Clinical trial NCT02310906
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne muscular dystrophy Exon Skipping DMD Exon 53 Ambulatory Pediatric
Sponsor: Sarepta Therapeutics, Inc.
Start date: 2015-01-13; Completion date: 2019-03-25
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a first-in-human, multiple-dose 2-part study to assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 53 skipping.

Detailed description:
Part 1: Randomized, placebo-controlled dose-titration to assess safety, tolerability and pharmacokinetics of 4 dose levels of SRP-4053 in genotypically-confirmed DMD patients with deletions amenable to exon 53 skipping.

Part 2: Open-label evaluation of SRP-4053 in patients from Part 1, along with newly enrolled DMD patients with deletions amenable to exon 53 skipping and an untreated group of DMD patients with deletions not amenable to exon 53 skipping.

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

Clinical efficacy, including functional tests such as the six-minute walk test (6MWT), will be assessed at regularly scheduled study visits. Patients in the treated groups will undergo one baseline and one follow-up muscle biopsy. Patients in the untreated group will not undergo biopsies and will follow an abbreviated schedule of study assessments.

Arms: arm 1: Patients will receive SRP-4053 (golodirsen) intravenous (IV) infusions, weekly, at escalating dose levels as follows: Weeks 1-2, 4 mg/kg/week; Weeks 3-4, 10 mg/kg/week; Weeks 5-6, 20 mg/kg/week; Weeks 7-12, 30 mg/kg/week. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator. arm 2: Patients will receive SRP-4053 placebo-matching IV infusions, weekly, for 12 weeks. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator. arm 3: All eligible patients from Part 1, as well as new patients, will receive SRP-4053 (golodirsen) 30 mg/kg/week IV infusions, weekly, for up to 168 weeks. arm 4: Patients with DMD who have a genotypically confirmed deletion of exon(s) not amenable to treatment by exon 53 skipping, but who otherwise meet the same eligibility criteria as treated patients newly recruited to Part 2, will undergo the same study assessments as treated Patients (except for pharmacokinetic \[PK\] sampling and muscle biopsies), but at a reduced schedule through Week 144. The untreated patients are not considered as control group.
Interventions: intervention 1: Placebo intervention 2: SRP-4053
Intervention descriptions: intervention 1: SRP-4053 placebo-matching solution for IV infusion. intervention 2: SRP-4053 (golodirsen) solution for IV infusion.

Protocol documents:
Prot_000.pdf: 
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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 3 of 83 
 
08 November 2017 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have read Protocol No. 4053-101 (Amendment 8) 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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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 8 of 83 
 
08 November 2017 
 
 
NAME OF COMPANY 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
Phone: +1-617-274-4000 
NAME OF FINISHED PRODUCT 
SRP-4053 Concentrate for solution for infusion 
 
NAME OF ACTIVE INGREDIENT 
SRP-4053 
Part 2: 168 weeks plus a 4-week safety follow up for a total of 172 weeks. 
Total duration for patients participating in both Parts 1 and 2: approximately 190 weeks.  
Total duration for untreated patients participating in Part 2: approximately 150 weeks. 
NUMBER OF PATIENTS: 
Part 1: 12 patients (8 SRP-4053 and 4 placebo) 
Part 2: Up to 48 (24 treated patients [12 from Part 1 and 12 new patients] and up to 24 untreated patients) 
INCLUSION CRITERIA: 
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1. Male aged 6 to 15 years, inclusive. 
2. For treated patients (all patients in Part 1 and 12 additional treated patients in Part 2), established clinical 
diagnosis of DMD with a mutation amenable to exon 53 skipping (e.g. deletions of exons such as 42-52, 
45-52, 47-52, 48-52, 49-52, 50-52, 52, or 54-58) as documented by a genetic report from an accredited 
laboratory confirming deletion endpoints by multiplex ligation-dependent probe amplification (MLPA) or 
sequencing. 
3. For Part 2 untreated patients, established clinical diagnosis of DMD with a confirmed genomic deletion of 
exon(s) not amenable to exon 53 skipping as documented by an accredited laboratory and genomic 
methodology. 
4. Have intact right and left biceps muscles or an alternative upper arm muscle group. 
5. Have stable cardiac and pulmonary function that, in the Investigator’s opinion, is unlikely to 
decompensate over the duration of the study. 
6. Achieve a mean 6MWT distance of ≥250 meters at both the Screening and Baseline visits (prior to 
Week 1). The mean 6MWT distance at the Screening and Baseline visits is the average of 2 separate 
assessments on 2 consecutive days at each visit. The Baseline mean (average of Baseline Day 1 and 2) 
must be within 15% of the Screening mean (average of Screening Day 1 and 2). (Personal assistance or 
use of any assistive devices for ambulation is not permitted during the 6MWT.) 
7. Patients must meet at least one of the following 2 criteria:  
• 
NSAA total score >17; or 
• 
Rise (Gowers’) time <7 seconds 
8. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 
and the dose is expected to remain constant (except for modifications to accommodate changes in weight) 
throughout the study. Note: patients are allowed to take other medications (excluding other ribonucleic 
acid [RNA] antisense or gene therapy agents) including angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin receptor blocking agents (ARBs), β-blockers, and potassium provided they have been on a 
stable dose for at least 12 weeks prior Week 1 and the dose is expected to remain constant throughout the 
study. 
9. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with the study 
procedure requirements. 
10. Be willing to provide informed assent and have (a) parent(s) or legal guardian(s) who is (are) willing to 
provide written informed consent for the patient to participate in the study. 
 
EXCLUSION CRITERIA: 
Patients who meet any of the following criteria will be excluded from this study. 
1. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle 
strength or function, within 12 weeks prior to study entry (e.g., growth hormone, anabolic steroids).  
2. Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.  


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 9 of 83 
 
08 November 2017 
 
 
NAME OF COMPANY 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
Phone: +1-617-274-4000 
NAME OF FINISHED PRODUCT 
SRP-4053 Concentrate for solution for infusion 
 
NAME OF ACTIVE INGREDIENT 
SRP-4053 
3. Current or previous treatment with any other experimental treatments within 12 weeks prior to study 
entry. Untreated patients only can be enrolled concurrently in other non-interventional trials, or in 
interventional trials in which participants are known to be treated with standard-of-care medication, 
provided they do not interfere with study assessments performed in Study 4053-101, and the patient meets 
all the protocol-required entry criteria.  
4. A left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional shortening) based on the 
Screening ECHO and QTc (Fridericia’s correction) >450 msec. 
5. A forced vital capacity (FVC) <50% of predicted value or requirement for nocturnal ventilation. 
6. Major surgery within 3 months prior to Week 1 or orthopedic surgery planned for any time during this 
study which would interfere with the ability to perform outcome measures. 
7. Planned use of any aminoglycoside antibiotic or statin within 12 weeks of Week 1 or need for use of an 
aminoglycoside antibiotic or statin during the study. 
8. Presence of other clinically significant illness, for example significant cardiac, pulmonary, hepatic, renal, 
hematologic, immunologic, behavioral disorder or malignancy. 
9. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to 
contracture (i.e. fixed loss of >10 degrees plantar flexion from plantigrade assuming normal range of 
dorsiflexion of 20 degrees). 
10. Change in contracture treatment such as serial casting, contracture control devices, night splints, 
stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such 
intervention during the study. 
11. Prior or ongoing medical condition that, in the Investigator’s opinion, could interfere with the patient’s 
participation in the study. 
DOSE/ROUTE/REGIMEN:  
SRP-4053 concentrate for solution for infusion is supplied as a sterile, clear, colorless, phosphate-buffered saline 
(PBS) solution in single-use, 2-mL vials with each vial containing 2 mL of SRP-4053 at 50 mg/mL. 
REFERENCE TREATMENT: 
Part 1: Placebo patients will receive normal saline. 
Part 2: None. 
CRITERIA FOR EVALUATION: 
Part 1 
The primary endpoints are: 
• 
Incidence of AEs 
• 
Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis) 
• 
Incidence of abnormalities in vital signs and physical examinations   
• 
Incidence of abnormalities on ECGs and ECHOs 
The secondary endpoints are the PK parameters of SRP-4053 (see below). 
Part 2 
Primary Efficacy Endpoint: 
Change from baseline at Week 144 in the 6MWT 
Primary Biological Endpoint: 
Change from baseline at Week 48 in dystrophin protein levels determined by Western blot. 
Secondary Efficacy Endpoint: 
Change from baseline through Week 144 in FVC percent predicted (FVC%p) 


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CCI


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 11 of 83 
 
08 November 2017 
 
 
NAME OF COMPANY 
Sarepta Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 USA 
Phone: +1-617-274-4000 
NAME OF FINISHED PRODUCT 
SRP-4053 Concentrate for solution for infusion 
 
NAME OF ACTIVE INGREDIENT 
SRP-4053 
Part 2: Plasma samples will be obtained from all 24 treated patients in Part 2 pre-infusion and between 5 and 
10 minutes postinfusion at Weeks 1, 24, 48, 96, and 144. PK analysis in Part 2 will be done using population PK 
methods. It may be necessary to combine the data for Parts 1 and 2 to perform population PK analysis adequately. 
The following PK parameters will be determined for both Parts 1 and 2, as appropriate: 
• 
Maximum plasma concentration (Cmax) 
• 
Time to maximum plasma concentration (tmax) 
• 
Area under the plasma concentration-time curve (AUC) 
• 
Apparent volume of distribution at steady state (Vss) 
• 
Elimination half-life (t½) 
• 
Total clearance (CL) 
• 
Mean residence time (MRT) 
• 
Urinary clearance (CLR), for Part 1 only 
SAMPLE SIZE: 
Sample size for this study is based upon qualitative considerations; no formal sample size calculations will be 
performed.  
STATISTICAL METHODS: 
Demographic and baseline characteristics will be summarized for Part 1 and Part 2.  
Efficacy and Pharmacodynamic Analyses: 
All efficacy and biological (ie, pharmacodynamics) endpoints will be summarized descriptively by time point and 
treatment group for both Part 1 and Part 2. Change from baseline for each of these endpoints will also be 
summarized by time point and treatment group, if appropriate. 
The primary efficacy endpoint of change from baseline at Week 144 (Part 2) in the 6MWT will be summarized by 
treatment group.  
The primary biological endpoint of change from baseline at Week 48 (Part 2) in dystrophin protein level as 
determined by Western blot will be analyzed based on a 1-sample permutation test.  
Other efficacy and biological endpoints will be analyzed similarly to the primary efficacy or biological efficacy 
endpoint, as appropriate, based on the type of endpoints and the number of assessments during Part 2 of this study. 
Safety Analyses: 
Safety analyses will be descriptive in nature. Adverse events will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term. An AE will be considered 
treatment-emergent if it occurs in the time period starting with the initiation of the first dose of study drug and 
ending 28 days after the last dose of study drug for treated patients and on or after the Week 1 visit of Part 2 for 
untreated patients. All AEs will be recorded in the data listings. In general, only treatment-emergent AEs (TEAEs) 
will be summarized. For all AE tables, the number and percentage of patients reporting AEs will be grouped using 
the MedDRA SOC and preferred term and summarized treatment group by dose level for the SRP-4053 group. In 
general, tables will have events categorized into all TEAEs and treatment-related TEAEs. 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 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.  
Descriptive statistics for ECGs, ECHOs, vital signs, physical examinations, and safety laboratory parameters will 
be generated. All safety data will be presented in the data listings. Additionally, shift and frequency tables of 
predefined change in abnormal values for select safety parameters will be generated. 
Descriptive statistics for the anti-phosphorodiamidate morpholino oligomer (PMO) immune response will be 
generated. The relationship between anti-PMO antibodies and clinical safety parameters may be assessed. If an 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 13 of 83 
 
08 November 2017 
 
 
2. 
SCHEDULES OF EVENTS 
A schedule of study events for Part 1 (double-blind dose titration) is provided in Table 2. The 
schedules of study events for treated patients are provided in Table 3 (for the first 48 weeks) and 
Table 4 (for Week 49 through end-of-study [EOS]). In addition, a separate schedule of events for 
untreated patients in Part 2 is provided in Table 5. 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 25 of 83 
 
