Clinical trial NCT04179409
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD Exon Skipping
Sponsor: Kevin Flanigan
Start date: 2020-02-18; Completion date: 2023-09-01
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an 48-week open-label study to determine the efficacy and safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 for the treatment of boys with duchenne muscular dystrophy who have a single exon duplication of either exon 45, 51 or 53, respectively. There will be weekly infusions and two muscle biopsies at baseline and at month 12.

Detailed description:
DMD is a rare, serious, debilitating, and ultimately fatal, disease for which there is an urgent need to develop safe and effective therapies. In order to efficiently meet this urgency and the needs of the subject community, the study evaluates the efficacy and safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 administration over approximately 1 year in DMD subjects with duplication mutations amenable to treatment by exon 45, 51 or exon 53 skipping. Skipping of a single copy of the duplicated exon is expected to result in a wild-type (WT) DMD transcript allowing the expression of a WT, full length dystrophin protein. Successful skipping of a single copy of the duplicated exon in in vitro and in vivo models has been reported in the literature. AMONDYS 45, EXONDYS 51, VYONDYS 53 have the potential to be disease-modifying treatments for boys with DMD mutations amenable to exon 45, 51 and exon 53 skipping, respectively.

The totality of the non-clinical data with these PMOs as well as AVI-4225 (targeting exon 23) and EXONDYS 51 suggests that PMOs are well tolerated in the non-clinical setting. Moreover, treatment with EXONDYS 51(at 30 mg/kg and 50 mg/kg) has been well-tolerated by boys with DMD deletion mutations amenable to skipping exon 51. The relatively low expected risk for subjects exposed to AMONDYS 45, EXONDYS 51, VYONDYS 53 and the urgent medical need for a treatment for this subject population support the conclusion that the potential benefits of exposing subjects to AMONDYS 45, EXONDYS 51, VYONDYS 53 outweigh the potential risks.

Arms: arm 1: This arm will involve the treatment of boys with DMD who have a duplication of exon 45, for which AMONDYS 45 will target skipping of this exon. arm 2: This arm will involve the treatment of boys with DMD who have a duplication of exon 51, for which EXONDYS 51 will target skipping of this exon. arm 3: This arm will involve the treatment of boys with DMD who have a duplication of exon 53, for which VYONDYS 53 will target skipping of this exon.
Interventions: intervention 1: Amondys 45 intervention 2: Exondys 51 intervention 3: Vyondys 53
Intervention descriptions: intervention 1: This drug is used to target skipping of exon 45 of the dystrophin gene. intervention 2: This drug is used to target skipping of exon 51 of the dystrophin gene. intervention 3: This drug is used to target skipping of exon 53 of the dystrophin gene.

Protocol documents:
Prot_SAP_000.pdf: 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
1-2  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
SIGNATURE PAGE 
 
Study Title: 
A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of 
Casimersen, Eteplirsen and Golodirsen in Subjects with Duchenne Muscular 
Dystrophy carrying eligible DMD duplications 
 
Financial Sponsor 
Sarepta Therapeutics 
 
Protocol Version 
v6.0 20Apr2021 
 
As Sponsor-Investigator, I agree to personally conduct this study in compliance with Principles of Good 
Clinical Practice as defined by federal, state, and local laws and regulations. I will abide by the current 
protocol (provided herein), including any protocol amendments that are approved by our institutional 
review board (IRB). 
 
 
___________________________ 
Kevin M. Flanigan, MD 
Sponsor-Investigator 
Nationwide Children’s Hospital 
 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
1-3  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
Contents 
1 
PROTOCOL SYNOPSIS ................................................................................................... 1-6 
2 
Administrative Information .............................................................................................. 2-11 
2.1 
Document History ............................................................................................. 2-11 
2.2 
Summary of Changes ........................................................................................ 2-11 
2.3 
Contact Information .......................................................................................... 2-13 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................... 15 
4 
INTRODUCTION ............................................................................................................... 17 
4.1 
Background of Duchenne Muscular Dystrophy ................................................... 17 
4.2 
Phosphorodiamidate Morpholino Oligomers (PMOs) for the Treatment of 
Duchenne Muscular Dystrophy ........................................................................................... 17 
4.3 
Clinical Experience with Eteplirsen, Casimersen and Golodirsen ....................... 18 
4.4 
Rationale for the Current Study ............................................................................ 20 
5 
STUDY OBJECTIVES ....................................................................................................... 20 
5.1 
Primary Objective ................................................................................................. 20 
5.2 
Secondary Objectives ........................................................................................... 20 
5.3 
Exploratory Objectives ......................................................................................... 21 
6 
INVESTIGATIONAL PLAN .............................................................................................. 21 
6.1 
Overall Study Design ........................................................................................... 21 
6.2 
Dose Selection Rationale ...................................................................................... 22 
6.3 
Study Endpoints ................................................................................................... 23 
6.3.1 Safety Endpoints .................................................................................................. 23 
6.3.2 Efficacy Endpoints ............................................................................................... 23 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................................... 24 
7.1 
Number of Subjects .............................................................................................. 24 
7.2 
Subject Inclusion Criteria ..................................................................................... 24 
7.3 
Subject Exclusion Criteria .................................................................................... 25 
7.4 
Completion of a Subject’s Participation in the Study ........................................... 27 
7.5 
Subject Withdrawal Criteria ................................................................................. 27 
7.6 
Study Discontinuation .......................................................................................... 27 
8 
TREATMENT OF SUBJECTS........................................................................................... 28 
8.1 
Investigational Products ....................................................................................... 28 
8.1.1 Packaging and Labeling ....................................................................................... 28 
8.1.2 Storage .................................................................................................................. 28 
8.2 
Treatments Administered ..................................................................................... 28 
8.2.1 Dose Modification, Reduction, or Delay ............................................................. 29 
8.3 
Prior and Concomitant Medications ..................................................................... 29 
8.4 
Treatment Compliance ......................................................................................... 30 
9 
STUDY VISITS................................................................................................................... 30 
9.1 
Screening and Baseline (Approximately 8 weeks prior to Week 1) .................... 31 
9.1.1 Informed Consent ................................................................................................. 31 
9.1.2 Screening .............................................................................................................. 31 
9.1.3 Baseline ................................................................................................................ 32 
9.2 
Week 1.................................................................................................................. 33 
9.3 
Week 4 (+/- 1 week) ............................................................................................. 34 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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Protocol v6.0 (20Apr2021) 
 
