50 mg/kg and 81 patients have been dosed for at least 1 year. The overall 
review of safety data for these 150 patients has not identify any significant safety concerns with 
eteplirsen. Further safety review was conducted in 26 patients who were 4 to 6 years of age and 
enrolled in Study 203. Overall, the safety data in Study 203 is consistent with the overall safety 
profile of eteplirsen with low rates of serious (11.5%) and severe (3.8%) AEs. Therefore, given 
the safety experience with eteplirsen to date, it is considered appropriate to increase the starting 
dose from 0.5 mg/kg, which was used in Study 28, to the 2 mg/kg proposed for Study 4658-102. 
As of 24 June 2019, 182 patients with DMD and 59 non-DMD subjects have been treated with 
eteplirsen in clinical studies, including 175 who received IV eteplirsen and 155 who received 30 
mg/kg or higher. Of the 182 patients, 17 and 135 patients received at least 48 and 96 weeks of 
eteplirsen treatment, respectively. This includes 12 patients from Study 201/202 who have been 
treated for over 5 years. These studies demonstrated that treatment with eteplirsen was generally 
well-tolerated at doses of 30 mg/kg (N=149) and 50 mg/kg (N=6) and there were no observed 
difference in safety between these 2 doses. 
7.3. 
Study Endpoints 
7.3.1. 
Primary Endpoint 
The primary endpoint is safety and tolerability of eteplirsen in this study population, as measured 
by: 
• 
Incidence of AEs 
• 
Abnormal changes from Baseline or clinically significant worsening of clinical safety 
laboratory abnormalities (hematology, chemistry, coagulation, urinalysis) 
• 
Abnormal changes from Baseline or worsening of vital signs 
• 
Abnormal changes from Baseline or worsening of physical examination findings 
• 
Abnormal changes from Baseline or clinically significant worsening of ECGs and 
ECHOs 
 
7.3.2. 
Secondary Endpoint 
The secondary endpoint is to determine the PK of eteplirsen by population PK methods, 
including assessment of the following PK parameters (if evaluable): 
• 
Cmax 


Sa re pta T hera pe utics, I nc. 
Pr ot oc ol  4 6 5 8 -1 0 2,  Versi o n  4  
Pa ge  3 2  of  7 0  
C o nfi de ntial  
 
 
•  Ti me  of Cma x  ( Tma x ) 
•  A U C  
•  A p pare nt v ol u me of distri b uti o n  at stea d y state ( Vss) 
•  Cleara nce  ( C L) 
•  Eli mi nati o n  half -life (t ½) 
•  A m o u nt of dr u g eli mi nate d i n uri ne ( Ae %) 
 
7.3.3. 
 
 
 
 
 
 
 
 
7.4. 
Disc ussi o n of  St u d y  Desi g n  
D M D is a rar e, seri o us, d e bilitati n g, a n d ulti matel y fatal, disease f or w hic h t here is a n ur g e nt  
nee d t o de vel o p saf e a n d effecti ve t hera pi es. I n or der t o effici e ntl y meet t his ur ge nc y a n d t he  
nee ds  of t h e patie nt  c o m m u nit y, t he st u d y is o pe n la bel wit h  n o place b o  c o ntr ol. 
 
 
 
 
N o  other disease - m o dif yi n g treat me nt e xists t o ser ve as a n a p pr o priate acti ve c o m parat or f or t his 
patie nt p o p ulati o n of b o ys a ge d 6 t o 4 8 m o nt hs; atal ure n is c o m merciall y a vaila ble i n t he 
E ur o pea n U ni o n, b ut is n ot i n dicate d f or use i n p atie nts  wit h  e x o n 5 1 a me n a ble m utati o ns  
(P T C  T hera pe utics ). 
T he patie nts i n t his st u d y will ha ve a n esta blis he d cli nical dia g n osis of D M D wit h a deleti o n  
m utati o n  a me na ble t o e x o n 5 1 s ki p pi n g. T hese  are t he patie nts f or  w h o m ete plirse n is p ote ntiall y  
effecti ve a n d ma y res ult i n sl o wi n g t heir disease pr o gressi o n. T he a g e ra n g e f or t he patie nts i n 
t his st u d y ( 6 t o 4 8 m o nt hs ol d, i ncl usi ve) was c h ose n i n or der t o esta blis h t he safet y pr ofile of 
ete plirse n  i n t his a ge gr o u p t o pr o vi de data  t o s u p p ort t he safet y of earl y i nt er ve nti o n. 
T o pr otect patie nt safet y, gra d ual d ose titrati o n of ete plirse n will occ ur o v er t he first 1 0 wee ks,  
f ollo we d b y o nce- wee kl y i nf usi o n of t he tar g et d ose of 3 0 m g/ k g, wit h wee kl y re vie ws of st u d y 
data  b y t he D M C  t hr o u g h t he first 1 2 wee ks  of d osi n g f or t he first 3 p atie nts of  eac h a ge  c o h ort, 
C CI


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and at least quarterly thereafter. In addition, study drug may be interrupted or discontinued for 
specific safety reasons. 
Patients will continue to receive once-weekly infusions for at least 48 weeks and up to 96 weeks 
to obtain safety data in this population. Refer to the Investigator’s Brochure for information on 
the safety of eteplirsen. 
Because DMD is a rare disease, the accrual of patients for enrollment may be challenging. To 
allow for efficient recruitment of the appropriate patient population, this study is being 
conducted at multiple sites. The selected sites for this study are centers of excellence for 
treatment of DMD, have extensive experience collaborating on clinical trials, and are therefore 
optimally suited to enroll and conduct the present study. 
7.5. 
Data Monitoring Committee 
The DMC will be comprised of a group of individuals with pertinent methodological and clinical 
expertise relevant to the study design and background population, that review the conduct of the 
study and the emerging safety, PK, and efficacy data on an ongoing basis in order to ensure that 
clinical trial participants are not exposed to unreasonable or unnecessary risks. The DMC will 
advise the study team and study investigators on safety aspects of dose interruption/continuation 
and dose escalation for the study. DMC membership will begin before the start of the clinical 
trial and continue for its duration. 
The activities and composition of this committee will be outlined in the DMC Charter, which 
will be ratified during the initial DMC meeting, prior to the commencement of dosing of the 
study patients. The reviews will be performed at least weekly through the first 12 weeks of 
dosing for the first 3 patients of each age cohort and at least quarterly thereafter. Oversight and 
monitoring of the clinical study by the DMC will be performed in compliance with International 
Council on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. These safety 
monitoring functions are distinct from the requirements for study review and approval by an 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Number of Patients 
Approximately 12 patients will be enrolled in this study. 
8.2. 
Patient Inclusion Criteria 
A patient must meet all of the following criteria to be eligible to participate in this study. 
• Be a male between 6 months to 48 months of age, inclusive. 
• Have an established clinical diagnosis of DMD with a deletion mutation amenable to 
exon 51 skipping (eg, deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63). 
• Have a parent(s) or legal guardian(s) who is able to understand and comply with the 
study requirements and is willing to provide written informed consent for the patient to 
participate in the study. 
8.3. 
Patient Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study. 
• Has received any pharmacologic treatment that might have an effect on muscle strength 
or function within 12 weeks prior to dosing at Week 1 (eg, growth hormone, anabolic 
steroids). 
• Has received previous or current treatment with any experimental treatment. Prior 
drisapersen therapy is permitted if a patient has not received drisapersen for 6 months 
prior to the Week 1 dose. 
• Has a clinically significant illness other than DMD, including cardiac, pulmonary, 
hepatic, renal, hematologic, immunologic, behavioral disease, or malignancy likely to 
impair the patient's ability to participate in this study. 
• Has a clinically significant laboratory abnormality that is either not expected or is of a 
greater severity than what is expected in DMD patients. 
• Has any other condition that, in the Investigator’s opinion, could interfere with the 
patient’s participation in the study. 
 
8.4. 
Completion of a Patient’s Participation in the Study 
Patients are considered completers for the purpose of analysis once the Week 48 assessments 
have been completed. Patients may continue in the study up to and including 96 weeks based on 
the judgement of the Investigator (described further in Section 7.1); however, a Safety Follow-up 
visit will occur approximately 4 weeks after the last dose administered regardless of the patient’s 
duration 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 Safety Follow-up visit (approximately 4 weeks 
after the last dose is administered). 


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8.5. 
Completion of the Trial 
The trial will be considered to have been completed upon the last visit of the last patient who had 
their treatment extended to Week 98. 
 
8.6. 
Patient Withdrawal Criteria 
Any patient can decide to withdraw from study participation at any time for any reason. A 
patient who discontinues may be replaced at the discretion of the Sponsor. In addition, the study 
Sponsor may decide to stop the study participation of any patient as deemed necessary. The 
Investigator may also stop the study participation of any patient at any time. Reasons for 
withdrawal from the study 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 without the prior written 
authorization of the Sponsor. 
The Investigator or study staff will document the reason(s) for treatment discontinuation. 
Patients who have received at least 1 dose of study treatment and who are withdrawn from 
treatment within 28 days after a functional assessment visit will be asked to return for an Early 
Termination visit (to complete the Week 96 assessments) approximately 28 days after their last 
dose. Patients who receive at least 1 dose of study treatment who are withdrawn from treatment 
more than 28 days after a functional assessment visit will be asked to complete all early 
termination (Week 96) assessments within approximately 28 days after the last dose. 
Patients withdrawn from treatment will not be replaced. 
 
8.7. 
Study Discontinuation 
If the Sponsor, the Investigator, the Medical Monitor, the study monitor, 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, the 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 
• 
Failure of the Investigator to enroll patients into the study at an acceptable rate 


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• 
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 the European Clinical 
Trial Directive 2001/20/EC 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product 
Eteplirsen drug product is supplied as a sterile, phosphate-buffered saline solution in single-use, 
2-mL vials each containing 2 mL of eteplirsen at 50 mg/mL. The solution is a clear to slightly 
opalescent and colorless liquid that may contain white to off white particles. Eteplirsen will be 
administered once a week by IV infusion. 
 
9.1.1. 
Packaging and Labeling 
Please refer to the study-specific Pharmacy Manual for information on packaging, labeling, and 
preparation instructions. 
The label text for the IP will at a minimum include the following information: product 
name/identifier, cautionary statement, lot number (or alternative code), storage conditions, and 
the name of the Sponsor pursuant to regional requirements. 
 
9.1.2. 
Storage 
Vials of IP must be stored in a secured, limited access area with appropriate temperature 
recording, controls, and monitoring. Details for storage can be found in the study-specific 
Pharmacy Manual. 
 
9.2. 
Treatments Administered 
Eligible patients will receive a once weekly IV infusion of eteplirsen for up to 96 weeks. 
Eteplirsen should be prepared for dosing by following the steps detailed in the study-specific 
Pharmacy Manual. 
The starting dose is 2 mg/kg eteplirsen, with escalation to 4, 10, 20, and 30 mg/kg over the 
course of the dose-titration period. 
The following guidelines for the timing of dosing should be followed throughout the study: 
• 
Patients should receive Eteplirsen once every 7 days starting on Week 1. A window 
of ±3 days from the scheduled dose is acceptable after the first infusion. 
• 
Patients may not receive 2 separate doses of Eteplirsen within the same 60-hour 
period. 
• 
The Medical Monitor should be contacted in the event of ≥2 consecutive missed 
doses. 
The administered dose is calculated by patient weight, which will be collected on a weekly basis 
and used to calculate the dose to be administered at the next visit(s). For example, the weight 
collected at Week 2 will be used to calculate the doses to be infused during the Week 3 visit. 
Eteplirsen should be diluted in a normal saline, where the final volume, after eteplirsen has been 
added, equals the volume appropriate for the patient’s weight. The drug delivery bag, syringe or 
flask is to be labeled in accordance with standard pharmacy practice and to include total volume 
as well as drug dose in milligrams. Eteplirsen will be diluted in normal saline to a total volume 
per Table 5 and infused IV for approximately 35 to 60 minutes using an infusion or syringe 


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pump. It is recommended that a topical anesthetic cream be applied to the infusion site prior to 
each administration of eteplirsen. 
Table 5: 
Example Eteplirsen Dilution Scheme 
 
Patient 
Weight 
Total Eteplirsen 
Dose (30 mg/kg) 
Total Volume of 
Eteplirsen Drug 
Product 
Dilution in Saline 
up to Total 
Volume of: 
Maximum 
Eteplirsen 
Concentration in 
Infusion 
<5 kg 
<150 mg 
<3 mL 
10 mL 
15 mg/mL 
5 to 10 kg 
150 to 300 mg 
3 to 6 mL 
15 mL 
20 mg/mL 
10 to 15 kg 
300 to 450 mg 
6 to 9 mL 
25 mL 
18 mg/mL 
15 to 25 kg 
450 to 750 mg 
9 to 15 mL 
50 mL 
15 mg/mL 
>25 kg 
>750 mg 
>15 mL 
100 mL 
Note: Refer to the Pharmacy Manual for other dosing dilution schemes. 
 