08 November 2017 
 
 
10.3.3. 
Clinical Laboratory Assessments ...............................................................................63 
10.3.3.1. 
Hematology .................................................................................................................63 
10.3.3.2. 
Coagulation .................................................................................................................63 
10.3.3.3. 
Serum Chemistry ........................................................................................................63 
10.3.3.4. 
Urinalysis ....................................................................................................................64 
10.3.3.5. 
Concomitant Medications and Therapies ...................................................................64 
10.3.4. 
Other Safety Assessments ...........................................................................................64 
10.3.4.1. 
Electrocardiogram (ECG) ...........................................................................................64 
10.3.4.2. 
Echocardiography (ECHO) ........................................................................................64 
10.3.4.3. 
Immunogenicity ..........................................................................................................64 
11. 
ADVERSE EVENTS ..................................................................................................65 
11.1. 
Collection of Adverse Events .....................................................................................65 
11.2. 
Definition of Adverse Events .....................................................................................65 
11.2.1. 
Adverse Event (AE) ....................................................................................................65 
11.2.2. 
Serious Adverse Event (SAE) ....................................................................................65 
11.3. 
Classification of Adverse Events ................................................................................66 
11.3.1. 
Relationship to Investigational Drug Product .............................................................66 
11.3.2. 
Relationship to Study Procedures ...............................................................................66 
11.3.3. 
Relationship to Underlying Disease ...........................................................................67 
11.3.4. 
Severity of Adverse Events ........................................................................................67 
11.3.5. 
Outcome ......................................................................................................................67 
11.3.6. 
Action Taken Regarding the Investigational Drug Product .......................................67 
11.3.7. 
Expectedness of an Adverse Event .............................................................................67 
11.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................................68 
11.4. 
Recording Adverse Events .........................................................................................68 
11.5. 
Reporting Serious Adverse Events .............................................................................68 
11.6. 
Special Situations ........................................................................................................68 
11.6.1. 
Overdose .....................................................................................................................68 
11.6.2. 
Death ...........................................................................................................................69 
11.6.3. 
Unblinding due to a Medical Emergency ...................................................................69 
11.6.4. 
Responsibilities of the Investigator ............................................................................69 
11.6.5. 
Responsibilities of the Sponsor ..................................................................................69 
11.7. 
Pharmacokinetic Assessments ....................................................................................70 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 26 of 83 
 
08 November 2017 
 
 
11.7.1. 
Blood Sample Collection ............................................................................................70 
11.7.2. 
Urine Sample Collection .............................................................................................70 
12. 
STATISTICS ..............................................................................................................71 
12.1. 
General Considerations ...............................................................................................71 
12.2. 
Determination of Sample Size ....................................................................................71 
12.3. 
Analysis Sets ...............................................................................................................72 
12.4. 
Statistical Analysis ......................................................................................................72 
12.4.1. 
Protocol Deviations ....................................................................................................72 
12.4.2. 
Disposition, Demographics, and Baseline Characteristics .........................................72 
12.4.3. 
Prior and Concomitant Medications ...........................................................................73 
12.4.4. 
Medical History ..........................................................................................................73 
12.4.5. 
Dosing .........................................................................................................................73 
12.5. 
Efficacy Analysis ........................................................................................................73 
12.6. 
Pharmacodynamic Analysis ........................................................................................73 
12.7. 
Safety Analyses ..........................................................................................................73 
12.7.1. 
Safety Variables ..........................................................................................................73 
12.7.2. 
Safety Analysis ...........................................................................................................74 
12.8. 
Pharmacokinetic Analyses ..........................................................................................75 
13. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ..........76 
13.1. 
Recording of Data .......................................................................................................76 
13.2. 
Quality Assurance .......................................................................................................76 
13.3. 
Retention of Study Documents ...................................................................................76 
13.4. 
Termination of Study or Study Site ............................................................................77 
14. 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................78 
14.1. 
Compliance with Ethical and Regulatory Guidelines .................................................78 
14.2. 
Regulatory and Independent Ethics Committee Review ............................................78 
14.3. 
Informed Consent/Assent ...........................................................................................78 
14.4. 
Compliance with the Protocol ....................................................................................78 
14.5. 
Confidentiality ............................................................................................................79 
14.5.1. 
Data .............................................................................................................................79 
14.5.2. 
Patient Anonymity ......................................................................................................79 
15. 
STUDY DOCUMENTATION AND GENERAL INFORMATION .........................80 
15.1. 
Essential Study Documents ........................................................................................80 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 27 of 83 
 
08 November 2017 
 
 
15.2. 
General Information ....................................................................................................80 
15.3. 
Dissemination of Study Results ..................................................................................80 
15.4. 
Product Handling and Complaints Reporting .............................................................81 
16. 
LIST OF REFERENCES ............................................................................................82 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events, Part 1: Double-Blind Dose Titration ..........................................14 
Table 3: 
Schedule of Events for Treated Patients in Part 2 (Screening Through First 
48 Weeks of Open-Label Treatment) .........................................................................16 
Table 4:  
Schedule of Events for Treated Patients in Part 2 (Week 49 Through End-of-
Study Follow up) ........................................................................................................18 
Table 5: 
Schedule of Events for the Untreated Group in Part 2 ...............................................20 
Table 6: 
Study Procedures after Part 1 Week 12 up to Start of Part 2 ......................................37 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic for Part 1, Double-Blind Dose Titration .........................................36 
Figure 2 
Study Schematic for Part 2, Open-Label and Untreated Patients ...............................39 
 
 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 42 of 83 
08 November 2017 
 
 
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.  
Part 1 is a randomized and placebo-controlled dose titration where patients will be randomized 
(2:1, SRP-4053:placebo) to receive once-weekly infusions at each dose level for at least 2 weeks 
beginning at 4 mg/kg/week and followed by 10 mg/kg/week, 20 mg/kg/week, and 
30 mg/kg/week. A double-blind, placebo-control design will be used to reduce potential bias 
during data collection and evaluation of clinical (safety) parameters. 
Part 2 will evaluate the proposed therapeutic dose (target of 30 mg/kg or the highest tolerated 
dose determined in Part 1) as a once-weekly open-label infusion for up to 168 weeks.  
Part 2 of this study will also enroll up to 24 patients with DMD with a confirmed deletion of 
exon(s) that are not amenable to exon 53 skipping that will not receive treatment with SRP-4053. 
This patient group will also have deletions in the spectrin-like repeating units and have a similar 
phenotype with regard to disease manifestations and rate of progression. 
7.3.2. 
Duration of Study 
In Part 1, a treatment duration of approximately 12 weeks (at least 2 weeks per dose level x 
4 dose levels in addition to a 3- to 4-week DSMB safety review) is considered appropriate for 
dose escalation (dose titration) of SRP-4053 to obtain sufficient safety data to determine whether 
dosing in Part 2 can be initiated. 
In Part 2, a treatment duration of up to 168 weeks was chosen for open-label dosing based on 
clinical studies of eteplirsen, a PMO designed to skip exon 51 of the dystrophin gene. Based on 
clinical experience with eteplirsen, dystrophin-positive fibers may be detectable by the 24th week 
of treatment; however, changes in functional clinical endpoints measuring endurance and muscle 
function may not be evident until at least 96 weeks of treatment. The 168-week treatment period 
and 4-week safety follow-up will also allow for long-term assessment of safety. 
7.3.3. 
Choice of Efficacy Endpoints 
The 6MWT was selected as the primary efficacy endpoint as it is the most reliable and sensitive 
instrument currently available to demonstrate a functional change in ambulation and endurance 
for DMD patients. The 6MWT is a frequently used measure of functional capacity with regard to 
both strength and endurance and is one that has been used as a primary outcome measure in 
clinical trials in ambulatory DMD patients to assess other potentially disease-modifying drugs 
such as ataluren and drisapersen. Based on data from natural history and placebo-controlled 
interventional studies, patients with DMD who have the walking distance and age range of the 
population as defined in the inclusion criteria (Section 8.1) are expected to lose up to 100 meters 
over the course of 1 year (McDonald 2010, Bushby 1993, Mazzone 2011). 
The percentage of dystrophin-positive fibers relative to normal (100%) was selected as the 
primary biological efficacy endpoint as the very low percentage of such fibers observed in DMD 
patients is a hallmark of the disease. The intended effect of exon skipping treatments such as 
SRP-4053 is to increase levels of dystrophin protein expression.  


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
Page 44 of 83 
08 November 2017 
 
8.
PATIENT POPULATION AND SELECTION
8.1. 
Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1. Male aged 6 to 15, inclusive.
2. For treated patients (all patients in Part 1 + 12 additional treated patients in Part 2),
established clinical diagnosis of DMD amenable to exon 53 skipping (e.g., deletions of
exons such as 42-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, or 54-58) as documented by
a genetic report from an accredited laboratory confirming deletion endpoints by multiplex
ligation-dependent probe amplification (MLPA) or sequencing.
3. For Part 2 untreated patients, established clinical diagnosis of DMD with a confirmed
genomic deletion of exon(s) not amenable to exon 53 skipping as documented by an
accredited laboratory and genomic methodology.
4. Have intact right and left biceps muscles or an alternative upper arm muscle group.
5. Have stable cardiac and pulmonary function that, in the Investigator’s opinion, is unlikely
to decompensate over the duration of the study.
6. Achieve a mean 6MWT distance of ≥250 meters at both the Screening and Baseline visits
(prior to Week 1). The mean 6MWT distance at the Screening and Baseline visits is the
average of 2 separate assessments on 2 consecutive days at each visit. The Baseline mean
(average of Baseline Day 1 and 2) must be within 15% of the Screening mean (average of
Screening Day 1 and 2). (Personal assistance or use of any assistive devices for
ambulation is not permitted during the 6MWT.)
7. Patients must meet one of the following 2 criteria:
•
NSAA
•
Rise (Gowers’) time <7 seconds
8. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks
prior to Week 1 and the dose is expected to remain constant (except for modifications to
accommodate changes in weight) throughout the study. Note: patients are allowed to take
other medication (excluding other RNA antisense or gene therapy agents) including
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents
(ARBs), β-blockers, and potassium provided they have been on a stable dose for at least
12 weeks prior Week 1 and the dose is expected to remain constant throughout the study.
9. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with
the study procedure requirements.
10. Be willing to provide informed assent and have a parent(s) or legal guardian(s) who is
(are) willing to provide written informed consent for the patient to participate in the
study.
total score >17; or


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 45 of 83 
08 November 2017 
 
 
8.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this study. 
1. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect 
on muscle strength or function, within 12 weeks prior to study entry (e.g., growth 
hormone, anabolic steroids).  
2. Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.  
3. Current or previous treatment with any other experimental treatments within 12 weeks 
prior to study entry. Untreated patients only can be enrolled concurrently in other non-
interventional trials, or in interventional trials in which participants are known to be 
treated with standard-of-care medication, provided they do not interfere with study 
assessments performed in Study 4053-101, and the patient meets all the protocol-required 
entry criteria. 
4. Have a left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional 
shortening) based on the Screening ECHO and QTc (Fridericia’s correction) >450 msec. 
5. Have a forced vital capacity (FVC) <50% of predicted value or require nocturnal 
ventilation. 
6. Major surgery within 3 months prior to Week 1 or planned orthopedic surgery for any 
time during this study, which would interfere with the ability to perform outcome 
measures. 
7. Use of any aminoglycoside antibiotic or statin within 12 weeks of Week 1 or need for use 
of an aminoglycoside antibiotic or statin during the study. 
8. Presence of other clinically significant illness including significant cardiac, pulmonary, 
hepatic, renal, hematologic, immunologic, behavioral disease or malignancy. 
9. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle 
joint due to contracture (i.e., fixed loss of >10 degrees plantar flexion from plantigrade 
assuming normal range of dorsiflexion of 20 degrees). 
10. Change in contracture treatment such as serial casting, contracture control devices, night 
splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or 
expected need for such intervention during the study. 
11. Prior or ongoing medical condition that, in the Investigator’s opinion, could interfere with 
the patient’s participation in the study. 
8.3. 
Completion of a Patient’s Participation and Overall Study 
Completion 
The length of a patient’s participation in Part 1 will be from the time the informed consent form 
is signed until completion of the Week 12 assessments or until the DSMB has met and evaluated 
Part 1 safety data prior to the beginning of Part 2, whichever is later. Patients who receive 
open-label treatment in Part 2 will have completed the study when they transition to a long-term 
extension study or complete the Week 168 study assessments in Part 2 plus the 4-week safety 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 46 of 83 
08 November 2017 
 
 
follow-up visit. Untreated patients in Part 2 will have completed the study when they complete 
the Week 144 assessments (the 4-week safety follow-up visit is not applicable).  
8.4. 
Patient Withdrawal Criteria 
Any patient in either Part 1 or Part 2 can decide to withdraw from study participation at any time 
for any reason. In addition, the study Sponsor may decide to stop the study participation of any 
patient as deemed necessary. The Principal Investigator may also stop the study participation of 
any patient at any time. Reasons for study withdrawal include but are not limited to: 
• The patient was erroneously included in the study (i.e., 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 Investigator or study staff will document the reason(s) for treatment discontinuation in 
source documents. Patients who receive at least one (1) dose of investigational drug product who 
are withdrawn from treatment will be asked to complete all early termination assessments within 
30 days of withdrawal. For Part 1, these assessments will include those listed for Week 12 
(Table 2); for Part 2 these assessments will include those listed for Week 168 (Table 4). Patients 
in the untreated group who complete Baseline assessments and who are withdrawn from the 
study will be asked to complete all early termination assessments within 30 days of withdrawal 
(see Week 144 assessments on Table 5). Patients who withdraw from the study will not be 
replaced. 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 47 of 83 
08 November 2017 
 