 
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9.4 
Week 8 (+/- 1 week) ............................................................................................. 35 
9.5 
Weeks 12 and 36 (Functional Assessment Visits) (+/- 1 week)........................... 35 
9.6 
Weeks 16, 20, 28, 32, 40 and 44 (+/- 1 week) ..................................................... 36 
9.7 
Week 24 (Functional Assessment Visit) (+/- 1 week) ......................................... 36 
9.8 
Week 48 (or Early Termination Visit, if more than 28 days after a Functional 
Assessment Visit) (+/- 1 week) ........................................................................................... 37 
9.8.1 Day 1 .................................................................................................................... 37 
9.8.2 Day 2 .................................................................................................................... 38 
9.9 
Schedule of Events ............................................................................................... 39 
9.10 
Muscle and Strength Test Schedule ..................................................................... 40 
10 
STUDY PROCEDURES ..................................................................................................... 40 
10.1 
Safety Assessments .............................................................................................. 40 
10.1.1 Adverse Events ..................................................................................................... 40 
10.1.2 Clinical Laboratory Evaluations ........................................................................... 40 
10.1.3 Electrocardiogram ................................................................................................ 41 
10.1.4 Echocardiogram ................................................................................................... 41 
10.1.5 Vital Signs, Weight, and Height ........................................................................... 41 
10.1.6 Adverse Events ..................................................................................................... 42 
10.1.7 Medical History..................................................................................................... 42 
10.1.8 Physical Examination ........................................................................................... 42 
10.1.9 Concomitant Medications and Therapies ............................................................. 42 
10.2 
Efficacy Assessments ........................................................................................... 42 
10.2.1 Functional Assessements ...................................................................................... 42 
10.2.2 Quality of Life Assessment: PODCI .................................................................... 44 
10.2.3 Quality of Life Assessment: PROMIS ................................................................. 44 
10.2.4 Muscle Biopsy ...................................................................................................... 44 
10.3 
Additional Assessments ....................................................................................... 44 
10.3.1 Genotype Confirmation ........................................................................................ 44 
11 
ADVERSE EVENTS AND SAFETY REPORTING ......................................................... 45 
11.1 
Collection of Adverse Events ............................................................................... 45 
11.2 
Definition of Adverse Events ............................................................................... 45 
11.2.1 Adverse Event (AE) ............................................................................................. 45 
11.2.2 Serious Adverse Event (SAE) .............................................................................. 45 
11.3 
Classification of Adverse Events .......................................................................... 46 
11.3.1 Relationship to Investigational Product ............................................................... 46 
11.3.2 Relationship to Study Procedures ........................................................................ 46 
11.3.3 Relationship to Underlying Disease ..................................................................... 46 
11.3.4 Severity of Adverse Events .................................................................................. 47 
11.3.5 Outcome ............................................................................................................... 47 
11.3.6 Action Taken Regarding the Investigational Drug Product ................................. 47 
11.3.7 Expectedness of an Adverse Event ...................................................................... 47 
11.3.8 Suspected Unexpected Serious Adverse Reactions (SUSARs) ........................... 47 
11.3.9 Adverse Event Reporting ..................................................................................... 47 
11.4 
Recording Adverse Events ................................................................................... 48 
11.5 
Safety Reporting ................................................................................................... 48 
11.5.1 Serious Adverse Event Reporting: Content and Format ...................................... 50 
11.5.2 Special Situations ................................................................................................. 50 
11.5.3 Responsibilities of the Investigator ...................................................................... 51 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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CONFIDENTAL  
 
 
 
 
 
11.5.4 Responsibilities of Sarepta ................................................................................... 51 
12 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ................... 51 
12.1 
Recording of Data ................................................................................................ 51 
12.2 
Quality Assurance ................................................................................................. 52 
12.3 
Retention of Study Documents ............................................................................. 52 
12.4 
Essential Study Documents .................................................................................. 52 
13 
STUDY REPORTS ............................................................................................................. 53 
13.1 
Final Study Report ............................................................................................... 53 
13.2 
Annual Study Report ............................................................................................ 53 
13.3 
Data and Safety Monitoring Plan ......................................................................... 53 
13.3.1 The Data Safety Monitoring Plan......................................................................... 53 
13.4 
Safety Reporting and Meetings ............................................................................ 54 
14 
Statistical Considerations .................................................................................................... 56 
14.1 
General Considerations ........................................................................................ 56 
14.2 
Determination of Sample Size .............................................................................. 56 
14.3 
Analysis Sets: ....................................................................................................... 56 
14.3.1 Efficacy Analyses ................................................................................................. 56 
14.3.2 Safety Analysis ..................................................................................................... 58 
14.4 
Statistics ............................................................................................................... 59 
14.4.1 Disposition, Demographics, and Baseline Characteristics ................................... 59 
14.4.2 Medical History .................................................................................................... 59 
14.4.3 Concomitant Medications and Therapies ............................................................. 59 
14.4.4 Dosing and Compliance........................................................................................ 59 
14.4.5 Protocol Deviations .............................................................................................. 59 
14.4.6 Other Statistical Issues ......................................................................................... 59 
15 
GENERAL INFORMATION ............................................................................................. 60 
15.1 
SPECIAL REQUIREMENTS AND PROCEDURES ......................................... 60 
15.1.1 Compliance with Ethical and Regulatory Guidelines .......................................... 60 
15.1.2 Institutional and Ethics Review ............................................................................ 60 
15.1.3 Informed Consent/Assent and Authorization for Use and Disclosure of Protected 
Health Information ............................................................................................... 60 
15.1.4 Compliance with the Protocol .............................................................................. 60 
15.1.5 Confidentiality ...................................................................................................... 61 
15.2 
General Information ............................................................................................. 61 
15.3 
Dissemination of Study Results ........................................................................... 61 
15.4 
Product Handling and Complaints Reporting ...................................................... 61 
16 
LIST OF REFERENCES .................................................................................................... 62 
 






Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
• 
Safety Follow-up: Subjects will be followed up with by phone call 
approximately 4 weeks (28 days) following last infusion to check for 
adverse events or other significant findings.  
 
Number of Subjects 
Approximately 6 subjects will be included in this study, to be enrolled by 
invitation. 
Subject Population 
INCLUSION/EXCLUSION CRITERIA: 
Inclusion Criteria: 
 