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. Patients 
are permitted to continue a chronic, stable regimen of corticosteroids; however, the corticosteroid 
should not be administered during the infusion of eteplirsen. 
All treated patients will be observed for at least 1 hour following the end of each eteplirsen 
infusion. 
 
9.2.1. 
Dose Modification, Reduction, or Delay 
 
9.2.1.1. 
Dose Interruption 
The following rules apply to individual dosing interruption, ie, the criteria for dosing interruption 
of 1 patient. Further administration of eteplirsen must be discontinued if any of the following 
occur: 
• 
Any serious adverse event (SAE) considered to be related to eteplirsen, unless the 
SAE is deemed related to the underlying disease 
• 
See Section Section 10.3.4 for Safety Monitoring, Additional Investigations and 
Stopping Rules 
If a patient meets one of the above criteria or under Section 10.3.4, the study monitor should be 
immediately notified, and dosing should be suspended until the patient’s safety information can 
be reviewed by the DMC. Dosing may resume only after approval of the DMC, Sponsor, and 
Investigator, and after approval of a substantial amendment by the competent authority. 


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Conditions that may warrant interrupting dosing for all patients in the study for additional safety 
review include, but are not limited to: 
• 
Any SAE of life-threatening or fatal outcome assessed as related by the Investigator 
• 
> 2 patients with severe AEs that result in interruption of individual patient dosing 
(described earlier in Section 10.3.4) 
• 
Any unexplained or drug-related organ failure (eg, liver or renal failure) 
The DMC will monitor safety data on an ongoing basis. If the DMC determines that the criteria 
for study interruption are met, dosing will be suspended until all available patient information 
related to the event of interest can be reviewed in more detail. Discontinuation of dosing for an 
individual patient may occur based on the recommendation of the DMC, investigator, the patient, 
and the local Independent Ethics Committee (IRB/IEC). 
 
 
 
Stopping rules are provided in Section 8.6 (Patient Withdrawal Criteria) and Section 8.7 (Study 
Discontinuation). 
 
9.2.1.2. 
Dose Escalation 
Increases in dosing up to 30 mg/kg are described in Section 9.2. 
9.3. 
Randomization and Blinding 
This is an open-label study, and therefore all patients will receive eteplirsen. 
9.4. 
Prior and Concomitant Medications 
No other medications may be administered concomitantly during the eteplirsen infusion. 
The following therapies are not permitted during the conduct of this study: 
• 
Previous or current investigational agents (with the exception of drisapersen: patients 
may be included in the study if they have not received drisapersen for 6 months prior 
to the Week 1 dose) 
• 
Immunosuppressants (other than oral or systemic corticosteroids; the corticosteroid 
should not be administered during the infusion of eteplirsen) 
• 
Previous (within 12 weeks prior to the Week 1 dose) or current systemic 
aminoglycoside antibiotic or statin 
In general, drug therapies that are not excluded per the entry criteria, including over-the-counter 
medications, may be used before enrollment and throughout the study. However, the number of 
over-the-counter medications should be limited and the dosage of any medication should be 
constant for at least 1 month prior to starting study treatment and throughout the study, especially 
during the dose-escalation period and throughout the first 6 months in the study, unless clinically 
indicated. 


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The Investigator should contact the Medical Monitor if he/she is unsure about changing a 
specific medication. 
9.5. 
Treatment Compliance 
Treatment compliance will be assessed via compliance with scheduled weekly infusions. 


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10. 
STUDY ASSESSMENTS 
10.1. 
Study Schedule of Events 
A detailed schedule of the study assessments and time points is shown in Table 2 and Table 3. 
10.2. 
Screening/Baseline Assessments 
10.2.1. 
Informed Consent 
Written informed consent from the parent/legal guardian(s) to participate in this study must be 
obtained prior to beginning any of the procedures for this study. 
 
10.2.2. 
Demographics and Medical History 
Demographic information (eg, age, race, ethnicity, body weight, height, body mass index) and 
medical history (including treatment history) will be obtained for all patients. 
 
10.2.3. 
Genotyping 
 
10.2.3.1. 
DMD 
A blood sample will be obtained to determine DMD genotype (or confirm if previously tested). 
Patients not previously genotyped may be consented and have genotype performed as part of the 
study. The blood sample for genotyping can be drawn at the Screening visit or any time prior to 
the Week 2 visit so that total blood volume taken for the Screening visit does not exceed 
recommendations (Section 17.1). Patients may start dosing based on historical genotyping 
results, provided that these results fulfill the required criteria described in Inclusion Criterion #2 
(Section 8.2); however, all patients must undergo genetic testing to confirm the deletion mutation 
amenable to exon 51 skipping. Patients whose genotype is not confirmed to be amenable to 
exon 51 skipping will be withdrawn from the study. 
 
10.2.3.2. 
LTBP4 and SPP-1 
A blood sample will be obtained for latent transforming growth factor beta (TGF) binding 
protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP-1) genotype for sensitivity analysis. The 
blood sample for single-nucleotide polymorphism analysis can be drawn at the Screening visit or 
any time during the dose-titration period, such that total blood volume taken at any given visit 
does not exceed recommendations (Section 17.1). 
 
10.2.4. 
Other Assessments 
Screening will also include clinical safety laboratory assessments, vital signs, physical 
examination, height/length and weight, a 12-lead ECG, an ECHO, assessment of previous and 
current medications/therapies, assessment of pre-treatment AEs, 
 
 


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10.3. 
Safety Assessments 
10.3.1. 
Physical Examination 
The Investigator or a medically qualified Subinvestigator will perform physical examinations at 
designated study visits, including examination of general appearance; head, ears, eyes, nose, and 
throat (HEENT); heart; lungs; chest; abdomen; skin; lymph nodes; musculoskeletal; and 
neurological systems. 
 
10.3.2. 
Vital Signs 
Vital signs (blood pressure, heart rate, respiration, and temperature) will be measured at the time 
points specified in Table 2 and Table 3. Refer to the Study Operations Manual for more details 
on the methods for obtaining vital signs. 
For infusion visits, vital signs are to be collected within 60 minutes prior to infusion and within 
5 (±2)after the end of infusion, and at 30 (±5), and 60 minutes (±10) after the end of the 
infusion. If the patient has not experienced an infusion reaction after the first 48 weeks of 
treatment, vital sign assessments may be limited to approximately 30 minutes prior to infusion 
and approximately 30 minutes after the end of the infusion. All assessments will be performed 
after patients have remained calm for 5 minutes. Pulse rate and respiratory rate should be 
measured over 1 minute. 
10.3.3. 
Height/Length and Weight 
Height/length and weight will be measured at the time points specified in Table 2 and Table 3 
prior to study drug infusions, to determine the volume of study drug to be administered. Details 
about how weight measurements are obtained are provided in the Study Operations Manual. If a 
patient’s weight or height/length varies by more than 10% from the prior visit, the patient should 
be re-weighed to confirm the result, and an explanation of the change should be documented. 
10.3.4. 
Safety Monitoring, Additional Investigations and Stopping Rules 
 
10.3.4.1. 
Safety Monitoring for Liver Chemistry Tests 
 
Liver chemistry tests need to be monitored as specified in the Schedule of Events (Table 2). 
Initial abnormal liver chemistry test result(s) needs to be confirmed if: 
• 
Gamma-glutamyl transferase (GGT) or glutamate dehydrogenase (GLDH) or 
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) measurement 
is > 3 x the upper limit of normal (ULN) (or > 2 x Baseline value if the Baseline 
value was > ULN) at any time during the study. 
 
Patients with confirmed liver chemistry test results (as above) need to have their liver chemistry 
tests (GGT, GLDH, ALT, AST, alkaline phosphatase (ALP), international normalized ratio 
(INR) and total bilirubin) retested two or three times weekly. Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize or the trial drug has been discontinued 
and the subject is asymptomatic. 


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Additional Investigations: 
Patients with confirmed abnormal liver chemistry test results (as above) are recommended to 
have the following evaluations performed: 
• 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• 
Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; Non-Alcoholic SteatoHepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
• 
Obtaining a history of exposure to environmental chemical agents. 
• 
Additional liver evaluations, including gastroenterology/hepatology consultations, 
hepatic computed tomography (CT) or magnetic resonance imaging (MRI) scans, 
may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor. 
 
Stopping Rules for Liver Test Results: 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with eteplirsen will be stopped permanently; values that are not confirmed due to failure to retest 
or missing lab values will be presumed confirmed: 
• 
GGT or GLDH > 8 x ULN, which is confirmed 
• 
GGT or GLDH > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
• 
GGT or GLDH > 3 x ULN, which is confirmed and total bilirubin > 2 x ULN or INR 
> 1.5 
• 
GGT or GLDH > 3 x ULN which is confirmed, and the new appearance (ie, onset 
coincides with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (> 5%) felt by the 
Investigator to be potentially related to hepatic inflammation. 
 
10.3.4.2. 
Safety Monitoring for Renal Function 
 
Renal tests need to be monitored as specified in the Schedule of Events (Table 2). Patients with 
the following test results need to undergo repeat testing for confirmation of abnormal test results: 
• 
Protein ≥ 2+ (dipstick) 
• 
Urine Protein to Creatinine Ratio (UPCR) ≥ 150mg/g 
• 
Urine Albumin to Creatinine Ratio (UACR) ≥ 30mg/g 
• 
Serum Creatinine ≥ 0.3 mg/dL above baseline 


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• 
Serum Creatinine ≥ 1.5x ULN 
• 
Estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73m2 
• 
Red blood cells (RBCs) > 1/hpf 
• 
Elevated Cystatin C > ULN 
• 
Elevated kidney injury molecule 1(KIM-1) > ULN 
 
Additional Investigations: 
24- hour urine collection needs to be undertaken to quantify any proteinuria and glomerular 
filtration rate (GFR) changes indicated by confirmed results as above. Additional evaluations 
including nephrology consultation, renal US/CT/MRI, renal biopsy, may be performed at the 
discretion of the Investigator in consultation with the Sponsor Medical Monitor. 
 
 
Stopping Rules for Renal Test Results: 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with eteplirsen will be stopped permanently: 
• 
Quantitative total urine protein measurement of ≥ 1 g/24 hours 
• 
Measured GFR (creatinine clearance) ≤ 45 mL/min/1.73m2 
• 
Gross hematuria 
• 
Any RBC Casts 
• 
Persistent microscopic hematuria ≥ 3 RBCs/hpf for 3 consecutive weeks 
 
Safety Monitoring for Hypersensitivity 
 
 
Patients will be monitored for occurrence of allergic reactions primarily via monitoring adverse 
events as specified in the Schedule of Events (Table 2). Patients will be instructed to promptly 
report any signs or symptoms of fever or constitutional symptoms that may arise during the study 
and the Investigator needs to closely evaluate all potential causes, including concomitant illness. 
 
Additional Investigations: 
Patients who experience significant or persistent constitutional symptoms need to be discussed 
with the Sponsor Medical Monitor to determine whether additional monitoring or laboratory tests 
are required. Additional evaluations including immunology consultation, tests for allergic 
reactions (absolute eosinophils, serum/plasma tryptase), may be performed at the discretion of 
the Investigator in consultation with the Sponsor Medical Monitor. 