 
9. 
TREATMENTS 
9.1. 
Investigational Drug Product 
Details regarding the investigational drug product in this study, SRP-4053 concentrate for 
solution for infusion, are described in the following sections. For dosing considerations, please 
refer to Section 9.7. 
9.2. 
Packaging and Labeling 
In Part 1, SRP-4053 concentrate for solution for infusion is supplied as a sterile, clear, colorless, 
phosphate-buffered saline (PBS) solution in single-use, 2-mL vials with each vial containing 
2 mL of SRP-4053 at a concentration of 50 mg/mL. 
The label text for the investigational product will comply with applicable regional, national, and 
local laws and regulations and will include at a minimum the contents of the vial, the appropriate 
cautionary statements, lot number, storage conditions, and the name of the Sponsor (Sarepta 
Therapeutics, Inc.). The protocol number will also be included on EU supplies only. 
Placebo patients in Part 1 will receive 0.9% normal saline, United States Pharmacopeia/European 
Pharmacopeia (USP/EP). 
For Part 2, SRP-4053 concentrate for solution for infusion will be packaged and labeled as 
described above for SRP-4053 in Part 1. 
9.3. 
Receipt of Investigational Drug Product 
A proof of receipt, which details the quantity and description of the investigational product, will 
accompany the shipment from the Sponsor or designee to the Investigator. Details for 
investigational product receipt, storage, and dispensation recordkeeping are located in the study-
specific Pharmacy Manual. The Investigator must ensure that the investigational product is 
maintained in a controlled location, with limited access and temperature monitoring, and under 
appropriate storage conditions. 
9.4. 
Storage 
Vials of investigational drug product must be stored according to manufacturer specifications at 
a consistent temperature from 2°C to 8°C in a secured, limited-access area with temperature 
recording, controls and monitoring. Details for preparation of the investigational drug product for 
administration can be found in the study-specific Pharmacy Manual.  
9.5. 
Disposition of Unused Investigational Drug Product 
All unused investigational drug product vials must be maintained under adequate storage 
conditions in a limited-access area until time of use. Upon completion of the study, any 
remaining unused investigational drug product vials will be returned to the Sponsor or be 
destroyed per the site-specific standard operating procedures. Final drug accountability will be 
monitored by the Sponsor or their representative. 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 51 of 83 
08 November 2017 
 
 
• The Medical Monitor will review safety data including clinical and laboratory 
information on an ongoing basis. Summary reports of these reviews will be 
distributed as warranted to all participating Investigators, specifically when treatment-
related AEs have been reported.  
• Prior to dose administration, the Investigator will review all AEs and all laboratory 
values for the specific patient and will only proceed with dosing if he or she deems 
that it is safe to do so based on all available information.  
9.8.3. 
Stopping Rules 
Safety data review including AEs and laboratory assessments will be performed on an ongoing 
basis. During the dose escalation in Part 1, sites are required to report all AEs as defined in 
Section 9.8.2 and Section 11. If safety concerns arise at any time, dosing may be stopped until 
these concerns have been addressed. Dosing in Part 1 will be interrupted to allow for review of 
cumulative safety data by the DSMB if any of the following conditions are met: 
• ≥2 severe AEs or ≥3 moderate AEs considered to be possibly/probably or definitely 
related to investigational drug product  
• Any SAE considered to be possibly/probably or definitely related to investigational 
drug product 
• ≥2 patients develop 2 consecutive serum creatinine levels ≥2X their respective 
average pretreatment values 
• ≥2 patients develop a confirmed unexplained proteinuria of >2+  
• Any unexplained gamma-glutamyl transferase (GGT) >3X upper limit of normal 
(ULN) in combination with bilirubin >2X ULN  
• Any unexplained partial thromboplastin time (PTT) >45 seconds 
The DSMB will be notified by the Sponsor within 24 hours of the Sponsor learning of any of the 
events listed above. Dosing may also be interrupted or halted if warranted at the discretion of the 
Sponsor or Investigator. Should this occur, re-initiation of dosing may be permitted via protocol 
amendment if deemed appropriate following safety data review by the Sponsor and the DSMB. 
Any decisions related to dose adjustment, delay, or stopping during dose titration will be 
communicated by the Sponsor to all sites immediately. In addition, Investigators may, in the 
event of an emergency, directly contact their peers at other sites to communicate safety concerns. 
9.8.4. 
Data Safety Monitoring Board 
An independent DSMB will be commissioned to assist in the evaluation of safety data during the 
blinded dose escalation in Part 1 and to review aggregate safety data before Part 2 dosing is 
initiated. This formal DSMB review will be based on all available safety data for all patients at 
the time point when the last patient in Part 1 has completed Week 8 dosing (received 2 doses of 
the highest dose of investigational drug product). This data review will be blinded unless the 
DSMB specifically requests unblinding based on safety data summaries. The DSMB will be 
charged with determining whether transitioning into Part 2 of the protocol is appropriate based 
on aggregate safety data from Part 1. After initiation of Part 2, periodic reviews of safety data 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 52 of 83 
08 November 2017 
 
 
will be conducted by the DSMB as outlined in the DSMB charter, and the Part 1 blind will be 
maintained unless knowledge of the treatment assignments is necessary for the evaluation of 
safety. 
Any decision to interrupt, restart, or discontinue the study will be made by the Sponsor in 
consultation with the DSMB.  
A formal DSMB meeting may be convened at any time if requested by one or more Investigators 
and/or the Sponsor of this study. The DSMB charter provides further detail on the meeting and 
decision-making process involving the DSMB. 
The outcome of any DSMB meeting will be communicated to the Investigators by the Sponsor or 
responsible designee. The relevant regulatory authorities will be promptly notified of study 
suspension or discontinuation related to safety concerns. Any suspension or discontinuation of 
the trial for any reason will also be promptly reported to the relevant Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). 
9.9. 
Randomization and Blinding 
9.9.1. 
Randomization 
After qualifying for study entry in Part 1, DMD patients with an out-of-frame deletion confirmed 
as amenable to exon 53 skipping will be randomized using a 2:1 ratio to either SRP-4053 
(8 patients) or placebo (4 patients). Randomization will be performed prior to dosing on Week 1 
using an interactive voice response (IVR) system.  
9.9.2. 
Blinding for Dose Administration 
Part 1 is a double-blind, placebo-controlled dose titration where all patients, parents, 
Investigators, and all site staff not involved with study drug preparation will be blinded to 
treatment assignment. A double-blind, placebo-controlled design will be used to reduce potential 
bias during data collection and evaluation of outcome parameters.  
Eight patients will receive weekly escalating IV doses of SRP-4053 and 4 patients will receive 
weekly escalating IV doses of placebo in a blinded fashion over 12 weeks. Other individuals 
(qualified back-up pharmacists) who are authorized to verify dose and dose assignment will be 
unblinded to treatment assignment. These individuals will not have interaction with study 
participants and will be instructed not to divulge randomization assignment to others under any 
circumstances unless directed to do so by the Investigator in the interest of patient safety. 
In Part 2, all treated patients (rollover patients from Part 1 and patients new to Part 2 who are 
amenable to exon 53 skipping) will receive open-label SRP-4053 (at the dose determined in 
Part 1) as a weekly IV infusion for 144 weeks. No blinding is required. 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 53 of 83 
08 November 2017 
 
 
9.9.3. 
Blinding for Clinical Evaluators 
To minimize assessment bias, clinical evaluators will be trained on how to maintain blinding to 
treatment as best as possible. Specifically, clinical evaluators will: 
• Not be involved in any aspect of care for the patients over the course of the study and 
will not have access to any clinical patient records including laboratory values, 
genetic analyses, or study-specific assessment and treatment schedules. 
• Avoid conversation with parents, caregivers and the patients about treatment, other 
assessments including muscle biopsies, and any other disease-related topics.  
In order to maintain the study blind, interaction between parents and clinical evaluators will be 
minimized. Parents, caregivers and patients will be instructed not to discuss their study 
participation with the clinical evaluators. Parents/caregivers of study participants will be 
informed that information on their child’s performance on assessment measures (unless of 
clinical significance and requiring intervention) will be not be shared during the course of the 
study. Parents/caregivers will also be discouraged from attempting to access information on 
performance of other study participants and will be instructed not to publicly discuss their child’s 
participation in this trial. 
9.9.4. 
Blinding for Laboratory Assessments 
Biological laboratory assessments, notably IHC and Western blotting, will be done in a blinded 
fashion so that the raters are unaware of the time point and treatment group under which the 
sample has been taken. Images will have all capture date information removed and will be 
secured in a location that is not accessible to the analyst or pathologist(s) who will perform the 
blinded automated algorithm analysis of dystrophin-positive fibers and assessment of dystrophin-
associated protein localization at the sarcolemma membrane.  
The total amount of dystrophin protein will be assessed using semi-quantitative IHC in a central 
laboratory utilizing predefined standardized methodology and evaluated by a blinded pathology 
expert. 
Processed muscle biopsy tissue from patients will be analyzed using Western blot to quantitate 
the amount of dystrophin protein. Western blot analysis will be performed by blinded personnel 
at the end of the study that will be blinded to the treatment group and time point of the patient’s 
muscle biopsy. 
The laboratory analysis of muscle biopsy tissue, IHC, and quantification of dystrophin (by 
Western blot) will be performed after all patients have completed the Week 48 muscle biopsy. 
Once the analysis is complete, the results will be unblinded to treatment status and patient study 
number. 
A detailed description of these procedures can be found in the Laboratory Manual.  
9.9.5. 
Unblinding Procedures 
In the event of a medical emergency wherein the knowledge of the patient’s treatment 
assignment may influence clinical decision-making, the Investigator has the option to unblind 
treatment assignment (applicable to Part 1 only) using the IVR system. Please see Section 11.6.3 
for additional information regarding unblinding in emergency situations.  


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 54 of 83 
08 November 2017 
 
 
The reasons for any unblinding must be noted in the source documentation. The Investigator 
must not disclose information about treatment assignment to anyone aside from specific 
individuals who need the information because of their direct involvement in patient care. 
If deemed necessary, the DSMB may request to review unblinded safety data at any time to 
ensure the safety of any individual patient or the study population as a whole. Data access will be 
restricted to DSMB members.  
Regulatory authorities and/or the IRB/IEC may request the unblinding of data from one or more 
patients at any time. 
9.10. 
Prior and Concomitant Medications and Therapeutic Procedures 
The following therapies may be used prior to enrollment and throughout the study at the 
discretion of the Investigator. However, attempts should be made to keep the dosage constant 
throughout the treatment period. 
• Oral corticosteroids for treatment of DMD including, but not limited to prednisolone, 
prednisone, and deflazacort. Patients entering the study must have been on a stable 
dose (or dose equivalent) of oral corticosteroids for at least 24 weeks prior to the first 
administration of study treatment at Week 1. Doses of corticosteroids are expected to 
remain constant (except for modifications to accommodate changes in weight) 
through the completion of study to the degree that is clinically feasible. Prior to and 
during the study, it is acceptable to change the specific oral corticosteroid as clinically 
necessary, as long as the dose is equivalent and the equivalent dose calculation is 
documented in the medical record. 
• Oral ACE inhibitors including but not limited to perindopril and lisinopril 
• Oral β-blockers including but not limited to carvedilol and atenolol 
• Angiotensin-receptor blockers including but not limited to losartan, irbesartan, 
valsartan, and candesartan 
• Oral laxatives including but not limited to lactulose, Senokot, and Movicol 
• Vitamin D and calcium supplements 
• Alendronate (Fosamax) or other bisphosphonates used to treat 
osteoporosis/osteopenia by inhibiting osteoclasts 
• Over-the-counter herbal preparations, including herbal supplements, vitamins, 
minerals, and homeopathic preparations, provided the patient had been on stable 
doses for at least 24 weeks before enrollment in this study 
Other concomitant medications (e.g., vitamins or other medications excluding RNA antisense 
and gene therapies) may also be taken, if, in the opinion of the Investigator, they are not deemed 
to interfere with study procedures or the investigation of SRP-4053 in this study. Every attempt 
must be made to keep the dosage constant throughout the study period. 
Introduction of new physiotherapy interventions during the course of the study must be avoided 
unless in the best interest of the patient. Should a contracture develop during the course of the 
study, and it is considered in the best interest of the patient to treat the contracture, then any of 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 55 of 83 
08 November 2017 
 