A subject must meet all of the following criteria to be eligible for this study. 
1. Is a male with DMD and has an out-of-frame duplication of either 
exon 45, 51, or 53, with a normal copy number of all other DMD 
exons.  
2. Is above age 6 months. 
3. Has pulmonary function, that in the Investigator’s opinion, is unlikely 
to decompensate significantly over the duration of the study. 
4. Has sufficient muscle mass in a pair of bilateral muscles that will 
allow for pre- and post-treatment muscle biopsies per PI discretion.  
5. If the subject is ambulant and 4 years old or greater and has been on a 
stable dose or dose equivalent of oral corticosteroids for at least 12 
weeks prior to Week 1 the dose is expected to remain constant (except 
for modifications to accommodate changes in weight) throughout the 
study.   
Note: Subjects are allowed to take other medications (excluding 
other RNA antisense or gene therapy agents) including 
angiotensin-converting enzyme (ACE) inhibitors, angiotensin 
receptor blocking agents (ARBs), β adrenergic blockers, 
potassium, and coenzyme Q, provided they have been on a stable 
dose for 12 weeks prior to Week 1. The dose is expected to remain 
constant throughout the study (modifications to doses to 
accomodate changes in weight are allowed). 
6. Has (a) parent(s) or legal guardian(s) who is (are) able to understand 
and comply with all the study requirements. 
7. Is willing to provide informed assent (if applicable) and has (a) 
parent(s) or legal guardian(s) who is (are) willing to provide written 
informed consent for the subject to participate in the study. 
 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from this 
study. 
1. Any additional missing exon for DMD that cannot be treated with 
study drugs. 
2. Subject has previously been treated with eteplirsen, casimersen, or 
golodirsen, or is currently being treated with other RNA antisense or 
gene therapy agents. 
3. Current or history of liver disease or impairment including one of the 
following at Screening: 
a. an INR value above 1.5  
b. a total bilirubin greater than 2 times the Upper Limit of 
Normal (ULN) or a GGT greater than 2 times the ULN 
4. Screening platelet count below the Lower Limit of Normal (LLN) for 
age. 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
5. Screening aPTT above the ULN 
6. History of significant medical disorder which may confound the 
interpretation of either efficacy or safety data e.g., inflammatory 
disease. 
7. Use of any pharmacologic treatment (other than corticosteroids) within 
12 weeks prior to Week 1 that may have an effect on muscle strength 
or function (e.g., growth hormone, anabolic steroids). 
8. Current or previous treatment with any other experimental treatment 
within 12 weeks prior to Week 1. 
9. Major surgery within 3 months prior to Week 1 or planned surgery for 
any time during this study, except for protocol-specified surgery, as 
applicable. 
10. Presence of other clinically significant illness including significant 
cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or 
behavioral disease, or malignancy. 
11. Use of any aminoglycoside antibiotic or statin within 12 weeks prior to 
Week 1 or anticipated need for an aminoglycoside antibiotic or statin 
during the study. 
12. QTcF ≥ 450 msec based on the Screening and/or Baseline ECG. 
13. Prior or ongoing medical condition that could, in the Investigator’s 
opinion, adversely affect the safety of the subject, make it unlikely that 
the course of treatment would be completed, or impair the assessment 
of study results. Additionally, subjects who seem unable/unwilling to 
comply with the study procedures, in the Investigator’s opinion, are to 
be excluded. 
14. Acute illness within 4 weeks of the first anticipated administration of 
study medication which may interfere with study assessments. 
15. Symptomatic cardiomyopathy. If the subject is asymptomatic but has a 
left ventricular ejection fraction <40% at Screening, the investigator 
should discuss inclusion of subject in the study with the Safety Review 
Committee. 
16. Use of anticoagulants, antithrombotics or antiplatelet agents within 4 
weeks prior to anticipated study drug administration. 
 
Dose/Route/Regimen 
(Test Article)  
Eteplirsen, casimersen, or golodirsen (each at 30 mg/kg) will be administered 
as an IV infusion over 35-60 minutes once a week for 48 weeks. 
Sample Size 
The sample size for this study was based on the availability of subjects with 
these unusual mutations for this open label study, and not on power estimates 
of effect size.  
 
Statistical Methods 
Efficacy Analyses: 
The analysis of changes in dystrophin expression by western blot analysis will 
make use of published protocols for protein expression quantification in 
comparison to normal samples. Changes from baseline to week 48 will be 
assessed using a 1-sample permuation test. 
  
Safety Analyses: 
Treatment emergent adverse events (TEAEs) will be summarized by the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
(SOC) and preferred term (PT) by treatment group. 
 
Non-treatment emergent events will be recorded in the data listings. For all AE 
tables, the number and percentage of subjects reporting AEs will be grouped 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
by SOC and PT. Multiple occurrences of the same AE (at the PT level) in the 
same subject will be counted only once in the frequency tables. If a subject 
experiences multiple episodes of the same event with different 
relationship/severity, the event with the strongest relationship or maximum 
severity to study treatment will be used to summarize AEs by relationship and 
severity. 
 
Descriptive statistics for ECG, ECHO, vital signs, and safety laboratory 
parameters will be generated. Summary statistics for each parameter at specific 
time points, as well as the change from Baseline to that time point, will also be 
displayed. All safety data will be presented in the data listings. 
Post-treatment Follow-
up/Clinical Transition 
Period 
Subjects will be followed up with by phone call approximately 4 weeks 
(28 days) following last infusion to check for adverse events or other 
significant findings. 
 
At the conclusion of the 48 week study period, subjects will be enrolled 
in  the Sarepta Clinical Transition Program and will be followed 
clinically in the NCH DMD clinic for safety, specifically for monitoring 
of renal function as per the prescribing information for casimersen and 
golodirsen.  All prescribing recommended testing will be performed for 
clinically monitoring only.  Those subjects receiving golodirsen or 
casimersen via this program will be monitored by urine dipstick every 
month, and serum cystatin C and urine protein to creatinine ratio 
(UPCR) every 3 months  There is no additional clinical safety testing 
recommended per the prescribing information for eteplirsen.- 
Additionally, through this program the subjects will be provided 
uninterrupted weekly drug access after conclusion of the 48 week study 
period. Subjects will remain on the Clinical Transition 
Program/SareptAssist until study samples can be analyzed and 
insurance authorization for the drug(s) can be obtained, or the efficacy 
of the drug is determined to not meet the standards for continuation. The 
threshold for study drug continuation in Sarepta’s Clinical Transition 
Program/SareptAssist is a 10 percent increase in dystrophin positive 
fibers (defined as fibers with 30 percent of the circumference positive 
for dystrophin) as determined by immunofluorescence staining of the 
baseline and 48-week post-treatment muscle biopsies.  Subjects will 
receive weekly drug infusions via home health care arranged by Sarepta 
Therapeutics and as noted above will be monitored clinically in the 
NCH DMD clinic. 
 
 
 
 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
2-11  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
2 
ADMINISTRATIVE INFORMATION 
2.1 
Document History 
Table 1: Document Record 
Document 
Version and Date 
Submission Purpose 
Clinical Protocol 
V1.0 26Oct2018 
IRB Submission 
Clinical Protocol 
V2.0 1Nov2018 
IRB Modification/FDA IND 
Submission S/N 0000 
Clinical Protocol 
V3.0 13Dec2018 
IRB Modification 
Clinical Protocol 
V4.0 06Dec2019 
IRB Modification/IND Update 
Submission S/N 0001 
Clinical Protocol  
V5.0 17Feb2020 
IRB Modification 
Clinical Protocol 
V6.0 20Apr2021 
IRB Modification 
 