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Stopping Rules for Hypersensitivity AEs: 
In the event of a confirmed hypersensitivity AE meeting the following criteria, and the event is 
without an alternative explanation as discussed with the Sponsor Medical Monitor, dosing 
of a patient with eteplirsen will have their treatment permanently discontinued. 
• 
Anaphylaxis, anaphylactoid reaction, or angioedema 
• 
Any serious allergic reaction 
 
Safety Monitoring for Platelet Count Results 
The platelet count needs to be monitored as specified in the Schedule of Events (Table 2). 
Patients who have a confirmed occurrence of platelets < 75,000/ mm3 need to have the following 
evaluations performed: 
• 
Complete blood count (CBC) with reticulocytes 
− Peripheral blood smear 
− Coagulation panel (prothrombin time /INR, activated partial thromboplastin time) 
− High-sensitivity C-reactive protein 
Additional Investigations: 
Additional platelet evaluations for confirmed, unexplained significant platelet count reductions, 
including hematology consultation, fibrinogen, fibrinogen split products/D-dimer, von 
Willebrand factor, total immunoglobulins, complement levels, viral serologies, auto-antibody 
screen, antiplatelet antibodies and anti-PF4 assay, may be performed at the discretion of the 
Investigator in consultation with the Sponsor Medical Monitor. 
 
 
Stopping Rules for Platelet Test Results: 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with eteplirsen will be stopped permanently: 
• 
Platelet count < 50,000/mm3 
 
 Safety Monitoring for Rhabdomyolysis 
 
 
Rhabdomyolysis must be monitored by urine dipstick and adverse events as specified in the 
Schedule of Events (Table 2). 
Patients who have confirmed heme+ dipstick urinalysis need to be evaluated for urine 
microscopy and the following AEs: 
• 
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• 
Acute onset or exacerbation of Myalgia 
• 
Myoglobinuria 
• 
Chromaturia (eg, tea-colored urine) 
 
Additional Investigations: 
In case of any of the adverse events above, subjects need to have evaluations of myoglobinuria, 
creatine kinase (CK), renal function (eg, serum cystatin C) and serum chemistry two or three 
times weekly until values reach usual/pre-event levels or stabilize. 
In addition, investigators should obtain a more detailed history of symptoms, preceding activity 
and hydration status, concomitant drug use, and recent or concurrent infections. Additional 
evaluations, including rheumatology/immunology consultations and anti-muscle antibodies, may 
be performed at the discretion of the Investigator in consultation with the Sponsor Medical 
Monitor. 
 
 
10.3.5. 
Clinical Safety Laboratory Evaluations 
The following routine clinical safety laboratory tests will be collected at the time points specified 
in Table 2 and Table 3, will be analyzed by an accredited central laboratory selected by the 
Sponsor, and will be 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, ALP, amylase, 
ALT, AST, GGT, GLDH, C-reactive protein (CRP), CK, and serum 
cystatin C 
Hematology: 
CBC with differential 
Coagulation Screen: 
Prothrombin time, International Normalized Ratio, and activated 
partial thromboplastin time 
Routine Renal 
Monitoring 
• Quantitative urinalysis: total protein to creatinine ratio 
(UPCR), urine albumin-to-creatinine ratio (UACR), kidney 
injury molecule 1 (KIM-1), and urinalysis (pH, specific 
gravity, protein, glucose, ketones, cytology, hemoglobin 
• Renal function blood tests: creatinine, blood urea nitrogen, and 
cystatin C 
• Urine dipstick testing 
 
Persistent, unexplained abnormalities on routine renal blood test monitoring will result in 
additional renal function tests such as eGFR and 24 hour urine testing for protein. 
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 


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results are clinically significant or not. Clinical significance is defined as any variation in 
assessment results that has medical relevance resulting in an alteration in medical care. If 
clinically significant deterioration from baseline levels is noted, the Investigator will continue to 
monitor the patient with additional assessments until: 
• 
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 are assessed to be not related to the administration of IP or other 
protocol-specific procedures, and additional assessments are not medically indicated. 
 
10.3.5.1. 
Laboratory Assessments of Interest 
The review of the DMC will include evaluation of laboratory assessments of interest, which 
include: 
• 
Any ≥Grade 2 (moderate) or serious event without an alternative etiology that the 
Investigator deems is related to study drug 
• 
Two consecutive drug-related serum creatinine levels ≥2 × ULN without an 
alternative etiology. 
• 
CK levels >50,000 U/L 
• 
A confirmed, unexplained, increase in GGT or GLDH >3 × ULN and either an 
increase in bilirubin >2 × ULN or nascent prothrombin time >2 × ULN concurrently, 
without an alternative etiology 
 
10.3.6. 
Electrocardiogram 
Twelve-lead ECGs will be obtained at the time points specified in Table 2 and Table 3. ECGs 
will be performed at a consistent time of day throughout the study, 
 
 but before performing 
any invasive procedures (ie, blood sampling or study drug infusions). ECGs should be performed 
by trained staff after the patient is in the supine position, resting, and quiet, when possible. 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. 
Clinical significance is defined as any variation in ECG findings that has medical relevance 
resulting in an alteration in medical care. If clinically significant worsening from baseline is 
noted, the Investigator will continue to monitor the patient with additional assessments until: 
• 
Findings have returned to normal and/or baseline levels; or 
• 
In the judgment of the Investigator together with the Sponsor’s Medical Monitor, 
abnormal findings are assessed to be not related to the administration of IP or other 
protocol-specific procedures, and additional assessments are not medically indicated. 
 
10.3.7. 
Echocardiogram 
A standard 2 dimensional ECHO will be obtained at the time points specified in Table 2 and 
Table 3. ECHOs will be performed at a consistent time of day throughout the study, and will be 


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performed 
 but 
before performing any invasive procedures (ie, blood sampling or study drug infusions). The 
ECHO will be obtained, reviewed, and interpreted by medically qualified personnel using a 
central vendor according to pre-specified criteria. Left ventricular ejection fraction (LVEF) will 
be noted. The Investigator will review the results of the ECHO report and determine if the 
findings are clinically significant. 
Clinical significance is defined as any variation in ECHO findings that has medical relevance 
resulting in an alteration in medical care. If clinically significant worsening from baseline is 
noted, the Investigator will continue to monitor the patient with additional assessments until: 
• 
Findings have returned to normal and/or baseline levels; or 
• 
In the judgment of the Investigator together with the Sponsor’s Medical Monitor, 
abnormal findings are assessed to be not related to the administration of IP or other 
protocol-specific procedures, and additional assessments are not medically indicated. 
 
10.3.8. 
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/legal guardian 
signs informed consent. Information on any physiotherapeutic intervention must be collected in 
detail for this study. See Section 9.4 for details on permitted concomitant medications. 
 
10.3.9. 
Adverse Events 
AEs will be monitored throughout the study, from signing of the informed consent through each 
patient’s safety follow-up visit, which will occur approximately 4 weeks after the last infusion 
regardless of the patient’s duration in the study. 
 
10.4. 
Pharmacokinetic Assessments 
10.4.1. 
Blood Sample Collection 
Serial plasma PK sampling will be performed on all patients at the visits specified in Table 2. 
Serial PK samples will be collected from the contralateral arm collected pre-dose, immediately 
prior to the end of infusion (prior to flush) and approximately 1 -3 hours and 6-8 hours after 
completion of study drug infusion. 
Refer to the Study Laboratory Manual for additional details on handling and processing PK 
samples. 
 
10.4.2. 
Urine Sample Collection 
Urine PK samples will be collected over the first 4 hours after start of infusion at the visits 
specified in Table 2. Refer to the Study Laboratory Manual for details on handling and 
processing urine samples. 
10.5. 
 
 


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10.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.5.2. 
 
 
 
 
 
 
 
10.5.3. 
 
 
 
 
 
 
 
 
 
 
 


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10.5.4. 
 
 
 
 
 
 
 
 
 
 


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11. 
ADVERSE EVENTS 
11.1. 
Collection of Adverse Events 
Over the entire duration of the study, site personnel will ensure that all AEs are recorded 
appropriately. If an AE occurs, the primary concern is for patient safety, and the Investigator will 
use professional judgment and expertise to determine the appropriate course of action. 
All AEs from the time of informed consent through the safety follow-up visit (which will occur 
approximately 4 weeks after the last infusion regardless of the patient’s duration in the study) 
will be recorded in each individual patient’s electronic case report form (eCRF). If at any time 
after the patient has completed participation in the study, the Investigator or study staff becomes 
aware of a SAE that the Investigator believes is related to the IP (Section 11.3.1) or is related to a 
study procedure (Section 11.3.2), then the event and any known details must be reported 
promptly to the Sponsor. 
11.2. 
Definition of Adverse Events 
11.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical trial participant, which does not 
necessarily have a causal relationship with the investigational drug. An AE can, therefore, be any 
unfavorable and unintended symptom, sign, disease, condition, or test abnormality that occurs 
during or after administration of an IP whether or not considered related to the IP. Adverse 
events include: 
• 
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. 
 
11.2.2. 
Serious Adverse Event 
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 
part of the study, only hospitalizations that are longer than expected based on 
Investigator judgment, will be considered prolonged hospitalizations. 


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• 
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. 
11.3. 
Classification of Adverse Events 
Each AE, whether serious or non-serious, will be classified by the Investigator according to the 
following rules and definitions. 
 
11.3.1. 
Relationship to Investigational Product 
For each AE, the Investigator determines whether there is a reasonable likelihood that the AE 
may have been caused by the study treatment according to the categories below: 
 
Unrelated: 
There is no reasonable possibility that the event is related to 
the investigational drug product. 
Possibly/Probably Related: 
The event could possibility be related/is likely related to the 
investigational drug product. 
Related: 
There is a reasonable possibility that the event is related to the 
investigational drug product. 
 
AEs that the Investigator or Sponsor considers to be related to the IP will be considered adverse 
drug reactions. 
 
11.3.2. 
Relationship to Study Procedures 
For each AE the Investigator determines whether there is a reasonable possibility that the AE 
may have been caused by the study procedures according to the categories below: 
 
Unrelated: 
There is no reasonable possibility that the event is related to 
the study procedures. 
Possibly/Probably Related: 
The event could possibility be related/is likely related to the 
study procedures. 
Related: 
There is a reasonable possibility that the event is related to the 
study procedures. 


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11.3.3. 
Relationship to Underlying Disease 
For each AE the Investigator determines whether there is a reasonable possibility that the AE 
may be related to the underlying disease according to the categories below: 
 
Unrelated: 
There is no reasonable possibility that the event is related to 
the underlying disease. 
Possibly/Probably Related: 
The event could possibility be related/is likely related to the 
underlying disease. 
Related: 
There is a reasonable possibility that the event is related to the 
underlying disease. 
 
Events of disease progression may be considered AEs, based on the Investigator’s discretion. 
 
11.3.4. 
Severity of Adverse Events 
Note that severity is not the same as “seriousness,” which is defined in Section 11.2.2 and which 
serves as a guide for defining regulatory reporting obligations. 
The Investigator will assess the severity of all AEs as mild, moderate, or severe, based on the 
following definitions: 
 
Mild: 
The event does not interfere with the patient’s usual activities. 
Moderate: 
The event interferes with the patient’s usual activities. 
Severe: 
The event prevents the patient from undertaking their usual activities and 
requires therapeutic intervention or cessation of the IP. 
 
11.3.5. 
Outcome 
Outcome describes the status of the AE. The Investigator will provide information regarding the 
patient outcome of each AE in the eCRF. 
 
11.3.6. 
Action Taken Regarding the Investigational Drug Product 
The Investigator will provide information regarding the action taken with respect to the IP in 
response to the AE in the eCRF. 
 
11.3.7. 
Expectedness of an Adverse Event 
The expectedness of all AEs will be determined according to the most recent version of the 
Investigator’s Brochure for eteplirsen. 
 