 
the following interventions may be used to reduce the contracture. Any intervention must be 
clearly documented. 
• Stretching exercises (passive, active, self) 
• Night splints  
• Contracture control devices  
• Serial casting  
If applicable, a patient who is ineligible for the study due to contracture severity (Exclusion 
Criterion 9) may be re-screened at the discretion of the Investigator when the contracture 
measures ≤10 degrees from plantigrade.  
The following therapies are not permitted during the conduct of this study: 
• Systemic or oral steroids for other conditions 
• Investigational agents for the treatment of DMD  
• Any medication with the potential to affect muscle mass, strength, and/or function, 
such as, but not limited to, growth hormone and PDE-5 inhibitors. As of 
Amendment 6, growth hormone for short stature and testosterone for delayed puberty 
are permitted if there has been confirmation and documentation of the endocrinologic 
diagnosis and necessity of treatment. 
• Immunosuppressants (other than oral or systemic corticosteroids prescribed for 
DMD)  
• Aminoglycoside antibiotics 
• Statins 
9.11. 
Treatment Compliance 
Treatment compliance with scheduled weekly infusions will be documented on the case report 
form (CRF). 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 63 of 83 
08 November 2017 
 
 
appearance, head, eyes, ears, nose, and throat (HEENT), heart, lungs, abdomen, extremities, 
skin, lymph nodes, musculoskeletal, and neurological systems. 
10.3.3. 
Clinical Laboratory Assessments 
Routine clinical laboratory testing will occur according the schedules of events for Part 1 
(Table 2) and Part 2 (Table 3 and Table 4 for treated patients; Table 5 for untreated patients). 
Laboratory results will be analyzed by an accredited central laboratory selected by the Sponsor 
(Sarepta Therapeutics). Assessments and shipment will be prepared according to the Laboratory 
Manual provided for the study. Specific laboratory parameters to be analyzed are presented in 
the subsections below. 
10.3.3.1. Hematology 
Hematology parameters to be analyzed include the following: 
Red blood cells (RBC) 
Lymphocytes 
White blood cells (WBC) 
Monocytes 
Hemoglobin 
Eosinophils 
Hematocrit 
Basophils 
Neutrophils 
Platelets 
10.3.3.2. Coagulation 
Coagulation parameters to be analyzed include the following: 
Prothrombin time (PT) 
International Normalized Ratio (INR) 
Activated partial thromboplastin time (PTT) 
 
10.3.3.3. Serum Chemistry 
Serum chemistry parameters to be analyzed include the following: 
Sodium 
Alkaline phosphatase 
Chloride 
Amylase 
Potassium 
Alanine aminotransferase (ALT) 
Calcium 
Aspartate aminotransferase (AST), 
Glucose 
Gamma-glutamyl transferase (GGT) 
Creatinine 
Lactase dehydrogenase (LDH) 
Blood urea nitrogen (BUN) 
C-reactive protein (CRP) 
Albumin 
Creatine kinase (CK) 
Uric acid 
Serum cystatin C 
Total bilirubin 
   


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 64 of 83 
08 November 2017 
 
 
10.3.3.4. Urinalysis 
The following parameters will be analyzed: 
pH 
Cytology 
Specific gravity 
Hemoglobin 
Protein 
Kidney injury molecule-1 (KIM-1) 
Glucose 
Ketones 
Any laboratory value(s) outside of the current reference range will be flagged.  
10.3.3.5. Concomitant Medications and Therapies 
The review of concomitant medications, changes in dosage of concomitant medications, and 
other concomitant therapies and procedures will occur at each visit beginning from the time the 
parents/patients sign written informed consent/assent. All information relating to concomitant 
medications and therapies will be recorded on the CRF. 
10.3.4. 
Other Safety Assessments 
10.3.4.1. Electrocardiogram (ECG) 
In Part 1, a 12-lead ECG will be performed during Screening, Baseline and at Week 12 
(Table 2). Rollover patients from Part 1 will have a 12-lead ECG every 12 weeks during the first 
48 weeks of Part 2. Patients new to Part 2 will have a 12-lead ECG performed during Screening, 
Baseline and then every 12 weeks during the first 48 weeks of in Part 2 (refer to Table 3 for 
treated patients and Table 5 for untreated patients. Thereafter, ECGs will be performed every 
24 weeks (Table 4 for treated patients and Table 5 for untreated patients) until Week 144. 
Twelve-lead ECGs will be performed only after the patient is positioned supine, resting, and is 
quiet for a minimum of 15 minutes. The ECG will be manually reviewed and interpreted by 
medically qualified personnel using a central vendor according to prespecified criteria. The 
Investigator will review the results of the ECG report and designate the findings as normal, 
abnormal (clinically significant [CS]) or abnormal (not clinically significant [NCS]). 
10.3.4.2. Echocardiography (ECHO) 
A standard 2-dimensional (2D) ECHO will be performed at Screening and Week 12 in Part 1 
(Table 2). Rollover patients from Part 1 will then have an ECHO every 24 weeks in Part 2. 
Patients new to Part 2 (treated and untreated) will have an ECHO at Screening and then every 
24 weeks in Part 2 (Table 3 and Table 4 for treated patients, and Table 5 for untreated patients) 
until Week 144. All ECHOs will be reviewed and interpreted by medically qualified personnel 
using a central vendor according to prespecified criteria. Ejection fraction and fractional 
shortening will be noted. The Investigator will review the results of the ECHO report and 
designate the findings as normal, abnormal (CS or NCS).  
10.3.4.3. Immunogenicity 
Serum samples to evaluate immunogenicity will be assessed at the time points indicated in the 
schedules of events (Table 2, Table 3, and Table 4 for treated patients; Table 5 for untreated 
patients). 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 65 of 83 
08 November 2017 
 
 
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 his/her judgment and expertise to determine the appropriate course of action. 
All AEs from the time of informed consent through the EOS visit (or early termination from the 
study) will be recorded in each individual patient’s CRF. For patients who prematurely 
discontinue from the study (see Section 8.3), AEs will continue to be recorded until 4 weeks after 
the last SRP-4053 infusion for the randomized group or through the EOS visit for the untreated 
group. 
If, at any time after the patient has completed participation in the study (see Section 8.3), the 
Investigator or study staff become aware of an SAE that the Investigator believes is 
possibly/probably or definitely related to the investigational drug product (Section 11.3.1) or is 
possibly/probably or definitely related to a study procedure (Section 11.3.2), then the event and 
any known details must be reported promptly to the Sponsor. 
11.2. 
Definition of Adverse Events 
11.2.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical trial participant, which does not 
necessarily have a causal relationship with the investigational drug. An AE can, therefore, be any 
unfavorable and unintended symptom, sign, disease, condition, or test abnormality that occurs 
during or after administration of an investigational drug product whether or not considered 
related to the investigational drug product. 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 (SAE) 
An SAE is defined as any AE that results in any of the following: 
Death: The patient died as the result of the event. 
Life-threatening event: Any AE that places the patient, in the view of the Investigator or 
Sponsor, at immediate risk of death from the AE as it occurred, i.e., 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 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 66 of 83 
08 November 2017 
 
 
hospitalizations that are longer than expected based on Investigator judgment will be considered 
prolonged hospitalizations. 
Persistent or significant disability/incapacity: An AE that results in a persistent or significant 
disability or 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 investigational product. 
Important medical events: An AE that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
event may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed above.  
11.3. 
Classification of Adverse Events 
Each AE whether serious or nonserious will be classified by the Investigator according to the 
following rules and definitions. 
11.3.1. 
Relationship to Investigational Drug Product 
For each AE the Investigator determines whether there is a reasonable likelihood that the AE 
may have been caused by the study treatment according to the categories below: 
Unrelated: 
The event is clearly not related to the investigational drug 
product 
Possibly/Probably Related: 
The event could be related/is likely to be related to the 
investigational drug product 
Definitely Related: 
The event is clearly related to the investigational drug 
product 
Adverse events that the Investigator or Sponsor considers to be possibly/probably or definitely 
related to the investigational drug product will be considered adverse drug reactions. 
11.3.2. 
Relationship to Study Procedures 
For each AE the Investigator determines whether there is a reasonable possibility that the AE 
may have been caused by the study procedures according to the categories below: 
Unrelated: 
The event is clearly not related to study procedures 
Possibly/Probably Related: 
The event could be related/is likely to be related to study 
procedures 
Definitely Related: 
The event is clearly related to study procedures 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 68 of 83 
08 November 2017 
 
 
11.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected unexpected serious adverse reactions (SUSARs) will be handled by appropriate 
personnel at the Sponsor (or its designee) and reported within the required timelines in an 
unblinded fashion to regulatory authorities and IRB/IEC(s) per the requirements of the concerned 
competent bodies. SUSARs will be reported to study Investigators in a blinded fashion. 
11.4. 
Recording Adverse Events 
All AEs/SAEs experienced from the time of informed consent/assent to the last follow-up visit 
(i.e., 4 weeks after the last dose of investigational drug product for treated patients) will be 
recorded within each patient’s CRF. Information should include: a concise description of the 
event; date and time of event onset and resolution; determination of seriousness, severity, 
corrective treatment, outcome, and relationship to investigational product, study procedure and 
underlying disease; and any action taken are to 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, an AE is to be recorded as a diagnosis, rather than symptoms or isolated 
laboratory abnormalities related to that diagnosis. Thus, multiple symptoms or laboratory results 
that are related to the same diagnosis are to be considered 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 the AE, completion of the 
patient’s study participation, or study termination, whichever occurs first. Serious AEs will be 
followed until resolution or until the condition stabilizes or returns to baseline status or until no 
further follow up is expected. 
11.5. 
Reporting Serious Adverse Events 
It is the responsibility of the Investigator that reporting is done adequately. In order to meet 
regulatory reporting timelines, the study site is obligated to report any SAE(s) to the Sponsor or 
designee immediately and no later than 24 hours after receiving information of an event that 
meets at least one of the criteria for seriousness as defined in Section 11.2.2.  
11.6. 
Special Situations 
11.6.1. 
Overdose 
Currently, there is no basis for determining a clinically meaningful definition of overdose for 
SRP-4053. Therefore, as a preliminary criterion, any dose >10% above the assigned dose level 
will be considered an overdose. 
An overdose is not an AE. An overdose will be reported even if it does not result in an AE. An 
overdose will be recorded on the appropriate form and sent to the Sponsor or designee within 
24 hours.  


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 69 of 83 
08 November 2017 
 
 
11.6.2. 
Death 
Death is an outcome of an event. All causes of death are SAEs. In the event of death, every effort 
should be made to obtain a death certificate and if possible, an autopsy report. If the cause of 
death is unknown, death will be recorded as the event. 
11.6.3. 
Unblinding due to a Medical Emergency 
In the event of a medical emergency wherein the knowledge of the patient’s treatment 
assignment may influence clinical decision-making, the Investigator has the option to unblind 
treatment assignment (applicable to Part 1 only) through the IVR system.  
The reasons for unblinding must be noted in the source documentation. The Investigator must 
not disclose information about treatment assignment to anyone who does not need the 
information due to their direct involvement in patient care. Disposition of patients who become 
unblinded due to medical emergency will be determined following discussion with the Sponsor. 
11.6.4. 
Responsibilities of the Investigator 
The responsibilities of the Investigator and his or her staff include the following: 
• Monitor and record all AEs/SAEs 
• Determine seriousness, severity, and relationship to investigational drug product 
and/or study procedure and/or underlying disease 
• Determine 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 a queries regarding AEs and SAEs in a timely manner 
• Ensure source documentation for all AEs/SAEs are accurate and complete 
11.6.5. 
Responsibilities of the Sponsor 
The responsibilities of the study Sponsor (Sarepta Therapeutics) include the following: 
• Training of Investigator and site staff on AE definitions, safety assessments, and site 
obligations related to safety monitoring and reporting of AEs 
• Training with regard to the accurate and legal reporting of SAEs to all applicable 
regulatory bodies, IRB/IEC(s), clinical trial sites, and other parties as appropriate and 
required within the regulated timing 
• Recording of SAEs in the Safety Database 
• Notification of SUSARs to sites 
• Reporting of all SUSARs to regulatory authorities and IRB/IEC(s) according to 
regional requirements 


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• Annual safety reporting to regulatory authorities and IRB/IEC(s) according to 
regional requirements 
11.7. 
Pharmacokinetic Assessments 
11.7.1. 
Blood Sample Collection 
In Part 1 (Table 2), blood collection for PK determination will occur at the following time points 
on Weeks 1, 3, 5, and 7: immediately predose, at approximately 5 to 10 minutes after completion 
of dosing, and then at approximately 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours after completion of 
dosing. At Week 12, blood samples will be obtained pre-infusion and between 5 and 10 minutes 
postinfusion. 
In Part 2 (Table 3 and Table 4), blood samples for PK determination will be obtained from all 
treated patients pre-infusion and between 5 and 10 minutes postinfusion on Weeks 1, 24, 48, 96, 
and 144. 
11.7.2. 
Urine Sample Collection 
In Part 1 (only), urine for PK determination will be collected on a cumulative basis during the 
following time intervals: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 12 to 24 hours after the 
initiation of dosing.  