2.2 
Summary of Changes 
The section below highlights content changes in this version of the protocol. Language deleted from the 
previous version of the protocol appears in red/strikethrough. Language added to the previous version of 
the protocol appears in bold. 
Table 2: Revision Record 
Protocol Version 
Description of Changes 
V4.0 06Dec2019 
• Administrative changes 
• Removed language about the NSAA
Revised and instead listed all 
applicable age ranges to receive the 
NSAA. 
• Removed the cognition and language 
skills portion of the Bayley. 
• Clarified Exclusion Criteria #2 from: 
o Subject has been treated with 
eteplirsen, or is amenable to or 
is currently being treated with 
other RNA antisense or gene 
therapy agents. 
To 
o Subject has previously been 
treated with eteplirsen, 
casimersen, or golodirsen, or is 
currently being treated with 
other RNA antisense or gene 
therapy agents. 
• Replaced reference of a “Pharmacy 
Manual” with the “Clinical Study 
Manual of Operations” 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
2-12  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
• In therapies not permitted during 
conduct of this trial, the item of 
“Systemic or oral steroids for non-
DMD conditions” was amended to 
further include “….that, in the 
Investigator’s opinion, could 
interfere with study assessments and 
outcomes.” 
• Changed weight based adjustments 
to be taken on a monthly schedule. 
This included adding weight to 
weeks 16, 20, 28, 32, 40, and 44 
• Removed height from weeks 1, 4, 8 
• Moved Height from screening day 1 to 
screening day 2 
• Updated table 1 and 2 
• Clarified source of determining 
expectedness of adverse an adverse 
event. 
• Removed reference to OBA 
• Addition of a summary of TEAE’s to 
be include in safety reporting 
meetings  
• Broadened the scheduling of port 
placement in case it cannot be 
completed at the same time as the 
muscle biopsy. 
• Removed Immunogenicity studies 
• Clarified Long-term Follow-up 
intentions. 
• Clarified that GGT and Amylase are 
not part of the CMP 
• Added PROMIS for Upper 
Extremity Report for ages 18+ 
• Added an upper age to the PODCI of 
17 years. 
• The Safety Review Committee was 
replaced with the Data and Safety 
Monitoring Board. 
• Removed KIM 1 assay 
• Removed MMP 9 and miRNA analysis 
(Biobanking for biomarkers section 
removed) 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
2-13  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
• Revised Section 11 to be in line with 
NCH IRB guidance 
V5.0 17Feb2020 
• Removed pharmacokinetics (PK) 
testing from the study. 
• Removed KIM 1 from the Schedule of 
Events.  
• Updated contact information for study 
staff to remove Rachel Heffern and 
add Maryann Kaler. 
V6.0 20Apr2021 
• Adding subject rollover to the 
Sarepta Clinical TransitionProgram. 
• Adding threshold of 10% dystrophin 
positive fibers for study drug 
continuation after completion of 48 
week trial.  
• Removal of Anti Dystrophin 
Antibodies.  
2.3 
Contact Information 
Table 3: Study Team 
Role in Study 
Name 
Address and Telephone Number 
Sponsor 
Investigator 
Kevin Flanigan, MD 
WA3011 700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-5615  
megan.waldrop@nationwidechildrens.org 
Co-Investigator 
Megan Waldrop 
WA3013 700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-2231  
Kevin.flanigan@nationwidechildrens.org 
Co-Investigator 
Cassandra Karingada, 
FNP 
700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-2216 
Cassandra.karingada@nationwidechildrens.org 
Co-Investigator 
Maryann Kaler, FNP 
700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-355-3572 
Maryann.kaler@nationwidechildrens.org 
Program Manager 
Tabatha Simmons, PhD 
WA2020 700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-6921 
Tabatha.simmons@nationwidechildrens.org 
 
Table 4: Data Safety Monitoring Board 
Name 
Address and Telephone Number 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
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Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
John Brandsema, M.D. 
Children’s Hospital of Philadelphia 
3401 Civic Center Blvd 
Philadelphia, PA 19104 
Ph: 215-590-1719 
brandsemaj@email.chop.edu 
Perry Shieh, M.D., Ph.D. 
UCLA Neuro 
BOX 956975, B200, 300 Medical Plaza 
Los Angeles, CA 90095 
Ph: 310-794-1195 
pshieh@mednet.ucla.edu 
Richard Shell, M.D. 
Nationwide Children’s Hospital 
700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-4766 
richard.shell@nationwidechildrens.org 
Garey Noritz, M.D. 
Nationwide Children’s Hospital 
700 Children’s Dr 
Columbus, OH 43205 
Ph: 614-722-3152 
Squiresr@upmc.edu 
 
 
Table 5: Study Vendor Listing 
Role in Study 
Name 
Address and Telephone 
Number 
Monitor 
IQVIA Biotech 
Terri Walker 
580 N. 4th Street, Suite 270 
Columbus, OH 43215 
Ph: 614-954-0435 
Terri.walker@iqvia.com 
Lab for 
Immunofluorescence 
Flagship Biosciences, Inc. 
Briana Kennedy 
7575 W. 103rd Ave., Suite 102 
Westminster, CO 80021 
bkennedy@flagshipbio.com 


Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
 
 
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Protocol v6.0 (20Apr2021) 
 
 
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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
2D 
2-dimensional 
AAOS 
American Academy of Orthopaedic Surgeons 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin receptor blocking agent 
AST 
aspartate aminotransferase 
BMD 
Becker muscular dystrophy 
BUN 
blood urea nitrogen 
CD 
compact disc 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CS 
clinically significant 
CSR 
clinical study report 
DMD 
Duchenne muscular dystrophy 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG(s) 
electrocardiogram(s) 
ECHO(s) 
echocardiogram(s) 
EDC 
electronic data capture 
EF 
ejection fraction 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HEENT 
head, ears, eyes, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
Injection 
US nomenclature equivalent to Concentrate for Solution for Infusion  
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous, intravenously 


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Abbreviation 
Definition 
IVR 
interactive voice response 
LDH 
lactate dehydrogenase 
LLN 
Lower Limit of Normal 
LVEF 
left ventricular ejection fraction 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
NSAA 
North Star Ambulatory Assessment 
QMT 
quantitative muscle testing 
PFT 
pulmonary function test 
PMO 
phosphorodiamidate morpholino oligomer 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
RBC 
red blood cells 
REML 
restricted maximum likelihood 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
Upper Limit of Normal 
US FDA 
United States Food and Drug Administration 
WBC 
white blood cell 
 
 


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4 INTRODUCTION 
4.1 
Background of Duchenne Muscular Dystrophy 
 
Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease with an X linked recessive 
inheritance caused by mutations in the dystrophin gene, with a worldwide incidence of approximately 1 in 
3500 newborn boys, irrespective of geographical region, race, or population density 1-3. The mutations 
that cause DMD typically disrupt the mRNA reading frame and prevent production of dystrophin, a 
critically important part of the protein complex that connects the cytoskeleton of a muscle fiber to the cell 
membrane and extracellular matrix. In the absence of dystrophin, the stress of repeated muscle contraction 
causes progressive muscle damage. The clinical effect of this disrupted dystrophin reading frame is 
progressive and ultimately fatal. 
 