11.3.8. 
Suspected Unexpected Serious Adverse Reactions 
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 


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fashion to regulatory authorities and the IRBs/IECs per the requirements of the concerned 
competent bodies. SUSARs will also be reported to study investigators. 
11.3.9. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are AEs (serious or nonserious) that are of special 
scientific and/or medical interest, for which ongoing and rapid communication by the 
Investigator to the sponsor is appropriate. 
AESIs for this study are listed below. All AESIs should be reported as AEs to the sponsor within 
24 hours of awareness irrespective of adverse event seriousness. This includes the events below 
that are based on lab abnormalities, which should be translated to an appropriate adverse even t 
term at the time of reporting. 
Nephrotoxicity 
• 
Proteinuria > 500 mg/24 hr 
• 
eGFR <60 ml/min/1.73 m2 
Hepatotoxicity 
• 
GGT or GLDH > 8 × ULN 
• 
GGT or GLDH > 5 × ULN for more than 2 weeks 
• 
GGT or GLDH > 3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio > 1.5) 
• 
GGT or GLDH > 3 × ULN with the appearance of the following signs or symptoms: 
fatigue, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%) 
Hypersensitivity 
• 
Anaphylaxis, anaphylactoid reaction, or angioedema 
• 
Any severe allergic reaction 
• 
Any severe complement mediated, inflammation event (eg, acute kidney injury, 
arteritis, myocarditis, pneumonitis) 
Thrombocytopenia 
• 
Platelet count < 75,000/mm3 
Infusion-related reactions 
• All infusion related reactions considered severe (see Section 11.3.4), occurring within 24 
hours of the eteplirsen infusion, should be reported to the Sponsor within 24 hours of 
awareness. 
Infusion-related reactions may include headache, vomiting, diarrhoea, pyrexia, abdominal pain, 
upper, flushing and nausea. There may be pain at the site of the infusion as well as bruising 
surrounding the infusion site. Infections are also possible at the site of the infusion. All reactions 
grade 3 or higher, occurring within 24 hours of the eteplirsen infusion, should be reported to the 
Sponsor within 24 hours of awareness. Infusion-related reactions considered severe should be 


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reported to the Sponsor within 24 hours. 
 
Rhabdomyolysis 
Rhabdomyolysis adverse events of any severity. 
 
11.4. 
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 eCRF. Information to be recorded should include: a concise 
description of the event; date and time of event onset and resolution; determination of 
seriousness, severity, corrective treatment, outcome, and relationship to IP or study procedure or 
underlying disease; and any action taken will be recorded. Resolution occurs when the patient 
has returned to his baseline state of health or further improvement or worsening of the event is 
not expected. 
Whenever possible, a diagnosis will be recorded as an AE, rather than symptoms or isolated 
laboratory abnormalities related to that diagnosis. Several symptoms or laboratory results that are 
related to the same diagnosis can thus be part of the same AE. A medical or surgical procedure is 
not an AE; rather the condition leading to the procedure should be recorded as the AE. Similarly, 
death is not an AE, but is rather the outcome of the AE(s) that resulted in death. If the AE(s) 
leading to death are not known, then death must be reported as an AE. All AEs will be followed 
until the resolution of AE, completion of the patient’s study participation, or study termination, 
whichever occurs first. SAEs will be followed until resolution or until the condition stabilizes or 
returns to baseline status. 
11.5. 
Reporting Adverse Events 
It is the responsibility of the Investigator that reporting is done adequately. In order to meet 
regulatory reporting timelines, the study site is obligated to report any SAE(s) to the Sponsor or 
designee immediately and no later than 24 hours after receiving information of an event that 
meets at least one of the criteria for seriousness as defined in Section 11.2.2. 
11.6. 
Special Situations 
11.6.1. 
Overdose 
An overdose is defined as administration of a dose that is >10% higher than the assigned dose 
per the protocol. 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 on the appropriate form and sent to the Sponsor or 
designee within 24 hours. 
11.6.2. 
Pregnancy 
If the female partner of a treated male subject becomes pregnant, the male subject must notify 
the Investigator within 24 hours of learning of the pregnancy. The Investigator must make every 
effort to ensure that the pregnant female is aware of the need to notify her healthcare provider 
regarding her male partner’s participation in this clinical trial and his potential exposure to IP. 
The study site must complete a pregnancy form and send to the Sponsor or designee within 24 


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hours of learning of the pregnancy. The study site will make every effort to follow the pregnancy 
till outcome is known. 
 
11.6.3. 
Medication Error 
Medication Error is any preventable incident that may cause or lead to inappropriate study 
treatment use or patient harm, while the study drug is in the control of the health care 
professional, or in certain cases, the patient. Such incident may be due to health care professional 
practice, product labeling, packaging, and preparation, procedures for administration, and 
systems, including the following: prescribing, order communication, dispensing, nomenclature, 
compounding, distribution, administration, education, monitoring, and use. A medication error 
will be recorded on the appropriate form and sent to the Sponsor or designee within 24 hours. 
11.6.4. 
Accidental/Occupational Exposure 
Accidental/Occupational Exposure is the unintentional exposure to a study treatment as a result 
of one’s professional or non-professional occupation, or accidental exposure to a 
non‑professional to whom exposure was not intended (eg, study drug given to wrong patient). 
An accidental/occupational exposure will be recorded on the appropriate form and sent to the 
Sponsor or designee within 24 hours. 
 
 
11.6.5. 
Death 
Death is an outcome of an event. All causes of death are SAEs. In the event of death, every effort 
should be made to obtain a death certificate and if possible, an autopsy report. If the cause of 
death is unknown, death will be recorded as the event. 
 
11.6.6. 
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 


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11.6.7. 
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 
• 
Safety monitoring and recording of AEs 
• 
AE processing and submission of expedited serious, unexpected, and related AEs to 
regulatory authorities per regulatory requirements 
• 
Notification of expedited SAEs to sites 
• 
Annual safety reporting to regulatory authorities and IRBs/IECs according to regional 
requirements 


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12. 
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT 
12.1. 
Recording of Data 
Clinical data for this study will be captured in an electronic format. Electronic data capture will 
be provided by a contract research organization (CRO). The Investigator, or personnel delegated 
by the Investigator, will perform primary data collection/perform assessments based on the 
protocol design and record in source documentation. All required study information must be 
recorded on the appropriate eCRF screens/forms using the eCRF Completion Guidelines for the 
study. An eCRF must be completed for each patient that is enrolled. The study monitor will 
conduct 100% source data verification to ensure maximum data integrity. All data must be 
carefully entered in a timely fashion to permit meaningful interpretation and study oversight. 
 
12.2. 
Quality Assurance 
The eCRFs 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 eCRF and for the 
Investigator or study coordinator to resolve. All changes to the eCRFs 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, eCRFs, 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. 
 
12.3. 
Retention of Study Documents 
At study completion, all eCRF data for an individual site will be copied onto a compact disc 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. 
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. 


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If off-site archiving is used, all records should be retrieved and made available for review at the 
time of an audit or regulatory authority inspection. 


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13. 
STATISTICS 
13.1. 
General Considerations 
This section describes the rules, conventions, statistical analysis, and presentation of data for this 
study. Full details will be provided in the Statistical Analysis Plan (SAP) for this study. 
Revisions during the study may be made to accommodate protocol amendments and to make 
changes to adapt to unexpected issues in study execution that could affect planned analyses. 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 fo r 
missing data will be performed. Percentages of patients with AEs or laboratory abnormalities 
will be based on non-missing values. 
All data collected in this study will be presented using summary tables and patient data listings. 
Summary statistics for raw and change from baseline data of continuous variables will minimally 
include n, mean, standard deviation, minimum, median, and maximum. For categorical variables, 
frequencies and percentages will be presented. Graphical displays will be provided as 
appropriate. 
Endpoints will be assessed primarily using simple descriptive statistics and/or inferential 
statistics. Baseline will generally be defined as the last available value before dosing. 
The primary analysis will be done using the Week 48 data. In addition, all data through the end 
of study will also be analyzed. 
13.2. 
 
 
 
13.3. 
Analysis Sets 
There will be one analysis population, the Safety set, which includes all patients who are 
enrolled in the study and receive at least 1 dose of eteplirsen. 
 
13.4. 
Protocol Deviations 
Protocol deviations will be listed. 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 
deviation, use of prohibited therapies, etc.). 


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13.5. 
Disposition, Demographics, and Baseline Characteristics 
The number and percentage of patients completing the study through Week 48 (ie, completers) 
or prematurely discontinuing before Week 48 will be summarized. Disposition will also be 
summarized over the entire 96-week duration of the study. Reasons for premature 
discontinuation will also be summarized. 
Demographic characteristics including age (years), race, ethnicity, and baseline characteristics 
including height/length (cm), and weight (kg) will be summarized by age cohort and overall. 
Demographic data and baseline characteristics will be presented in data listings. 
 
13.6. 
Medical History 
Medical history will be presented in data listings. 
13.7. 
Dosing and Compliance 
The cumulative exposure to eteplirsen, total volume of drug administered (mL), total number of 
infusions received, and the cumulative amount of drug received will be summarized by age 
cohort and overall for all treated patients. Dosing information will be provided in a data listing. 
 
13.8. 
Safety Analysis 
13.8.1. 
Safety Variables 
The safety variables are: 
• 
Incidence of AEs 
• 
Abnormal changes in clinical safety laboratory parameters 
• 
Abnormal changes in vital signs 
• 
Abnormal changes in physical examination findings 
• 
Abnormal changes in ECG and/or ECHO parameters 
 
13.8.2. 
Safety Analyses 
Safety analyses will be descriptive in nature. Summary statistics for each parameter at a specific 
visit, as well as the change from baseline to that visit, will also be displayed. All safety data will 
be presented in the data listings. 
 
13.8.2.1. 
Adverse Events 
Only treatment-emergent adverse events (TEAEs) will be summarized by the Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term. Non- 
treatment-emergent events will be recorded in data listings. For all AE tables, the number and 
percentage of patients reporting AEs will be grouped by MedDRA SOC and preferred term for 
each age cohort and overall. 
Multiple occurrences of the same AE (at the preferred term level) in the same patient will be 
counted only once in frequency tables. If a patient experiences multiple episodes of the same 


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event with different severity, the event with the maximum severity will be used to summarize 
AEs by severity (likewise for relationship). Treatment-related TEAEs will be defined as those 
that the Investigator considers related to the IP. 
The following summary tables will be produced: 
• 
TEAEs 
• 
TEAEs by severity 
• 
Treatment-related TEAEs 
• 
Treatment-related TEAEs by severity 
• 
TEAEs related to study procedures 
• 
TEAEs related to the underlying disease 
• 
SAEs 
In addition, all SAEs, regardless of their treatment-emergent status will be summarized. 
The following listings will be produced: 
• 
Non-treatment-emergent AEs 
• 
All TEAEs 
• 
AEs leading to discontinuation 
• 
SAEs 
 
13.8.2.2. 
Physical Examinations, Vital Signs, Height, and Weight 
Vital signs, height/length, and weight will be presented by visit for each age cohort and overall, 
summarizing the actual values and change from baseline to each visit for each parameter using 
descriptive statistics. Frequency tables of predefined change to abnormal in vital sign values will 
be generated. 
Data obtained from physical examinations will be presented in patient data listings. Any 
clinically significant findings will be recorded as AEs. 
 
13.8.2.3. 
Clinical Safety Laboratory Tests 
Clinical chemistry, hematology, renal function, coagulation, and urinalysis will be presented by 
visit for each age cohort and overall, summarizing the actual value 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 to abnormal of select 
laboratory parameter values will be generated. 
13.8.2.4. 
Electrocardiograms 
The actual value and change from baseline to each visit will be presented by visit for each age 
cohort and overall, summarizing the actual values and change from baseline to each visit for each 
parameter using descriptive statistics. 


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13.8.2.5. 
Echocardiograms 
ECHO parameters, including the LVEF value and change from baseline in LVEF to each visit, 
will be summarized by visit for each age cohort and overall. 
 
13.8.2.6. 
Prior and Concomitant Medications and Physiotherapeutic Interventions 
All prior medications (including prior DMD medication) and concomitant medications, as well 
as physiotherapeutic interventions, will be presented in data listings. 
 
13.9. 
 