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1 AE within any particular dose level, for various incidence rates and sample sizes, and is 
applicable to Part 1 of the study. 
Sample size 
Incidence Rate 
0.02 
0.10 
0.30 
6 
0.11 
0.47 
0.88 
8 
0.15 
0.57 
0.94 
10 
0.18 
0.65 
0.97 
12 
0.22 
0.72 
0.99 
24 
0.38 
0.92 
1.00 
For example, if a rare event occurs 2% of the time, the probability that at least 1 patient 
experiences this event is 15% (in 8 patients) or 38% (in 24 patients) receiving SRP-4053. 
12.3. 
Analysis Sets 
Three analysis sets will be utilized with the definitions below applying to patients amenable to 
exon 53 skipping and patients in the untreated group (nonamenable to exon 53 skipping) as 
appropriate.  
Safety Set: For Part 1, the safety set will include all randomized patients who receive at least one 
dose of study drug. For Part 2, the safety set will include all randomized patients from Part 1 and 
all Part 2 patients who receive any amount of investigational drug product and all untreated 
patients who enrolled in Part 2. 
Efficacy Set: All randomized patients from Part 1 and all Part 2 patients who have at least one 
post baseline functional assessment. 
Pharmacokinetic Set: All randomized patients from Part 1 who receive the full dose of 
investigational drug product and for whom there are adequate PK samples from which to 
estimate PK parameters. 
12.4. 
Statistical Analysis 
12.4.1. 
Protocol Deviations 
A listing and summary of protocol deviations will be provided. This deviation listing will be 
based on the review of study data prior to locking the database and will include the nature of the 
deviation (e.g., inclusion/exclusion, prohibited therapies). 
12.4.2. 
Disposition, Demographics, and Baseline Characteristics 
Disposition will be summarized for Part 1 and Part 2. The number and percentage of patients 
completing or prematurely discontinuing the study will be summarized by treatment group. 
Reasons for premature discontinuation will also be summarized. 
Demographic and baseline characteristics such as age (years), height (cm), weight (kg), body 
mass index (kg/m2), and genotype of selected genes (Section 10.2.6.2) will be summarized by 
treatment group. Demographic data will be presented in data listings. 


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12.4.3. 
Prior and Concomitant Medications 
All prior and concomitant medications will be presented in data listings. 
12.4.4. Medical History 
Medical history will presented in data listings. 
12.4.5. Dosing 
The cumulative exposure to SRP-4053, total volume of drug administered (mL), the total number 
of infusions received, and the cumulative amount of drug received will be summarized by dose 
group for all treated patients. Dosing information will be provided in a data listing. 
12.5. 
Efficacy Analysis 
Efficacy endpoints are listed in Section 7.2.  
All efficacy endpoints will be summarized descriptively by time point and treatment group for 
both Part 1 and Part 2. Change from baseline for each endpoint will also be summarized by time 
point and treatment group, if applicable. 
The primary efficacy endpoint of change from baseline at Week 144 (Part 2) in the 6MWT will 
be summarized by treatment group.  
The secondary efficacy endpoints will be analyzed similarly to the primary endpoint, as 
appropriate, based on the type of endpoints and the number of assessments during Part 2 of this 
study. 
12.6. 
Pharmacodynamic Analysis 
The primary biological endpoint of change from baseline at Week 48 (Part 2) in dystrophin 
protein levels as determined by Western blot will be analyzed based on a 1-sample permutation 
test. 
The secondary biological endpoints will be analyzed similarly to the primary biological 
endpoint, as appropriate, based on the type of endpoints and the number of assessments during 
Part 2 of this study.  
12.7. 
Safety Analyses 
12.7.1. Safety Variables 
The safety and tolerability of SRP-4053 will be assessed beginning at the start of Part 1 through 
the end of Part 2 by the review of: 
• The type, frequency, severity, timing, and relationship to investigational drug product 
of AEs, SAEs, and discontinuations due to AEs. Adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be reported by 
primary system organ class (SOC) and preferred term (PT). 
• Adverse events will be classified as treatment-emergent (TEAE) and non-emergent. 
An AE will be considered treatment-emergent if it occurs in the time period starting 


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with the initiation of the first dose of study drug and ending 28 days after the last dose 
of study drug for treated patients and on or after the Week 1 visit of Part 2 for 
untreated patients.  
• Safety laboratory testing including hematology, coagulation, serum chemistry, and 
urinalysis  
• Vital signs 
• Physical examinations 
• 12-lead ECGs (through Week 144) 
• ECHOs (through Week 144) 
• Immunogenicity 
12.7.2. Safety Analysis 
Safety analyses will be descriptive in nature. 
In general, only TEAEs will be summarized. Nontreatment-emergent events will be recorded in 
the data listings. For all AE tables, the number and percentage of patients reporting AEs will be 
grouped using the MedDRA SOC and PT and summarized by treatment group and by dose level 
for the SRP-4053 group. In general, tables will have events categorized into all TEAEs and 
treatment-related TEAEs. 
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 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 
• TEAEs by severity 
• Treatment-related TEAEs 
• Treatment-related TEAEs by severity 
• SAEs 
In addition, all SAEs, regardless of their treatment-emergent status will be summarized by SOC 
and PT.  
The following listings will be produced: 
• Nontreatment-emergent AEs 
• All TEAEs 
• AEs leading to discontinuation  
• SAEs 


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Descriptive statistics for ECGs, ECHOs, vital signs, physical examinations, and safety laboratory 
parameters will be generated. All safety data will be presented in the data listings. Additionally, 
shift and frequency tables of predefined change in abnormal values for select safety parameters 
will be generated. 
Descriptive statistics for the anti-PMO immune response will be generated. The relationship 
between anti-PMO antibodies and clinical safety parameters may be assessed. If an 
anti-dystrophin antibody assay or other immunogenicity assays become available during the 
study, the analysis for these endpoints will be detailed in the SAP. 
12.8. 
Pharmacokinetic Analyses 
The PK of SRP-4053 will be determined from multiple plasma and urine samples collected 
serially following the first weekly doses of the dose-titration phase on Weeks 1, 3, 5, and 7 of 
Part 1 and from plasma samples collected at Weeks 1, 24, 48, 96, and 144 in Part 2. Individual 
plasma levels of SRP-4053 will be listed with the corresponding time related to investigational 
drug product administration and summary statistics will be generated by per-protocol time of 
collection. Pharmacokinetic parameters for SRP-4053 will be calculated using 
noncompartmental analysis for Part 1 and using population PK analysis in Part 2. It may be 
necessary to combine the data from Parts 1 and 2 to adequately perform the population PK 
analysis. Data collected on Week 12 in Part 1 will be included in the population PK analysis but 
not used for the noncompartmental analysis. Actual sampling times will be used in all final PK 
analyses. Per-protocol times will be used to calculate mean plasma concentrations for graphical 
displays. The PK parameters that will be determined include: 
• Cmax 
• tmax 
• AUC 
• Vss 
• t½ 
• CL 
• MRT 
• CLR, Part 1 only 
Pharmacokinetic data from Part 2 will be analyzed based on a population PK model using 
plasma concentration data and appropriate demographic and baseline characteristics. 


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13. 
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT 
13.1. 
Recording of Data 
Clinical data for this study will be captured using an electronic data capture (EDC) system which 
will be set up and maintained by a contract research organization. The Investigator or personnel 
delegated by the Investigator will perform primary data collection/perform assessments based on 
the protocol design and capture source documentation. All required study information must be 
entered into the EDC system on the appropriate CRF screens according to the CRF Completion 
Guidelines for the study. A CRF must be completed for each patient that is enrolled. The study 
monitor will conduct 100% source data verification to ensure maximum data integrity. All data 
must be carefully entered in a timely fashion to permit meaningful interpretation and study 
oversight. 
13.2. 
Quality Assurance 
The CRFs will be reviewed by a clinical monitor from the Sponsor or a representative of the 
Sponsor 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 issues. Requests for data clarification or correction will be documented as electronic 
queries within the CRF for the Investigator or study coordinator to resolve. All changes to the 
CRFs will be tracked in an electronic audit trail. Site Study Files will be reviewed for 
compliance. 
Audits may be carried out by the Sponsor’s representatives, and inspections may be performed 
by regulatory authorities and/or IRB/IEC(s) before, during, or after the study. The Investigator 
will allow and assist the Sponsor’s representatives and any regulatory agency to have direct 
access to all study records, CRFs, patient medical records and other source documentation, 
investigational product dispensing records and investigational product 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.  
13.3. 
Retention of Study Documents 
At study completion, all CRF data including queries and audit trail for an individual site will be 
generated and copied onto a CD-ROM 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 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and regulatory authorities are 
notified. 
These documents will be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. No study documents will be 
destroyed or moved to a new location without prior written approval from the Sponsor. If the 


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Investigator relocates, retires, or withdraws from the clinical study for any reason, all records 
that are required to be maintained for the study will be transferred to an agreed-upon designee. 
Patient records or other source data must be kept for the maximum period of time mandated by 
the hospital, institution, or private practice, but not less than 15 years. 
If off-site archiving is used, all records will be retrieved and made available for review at the 
time of an audit or regulatory authority inspection. 
13.4. 
Termination of Study or Study Site 
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 must be 
halted or that the study center should be terminated, appropriate action must be taken after 
consultation among (at a minimum) the Sponsor, the Investigator, IRB/IEC and the Medical 
Monitor (Section 8.3). The Sponsor may terminate the study at any time. 
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 
• Failure of the Investigator to comply with pertinent regulations of the 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  
Study termination and follow up will be performed in compliance with the conditions set forth in 
International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) as well as 
21 CFR 312.56b and the European Clinical Trial Directive 2001/20/EC which require a Sponsor 
to ensure an Investigator’s compliance with these requirements and to promptly secure a plan for 
compliance or discontinue shipments of the investigational drug product to the Investigator and 
end the Investigator's participation in the investigation. 