DMD is usually first diagnosed between the ages of 3 to 5 years4, when toddlers develop a waddling gait, 
lordosis, toe walking, calf hypertrophy, and a difficulty in climbing stairs. Over time, ambulation becomes 
increasingly abnormal. By 8 years of age, most subjects have lost the ability to rise from the floor and to 
climb stairs, show an increasingly labored gait, and often fall while walking, which leads to use of 
mobility devices such as strollers and scooters. Subjects with DMD walk slower than healthy boys and 
spend less time walking5 and they are significantly less active compared to healthy boys of similar age5, 6. 
By 10 to 14 years of age, most are wheelchair dependent. Weakness of the arms and increasingly limited 
upper limb function, contractures, decubitus ulcers, and scoliosis (which often requires surgery), occur 
frequently. While pulmonary and cardiac functions are generally normal during early childhood, cardiac 
and diaphragmatic muscles progressively weaken during late childhood and adolescence leading to 
eventual dependence on ventilation support. Historically, subjects typically died from respiratory or 
cardiac failure in their late teens or early 20s7, 8. Recent research suggests that use of ventilation support 
and steroids may increase life span by several years; however, DMD still has a mortality rate of 100%9. 
Corticosteroids used for palliative treatmemt of DMD can prolong ambulation and reduce the incidence 
of severe scoliosis; however, they are often associated with serious side effects10, 11 and are not always 
employed. 
 
4.2 
Phosphorodiamidate Morpholino Oligomers (PMOs) for the Treatment of Duchenne 
Muscular Dystrophy 
 
Antisense ribonucleic acid (RNA) therapeutics are compounds composed of heterocyclic nucleobases 
(adenine, cytosine, guanine, and uracil or analogs) linked together on an oligomer backbone that hybridizes 
to complementary RNA targets. RNA therapeutics can be synthesized to bind to specific RNA sequences 
to regulate gene expression, thus they can be used to treat a wide range of diseases. A relatively new use of 
RNA therapeutics is to target a pre-mRNA sequence in the cell nucleus to influence the splicing process 
that creates the mature mRNA; this is referred as“exon skipping,” as it determines which exons will be 
incorporated into the mature mRNA that is then translated into the protein product.


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Phosphorodiamidate morpholino oligomers (PMOs) are a class of synthetic molecules based on a 
redesign of the natural nucleic acid structure. PMOs differ from 2′-O-methyl and other oligonucleotide 
therapeutic platforms because of their six-membered morpholino ring, which replaces the five-
membered ribofuranosyl. Moreover, PMOs also have each morpholino ring bound to each other through 
an uncharged phosphorodiamidate moiety, as opposed other RNA therapeutics and backbones which 
have a negatively-charged phosphorothioate.  
 
Several PMOs are being evaluated by Sarepta Therapeutics, Inc., (Sarepta) for the treatment of DMD. 
The investigational drug products, casimersen (previously SRP-4045), eteplirsen (previously AVI-4658), 
and golodirsen (previously SRP-4053), are charge-neutral PMOs that selectively bind to exon 45, 51, or 
53, respectively, of dystrophin pre-mRNA and cause the exon to be skipped during processing. This 
restores the open reading frame in DMD subjects with mutations amenable to skipping exon 45, exon 51 
or exon 53 of the dystrophin pre-mRNA, each of which represents approximately 8%, 13% and 8% of all 
DMD subjects, respectively12. This mechanism is expected to enable the production of an internally 
deleted, yet partially functional, dystrophin protein, similar to that observed in Becker muscular dystrophy 
(BMD), a much less severe form of dystrophinopathy. In contrast to DMD, most BMD subjects remain 
ambulatory and have a near-normal life expectancy13, 14. Treatment with casimersen. eteplirsen, or 
golodirsen is expected to result in sustained production of partially functional dystrophin protein and 
potentially improve the quality of life and prognosis for DMD subjects, essentially switching their clinical 
symptoms and prognosis to be more similar to those of subjects with BMD. Over time, treatment with 
casimersen, eteplirsen or golodirsen is expected to delay or potentially halt disease progression in boys 
with DMD who have gene mutations amenable to exon 45, exon 51 or exon 53 skipping, respectively. 
Nonclinical data for casimersen, eteplirsen, and golodirsen are described in the respective Investigator’s 
Brochures. 
4.3 
Clinical Experience with Eteplirsen, Casimersen and Golodirsen 
 
Available clinical data for the three PMOs is discussed here.  
Eteplirsen  
Eteplirsen is a charge neutral PMO that selectively binds to exon 51 of dystrophin pre-mRNA and it is 
conditionally approved for the treatment of subjects with DMD that are amenable to skipping exon 51. 
 
Two Phase 1 clinical studies of eteplirsen have provided initial support and proof-of-concept for the 
safety and potential efficacy of eteplirsen in the treatment of DMD. In light of the positive findings from 
the 2 Phase 1 studies15, 16, a 28-week, double-blind, placebo-controlled Phase 2 study (Study 4658-us-
201)17 was initiated to assess efficacy, safety, tolerability, and pharmacokinetics (PK) of eteplirsen. 
Twelve patients aged 7 to 13 years were randomized to receive once-weekly intravenous (IV) infusions of 
eteplirsen (30 or 50 mg/kg) for 28 weeks, or once-weekly placebo infusions for 24 weeks followed by 
eteplirsen infusion (30 or 50 mg/kg) for 4 weeks. At Week 28, these same 12 patients were enrolled in the 
extension study (Study 4658-us-202)18 where they continued open-label eteplirsen at the same dose they 
were receiving upon completion of the parent study. This extension study has been completed, and 
enrolled DMD patients received eteplirsen for more than 4 years. Four other eteplirsen studies have been 
conducted in patients with DMD: 
• 
Study 4658-20319, a Phase 2 study in patients 4 to 6 years of age 
• 
Study 4658-20420, a Phase 2 study in patients with advanced stage DMD 
• 
Study 4658-30121, a Phase 3 safety and efficacy study in a population of patients in late-
ambulatory decline 
• 
Study 4658-10222, a Phase 2 study in patients aged 6-48 months 
  


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Based on the cumulative available safety data from these studies, eteplirsen has been shown to be well 
tolerated, with low rates of treatment-related serious or severe adverse events (AEs).  
Analysis of biopsies taken at combined Study 201/202 Week 180 showed a significant increase in 
dystrophin protein by western blot in eteplirsen-treated subjects as compared to untreated controls 
(p=0.007) contributing to its approval by the FDA for use in subjects with deletion mutations amenable 
to exon 51 skipping23. 
Further, after 4 years on treatment in pivotal Study 201/202, subjects in the 30 mg/kg and 50 mg/kg 
eteplirsen cohorts experienced a decline on the six-minute walk test that was 165 meters less (p=0.001) 
than that observed in an external control group with comparable baseline characteristics that was 
identified using pre-defined filters of steroid use, age ≥7 and amenability to exon 51 skipping. Two of 
twelve eteplirsen-treated subjects lost ambulation versus 9 of 12 external control subjects.  
Refer to the Investigator’s Brochure for additional clinical data for eteplirsen. 
 
Casimersen 
Casimersen is being evaluated in 2 clinical studies: 
• 
4045-10124 is a Phase 1, randomized, double-blind, placebo-controlled, dose-titration, safety, 
tolerability, and PK study in patients with DMD amenable to exon 45 skipping. The study is 
being conducted as a double-blind, placebo-controlled, dosetitration portion followed by an open-
label extension. 
• 
4045-30125 is a Phase 3, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of casimersen and golodirsen in patients with DMD who are amenable to 
skipping either exon 45 or 53, respectively. 
 