 
 
 
 
 
 
13.10. 
Pharmacokinetic Analysis 
Results of all PK analyses will be provided as a separate PK report which will be appended to the 
final CSR and summarized in the CSR. 
Pharmacokinetic parameters of eteplirsen will be determined from plasma and urine 
concentration data. Individual plasma and urine levels of eteplirsen will be listed with the 
corresponding time relative to eteplirsen administration, and summary statistics will be generated 
by per-protocol time of collection. PK parameters for eteplirsen will be calculated using 
non-compartmental analysis and/or using population PK methodology, as appropriate. 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 and urine concentrations will be listed. PK parameters in plasma and urine will be 
summarized by dose level and age cohort. Plasma concentrations will be plotted versus elapsed 
time for dose level means and for individual patients. Dose proportionality will be evaluated 
across the range of doses studied. 
13.11. 
Interim Analysis 
An interim analysis of the PK and safety data following completion of dose escalation for one or 
both age cohorts may be done for administrative purposes. Detailed plans for data analysis will 
be documented in the study SAP or in a separate SAP for interim analysis only. 
 
13.12. 
Other Statistical Issues 
Additional analyses may be conducted. Any such analyses will be detailed in the SAP. 


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14. 
SPECIAL REQUIREMENTS AND PROCEDURES 
14.1. 
Compliance with Ethical and Regulatory Guidelines 
This study will comply with ICH-GCP, with the latest version of the Helsinki declaration and 
with applicable national regulations, as well as with the European Union Directive 2001/20/EC. 
 
14.2. 
Institutional and Ethics Review 
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 all substantial changes to the trial documentation will be 
subjected to the same IRB/IEC and regulatory authority review requirements as the original 
protocol. The Investigator will promptly notify the IRB/IEC and Sponsor of any SAEs or of any 
other information that might affect the safe use of the IP during the study. IRB approvals/IEC 
positive opinions and regulatory authorities’ approvals must be sent to the Sponsor, or its 
designee, before initiation of the study or before an amendment is instituted. All correspondence 
with the IRB/IEC and the regulatory authority should be retained in the study regulatory files. 
 
14.3. 
Informed Consent and Authorization for Use and Disclosure of 
Protected Health Information 
Written informed consent from each patient, patient’s parent(s) or legal guardian(s), must be 
obtained prior to any study-specific screening evaluations being performed. A copy of the signed 
informed consent documents will be given to the patient, patient’s parent(s) or legal guardian(s); 
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 per regional requirements. 
14.4. 
Compliance with the Protocol 
All processes and procedures defined in this protocol will be adhered to. Emergency departures 
from the protocol that eliminate an apparent immediate hazard to a particular patient and that are 
deemed by the Investigator as crucial for the safety and wellbeing of that patient may be 
instituted for that patient only and documented as deviations. The Investigator will contact the 
Medical Monitor as soon as possible regarding such a deviation. These departures do not require 
preapproval by the IRB/IEC; however, the IRB/IEC and Medical Monitor must be notified in 
writing as soon as possible in accordance with the IRB/IEC policies after the departure has been 
made. 
 
14.5. 
Confidentiality 
14.5.1. 
Data 
All information regarding the nature of the proposed investigation that is provided to the 
Investigator by the Sponsor, the Sponsor’s designee, or the study monitor, with the exception of 


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information that is required by law or regulations to be disclosed to the IRB/IEC, the patient’s 
parent(s) or legal guardian(s) or the appropriate regulatory authority, must be kept in confidence 
by the Investigator in accordance with current Health Insurance Portability and Accountability 
Act (HIPAA) standards and/or European standards. 
14.5.2. 
Patient Confidentiality 
The anonymity of participating patients will be maintained to the extent required by applicable 
laws and in accordance with current HIPAA standards. Patients may be referenced by their 
initials and an assigned patient identification number on the eCRFs 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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15. 
STUDY DOCUMENTATION AND GENERAL INFORMATION 
15.1. 
Essential Study Documents 
Essential study documents are among the critical documents required before study enrollment is 
to occur. Essential documents, as well as supplemental information such as the Investigator’s 
Brochure, Pharmacy Manual, eCRF Completion Guidelines, as specified in the Study Operations 
Manual and/or regulatory binder, must be kept on-site in a designated study site file. 
The study site files will also contain, including but not limited to, patient accountability records, 
drug accountability (receipt/dispensing) records, Sponsor/Investigator correspondence, IRB/IEC 
correspondence, deviations, biological sample records, and SAE and Investigational New Drug 
(IND) safety reports/Safety Alert Letters. 
15.2. 
General Information 
The Investigator should refer to the current Investigator’s Brochure along with subsequent Safety 
Alert Letters, the Study Operations Manual, Pharmacy Manual, Laboratory Manual, eCRF 
Completion Guidelines, and all other study-specific information that is provided during the study 
initiation visit or by the study monitor. 
15.3. 
Dissemination of Study Results 
The information that is developed during the conduct of this clinical study is considered to be 
strictly confidential. This information may be disclosed only as deemed necessary by Sarepta 
Therapeutics, Inc. However, at the conclusion of this clinical study, a CSR 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 the EudraCT database and on ClinicalTrials.gov. After 
completion of the study, results will be disseminated in accordance with regional requirements. 
 
15.4. 
Product Handling and Complaints Reporting 
If there are any issues during the course of the study related to the quality of the IP, the 
Investigator, clinical site pharmacist or pharmacy designee should contact the Sponsor or 
designated CRO. 


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16. 
LIST OF REFERENCES 
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." Archives of Neurol. 2005;62(1):128 -32. 
Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for 
boys with Duchenne muscular dystrophy in their second decade. Neuromuscular Dis. 2006 
Apr;16(4):249-55. 
Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, 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 of Neurol. 1993;240(2):98-104. 
CDC-MMWR. Prevalence of Duchenne/Becker Muscular Dystrophy Among Males Aged 
5-24 Years – Four States, 2007. 2009;1119. 
Connolly AM, Florence JM, Cradock MM, Malkus EC, Schierbecker JR, Siener CA, et al. Motor 
and cognitive assessment of infants and young boys with Duchenne muscular dystrophy: results 
from the Muscular Dystrophy Association DMD Clinical Research Network. Neuromuscul 
Disord. 2013;23(7):529-39. 
 
 
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne 
muscular dystrophy: improvements in life expectancy since 1967 and the impact of home 
nocturnal ventilation. Neuromuscular Dis. 2002 Dec;12(10):926-9. 
Emery AE. Population frequencies of inherited neuromuscular diseases – a world survey. 
Neuromuscular Dis. 1991;1(1):19-29. 
 
 
Howie, SR. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89:46-53. 
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. 
Developmental pharmacology--drug disposition, action, and therapy in infants and children. 
N Engl J Med. 2003;349(12):1157-67. 
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. 


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Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular 
dystrophy. Cochrane Database Syst Rev. 2004;(2):CD003725. 
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. Neurology. 
2011;77(3):250-6. 
 
 
Pradhan S, 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. 
PTC Therapeutics International Limited. Summary of Product Characteristics for Translarna 
(ataluren) in the European Public Assessment Report (last updated 14 January 2016). Available 
from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002720/huma 
n_med_001742.jsp&mid=WC0b01ac058001d124 


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17. 
APPENDICES 
17.1. 
Estimated Blood Volumes to be Drawn 
World Health Organization (WHO) recommended blood volume limits should be used as a guide 
for blood sampling in this study (Howie 2011). Per individual, the study-related blood loss 
should not exceed 3% of the total volume during a 4-week period or 1% of total blood volume 
within a 24-hour period. Table 6 summarizes the mean blood volume per body weight for 
children ≤10 kg and Table 7 summarizes the amount of blood required for individual sample 
collection. 
Due to the limitations on the volume of blood collection that is considered to be acceptable in 
young children with very small total circulating blood volumes, adjustments to sample collection 
will be made for children weighing <10 kg. These adjustments include the use of 0.5 mL 
collection tubes for PK samples and utilization of local laboratories for the coagulation panel. 
Table 6: 
Mean Blood Volume per Body Weight 
 
Body Weight (kg) 
Mean Total Body 
Blood Volume (mL) 
Maximum Blood Collection Volume (mL) 
24-Hour Period (1%) 
30-Day Period (3%) 
5.0 
400 
4.0 
12.0 
6.0 
480 
4.8 
14.4 
7.0 
560 
5.6 
16.8 
8.0 
640 
6.4 
19.2 
9.0 
720 
7.2 
21.6 
10.0 
800 
8.0 
24.0 
 
Table 7: 
Blood Volume Requirements per Test 
 
Test 
Volume (mL) 
Chemistry panel 
2.0 
Hematology panel 
1.0 
Coagulation panela 
2.7 
DMD sequencing 
2.0 
LTBP4 and SPP-1 
2.0 
PK (per sample)b 
1.0 
DMD = Duchenne muscular dystrophy; LTBP4 = latent transforming growth 
factor beta binding protein 4; PK = pharmacokinetic; SSP-1 = secreted 
phosphoprotein 1. 
a Can be done at local laboratory in the event of blood volume limitations 
b 0.5 mL for children weighing <10.0 kg 


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Source: 
Howie, SR. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89:46-53. doi:10/2471/BLT.10.080010. Available from: 
http://www.who.int/bulletin/volumes/89/1/10-080010/en/ 

SAP_001.pdf: 
Sarepta Therapeutics, Inc. 
Protocol 4658-102 
 
 
Statistical Analysis Plan for Final Analysis 
Final Version 
Confidential 
Page 1 of 34 
STATISTICAL ANALYSIS PLAN 
Protocol 4658-102 
 
An Open-Label Safety, Tolerability, and Pharmacokinetics Study of 
Eteplirsen in Young Patients with Duchenne Muscular Dystrophy Amenable 
to Exon 51 Skipping 
 
 
 
4658-102: Version 4, 07 February 2020 
 
Date: 
14 April 2021 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
NCT # NCT03985878


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Date: Apr 14, 2021 11:29 EDT 
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Sarepta Therapeutics, Inc. 
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Statistical Analysis Plan for Final Analysis 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................... 5 
1. 
Introduction ............................................................................................................ 7 
2. 
Study Objectives ..................................................................................................... 8 
3. 
Study endpoints and other variables...................................................................... 9 
4. 
Study Description ................................................................................................. 11 
4.1. 
Study Overview ................................................................................................... 11 
4.2. 
 ....................................................................................... 12 
4.3. 
Randomization and Blinding ............................................................................. 12 
4.4. 
Planned Analyses ................................................................................................ 12 
4.4.1 Safety Review ....................................................................................................... 12 
4.4.2 Final Analysis ....................................................................................................... 13 
4.5. 
Analysis Set .......................................................................................................... 13 
5. 
General Statistical Methods and Conventions .................................................... 14 
5.1. 
General Methods ................................................................................................. 14 
5.2. 
Handling of Missing Data ................................................................................... 14 
5.2.1 
 ......................................................... 14 
5.2.2 
 ............................................................ 15 
5.2.3 
 .............................. 15 
5.2.4 
 ........................................................... 15 
5.2.5 Imputation of Missing Laboratory Values ............................................................ 15 
5.2.6 Handling of Incomplete Dates ............................................................................ 15 
5.2.7 Imputation of Relationship or Severity for Adverse Events ........................... 16 
5.3. 
Multiple Testing and Comparisons ................................................................... 16 
5.4. 
Adjustment for Covariates ................................................................................. 16 
5.5. 
Subgroups ............................................................................................................ 16 
5.6. 
Presentation Over Time ..................................................................................... 16 
5.7. 
Algorithm, Computation and Definition of Derived Variables ...................... 17 
5.8. 
Programming Conventions ................................................................................ 21 
6. 
Statistical Analyses ............................................................................................... 22 
6.1. 
Patient Disposition .............................................................................................. 22 
6.2. 
Demographics and Baseline Characteristics .................................................... 22 
6.3. 
Prior and Concomitant Medications ................................................................. 22 
6.4. 
Medical History ................................................................................................... 23 