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14. 
SPECIAL REQUIREMENTS AND PROCEDURES 
14.1. 
Compliance with Ethical and Regulatory Guidelines 
This study was designed and will be conducted in accordance with the ethical principles that 
have their origins in the Declaration of Helsinki and in conformance with ICH and GCP E6 
guidance documents. This study will comply with the requirements that are enunciated in the 
European Clinical Trial Directive 2001/20/EC and in the United States (US) Code of Federal 
Regulations (CFR). 
14.2. 
Regulatory and Independent Ethics Committee Review 
This study will be conducted in full compliance with the European Clinical Trial Directive 
2001/20/EC and/or 21 CFR 56. Before enrollment of patients into the study, the protocol and 
documents for informed assent (for patients) and informed consent (for parents/legal guardians) 
will be reviewed and approved by the appropriate IRB/IEC and regulatory authority. 
Amendments to the protocol will be presented to the same IRB/IEC and regulatory authority as 
the original protocol. The Investigator will promptly notify the Sponsor of any SAEs or of any 
other information that might affect the safe use of the investigational drug product during the 
study. IRB/IEC positive opinion and regulatory authority approval 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 will be retained in the study 
regulatory files. 
14.3. 
Informed Consent/Assent 
Written informed consent from each patient’s parent(s) or legal guardian(s) and written assent 
from each patient for whom it is applicable must be obtained before any study-specific Screening 
or Baseline period evaluations are performed. One copy of the signed informed consent/assent 
documents will be given to the patient; the Investigator will retain the original copies of these 
documents.  
The informed consent/assent documents, as prepared by the Sponsor or designee, must be 
reviewed and approved by the IRB/IEC and regulatory authorities, as applicable, before initiation 
of the study. The informed consent document must contain the basic required elements of 
consent and additional elements, as applicable, as specified in the European Clinical Trial 
Directive 2001/20/EC and/or 21 CFR 50.25.  
14.4. 
Compliance with the Protocol 
All processes and procedures defined in this protocol will be adhered to. Emergency departures 
from the protocol that eliminate an apparent immediate hazard to a particular patient and that are 
deemed by the Investigator as crucial for the safety and well-being 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 


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


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15. 
STUDY DOCUMENTATION AND GENERAL INFORMATION 
15.1. 
Essential Study Documents 
The following documentation will be collected prior to study enrollment: 
• Regulatory authority and IRB/IEC approval for all study materials (informed consent 
form, Protocol, any recruitment materials, etc.) 
• Clinical laboratory normal ranges, when appropriate 
• Signed Final Protocol page  
• Investigator’s Brochure review and acknowledgement 
• A blank copy of the IRB/IEC-approved informed consent and assent documents and 
authorization 
• A fully executed Clinical Trial Agreement and Confidentiality Agreement 
• Signed Financial Disclosure Forms  
These documents are among the critical documents required before study enrollment is to occur. 
Copies of these documents, as well as supplemental information, such as the Investigator’s 
Brochure, Pharmacy Manual, CRF Completion Guidelines, final protocol, as specified in the 
relevant study manuals and/or Regulatory Binder must be kept on-site in a designated study site 
file.  
The study files will also contain, patient accountability records, drug accountability 
(receipt/dispensing) records, Sponsor/Investigator correspondence, regulatory authority and 
IRB/IEC correspondence, deviations, biological sample records, and SAE and 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 relevant study manuals, Pharmacy Manual, Laboratory Manual, CRF 
Completion Guidelines, and all other study-specific information that is provided during the study 
initiation visit or by the study monitor. 
15.3. 
Dissemination of Study Results 
The information that is developed during the conduct of this clinical study is considered to be 
strictly confidential. This information may be disclosed only as deemed necessary by Sarepta 
Therapeutics Inc. However, at the conclusion of this clinical study, a CSR will be prepared. In 
addition, a manuscript will be prepared for publication in a reputable scientific journal under the 
direction of Sarepta Therapeutics Inc. The Sponsor (Sarepta Therapeutics) and the Investigators 
intend to publish and communicate the clinical study results, irrespective of positive or negative 
findings. Data generated for this study will be exclusively owned by Sarepta Therapeutics Inc., 
as detailed in the Clinical Trial Agreement. The study will be registered on clinicaltrials.gov, on 
clinicaltrialregister.eu, and on any national registry, as appropriate. After completion of the 
study, results will be disseminated through these registries. 


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15.4. 
Product Handling and Complaints Reporting 
If there are any issues during the course of the study related to the quality of the investigational 
product, the Investigator, clinical site pharmacist or pharmacy designee must contact the Sponsor 
or designated contract research organization (CRO). 


Sarepta Therapeutics, Inc. 
Protocol 4053-101 (Amendment 8) 
 
Page 82 of 83 
08 November 2017 
 
 
16. 
LIST OF REFERENCES 
American Academy of Orthopedic Surgeons (AAOS). Pediatric Outcomes Questionnaire. 
Pediatric Orthopaedic Society of North America, American Academy of Pediatrics, Shriner’s 
Hospitals, eds. Version 2.0, August 2005. Available from: 
http://www.aaos.org/uploadedFiles/PreProduction/Quality/About_Quality/outcomes/Pediatric.pd
f. Accessed March 2016. 
Amor CJ, Spaeth MC, Chafey DH, Gogola GR. Use of the Pediatric Outcomes Data Collection 
Instrument to evaluate functional outcomes in arthrogryposis. J Pediatr Orthop. 
2011;31(3):293-6. 
Aartsma-Rus A, Fokkema I, Verschuuren J, et al. Theoretic applicability of antisense-mediated 
exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009;30(3):293-9. 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. 
ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 
2002;166(1):111-7. 
Beenakker EA, Fock JM, Van Tol MJ, et al. Intermittent prednisone therapy in Duchenne 
muscular dystrophy: a randomized controlled trial. Arch Neurol. 2005;62(1):128-32. 
Biggar WD, Harris VA, Eliasoph L, et al. Long-term benefits of deflazacort treatment for boys 
with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord. 
2006;16(4):249-55. 
Brooke MH, Fenichel GM, Griggs RC, et al. Duchenne muscular dystrophy: patterns of clinical 
progression and effects of supportive therapy. Neurology. 1989;39(4):475-81. 
Bushby KM, Gardner-Medwin D. The clinical, genetic and dystrophin characteristics of Becker 
muscular dystrophy. I. Natural history. J Neurol. 1993;240(2):98-104. 
Centers for Disease Control, Prevention. Prevalence of Duchenne/Becker muscular dystrophy 
among males aged 5-24 years - four states, 2007. MMWR Morb Mortal Wkly Rep. 
2009;58(40):1119-22. 
Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in 
patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino 
oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 
2011;378(9791):595-605. 
Eagle M, Baudouin SV, Chandler C, et al. Survival in Duchenne muscular dystrophy: 
improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. 
Neuromuscul Disord. 2002;12(10):926-9. 
Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. 
Neuromuscul Disord. 1991;1(1):19-29. 
Flanigan KM, Ceco E, Lamar KM, et al. LTBP4 genotype predicts age of ambulatory loss in 
Duchenne muscular dystrophy. Ann Neurol. 2013;73(4):481-8. 
Gauld LM, Kappers J, Carlin JB, et al. Height prediction from ulna length. Dev Med Child 
Neurol. 2004;46(7):475-80. 


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SAP_001.pdf: 
Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 1 of 36 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol 4053-101 
 
A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-
Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) 
Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of 
SRP-4053 in Patients with Duchenne Muscular Dystrophy Amenable to 
Exon 53 Skipping 
 
SPONSOR: 
Sarepta Therapeutics, Inc. 
215 First Street  
Cambridge, MA 02142 USA 
Phone:  +1-617-274-4000 
 
 
 
 
 
 
 
VERSION:  Final 1.0 
 
PROTOCOL VERSION:  8 (08 November 2017) 
 
 
 
DATE:         30 May 2018 
 
 
 


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD
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Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 7 of 36 
2. 
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 4053-101, titled “A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-
Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an 
Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients with 
Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping”. 
 
This SAP has been prepared based on Protocol Amendment 8, dated 08 November 2017.   
 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 9 of 36 
4. 
STUDY DESCRIPTION 
4.1. 
Study Overview 
This is a first-in-human, multicenter, multiple-dose study to assess the safety, tolerability, 
efficacy, and PK of once-weekly IV infusions of golodirsen in patients with 
genotypically confirmed Duchenne muscular dystrophy (DMD) with an eligible deletion 
amenable to exon 53 skipping (eg, 42-52, 45-52, 47-52, 48-52, 49-52, 50-52; 52; 54-58). 
This study will be conducted in 2 parts. 
Part 1 is a randomized, double-blind, placebo-controlled, dose-titration evaluation to 
assess the safety, tolerability, and PK of 4 dose levels of golodirsen in 12 patients with 
DMD over approximately 12 weeks. 
Part 2 is a long-term, 168-week, open-label evaluation to assess the efficacy and safety of 
the selected dose level of golodirsen (determined in Part 1) with untreated patients 
participating in scheduled assessments for 144 weeks. All 12 treated patients from Part 1 
will continue in Part 2. Part 2 will also enroll 12 new patients for open-label treatment 
with golodirsen. These patients must have a clinical diagnosis of DMD confirmed by the 
finding of a genomic deletion amenable to exon 53 skipping. In addition, up to 24 
patients, who will not receive treatment, will be enrolled in Part 2 to serve as an untreated 
group. The patients in the untreated group will be DMD patients with a genetically 
confirmed deletion of exon(s) not amenable to treatment by exon 53 skipping, but who 
otherwise meet the same eligibility criteria as treated patients newly recruited to Part 2. 
Patients in the untreated group will discontinue the Treatment Phase at Week 144. 
Part 1 will be approximately 12 weeks in duration. Part 2 will last approximately up to 
168 weeks. 
4.2. 
Part 1 (Randomized Double-Blind Dose Titration) 
DMD patients will participate in a 4- to 6-week Screening period to ensure eligibility, 
prior to randomization to golodirsen or placebo. Twelve patients will be randomized (2:1) 
to receive golodirsen (n = 8) or placebo (n = 4). Patients will receive a weekly IV 
infusion of placebo or golodirsen at escalating dose levels, each for at least 2 weeks: 
4 mg/kg/week in Weeks 1 to 2; 10 mg/kg/week in Weeks 3 to 4; 20 mg/kg/week in 
Weeks 5 to 6; and 30 mg/kg/week beginning at Week 7. Demographic data, baseline 
assessments and disease characteristics, and muscle biopsy will be collected before 
randomization.  Patients will undergo scheduled assessments as well as routine safety 
evaluations over the course of Part 1. 
 
Figure 1  is a schematic of the study design for Part 1. 
 
 
 
 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 10 of 36 
Figure 1: 
Study Schematic for Part 1, Randomized, Double-blind Dose Titration 
 
 
4.3. 
Part 2 (Open Label and Untreated Patient Group) 
All 12 DMD patients (both golodirsen and placebo) from Part 1 will rollover to Part 2 
and begin open-label treatment with golodirsen at 30 mg/kg/week (or the highest 
tolerated dose determined in Part 1) on Week 1 of Part 2. In addition, 12 new treatment-
naïve DMD patients with mutations amenable to exon 53 skipping will be enrolled for 
open-label treatment, along with up to 24 untreated DMD patients with deletion 
mutations not amenable to exon 53 skipping, who will participate through Week 144. All 
new Part 2 patients will be evaluated within a 4- to 6-week Screening period to confirm 
eligibility.  
Demographic data, baseline assessments and disease characteristics, and muscle biopsy 
samples (for patients amenable to exon 53 skipping only) of newly enrolled patients in 
Part 2 will be collected during the screening period. Patients will undergo scheduled 
assessments as well as routine safety evaluations over the course of Part 2; however, 
untreated patients will undergo the required assessments at a reduced schedule until 
Week 144. 
In Part 2, all treated patients will receive golodirsen at 30 mg/kg weekly (or the highest 
tolerated dose determined in Part 1) for up to 168 weeks. Untreated patients will 
discontinue the Treatment Phase (period) at Week 144. All treated patients in Part 2 will 
be required to undergo a second muscle biopsy at Week 48 of Part 2. Biopsies at 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 11 of 36 
Week 48 must occur:  a) within 2 weeks after the Week 48 visit, b) after the clinical 
evaluation for Week 48, and c) at least 48 hours after the most recent infusion. Figure 2  
is a schematic of the study design for Part 2. 
Figure 2: 
Study Schematic for Part 2, Open-Label and Untreated Patient Group 
 