No deaths or discontinuations from the study due to an adverse event (AE) have been reported. The 
majority of all TEAEs were nonserious, mild, and unrelated to study drug.  
 
Refer to the Investigator’s Brochure for additional clinical data for casimersen. 
 
Golodirsen 
Golodirsen is being evaluated in 2 clinical studies: 
• 
4053-10126 is a Phase 1/2, randomized, double-blind, placebo-controlled, dose-titration, safety, 
tolerability, and pharmacokinetic (PK) study evaluating golodirsen in patients with advanced-
stage DMD who are amenable to exon 53 skipping. The study is being conducted in 2 parts: Part 
1 consists of a double-blind placebo-controlled, dose-titration and Part 2 is an open-label safety 
and efficacy evaluation. 
• 
4045-30125 is a Phase 3, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of casimersen and golodirsen in patients with DMD who are amenable to 
skipping either exon 45 or 53, respectively. 
 
No deaths or discontinuations from the study due to an AE have been reported. The majority of all 
TEAEs were nonserious, mild, and unrelated to study drug.  
 
In a Phase I/II clinical trial (4053-101) an analysis of biopsied muscle tissue at Week 48 of 4053-101 
showed a significant increase in dystrophin protein by western blot (p<0.001) in golodirsen-treated 
subjects over their own pre-treatment muscle tissue. The study is ongoing and results from outcome 
measures of clinical efficacy are not available at this time.  
Refer to the Investigator’s Brochure for additional clinical data for golodirsen. 


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4.4 
Rationale for the Current Study 
DMD is a rare, serious, debilitating, and ultimately fatal, disease for which there is an urgent need to 
develop safe and effective therapies. In order to efficiently meet this urgency and the needs of the 
subject community, the study evaluates the efficacy and safety of casimersen, eteplirsen, and of 
golodirsen administration over approximately 1 year in DMD subjects with duplication mutations 
amenable to treatment by exon 45, 51 or exon 53 skipping. Skipping of a single copy of the duplicated 
exon is expected to result in a wild-type (WT) DMD transcript allowing the expression of a WT, full 
length dystrophin protein. Successful skipping of a single copy of the duplicated exon in in vitro and in 
vivo models has been reported in the literature27-29. Casimersen, eteplirsen, and golodirsen have the 
potential to be disease-modifying treatments for boys with DMD mutations amenable to exon 45, 51 and 
exon 53 skipping, respectively.  
 
As summarized in Section 4.3 and in the casimersen and golodirsen Investigator’s Brochures, the totality 
of the non-clinical data with these PMOs as well as AVI-4225 (targeting exon 23) and eteplirsen 
suggests that PMOs are well tolerated in the non-clinical setting. Moreover, treatment with eteplirsen (at 
30 mg/kg and 50 mg/kg) has been well-tolerated by boys with DMD deletion mutations amenable to 
skipping exon 51.  
The relatively low expected risk for subjects exposed to casimersen, eteplirsen, or golodirsen and the 
urgent medical need for a treatment for this subject population support the conclusion that the potential 
benefits of exposing subjects to casimersen, eteplirsen, or golodirsen outweigh the potential risks. 
 
5 STUDY OBJECTIVES 
5.1 
Primary Objective 
Primary objective are to evaluate the effect of either casimersen, eteplirsen, or golodirsen on: 
• 
To evaluate the efficacy of casimersen (previously SRP-4045), eteplirsen (previously AVI-
4658), or golodirsen (previously SRP-4053) on dystrophin expression as assessed by  
quantification of protein in muscle biopsy tissue by western blot. 
• 
Safety and tolerability in a population of subjects with relevant exon duplications using the 
following outcome measures: 
o Adverse events (AEs), serious adverse events (SAEs), deaths, and discontinuations 
due to AEs 
o Laboratory testing may include the following (See Section 9 for details): 
 
Hematology 
 
Coagulation 
 
Chemistry 
 
Urinalysis  
o Cardiac function including ECG and ECHO 
o Vital signs 
o Physical examination findings 
 
 
5.2 
Secondary Objectives 
 
Secondary objectives of this study is to evaluate the effect of either casimersen, eteplirsen, or golodirsen 
after 48 weeks of treatment on: 
 


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• 
Expression of dystrophin as measured by immunofluorescent signal intensity and percent 
dystrophin positive fibers (PDPF) in muscle tissue sections in comparison to baseline 
values. 
• 
The efficiency of splicing alteration will be measured by RNA Sequencing (RNA-Seq) to 
establish DMD mRNA copy number and the exon-exon junction frequency quantified, with 
normalization to exon junction read values from an exon junction in regions distinct from 
the targeted exon. 
5.3 
Exploratory Objectives 
 
Additional objectives are to evaluate the effect of casimersen, eteplirsen, or golodirsen analysing the 
changes from baseline to week 48 in the following: 
 
• 
Functional abilities of subjects in comparison to the expected natural history using the 
following measures: 
o Subjects between 6 to 36 months of age at enrollment: Bayley Scales of Infant 
Development - Gross motor functions and fine motor functions. 
o Motor function as measured on the North Star Ambulatory Assessment (NSAA, 
ambulant boys age 3 years and older). 
o Ambulant subjects over age 3.5 years: endurance and muscle function as measured 
by the 100-Meter Walk / Run Test (100M)  
o ACTIVE-seated for boys over 5 years of age. 
o Forced vital capacity, as measured in absolute values and by % predicted forced 
vital capacity (FVC%) in patients aged ≥10 years 
o Peak expiratory flow as reported as % predicted by age and height (%PEF) 
o Timed functional tests for ambulant subjects 3 years or older: 
 
time to complete 10-meter run 
 
time to rise from the floor 
 
time to climb 4 steps 
 
time to descend 4 steps 
• 
Pediatric Outcomes Data Collection Instrument (PODCI) for patients ages 2-17. 
• 
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) Upper 
Extremity Report for patients 18+ years. 
• 
Immune staining may be performed on biopsy specimens for members of the dystrophin-
associated protein complex, such as the sarcoglycans, dystroglycans and n-Nos. 
• 
Muscle morphometrics may also be performed, including fiber size histograms and 
quantification of central nucleation.  
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
 
This is a open label, 48-week study to evaluate the efficacy and safety of three PMOs – casimersen, 
eteplirsen, and golodirsen – in 6 subjects with genotypically confirmed DMD with duplication mutations 
amenable to correction by skipping exon 45, 51, and 53, respectively.  
 
Subjects will be evaluated for inclusion during a Screening period of approximately 8 weeks. Eligible 
subjects who have out-of-frame duplications of a single exon that may be corrected by skipping exon 
45, 51, or 53 will receive once weekly intravenous (IV) infusions of 30 mg/kg casimersen, 30 mg/kg 
eteplirsen, or 30 mg/kg golodirsen respectively for 48 weeks. 


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Upon qualification for the study based on Screening and Baseline assessments, all subjects will undergo a 
muscle biopsy for baseline assessment of dystrophin expression. All subjects will undergo a second 
biopsy at 48 weeks of treatment.   
 