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6.5. 
Physiotherapeutic Interventions ........................................................................ 23 
6.6. 
Protocol Deviations ............................................................................................. 23 
6.7. 
Exposure to Study Drug ..................................................................................... 23 
6.8. 
Safety Analyses .................................................................................................... 23 
6.8.1 Adverse Events ..................................................................................................... 23 
6.8.2 Adverse Events of Special Interests ...................................................................... 25 
6.8.3 Important Risks ..................................................................................................... 26 
6.8.4 Risks Associated with Other Antisense Oligonucleotides .................................... 27 
6.8.5 Risks Associated with the Studied Population ...................................................... 27 
6.8.6 A corresponding listing will be generated for each of AE of risks associated with 
the studied population. Clinical Laboratory Evaluation ....................................... 28 
6.8.7 Vital Signs ............................................................................................................. 29 
6.8.8 Electrocardiograms and Echocardiograms............................................................ 29 
6.8.9 Other Safety Assessments ..................................................................................... 29 
6.9. 
 .......................................................................................... 29 
6.10. Pharmacokinetic Analyses ................................................................................. 30 
7. 
Changes in Planned Analyses ............................................................................. 31 
7.1. 
Changes from Clinical Protocol-Planned Analyses ......................................... 31 
7.2. 
Changes from Previous Statistical Analysis Plans ........................................... 31 
8. 
AppendIx .............................................................................................................. 32 
8.1. 
Criteria of Abnormalities ................................................................................... 32 
8.1.1 Appendix Table 1. Chemistry Laboratory Abnormalities of Interest ................... 32 
8.1.2 Appendix Table 2. Hematology Laboratory Abnormalities of Interest ................ 33 
8.1.3 Appendix Table 3. Urinalysis Laboratory Abnormalities of Interest ................... 33 
8.1.4 Appendix Table 4. Vital Sign Abnormalities of Interest ...................................... 33 
8.1.5 Appendix Table 5. Electrocardiogram and Echocardiogram Abnormalities of 
Interest................................................................................................................... 34 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Expanded Term 
ADaM IG 
Analysis Data Model Implementation Guide 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
Ae% 
Amount of drug eliminated in urine 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration-curve 
CL 
Total clearance 
Cmax 
Maximum plasma concentration 
 
 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DMD 
Duchenne Muscular Dystrophy 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram/Echocardiography 
GCP 
Good Clinical Practices 
 
 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVAD 
Implantable Venous Access Device 
KIM-1 
Kidney Injury Moledule-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
 


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PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM IG 
Study Data Tabulation Model Implementation Guide 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
t½ 
Elimination half-life 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to maximum plasma concentration 
Vss 
Apparent volume of distribution at steady state 
WHO Drug 
World Health Organization Drug Dictionary 


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Statistical Analysis Plan for Final Analysis 
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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 4658-102, entitled “An Open-Label Safety, Tolerability, and Pharmacokinetics 
Study of Eteplirsen in Young Patients with Duchenne Muscular Dystrophy Amenable to 
Exon 51 Skipping” 
 
 
 
This SAP has been prepared based on Protocol Version 4, dated 07 February 2020 for 
Study 4658-102, 
 
 


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2. 
STUDY OBJECTIVES 
Study 4658-102 
Primary Objective: 
The primary objective of Study 4658-102 is to evaluate the safety and tolerability of 
eteplirsen administered once weekly by intravenous (IV) infusion in male Duchenne 
muscular dystrophy (DMD) patients ages 6 months to 48 months, inclusive. 
Secondary Objective: 
The secondary objective of Study 4658-102 is to determine the pharmacokinetics (PK) of 
eteplirsen at the 2, 10, 20, and 30-mg/kg dose levels administered once weekly by IV 
infusion in male DMD patients ages 6 months to 48 months, inclusive. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
STUDY ENDPOINTS AND OTHER VARIABLES 
The study endpoints for which the statistical methods will be described in this SAP 
comprise of safety, PK, and efficacy endpoints. 
 
Study 4658-102 
The primary endpoint is safety and tolerability of eteplirsen in the study population, as 
measured by: 
• Incidence of adverse events (AEs) 
• Abnormal changes from Baseline or clinically significant worsening of clinical 
safety laboratory abnormalities (hematology, chemistry, coagulation, urinalysis) 
• Abnormal changes from Baseline or worsening of vital signs 
• Abnormal changes from Baseline or worsening of physical examination findings 
• Abnormal changes from Baseline or clinically significant worsening of 
electrocardiograms (ECGs) 
• Abnormal changes from Baseline or clinically significant worsening of 
echocardiograms (ECHOs). 
The secondary endpoint is to determine the PK of eteplirsen by population PK methods, 
including assessment of the following PK parameters if evaluable: 
• Maximum plasma concentration (Cmax) 
• Time of Cmax (Tmax) 
• Area under the plasma concentration-curve (AUC) 
• Apparent volume of distribution at steady state (Vss) 
• Elimination half-life (t½) 
• Clearance (CL) 
• Amount of drug eliminated in urine (Ae%). 
 
• 
 
 
• 
 
 
 
 
 


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• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
 
• 
 
• 
 
• 
 


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Statistical Analysis Plan for Final Analysis 
Final Version 
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4.
STUDY DESCRIPTION
4.1. 
Study Overview 
Study 4658-102 
This is a multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, 
PK, and efficacy of once-weekly IV infusions of eteplirsen in approximately 12 male 
patients, ages 6 months to 48 months (inclusive), who have genotypically confirmed 
DMD with a deletion mutation amenable to exon 51 skipping. 
Patients will be evaluated for inclusion during the Screening Period of up to 2 weeks to 
assess eligibility. Written informed consent from the parent/legal guardian to participate 
in the study must be obtained prior to beginning any study-related procedures. 
Patients will be enrolled into 1 of 2 age cohorts: Cohort 1 of approximately 6 male 
patients age 24 to 48 months and Cohort 2 of approximately 6 male patients age 6 months 
to <24 months. 
After the first 3 patients in Cohort 1 have completed 12 weeks of eteplirsen therapy, 
including 2 infusions each at 2, 4, 10 and 20 mg/kg and 4 infusions at 30 mg/kg, the Data 
Monitoring Committee (DMC) will review the safety data and determine whether to 
begin enrollment of the younger patients (Cohort 2). The DMC will also review safety 
data at least weekly through the first 12 weeks of dosing for the first 3 patients of each 
age cohort. Reviews will be at least quarterly thereafter. 
The dose-titration period will last 10 weeks overall (1 infusion/week) to slowly achieve 
the target dose of 30 mg/kg. Eteplirsen dosing will begin at 2 mg/kg for 2 weeks (Weeks 
1 and 2) and will escalate to 4 mg/kg (Weeks 3 and 4), 10 mg/kg (Weeks 5 and 6), 20 
mg/kg (Weeks 7 and 8), and 30 mg/kg (Weeks 9 and 10). Patients will continue to 
receive 30 mg/kg eteplirsen for the duration of the study. The duration of each patient’s 
treatment in the study is expected to be at least 48 weeks (including the 10-week titration 
period), and patients may continue to receive treatment in the study for up to 96 weeks. 
Study drug may be interrupted or discontinued for specific safety reasons. 
Safety will be regularly assessed throughout the study via the collection of AEs, clinical 
safety laboratory test results (blood chemistry, hematology, coagulation, urinalysis), 
ECGs, ECHOs, vital signs, and physical examinations. 
Plasma and urine samples for PK assessments will be collected at Week 2 (2 mg/kg dose 
level), Week 6 (1 -mg/kg dose level), Week 8 (20 mg/kg dose level) and at Weeks 10 and 
24 (3 -mg/kg dose level). Serial PK samples will be collected pre-dose, immediately prior 
to the end of infusion (prior to flush), and approximately 1 to 3 hours and 6 to 8 hours 
after completion of study drug infusion. Urine PK samples will be collected over the first 
4 hours after start of infusion. 
 
 
 


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Approximately 4 weeks after the last eteplirsen infusion (regardless of the duration of the 
patient’s participation in the study), patients will be required to return to the study site for 
safety evaluations. The total duration of patient participation, including Screening, 
Titration/Treatment, and Safety Follow-up periods is up to 101 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2. 
 
 
 
 
4.3. 
Randomization and Blinding 
Both 4658-102 
 are open-label single arm studies and, therefore, all 
patients will receive eteplirsen. 
 
4.4. 
Planned Analyses 
4.4.1 
Safety Review 
The DMC will be comprised of a group of individuals with pertinent methodological and 
clinical expertise relevant to the study design and background population, to review the 
conduct of the study and the emerging safety, PK, and efficacy data on an ongoing basis 


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in order to ensure that clinical trial participants are not exposed to unreasonable or 
unnecessary risks. The DMC will advise the study team and study investigators on safety 
aspects of dose interruption/continuation and dose escalation for the study. The DMC 
will begin their duty before the start of the clinical trial and will continue for the entire 
duration of the study. 
The activities and composition of this committee are outlined in the DMC Charter which 
was ratified during the initial DMC meeting, prior to the commencement of dosing of the 
study patients, on 24 June 2019. The reviews will be performed at least weekly through 
the first 12 weeks of dosing for the first 3 patients of each age cohort and at least 
quarterly thereafter. Oversight and monitoring of the clinical study by the DMC will be 
performed in compliance with International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines. These safety monitoring functions are distinct from 
the requirements for study review and approval by an Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC). 
 
4.4.2 
Final Analysis 
Study 4658-102 final analysis of safety and efficacy will be conducted once the last 
patient completes the efficacy visit and the resulting database including AEs and 
concomitant medications is cleaned, quality assured, and locked through the data cut. 
 
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. 
 
4.5. 
Analysis Set 
 
The Safety set includes all patients who are enrolled in Study 4658-102 and receive at 
least 1 dose of eteplirsen while in Study 4658-102. This analysis set will be used for 
analyses of all endpoints for the 4658-102 Final Analysis, unless stated otherwise. 
 
 


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5. 
GENERAL STATISTICAL METHODS AND 
CONVENTIONS 
5.1. 
General Methods 
Summary statistics will be presented by cohort, unless stated otherwise. 
For continuous variables, descriptive statistics will include the number of patients with 
data to be summarized (n), mean, standard deviation (SD), median, minimum, and 
maximum. 
For categorical/qualitative variables, descriptive statistics will include frequency counts 
and percentages. The total number of patients in the cohort will be used as the 
denominator for percentage calculations, unless stated otherwise. 
Summaries will be for the following cohorts: 
• Cohort 1 (age 24 to 48 months) 
• Cohort 2 (age 6 to <24 months) 
 
 All analyses will be displayed on the 
safety set for the final analysis of 4658-102. 
 
 
 
5.2. 
Handling of Missing Data 
5.2.1 
 
 
 
 
 
 
 
 
 


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5.2.2 
 
 
 
 
5.2.3 
 
 
 
5.2.4 
 
 
 
 
 
 
 
5.2.5 
Imputation of Missing Laboratory Values 
Laboratory data that are continuous in nature, but are less than the lower limit of 
quantitation or above the upper limit of quantitation will be imputed to the value of the 
lower or upper limit plus or minus 2 significant digits, respectively (e.g., if the results of 
the continuous laboratory test is <20 or <2.0, a value of 19.99 or 1.999, respectively, will 
be assigned in computing summary statistics; if the results of the continuous laboratory 
test is >20 or >2.0, a value of 20.01 or 2.001, respectively, will be assigned in computing 
summary statistics). Kidney injury molecule-1 (KIM-1) values that are reported as below 
the level of quantitation (<0.112) will deviate from the above rule and will be imputed as 
0.099. 
5.2.6 
Handling of Incomplete Dates 
An incomplete date will occur when the exact date an event occurred or ended cannot be 
obtained for a patient. Incomplete dates will be imputed as described below. No other 
imputation of missing data will be performed. 
• For a partial or missing medication date, the medication will be classified as a 
concomitant medication unless the available part of the date indicates it is 
impossible for the drug to be concomitant. For example, if only the year for the 
stop date is available and the year is prior to the year of dosing, the medication 
will be classified as a prior medication. 
• For a partial or missing 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 and within 28 days of the last dose of eteplirsen. If a partial AE onset 


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date is after the treatment end date, then the date will be imputed as the first day 
of the month. 
• 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. 
 
5.2.7 
Imputation of Relationship or Severity for Adverse Events 
In the summary of AEs, events with missing relationship or severity will be presented as 
“Related” or "Severe", respectively. However, missing values will be presented in the 
data listings as missing. 
 
5.3. 
Multiple Testing and Comparisons 
No adjustment will be made for the testing of multiple endpoints. 
 
5.4. 
Adjustment for Covariates 
Not applicable. 
 
5.5. 
Subgroups 
Due to small sample size, no subgroups will be identified for this study. 
 
5.6. 
Presentation Over Time 
For endpoints that are collected serially over time, assessments/test values will be 
assigned to a specific timepoint (e.g., study week) based upon the electronic case report 
form (eCRF) page on which the assessments/test values were reported. 
 