4.4. 
Sample Size and Power 
Sample size for this study is based upon qualitative considerations; no formal sample size 
calculations will be performed. The anticipated sample size is approximately up to 48 
total patients, including 12 patients (8 golodirsen and 4 placebo) in Part 1 and up to 48 
(24 treated patients [12 from Part 1 and 12 new patients] and up to 24 untreated patients) 
in Part 2. 
4.5. 
Randomization and Blinding 
4.5.1. 
Randomization of Treatments 
After qualifying for study entry in Part 1, DMD patients with an out-of-frame deletion 
confirmed as amenable to exon 53 skipping will be randomized using a 2:1 ratio to either 
golodirsen (8 patients) or placebo (4 patients). Randomization will be performed prior to 
dosing on Week 1 using an interactive voice response (IVR) system. 
There will be no randomization in Part 2 of the study. 
4.5.2. 
Blinding of Treatment in Part 1 
Part 1 is a double-blind, placebo-controlled dose titration where all patients, parents, 
Investigators, and all site staff not involved with study drug preparation will be blinded to 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 12 of 36 
treatment assignment. The double-blind, placebo-control design is intended to reduce 
potential bias during data collection and evaluation of clinical (safety) parameters. 
In Part 2, all treated patients (rollover patients from Part 1 and patients new to Part 2 who 
are amenable to exon 53 skipping) will receive open-label golodirsen (at the dose 
determined in Part 1) as weekly IV infusions. No blinding is required. 
4.6. 
Study Endpoints and Other Variables 
The study endpoints for which the statistical methods will be described in this SAP 
comprise all safety, muscle biopsy-based endpoints, and efficacy endpoints.   
4.6.1. 
Safety Endpoints 
The safety and tolerability of a golodirsen dosed at 4, 10, 20, and 30 mg/kg/week for at 
least 2 weeks per dose will be assessed through a review and evaluation of the following: 
• incidence of Treatment-emergent Adverse Events (TEAEs) 
• incidence of Treatment-emergent Serious adverse events (SAEs) 
• incidence of clinical laboratory abnormalities (hematology, chemistry, 
coagulation, urinalysis) 
• incidence of abnormalities in vital signs and physical examinations 
• incidence of abnormalities on electrocardiograms (ECGs) and 
echocardiograms/echocardiography (ECHOs) 
4.6.2. 
Pharmacokinetic Endpoints 
The following PK parameters will be determined for both Parts 1 and 2, as appropriate: 
• maximum plasma concentration (Cmax) 
• time to maximum plasma concentration (tmax) 
• area under the plasma concentration-curve (AUC) 
• apparent volume of distribution at steady state (Vss) 
• elimination half-life (t½) 
• total clearance (CL) 
• mean residence time (MRT) 
• urinary clearance (CLR), for Part 1 only 
4.6.3. 
Muscle Biopsy Biological Endpoints (Part 2 Only) 
The following biological endpoints will be derived from muscle biopsy samples:  
• change from Baseline at Week 48 in dystrophin protein levels determined by 
Western blot. 
• change from Baseline at Week 48 for the following: 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 15 of 36 
5. 
GENERAL STATISTICAL METHODS AND 
CONVENTIONS 
5.1. 
General Methods 
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 a treatment group will be used as the 
denominator for percentage calculations, unless stated otherwise. 
For time-to-event data with censoring, the Kaplan-Meier method will be used to 
summarize the data if appropriate.  
Unless stated otherwise, summaries of all endpoints will be by treatment group (see 
below for definitions of treatment groups) for 2 "Analysis Parts" (Part 1, and Combined 
Parts 1 and 2): 
Part 1: Patients in Part 1 include all patients who entered Part 1 of the study and who 
received either golodirsen or placebo. Data will include all assessments and events that 
occurred prior to the Part 2, Week 1 dose of 30 mg/kg of golodirsen. The analyses for 
Part 1 will be primarily for safety. 
Part 1 analysis treatment groups are: 
• patients who received golodirsen at 30 mg/kg during Weeks 7 to 12 (+ Part 1 
unscheduled dosing) 
• patients who received golodirsen at <=20 mg/kg during Weeks 1 to 6 
• patients who received golodirsen at any dose level during Weeks 1 to 12 (+ Part1 
unscheduled dosing) 
• patients who receive placebo in Part 1 
Combined Parts 1 and 2:  Patients in Combined Parts 1 and 2 include all patients who 
entered in Part 1 or Part 2. Assessments and events that occurred in Part 1 for patients 
who were on placebo during Part 1 will be excluded. Assessments and events that 
occurred in Part 1 for patients who received golodirsen will be included. Combined 
Parts 1 and 2 Analysis treatment groups will be for both efficacy and safety data analyses. 
 Combined Parts 1 and 2 Analysis treatment groups are: 
• all golodirsen treated patients: Patients who receive golodirsen in any part of the 
study 
• Group 1: Patients who receive placebo in Part 1 followed by golodirsen in Part 2, 
or patients who enter Part 2 and receive golodirsen 
• Group 2: Patients who receive golodirsen in Part 1 and continue golodirsen in 
Part  2 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 17 of 36 
• For a partial or missing adverse event (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 treatment (golodirsen or placebo, as appropriate) and within 28 
days of the last dose of treatment for treated patients, or if the month and/or year 
of the onset date are on or after the date of the qualifying visit for untreated 
patients.  
• 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. 
5.2.4. 
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. 
Analysis Sets 
Three analysis sets will be utilized with the definitions below applying to patients 
amenable to exon 53 skipping and patients in the untreated group (nonamenable to exon 
53 skipping), as appropriate. 
Safety Set: For Part 1, the safety set will include all randomized patients who receive at 
least 1 dose of study drug. For Part 2, the safety set will include all randomized patients 
from Part 1 and all Part 2 patients amenable to exon 53 skipping who receive any amount 
of investigational drug product, and all untreated patients who enter Part 2. 
Efficacy Set: All randomized patients from Part 1 and all Part 2 patients who have at 
least 1 postbaseline functional assessment. 
Pharmacokinetic Set: All randomized patients from Part 1 who receive the planned full 
dose of investigational drug product and for whom there are adequate PK samples from 
which to estimate PK parameters. The PK Set will be further described in a separate PK 
SAP. 
5.4. 
Multiple Testing and Comparisons 
No adjustment will be made for the testing of multiple endpoints. 
5.5. 
Adjustment for Covariates 
Not applicable.  
5.6. 
Subgroups 
Due to small sample size, no subgroup will be identified for this study. 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 18 of 36 
5.7. 
Presentation Over Time 
For endpoints that are collected serially over time (eg, 6MWT distance, clinical 
laboratory tests), assessments/test values will be assigned to a specific timepoint (eg, 
study week) based upon the eCRF page on which the assessments/test values were 
reported. However, if a patient discontinues from the study early, then the end-of-study 
(EOS) visit will be assigned to the nearest scheduled visit based on the duration on study 
provided that the EOS visit is within ±2 weeks (14 days) of that scheduled visit. 
Only for an efficacy endpoint, an unscheduled assessment may be used in the summary 
by timepoint if the unscheduled assessment was within 2 weeks of a missing scheduled 
assessment. Summaries of efficacy endpoints will include Part 2 visits and results will be 
summarized by the nominal visit from Part 2. 
For safety endpoints, unscheduled assessments will not be included in the summary by 
timepoint. 
5.8. 
Algorithm, Computation and Definition of Derived Variables 
Day 1 
Day 1 will be defined as the date of the first study drug (golodirsen or placebo) 
administration for golodirsen or placebo-treated patients, or the date immediately after 
the latest day of the Baseline Visit (ie, Baseline, Day 2) for untreated patients.   
Golodirsen Day 1 
Golodirsen Day 1 will be defined as the day of the first golodirsen drug administration. 
Untreated patients will not have a Golodirsen Day 1.   
Study Day 
Study day will be defined as Event Date - Day 1 + 1, if the Event Date is on or after Day 
1; otherwise, as Event Date - Day 1, if the Event Date precedes Day 1. 
Golodirsen Study Day 
Golodirsen study day will be defined as Event Date - Golodirsen Day 1 + 1 if the Event 
Date is on or after Golodirsen Day 1; otherwise, as Event Date - Golodirsen Day 1, if the 
Event Date precedes Golodirsen Day 1.  Untreated patients will not have a Golodirsen 
Study Day. 
Duration of Study 
Duration of 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. 
Duration of Treatment 
Duration of golodirsen treatment will be calculated as the duration in weeks from the date 
of first dose of golodirsen to the date of the last golodirsen administration as recorded on 
the STUDY DRUG ADMINISTRATION eCRF plus 6 days, (ie, last dose date - first 
dose date + 1 + 6)/7. Similarly, duration of golodirsen treatment at dose <=20mg/kg will 


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Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 23 of 36 
will be presented.  For example, a date with a missing month and day will be 
presented as UNUNKYYYY.   
• SAS Version 9.4 or higher will be the statistical software package used for all 
analyses, unless otherwise specified.   
• R version 3.2.2 or higher and DAAG package 1.22 or higher will be used for 
1-sample permutation test. 
• The Clinical Data Interchange Standards Consortium (CDISC) Analysis Data 
Model (ADaM) Implementation Guide (ADaMIG) V1.0 for preparing data sets 
will be used for this study. 
• The CDISC Study Data Tabulation Model Implementation Guide (SDTMIG) 
V3.2 will be used 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 treatment sequence, patient, and date, unless otherwise 
specified. 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 24 of 36 
6. 
STATISTICAL ANALYSES 
6.1. 
Patient Disposition 
Patient disposition will be summarized for Combined Parts 1 and 2 for the 4 analysis 
treatment groups described in Section 5.1 for all patients enrolled, and will include the 
frequency count and percentage for the following categories:  patients who enrolled into 
the study, patients randomized in Part 1, patients who entered study in Part 2, patients 
who completed the study, patients who are ongoing in the study (if applicable), and 
patients who discontinued early. The reasons for discontinuation will also be 
summarized. Descriptive statistics will be presented for duration of study (weeks). 
Patient disposition and patient eligibility (including inclusion/exclusion criteria) will be 
presented in data listings. 
6.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by Analysis Part and 
treatment groups described in Section 5.1 for the Safety Analysis Set. These variables 
will include age (years), race, ethnicity, Baseline height (cm), Baseline weight (kg), 
Baseline body mass index (BMI; kg/m2), time since DMD diagnosis (months) to 
Baseline, corticosteroid type (Deflazacort or Prednisone), corticosteroid frequency 
(continuous versus intermittent), mutation type(s), duration of prior corticosteroid 
treatment (months) to Day 1, and Baseline 6MWT distance (m).  Additional baseline 
variables may be included.  
Patient-level demographic data and baseline characteristics will be presented in a data 
listing.  
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, 01DEC2013). The number 
and percentage of subjects in the safety population taking concomitant medications will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug preferred term by Analysis Part and treatment groups described 
in Section 5.1 . At each level of summarization, a patient is counted once if he/she 
reported 1 or more medications at that level. 
All medications, whether prior or concomitant, will be presented in data listings. Separate 
listings of glucocorticoids and prior experimental DMD drugs will be provided. 
6.4. 
Medical History  
Medical history data for the safety set will be presented in data listings. 
6.4.1. 
Physiotherapeutic Interventions 
A listing of all physiotherapeutic interventions will be provided. 


Sarepta Therapeutics, Inc. 
Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 25 of 36 
6.5. 
Protocol Deviations 
A listing of major protocol deviations will be provided. The major 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 (eg, inclusion/exclusion, prohibited therapies). 
6.6. 
Exposure to Study Drug 
The exposure to golodirsen and placebo will be summarized by Analysis Part and 
treatment groups described in Section 4.1 for the Safety Analysis Set. The variables will 
include the following (as applicable): cumulative exposure administered (mg), number of 
infusions of treatment, number of infusions of golodirsen at 30 mg/kg, and duration on 
golodirsen or placebo (weeks). Additionally, for the summary of Combined Parts 1 and 2 
exposure, duration on golodirsen category will be summarized for the following intervals: 
< 24 Weeks, 24 to < 48 Weeks, 48 to < 72 Weeks, 72 to < 96 Weeks, and ≥ 96 Weeks. 
Patient-level dosing information will be provided in a data listing. 
6.7. 
Safety Analyses  
Safety analyses byAnalysis Part and treatment groups described in Section 5.1  (both Part 
1 and combined Part 1 and Part 2 treatment groups) will include summaries of the 
following:  
• the type, frequency, severity, timing, and relationship to the investigational drug 
product of AEs, SAEs, and discontinuations due to AEs. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA 17.1 or 
higher) and will be reported by primary system organ class (SOC) and preferred 
term (PT). 
• safety laboratory testing including hematology, coagulation, serum chemistry, and 
urinalysis  
• vital signs  
• physical examinations  
• 12-lead ECGs (through Week 144)  
• ECHOs (through Week 144)  
6.7.1. 
Adverse Events 
In general, only TEAEs will be summarized. Nontreatment-emergent events will be 
recorded in the data listings. For all AE tables, the number and percentage of patients 
reporting AEs will be grouped using the MedDRA SOC and PT and summarized by 
Analysis Part, the treatment group as described in Section 5.1, and by dose level for the 
Part 1 summary. 
• an overall summary table of AEs will be produced and will include the 
frequency and percentage of patients with TEAE 
• treatment-related TEAE 


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• severe TEAE 
• SAE 
• treatment-related SAE 
• AE leading to discontinuation of study drug 
• the number of events at each severity level (mild, moderate, or severe) 
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 a different relationship/severity, the event with the strongest 
relationship or maximum severity to the 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 PT 
• treatment-related TEAEs by SOC and PT 
• treatment-related TEAEs by SOC, PT, and severity 
• treatment-related TEAEs by PT 
• treatment-emergent SAEs 
• treatment-related, treatment-emergent SAEs 
In addition, all SAEs, regardless of their treatment-emergent status will be summarized 
by SOC and preferred term PT. 
The following listings will be produced: 
• nontreatment-emergent AEs 
• all TEAEs 
• AEs leading to discontinuation 
• SAEs 
6.7.2. 
Deaths 
A summary of deaths and reasons for deaths will be presented by Analysis Part and 
treatment group. A patient-level listing will be provided.  
 