Efficacy will be assessed at regularly scheduled (12 week intervals) study visits and safety will be 
monitored on an ongoing basis for all subjects. 
 
Safety will be assessed through the collection of adverse events (AEs), laboratory tests, 
electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations 
throughout the study as described in the Schedule of Events (Table 6). A Safety Follow Up phone call 
will be placed approximately 4 weeks (28 days) after the last study infusion to check for new adverse 
events,  to obtain any new information regarding ongoing AEs and/or any other noteworthy subject 
progress.  
 
At the conclusion of the 48 week study period, subjects will be  enrolled in the Sarepta Clinical Transition 
Program via the SareptAssist patient support program.  Subjects will be followed clinically in the NCH 
DMD clinic for safety, specifically for monitoring of renal function as per the prescribing information for 
casimersen and golodrisen. All prescribing recommended testing will be performed for clinical 
monitoring only.Those subjects receiving golodirsen or casimersen via this program will be monitored by 
urine dipstick every month, and serum cystatin C and urine protein to creatinine ratio (UPCR) every three 
months.    There is no additional clinical safety testing recommended per the prescribing information 
for eteplirsen. 
 
Additionally, through this program the subjects will be provided uninterrupted weekly drug access after 
conclusion of the 48 week study period. Subjects will remain on the Clinical 
TransitionProgram/SareptAssist until study samples can be analyzed and insurance authorization for the 
drug(s) can be obtained, or the efficacy of the drug is determined to not meet the standards for 
continuation. The threshold for study drug continuation in Sarepta’s Clinical 
TransitionProgram/SareptAssist is a 10 percent increase in dystrophin positive fibers (defined as fibers 
with 30 percent of the circumference positive for dystrophin) as determined by immunofluorescence 
staining of the baseline and 48-week post-treatment muscle biopsies.  
Subjects will receive weekly drug infusions via home health care arranged by Sarepta Therapeutics and as 
noted above will be monitored clinically in the NCH DMD clinic. 
6.2 
Dose Selection Rationale 
 
A dose of 30 mg/kg casimersen, eteplirsen, or golodirsen was selected to use in this study. Doses were 
chosen based on results from animal and phase 1 clinical studies with casimersen and golodirsen and on 
additional clinical data from eteplirsen. There are three ongoing clinical studies with golodirsen and 
casimersen in DMD patients (Study 4053-101, Study 4045-101 and Study 4045-301)24-26.  
 
As described in Section 4.3,  clinical studies 4658-us-20117 and 4658-us-20218 with eteplirsen assessed 
the efficacy, safety, and tolerability of eteplirsen (50 mg/kg and 30 mg/kg) administered as IV infusions 
in twelve 7- to 13-year old pediatric subjects diagnosed with DMD with out of frame mutations 
amenable to treatment by skipping exon 51. 
 
At Week 48, the increases in the percent of dystrophin-positive fibers were similar for subjects who had 
received weekly 30 mg/kg and 50 mg/kg eteplirsen without interruption from Week 1 (52% and 42% of 
normal respectively, or 47% for the combined groups). These data suggest that the effect of eteplirsen 
on the production of novel dystrophin is not significantly different between the two doses tested in this 


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study. Thus, the lower dose of eteplirsen (30 mg/kg) was selected for further clinical study, as it is a 
more conservative choice given that subjects would receive eteplirsen as a life-long treatment. 
 
Like eteplirsen, the PMOs casimersen and golodirsen have been evaluated in non-clinical studies to 
assess their pharmacological activity, pharmacokinetic, safety, and toxicology/toxicokinetic proprieties. 
RT-PCR studies using cultured muscle cells and demonstrated strong exon 45 (casimersen) and exon 
53 (golodirsen) skipping activities. Both casimersen and golodirsen have shown low protein binding 
activity and low potential for drug-drug interactions, since they did not interact with cytochrome P450 
isoenzymes at biologically relevant concentrations in vitro. 
 
The non-clinical safety profiles of casimersen and golodirsen are similar to other PMOs tested to date; 
no cardiovascular, respiratory or central nervous system effects, genotoxicity, male reproductive 
toxicity, or immunotoxicity have been detected. The kidneys were the main target organ in mice and 
monkeys after 12 weeks of repeat dosing (weekly IV injections of casimersen and golodirsen) which is 
consistent with the renal excretion being the major elimination pathway for PMOs. No adverse effect 
were observed in mice using 960 mg/kg and 120 mg/kg of casimersenand golodirsen, and the maximum 
feasible dose for IV administration in monkeys was of 320 mg/kg for both PMOs. Because the potential 
target organ of toxicity (the kidney) can be monitored in the clinic, doses of 30 mg/kg casimersen or 
golodirsen are considered safe for once weekly IV infusions in DMD subjects with mutations amenable 
to exon 45 or exon 53 skipping. Additional non-clinical data for casimersen and golodirsen are described 
in the respective Investigator’s Brochures. 
Further, 30 mg/kg/wk golodirsen treatment in clinical trial 4053-101 resulted in a significant mean 
increase in dystrophin protein from baseline (N=25, p<0.001) at Week 48. 
Due to the expected similarities among investigational PMOs for the treatment of subjects with DMD, a 
30 mg/kg dose for eteplirsen, casimersen and golodirsen was selected for evaluation in this study. 
 
6.3 
Study Endpoints 
6.3.1 Safety Endpoints 
 
The safety and tolerability of casimersen and golodirsen will be assessed through a review and 
evaluation of the following: 
• 
Adverse events (AEs), serious adverse events (SAEs), deaths, and discontinuations due to 
AEs 
• 
Laboratory testing may include the following (See Section 9 for complete details): 
o Hematology 
o Coagulation 
o Chemistry 
o Urinalysis 
• 
Cardiac function including ECG and ECHO 
• 
Vital signs 
• 
Physical examination findings 
6.3.2 Efficacy Endpoints 
6.3.2.1 Primary Efficacy Endpoint 
 
The primary efficacy endpoint is: 


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• 
Change from Baseline to Week 48 in dystrophin expression quantified by western blot  in muscle 
biopsy tissue. 
6.3.2.2 Secondary Efficacy Endpoints 
 
Secondary efficacy endpoints are: 
• 
Change from Baseline to Week 48 in expression of dystrophin as measured by immunofluorescent 
signal intensity and percent dystrophin positive fibers (PDPF) in muscle tissue sections in 
comparison to baseline values. 
• 
The efficiency of splicing alteration will be measured by RNA Sequencing (RNA-Seq) to establish 
DMD mRNA copy number and the exon-exon junction frequency quantified, with normalization 
to exon junction read values from an exon junction in regions distinct from the targeted exon. 
 