 
 
 
 
 
 
 
 
For safety endpoints, unscheduled assessments will not be included in the summary by 
timepoint. 


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5.7. 
Algorithm, Computation and Definition of Derived Variables 
Day 1 
Day 1 in Study 4658-102 will be defined as the date of the first eteplirsen administration 
in Study 4658-102. 
 
 
Study Day 
Study day will be defined as Event Date – Day 1 + 1, if Event Date is on or after Day 1; 
otherwise, as Event Date – Day 1, if Event Date precedes Day 1. Study Day will be 
defined for Study 4658-102 
. 
Duration on Study 
Duration on study will be calculated as the duration in weeks from Day 1 to the date of 
study completion/discontinuation as recorded on the END OF STUDY eCRF (if 
completed) or the date of the last study assessment or procedure plus 7 days. This 
calculation will be performed for each study. 
Duration on Eteplirsen 
Duration on eteplirsen will be calculated as the duration in weeks from Day 1 to the date 
of the last eteplirsen administration as recorded on the study drug administration eCRF 
plus 6 days (i.e., [last dose – first dose date + 7]/7). 
Duration in weeks calculated above will be then categorized to 1 of the following 
intervals for Study 4658-102: <24, 24 to <48, 48 to <72, 72 to < 96, and 96 weeks. 
 
 
 
 
Planned Dose and Overdose 
The body weight-based planned dose was calculated based on most recent weight of 
previous visits. When calculating the planned dose, the body weight is rounded to a 
single decimal using conventional rounding rules. While in preparing actual dose, an 
unconventional rule is applied for calculating the volume of the concentrated drug 
(50 mg/mL) in milliliter. Any volume of 0.1 or above is rounded up (e.g. 25.14 mL is 
rounded up to 26 mL) and any volume below 0.1 is rounded down (e.g. 25.09 mL is 
round up to 25 mL. The overdose is defined as any actual dose >10% above the planned 
body weight-based dose. 
Patient Years on Eteplirsen 
The patient years on eteplirsen will be calculated as (Last Treatment Date - First 
Treatment Date + 7)/365.25. 


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Baseline Visit 
Baseline visit in Study 4658-102 will be considered the last visit prior to the initiation of 
eteplirsen in Study 4658-102. 
 
 
Change from Baseline 
Change from Baseline will be calculated as follows: 
Change from Baseline = Post-Baseline Value – Baseline Value 
The change may be classified into a categorical variable, as appropriate. 
Percent Change from Baseline 
Percent change from Baseline will be calculated as follows: 
Percent change from Baseline = (Change from Baseline / Baseline Value)*100 
Percent change from Baseline will not be calculated if Baseline value is 0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment-emergent Adverse Event (TEAE) 
An AE will be considered treatment-emergent if it starts in the time period starting with 
the initiation of the first dose of eteplirsen and ending 28 days after the last dose of 
eteplirsen. 
Treatment-related Adverse Event 
A treatment-related AE is any AE reported on the ADVERSE EVENTS eCRF that is 
marked as definitely related, or possibly/probably related to study drug. 
Treatment-Emergent Laboratory, Vital Signs, ECGs, and ECHO Abnormality 
A treatment-emergent laboratory, vital signs, ECGs, and ECHO abnormality will be 
defined as any laboratory, vital signs, ECGs, and ECHO abnormality occurring or 
worsening after the initiation of eteplirsen dosing and within 28 days of the last dose of 
eteplirsen. 
Prior Medication 
A prior medication will be any medication taken and completed prior to the first dose of 
eteplirsen. 
Concomitant Medication 
A concomitant medication will be any medication that is taken in the time period starting 
with the initiation of the first dose of eteplirsen dosing and ending within 28 days after 
the last dose of eteplirsen. 
Time since DMD Diagnosis 
The time since DMD diagnosis, in months, will be calculated as (Day 1 – Date of DMD 
diagnosis + 1)/30.4375. 
Duration of Corticosteroid Treatment 
The duration of corticosteroid treatment, in months, will be calculated as (Day 1 – Date 
on which the patient started corticosteroid treatment + 1)/30.4375. 
Corticosteroid Schedule 
Corticosteroid schedules will include continuous (daily) or other (including intermittent 
dosing such as Saturday and Sunday dosing only). 
EudraCT Category 
• In utero: Unborn infants, still in the womb. 
• Preterm newborn: Subjects born before 37 weeks from their conception. 
• Newborns: Newborn aged from birth to less than 28 days. 
• Infants and toddlers: Subjects aged 28 days to less than 2 years. 
• Children: Subjects aged 2 to 11 years. 
• Adolescents: Subjects aged 12 to less than 18 years. 


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• Adults: Subjects aged 18 to 64 years. 
• Adults: Subjects aged 65 to 84 years. 
• Adults: Subjects aged 85 years and over. 
5.8. 
Programming Conventions 
This section details general conventions to be used for the production of tables, figures 
and listings. Departures from these general conventions will be specified in appropriate 
sections. 
• For continuous or quantitative variables, mean and median values will be 
formatted to 1 more decimal place than the measured value on the eCRF or 
provided file by vendor. Standard deviation and standard error values will be 
formatted to 2 more decimal places than the measured value on the eCRF. 
Minimum and maximum values will be presented with the same number of 
decimal places as the measured value on the eCRF. Percentages will be presented 
with 1 decimal place. 
• For categorical variables, the number and percentage of a category will be 
presented in the form XX (YY.Y%), where the percentage is YY.Y. 
• Percentages of patients with treatment-emergent abnormalities will be based on 
non-missing values unless stated otherwise. 
• Study Day will appear in the data listings as appropriate. 
• Date variables will be formatted as DDMMMYYYY for presentation. 
• SAS Version 9.4 or higher will be the statistical software package used for all 
analyses unless otherwise specified. 
• The Clinical Data Interchange Standards Consortium (CDISC) Analysis Data 
Model Implementation Guide V1.1 for preparing data sets will be used for this 
study. 
• The CDISC Study Tabulation Model Implementation Guide V3.2 for preparing 
data sets will be used for this study. 
• Tables, figures, and listings will be presented in landscape orientation. 
• Listings will be sorted by cohort, patient and then date unless otherwise specified. 


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6. 
STATISTICAL ANALYSES 
6.1. 
Patient Disposition 
For Study 4658-102, the number of patients enrolled, the number in Safety Set, the 
number and percentage of patients completing the study through Week 96, the number 
and percentage of patients prematurely discontinuing before Week 96, and the duration of 
study (weeks) will be summarized. Reasons for premature discontinuation will also be 
summarized. All analyses will be performed overall and by age cohort. 
 
 
 
 
 
Patient eligibility and disposition will be presented in a listing. 
 
6.2. 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized overall and by age cohort. 
These variables will include age (months), EudraCT age category, race, ethnicity, 
height/length (cm), weight (kg), BMI (kg/m2), mutation, time from DMD diagnosis 
(months) to Baseline, corticosteroid medication type, corticosteroid frequency, duration 
of prior corticosteroid use at Baseline. 
Patient-level demographic data and Baseline characteristics will be presented in data 
listings. 
 
6.3. 
Prior and Concomitant Medications 
Concomitant medications will be coded by preferred term using the most recent World 
Health Organization (WHO) Drug Dictionary (WHODRUG, December 2013). 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 preferred term by cohort. At each level of 
summarization, a patient is counted once if he/she reported one or more medications at 
that level. The summarization of concomitant medications for the Study 4658-102 final 
analysis will include all concomitant medications collected at the time of the Study 4658- 
102 data lock.
 
 
 
All prior medications and concomitant medications will be presented in data listings. 


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6.4. 
Medical History 
Medical history data for the safety set will be presented in data listings. The 
summarization will only be included for the Study 4658-102 final analysis 
 
 
 
6.5. 
Physiotherapeutic Interventions 
A listing of all physiotherapeutic interventions will be provided. 
 
6.6. 
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). Additionally, 
major deviations will be summarized by deviation type. The listing and table will be 
summarized separately by whether the protocol deviations are related to COVID-19 or 
not. 
6.7. 
Exposure to Study Drug 
The exposure to eteplirsen will be summarized for eteplirsen-treated patients in the Safety 
Analysis Set. The variables will include the following (as applicable): total number of 
infusions received, total number of infusions on 30 mg/kg of eteplirsen received, 
cumulative amount of drug received (mg), duration on eteplirsen in 24-week intervals, 
and patient years on eteplirsen. For both the 4658-102 
 final analyses, 
these endpoints will be calculated cumulatively 
 
 
Patient-level study drug information will be provided in a data listing. Additionally, a 
listing of the derived exposure parameters above will be generated as well as a listing of 
overdoses. The actual dose will be compared to the planned dose. Any actual dose that is 
greater than 1.10 times of the planned dose will be considered an overdose. Planned dose 
is calculated as the dose level in mg/kg multiplied by the patient’s most recent weight 
prior to the dose (or on the same day with no time). 
6.8. 
Safety Analyses 
Safety analyses will be descriptive in nature. Summary statistics for each parameter at a 
specific visit, as well as the change from Baseline to that visit, will also be displayed. All 
safety data will be presented in the data listings. 
6.8.1 
Adverse Events 
The final analysis of 4658-102 AE will include all data collected in 4658-102. 
 
 
 
In general, only TEAEs will be summarized. Nontreatment-emergent events will be 
recorded in the data listings. Unless noted otherwise, for all AE tables, the number and 


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percentage of patients reporting AEs will be grouped using the MedDRA System Organ 
Class (SOC) and Preferred Term (PT) and summarized overall and by age cohort. 
An overall summary table of adverse events will be produced and will include: 
• The frequency count and percentage of patients with: 
o A TEAE 
o A Treatment-related TEAE 
o A Severe TEAE 
o A Treatment-Emergent SAE 
o A Treatment-Emergent Related SAE 
o A TEAE leading to discontinuation of study drug 
o A TEAE leading to death 
o A Non-Serious TEAE 
• The number of events 
o at each severity level (mild, moderate, severe) 
o that are non-serious 
o that are serious 
Multiple occurrences of the same AE (at the preferred term 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 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 
• TEAEs by descending frequency of PT 
• Treatment-related TEAEs by SOC and PT 
• Treatment-related TEAEs by SOC, PT, and severity 
• Treatment-related TEAEs by descending frequency of PT 
• TEAEs related to study procedures by SOC and PT 
• TEAEs related to underlying disease by SOC and PT 
• Treatment-Emergent SAEs by SOC and PT 
• Treatment-related Treatment-Emergent SAEs by SOC and PT 
• Non-Serious TEAEs by SOC and PT 


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In addition, all SAEs, regardless of their treatment-emergent status will be summarized. 
The following listings will be produced: 
• Non-treatment-emergent AEs 
• All TEAEs 
• AEs leading to discontinuation 
• SAEs 
Additionally, summary tables of AEs by each one-year duration of eteplirsen (i.e., AEs at 
the 1st year of eterplirsen treatment, 2nd year, 3rd year, …, 6th year) will be provided. 
6.8.2 
Adverse Events of Special Interests 
Summaries of TEAEs of special interest by SOC and PT will be summarized overall and 
by age cohort. 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: 
• Nephrotoxicity 
o Proteinuria > 500 mg/24 hr 
o eGFR <60 ml/min/1.73 m2 
• Hepatotoxicity 
o GGT or GLDH > 8 × ULN 
o GGT or GLDH > 5 × ULN for more than 2 weeks 
o GGT or GLDH > 3 × ULN and (total bilirubin >2 × ULN or international 
normalized ratio > 1.5) 
o GGT or GLDH > 3 × ULN with the appearance of the following signs or 
symptoms: fatigue, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%). 
• Hypersensitivity 
o Anaphylaxis, anaphylactoid reaction, or angioedema 
- 
for Anaphylaxis use PT anaphylactic reaction, anaphylactic shock 
- 
for Anaphylactoid reaction use PT anaphylactoid reaction, 
anaphylactoid shock 
- 
for Angioedema use PTs angioedema, epiglottic oedema, laryngeal 
oedema, laryngotracheal oedema, lip oedema, swollen tongue, 
tongue oedema, tracheal oedema 
o Any severe allergic reaction (Hypersensitivity SMQ Broad & Narrow) 
o Any severe (Grade ≥3) infusion related reactions (IRRs) that occurred 
within 24 hrs. 