6.7.3. 
Adverse Events of Special Interest 
Summaries of TEAEs of special interest will be summarized by SOC and PT for each 
Analysis Part and treatment group as defined in Section 5.1 and by dose level for the 
Part 1 summary. All standard MedDRA queries ([SMQs] based on MedDRA 


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Statistical Analysis Plan  
Final Version 1.0  
 
Page 27 of 36 
Version 17.1) listed below will include broad and narrow terms. The AEs of special 
interest (AESI) are: 
• 
infusion-related reaction (AEs occurring within 24 hours of the start of any 
infusion [including events occurring on the same date as an infusion where 
infusion start time or AE onset time was not reported]) 
• 
hypersensitivity (hypersensitivity SMQ)  
• 
infusion site reaction (extravasation events SMQ and the following PTs: 
application site erythema, application site rash, catheter site hematoma, catheter 
site hemorrhage, catheter site-related reaction, infusion site rash, infusion site 
swelling)  
• 
renal toxicity (acute renal failure SMQ) 
• 
leukopenia and neutropenia (hematopoietic leukopenia SMQ) 
• 
severe cutaneous adverse reactions (severe cutaneous adverse reactions SMQ) 
• 
drug-induced hepatotoxicities (cholestasis and jaundice of hepatic origin SMQ, 
hepatic failure, fibrosis, cirrhosis and other liver damage-related conditions SMQ, 
hepatitis, noninfectious SMQ, liver neoplasms, benign [including cysts and 
polyps] SMQ, liver malignant tumors SMQ, liver tumors of unspecified 
malignancy SMQ, liver-related investigations, signs and symptoms SMQ, liver-
related coagulation and bleeding disturbances SMQ) 
• 
cardiac events (cardiomyopathy SMQ, cardiac failure SMQ, and arrhythmia-
related investigations, sign and symptoms SMQ) 
• 
coagulopathy (hemorrhage terms [excluding lab terms] SMQ, hematopoietic 
thrombocytopenia SMQ, PTs in the embolism and thrombosis High Level Group 
Terms [HLGT]) 
An overall summary of AESI events will include total number of events, number of 
serious events, number of related events, number of not related events, number of mild 
events, number of moderate events, number of severe events, and number of events 
occurring on the same day as an infusion. 
6.7.4. 
Clinical Laboratory Evaluation 
A shift table will present the number and percentage of patients in each cell resulting 
from cross-tabulating the status (low, normal, and high) of the highest/lowest 
postbaseline value versus that of the baseline for each laboratory test, if applicable, by 
Analysis Part and treatment group as defined in Section 5.1 . If a specific test can have 
both a significant low and high, then a shift table will be generated for each direction. 
The percentage will be based on the total number of patients in the Safety Set. A status of 
missing may be added, if necessary. This analysis will be repeated for last postbaseline 
result. For golodirsen treated patients, only results that occurred within 28 days of the last 
dose of golodirsen will be included. 
Only the highest value will be summarized for alanine aminotransferase (ALT), alkaline 
phosphatase, amylase, aspartate aminotransferase (AST), cholesterol, C-reactive protein, 


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Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 28 of 36 
creatine kinase, creatinine, cystatin C, gamma glutamyl transferase (GGT), lactate 
dehydrogenase (LDH), total bilirubin, triglycerides, uric acid, absolute basophils, 
absolute eosinophils, basophil percent, eosinophil percent, activated partial 
thromboplastin time, international normalized ratio, prothrombin time, and urine KIM-1, 
and urine protein.  Only the lowest value will be summarized for albumin, creatinine 
clearance, and platelets. Both the highest and lowest values will be summarized for 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, glucose, potassium, protein, 
sodium, absolute lymphocytes, absolute monocytes, absolute neutrophils, hematocrit, 
hemoglobin, lymphocyte percent, monocyte percent, neutrophils percent, white blood cell 
(WBC) count, and urine pH and specific gravity. 
The frequency and percentage of patients meeting the potentially clinically significant 
abnormality criteria (defined in Appendix Table 1, Appendix Table 2, Appendix Table 3) 
at any time point postbaseline will be summarized by Analysis Part and treatment group. 
Additionally, the total number of potentially clinically significant abnormalities will be 
summarized.  
Baseline value, most extreme and last observation and the corresponding change from 
Baseline will be summarized by Analysis Part and treatment group. 
All patient-level clinical laboratory values will be displayed in data listings.  In addition, 
values meeting the potentially clinically significant abnormalities criteria will be 
presented in data listings.  Treatment-emergent abnormalities will be indicated in the 
listing.  
6.7.5. 
Vital Signs and Other Physical Findings 
The frequency and percentage of patients meeting any of the potentially clinically 
significant abnormality criteria (defined in Appendix Table 4) at any time point 
postbaseline will be summarized by Analysis Part and treatment group as defined in 
Section 5.1 . Additionally, the total number of potentially clinically significant 
abnormalities will be summarized.  
Baseline value, most extreme and last observation and the corresponding change from 
Baseline will be summarized by Analysis Part and treatment group. Most extreme value 
is considered as the largest absolute change from Baseline for systolic blood pressure, 
diastolic blood pressure, and respiratory rate, and highest value for pulse and 
temperature. Most extreme value will not be summarized for height, weight, BMI, ulnar 
length, or calculated height. For golodirsen treated patients, only results that occurred 
within 28 days of the last dose of golodirsen will be included. 
Vital signs will be listed for all patients.  In addition, values meeting the predefined 
markedly abnormal criteria will be presented in a data listing.  Treatment-emergent 
abnormalities will be indicated. Height and weight will also be listed. 
6.7.6. 
Electrocardiograms and Echocardiogram 
The frequency and percentage of patients with values meeting the potentially clinically 
significant abnormality criteria (defined in Appendix Table 5) at any time point will be 
summarized by Analysis Part and treatment group as defined in Section 5.1 for both 


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Protocol 4053-101  
Statistical Analysis Plan  
Final Version 1.0  
 
Page 29 of 36 
ECGs and ECHOs. The number of potentially clinically significant abnormalities will 
also be presented.  
Baseline value, most extreme (ECGs only) and last observation and the corresponding 
change from Baseline will be summarized by treatment group. Most extreme ECG value 
is the largest change for QTcF, QRS and PR intervals, highest value for QT and largest 
absolute change for heart rate. For golodirsen treated patients, only results that occurred 
within 28 days of the last dose of golodirsen will be included.  
All patient-level values for ECG and ECHO variables will be displayed in a data listing.  
In addition, values meeting the predefined markedly abnormal criteria will be presented 
in a data listing.  Treatment-emergent abnormality will be indicated. 
6.7.6.1. 
Other Safety Assessments 
Abnormal physical examination results will be listed. 
6.8. 
Efficacy Analyses 
For any efficacy assessment that is taken on 2 consecutive days within a visit (ie, 6MWT 
at Baseline and Screening), the average value will be used. If the assessment is taken only 
on 1 day, then the value on that day will be used.  A value that is marked as invalid on the 
eCRF will be considered a missing value. 
All efficacy endpoints will be summarized descriptively by time point and treatment 
group for Combined Parts 1 and 2 as defined in Section 5.1 . Change from Baseline for 
each endpoint will also be summarized by time point and treatment group, if applicable. 
6.8.1. 
Analysis of Primary Efficacy Endpoint 
The primary functional efficacy endpoint of change from Baseline at Week 144 (Part 2) 
in the 6MWT will be summarized by treatment group. Additionally, all other Part 2 visits 
will be displayed. Missing values of 6MWT distance will be imputed as specified in 
Section 5.2.1 .  
The mean values with bars for standard errors will be displayed graphically over time by 
treatment group. 
6.8.2. 
Analysis of Secondary Efficacy Endpoint 
The secondary functional efficacy endpoint of change from baseline through Week 144 
(Part 2) in forced vital capacity percent predicted (FVC%p) will be summarized by 
treatment group. 
The mean values with bars for standard errors will be displayed graphically over time by 
treatment group. 
6.9. 
Pharmacokinetic Analyses 
The PK of golodirsen will be determined from multiple plasma and urine samples 
collected serially following the first weekly doses of the dose-titration phase on Weeks 1, 
3, 5, and 7 of Part 1 and from plasma samples collected at Weeks 1, 24, 48, 96, and 144 


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Statistical Analysis Plan  
Final Version 1.0  
 
Page 32 of 36 
7. 
CHANGES IN PLANNED ANALYSES 
7.1. 
Changes from Clinical Protocol-Planned Analyses 
Compared to the clinical protocol (Amendment 7, dated 08 November, 2017), there is no 
change in this SAP.   
7.2. 
Changes from Previous Statistical Analysis Plans 
Not applicable. 
 


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Statistical Analysis Plan  
Final Version 1.0  
 
Page 34 of 36 
9. 
APPENDIX: Criteria of Abnormalities 
Appendix Table 1  Chemistry Laboratory Abnormalities of Interest 
 
 
Predefined Change 
 
Test 
Unit 
Decrease 
Increase 
Markedly Abnormal 
Criteria 
Fasting blood glucosea 
mmol/L 3.1 
3.2 
NA 
BUN 
mmol/L NA 
NA 
Value >1.5× Baseline and 
>ULN 
Creatinine 
µmol/L 
NA 
35 
Value > ULN 
Sodium 
mmol/L 8 
8 
NA 
Potassium 
mmol/L 1.1 
1.0 
Value > 5.5 mmol/L or  
<3 mmol/L 
Chloride 
mmol/L 9 
8 
NA 
Uric acid 
µmol/L 
NA 
NA 
>1× ULN 
Calciumb 
mmol/L 0.30 
0.30 
NA 
Total cholesterol 
mmol/L NA 
1.73 
NA 
AST (SGOT) 
U/L 
NA 
NA 
Value ≥ 3× Baseline Value 
ALT (SGPT) 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
Gamma glutamyl 
transferaxe 
U/L 
NA 
NA 
Value > 3X Baseline OR  > 
ULN 
Alkaline phosphatase 
U/L 
NA 
NA 
Value > 1.5 × ULN 
Total proteinc 
g/L 
11 
10 
NA 
Albumin 
g/dL 
1  
1    
 < LLN or > ULN 
Total bilirubind 
µmol/L 
NA 
10 
Value > 1.5× ULN 
Lactate dehyrogenase 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
Creatine phosphokinase 
U/L 
NA 
NA 
Value ≥ 2× Baseline Value 
Triglycerides 
mmol/L NA 
2.88 
NA 
Cystatin C 
mg/L 
NA 
NA 
> ULN 
aConvert to SI unit by multiplying mg/dL value by 0.0555 
bmultiply mg/dL value by 0.25;  
cmultiply g/dL value by 10 
dmultiply mg/dL value by 17.1. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; LLN = 
lower limit of normal; NA = Not Applicable; ULN = upper limit of normal 


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Final Version 1.0  
 
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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 <1000 
LLN = lower limit of normal; ULN = upper limit of normal 
 
Appendix Table 3  Urinalysis Laboratory Abnormalities of Interest 
Test 
Markedly Abnormal Criteria 
Protein in urine 
> 1+  
 
Appendix Table 4  Vital Sign Abnormalities of Interest 
Variable 
Units 
Markedly Abnormal 
Criteria Lower limit 
Markedly Abnormal 
Criteria Upper limit 
Systolic blood pressure 
mmHg 
<80 
>130 
Diastolic blood pressure 
mmHg 
<40 
>90 
Pulse Rate 
beats/minute 
<50 
>130 
 
 
 
 


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Appendix Table 5  Electrocardiogram and Echocardiogram Abnormalities of 
Interest 
Variable 
Units 
LLN 
ULN 
Age Group 
(years) 
Markedly Abnormal 
Criteria 
Heart Rate 
Beats / 
minute 
50 
120 
 
NA 
QTcF Interval 
 
 
msec 
 
 
 
 
NA 
 
 
NA 
All 
Screening Visit > 450 
< 12 
> 480 
≥ 12 
> 500 
All 
< 320 
Increase > 60 
QRS Interval 
 
msec 
 
NA 
NA 
< 12 
Intraventricular conduction 
delay (IVCD) or any QRS 
conduction disturbance 
with a QRS > 110 msec 
≥ 12 
IVCD or any QRS 
conduction disturbance 
with a QRS > 120msec 
PR Interval 
 
msec 
 
NA 
NA 
< 12 
> 190 
≥ 12 
> 220 
LVEF 
% 
NA 
NA 
All 
 < 55% 
Fractional 
Shortening 
% 
NA 
NA 
All 
< 29% 
LLN = lower limit of normal; ULN = upper limit of normal