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o Any severe complement mediated, inflammation event (eg, acute kidney 
injury, arteritis, myocarditis, pneumonitis) 
• Thrombocytopenia 
o Platelet count < 75,000/mm3 
• Infusion-related reactions 
o All adverse events with reported start time within 24 hours of the 
eteplirsen infusion if AE start clock time and infusion clock time is 
available OR occurred by the next calendar date if either AE start clock 
time or infusion clock time is not available. 
An overall summary of adverse events of special interest include total number of events, 
number of SAEs, number of treatment-related events, number of unrelated 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. 
A corresponding listing will be generated for each table of AE of special interest. If 
applicable, a table corresponding to the adverse events of special interest that were 
related to study drug and/or moderate or severe will be produced. 
6.8.3 
Important Risks 
Summaries of TEAEs possibly indicative of important risks by SOC and PT will be 
summarized overall and by age cohort. All standard MedDRA queries (SMQs based on 
MedDRA version 17.1) listed below will include broad and narrow terms unless noted. 
• Nephrotoxicity: 
o Acute renal failure SMQ 
o HLT Glomerulonephritis and nephrotic syndrome 
o HLT Nephritis NEC 
o HLT Nephropathies and tubular disorder NEC 
o PT Hematuria (10018867) 
• Hypersensitivity 
o Hypersensitivity SMQ 
o HLT Immune response protein analyses NEC 
• Infusion related reaction: events occurring within 24 hours of infusion or the next 
calendar day if the time (AE onset or start of infusion) is missing. Medical 
adjudication will be performed to determine whether the event is a possible 
infusion related reaction. 
• Hypersensitivity excluding medically reviewed infusion related reaction: 
Hypersensitivity SMQ events minus events adjudicated as possible IRRs. 


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An overall summary of adverse events of important risks include total number of events, 
number of SAEs, number of treatment-related events, number of unrelated 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. 
A corresponding listing will be generated for each table of AE of important risks. If 
applicable, a table corresponding to the adverse events of important risks that were 
related to study drug and/or moderate or severe will be produced. 
6.8.4 
Risks Associated with Other Antisense Oligonucleotides 
All standard MedDRA queries (SMQs based on MedDRA version 17.1) listed below will 
include broad and narrow terms unless noted. 
• Hepatotoxicity: 
o Hepatic failure SMQ 
o Fibrosis and cirrhosis and other liver damage-related conditions SMQ 
o Hepatitis, non-infectious SMQ 
o Cholestasis and jaundice of hepatic origin SMQ 
o Liver related investigations, signs and symptoms SMQ 
o Liver-related coagulation and bleeding disturbances SMQ 
• Thrombocytopenia: Hematopoietic thrombocytopenia SMQ 
An overall summary of adverse events of risks associated with other antisense 
oligonucleotides include total number of events, number of SAEs, number of treatment- 
related events, number of unrelated 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. 
A corresponding listing will be generated for each of AE of risks associated with other 
antisense oligonucleotides. 
6.8.5 
Risks Associated with the Studied Population 
All standard MedDRA queries (SMQs based on MedDRA version 17.1) listed below will 
include broad and narrow terms unless noted. 
• Serious blood stream infections with implantable venous access device (IVAD): 
o Sepsis SMQ (available in MedDRA V22.1) 
o Toxic septic shock conditions SMQ Narrow 
o PT Vascular device infection 
o PT Bacteraemia, Viremia, Fungemia, Sepsis, or Septic shock 
o HLT Implant and catheter site reactions 
o HLGT Device issues 


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o Verbatim terms containing “port”, “central venous”, and “central line” 
• Rhabdomyolysis: Rhabdomyolysis/myopathy SMQ 
An overall summary of adverse events of risks associated with the studied population 
include total number of events, number of SAEs, number of treatment-related events, 
number of unrelated 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. 
 
6.8.6 
A corresponding listing will be generated for each of AE of risks associated 
with the studied population. Clinical Laboratory Evaluation 
Analyses of clinical laboratory values will be performed. Normal ranges will be 
determined based on the ranges supplied by the central laboratory (with appropriate 
conversion to standard units). Baseline, the highest/lowest value post-Baseline, and the 
final observation (within 28 days of the last dose of eteplirsen) will be presented for each 
laboratory assessment for each treatment group. 
Descriptive statistics will be calculated for the observed values as well as the change 
from Baseline values. The highest value will be summarized for alanine aminotransferase 
(ALT), alkaline phosphatase, amylase, aspartate aminotransferase (AST), C-reactive 
protein, creatine kinase, creatinine, cystatin C, gamma glutamyltransferase, lactate 
dehydrogenase, total bilirubin, uric acid, absolute basophils, absolute eosinophils, 
basophil percent, eosinophil percent, activated partial thromboplastin time, international 
normalized ratio, prothrombin time, urine KIM-1, and urine protein. The lowest 
observation will be summarized for albumin and platelets. 
Both the highest value and the lowest value will be summarized for blood urea nitrogen, 
calcium, chloride, glucose, potassium, protein, sodium, absolute lymphocytes, absolute 
monocytes, absolute neutrophils, hematocrit, hemoglobin, lymphocyte percent, monocyte 
percent, neutrophils percent, white blood cell count, urine pH, and specific gravity. 
Shifts from Baseline to the highest/lowest post-Baseline value and final observation will 
be summarized for age cohort and overall. Additionally, the highest/lowest and final 
observation in the treatment period will be presented for summary of laboratory shifts. 
Frequencies in a shift table will be calculated within each treatment and Baseline 
classification. 
A table of treatment-emergent markedly abnormal results that occur after Baseline as 
defined in Appendix Table 1, Appendix Table 2, and Appendix Table 3 will be generated 
overall and by age cohort Additionally, a table of patients who met Hy’s law will be 
generated by treatment. Hy’s law will be defined as: 
• (ALT or AST > 2 x Baseline) and/or 
• (Total Bilirubin > 2 x Upper Limit of Normal [ULN]) 
All laboratory values with any abnormalities of interest will be listed. Additionally, 
laboratory values that are outside of the normal range will be listed separately. 


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6.8.7 
Vital Signs 
Vital signs will be summarized overall and by age cohort using descriptive statistics. For 
each vital sign, the Baseline and final observations (within 28 days of the last dose of 
eteplirsen) will be presented overall and by age cohort. Additionally, the largest absolute 
change from Baseline will be summarized. Descriptive statistics will be calculated for the 
observed values as well as the change from Baseline values. 
A table of treatment-emergent markedly abnormal results of vital signs that occur after 
Baseline as defined in Appendix Table 4 will be generated overall and by age cohort. The 
number and percentage of patients experiencing the abnormality as well as the total 
number of abnormalities will be presented. All vital sign values with an abnormality of 
interest will be listed. 
6.8.8 
Electrocardiograms and Echocardiograms 
ECG and ECHO assessments will be summarized overall and by age cohort using 
descriptive statistics. For each ECG and ECHO parameter, the Baseline and final 
observations (within 28 days of the last dose of eteplirsen) will be presented overall and 
by age cohort. Additionally, the largest absolute change will be summarized. Descriptive 
statistics will be calculated for the observed values as well as the change from Baseline 
values. 
A table of treatment-emergent markedly abnormal results of ECG and ECHO that occur 
after Baseline as defined in Appendix Table 5 will be generated overall and by age 
cohort. The number and percentage of patients experiencing the abnormality as well as 
the total number of abnormalities will be presented. All ECGs and ECHOs with an 
abnormality will be listed. 
6.8.9 
Other Safety Assessments 
Treatment-emergent markedly abnormal physical examination results will be summarized 
overall and by age cohort. Abnormal physical exam findings related to neurological and 
musculoskeletal system, related to DMD, occurred during Screening and Baseline visit, 
or showing no change from Baseline/Screening will be excluded. 
All physical examination, unintended therapeutic benefits, and procedures will be listed. 
 
6.9. 
 
 
 
 
 
 


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6.10. 
Pharmacokinetic Analyses 
For only Study 4658-102, results of all PK analyses will be provided as a separate PK 
report which will be appended to the final clinical study report (CSR) and summarized in 
the CSR. 
Pharmacokinetic parameters of eteplirsen will be determined from plasma and urine 
concentration data. Individual plasma and urine levels of eteplirsen will be listed with the 
corresponding time relative to eteplirsen administration, and summary statistics will be 
generated by per-protocol time of collection. PK parameters for eteplirsen will be 
calculated using non-compartmental analysis and/or using population PK methodology, 
as appropriate. 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 and urine concentrations will be listed. PK parameters in plasma and urine will be 
summarized by dose level and age cohort. Plasma concentrations will be plotted versus 
elapsed time for dose level means and for individual patients. Dose proportionality will 
be evaluated across the range of doses studied. 


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Protocol 4658-102 
 
 
Statistical Analysis Plan for Final Analysis 
Final Version 
Confidential 
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7. 
CHANGES IN PLANNED ANALYSES 
7.1. 
Changes from Clinical Protocol-Planned Analyses 
Compared to the clinical protocol of 4658-102 (Version 4, dated 07 February 2020) 
 
 the interim analysis 4658-102 is 
removed. There are no other changes in this SAP. 
 
7.2. 
Changes from Previous Statistical Analysis Plans 
Not applicable. 


Sarepta Therapeutics, Inc. 
Protocol 4658-102 
 
 
Statistical Analysis Plan for Final Analysis 
Final Version 
Confidential 
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8. 
APPENDIX 
8.1. 
Criteria of Abnormalities 
8.1.1 
Appendix Table 1. Chemistry Laboratory Abnormalities of Interest 
 
Test 
Unit 
Predefined Change 
Markedly Abnormal 
Criteria 
Decrease 
Increase 
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 
> ULN 
Calciuma 
mmol/L 
0.30 
0.30 
NA 
AST (SGOT) 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
ALT (SGPT) 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
Gamma Glutamyl 
Transferase 
U/L 
NA 
NA 
Value > 3× Baseline or > 
ULN 
Alkaline phosphatase 
U/L 
NA 
NA 
Value > 1.5× ULN 
Albumin 
g/dL 
1 
1 
< LLN or > ULN 
Total bilirubinb 
µmol/L 
NA 
10 
Value > 1.5× ULN 
Creatine phosphokinase 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
Cystatin C 
mg/L 
NA 
NA 
> ULN 
amultiply mg/dL value by 0.25 
bmultiply mg/dL value by 17.1 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; LLN = 
lower limit of normal; ULN = upper limit of normal; NA = Not Applicable 


Sarepta Therapeutics, Inc. 
Protocol 4658-102 
 
 
Statistical Analysis Plan for Final Analysis 
Final Version 
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8.1.2 
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 
LLN = lower limit of normal; ULN = upper limit of normal 
 
8.1.3 
Appendix Table 3. Urinalysis Laboratory Abnormalities of Interest 
 
Test 
Markedly Abnormal Criteria 
Protein in urine 
> 1+ 
Blood in urine 
Positive (+) 
RBC in urine 
> 0 
 
8.1.4 
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 from Baseline 


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Protocol 4658-102 
 
 
Statistical Analysis Plan for Final Analysis 
Final Version 
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8.1.5 
Appendix Table 5. Electrocardiogram and Echocardiogram 
Abnormalities of Interest 
 
Variable 
Units 
LLN ULN 
Age Group 
(years) 
Markedly Abnormal Criteria 
Heart Rate 
beats/min 60 
130 
NA 
QTcF Interval 
msec 
NA 
NA 
< 12 
> 480 
All 
< 320 
Increase > 60 
> 450 
> 480 
> 500 
QRS Interval 
msec 
NA 
NA 
< 12 
Intraventricular conduction 
delay (IVCD) or any QRS 
conduction disturbance with a 
QRS > 110 msec 
PR Interval 
msec 
NA 
NA 
< 12 
> 190 
LVEF 
% 
NA 
NA 
All 
< 55% 
Fractional Shortening % 
NA 
NA 
All 
< 29% 
LLN = lower limit of normal; ULN = upper limit of normal 


 
 
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