6.3.2.3 Exploratory Efficacy Endpoints 
 
Exploratory efficacy endpoints are based on the change from Baseline to Week 48 in the following 
measures: 
• 
Subjects 6 to 36 months of age at enrollment: Change from baseline in scores on the Bayley Scales 
of Infant Development – gross motor functions and fine motor functions. 
• 
Change from Baseline to Week 48 in NSAA (subjects 3 years or greater). 
• 
Change from Baseline to Week 48 on the 100M in ambulant subjects over the age of 3.5 years. 
• 
Change from Baseline to Week 48 in ACTIVE-seated for boys over 5 years of age. 
• 
Changes in FVC and FVC% predicted in patients aged ≥ 10 years. 
• 
Peak expiratory flow as reported as % predicted by age and height (%PEF). 
• 
Timed functional tests for ambulant subjects 3 years or older: 
o time to complete 10-meter run 
o time to rise from the floor 
o time to climb 4 steps 
o time to descend 4 steps 
• 
Pediatric Outcomes Data Collection Instrument (PODCI) for patients ages 2-17. 
• 
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity 
Report for patients 18+ years. 
• 
Immune staining may be performed on biopsy specimens for members of the dystrophin-
associated protein complex, such as the sarcoglycans, dystroglycans and n-Nos. 
• 
Muscle morphometrics may also be performed, including fiber size histograms and quantification 
of central nucleation. 
 
7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Number of Subjects 
 
Six subjects will be included in this study to be enrolled by invitation. They will receive either 
casimersen, eteplirsen, or golodirsen according to their genotype. 
7.2 
Subject Inclusion Criteria 
A subject must meet all of the following criteria to be eligible for this study. 


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1. Is a male with DMD and has an out-of-frame duplication of either exon 45, 51, or 53, with a 
normal copy number of all other DMD exons.  
2. Is above age 6 months. 
3. Has pulmonary function, that in the Investigator’s opinion, is unlikely to decompensate 
significantly over the duration of the study. 
4. Has sufficient muscle mass in a pair of bilateral muscles that will allow for pre- and post-
treatment muscle biopsies per PI discretion. 
5. If the subject is ambulant and 4 years old or greater and has been on a stable dose or dose 
equivalent of oral corticosteroids for at least 12 weeks prior to Week 1 the dose is expected to 
remain constant (except for modifications to accommodate changes in weight) throughout the 
study.  
Note: Subjects are allowed to take other medications (excluding other RNA antisense or gene 
therapy agents) including angiotensin-converting enzyme (ACE) inhibitors, angiotensin 
receptor blocking agents (ARBs), β adrenergic blockers, potassium, and coenzyme Q, 
provided they have been on a stable dose for 12 weeks prior to Week 1. The dose is expected 
to remain constant throughout the study (modifications to doses to accomodate changes in 
weight are allowed). 
6. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the 
study requirements. 
7. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who 
is (are) willing to provide written informed consent for the subject to participate in the study. 
7.3 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from this study. 
1. Any additional missing exon for DMD that cannot be treated with study drugs. 
2. Subject has previously been treated with eteplirsen, casimersen, or golodirsen, or is currently 
being treated with other RNA antisense or gene therapy agents. 
3. Current or history of liver disease or impairment including: 
a. an INR value above 1.5  
b. a total bilirubin greater than 2 times the Upper Limit of Normal (ULN) or a GGT greater 
than 2 times the ULN  
4. Baseline platelet count below the Lower Limit of Normal (LLN) for age. 
5. aPPT above the ULN. 
6. History of significant medical disorder which may confound the interpretation of either efficacy 
or safety data e.g., inflammatory disease. 
7. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to Week 1 
that may have an effect on muscle strength or function (e.g., growth hormone, anabolic steroids). 
8. Current or previous treatment with any other experimental treatment within 12 weeks prior to 
Week 1. 
9. Major surgery within 3 months prior to Week 1 or planned surgery for any time during this study, 
except for protocol-specified surgery, as applicable. 
10. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, 
renal, hematologic, immunologic, or behavioral disease, or malignancy. 
11. Use of any aminoglycoside antibiotic or statin within 12 weeks prior to Week 1 or anticipated 
need for an aminoglycoside antibiotic or statin during the study. 
12. QTcF ≥ 450 msec based on the Screening and/or Baseline ECG. 
13. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the 
safety of the subject, make it unlikely that the course of treatment would be completed, or impair 
the assessment of study results. Additionally, subjects who seem unable/unwilling to comply with 
the study procedures, in the Investigator’s opinion, are to be excluded. 


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14. Acute illness within 4 weeks of the first anticipated administration of study medication which 
may interfere with study assessments. 
15. Symptomatic cardiomyopathy. If the subject is asymptomatic but has a left ventricular ejection 
fraction <40% at Screening, the investigator should discuss inclusion of subject in the study with 
the medical monitor. 
16. Use of anticoagulants, antithrombotics or antiplatelet agents, previous treatment with 
investigational drugs within 4 weeks prior to anticipated study drug administration. 
 
NOTE: Potential subjects with abnormal laboratory values may be re-screened for specific laboratory 
tests within the screening period (the 45 days prior to dosing) before being designated a screen failure.  
Repeat values within the normal range will be acceptable for inclusion. Additionally, if a subject should 
have an acute illness within 4 weeks of the first anticipated dose, the PI will discuss with the DSMB 
about the potential to delay treatment until the illness has resolved. 
 


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7.4 
Completion of a Subject’s Participation in the Study 
 
The length of a subject’s participation will be from the time the informed consent form is signed until 
completion of the End of Study (Week 48) visit (up to 60 weeks). 
 
7.5 
Subject Withdrawal Criteria 
 
Any subject can withdraw from study participation at any time for any reason. In addition, the Study 
Sponsor/Investigator may stop the study participation of any subject at any time. Reasons for study 
withdrawal include but are not limited to: 
 
• 
The subject was erroneously included in the study (i.e. was found to have not met the 
eligibility criteria). 
• 
The subject is unable to comply with the requirements of the protocol. 
• 
The subject participates in another investigational study without the prior written 
authorization of the Study Sponsor. 
• 
The subject experiences an intolerable or unacceptable AE. 
 
 
The Investigator or study staff will document the reason(s) for treatment discontinuation on the case 
report form (CRF). 
 
Subjects who have received at least (1) one dose of study treatment and who are withdrawn from 
treatment within 28 days after a functional assessment visit will not be asked to return for an End of 
Study visit (to complete the Week 48 assessments. Subjects who receive at least one (1) dose of study 
treatment who are withdrawn from treatment more than 28 days after a functional assessment visit will 
be asked to complete all early termination (Week 48) assessments within approximately 28 days of 
withdrawal. 
 
Subjects withdrawn from treatment will not be replaced. 
7.6 
Study Discontinuation 
 
If the Study Sponsor/Investigator, the DSMB, the study monitor, institutional review board/independent 
ethics committee(s) (IRB), and/or appropriate regulatory officials discover conditions arising during the 
study that indicate the study should be halted or that the study center should be terminated, appropriate 
action may be taken after consultation among (at a minimum) the Study Sponsor/Investigator, IRB and 
the DSMB. 
 
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 subjects enrolled in the 
study 
• 
A decision by the Drug Manufacturer to suspend or discontinue testing, 
evaluation, or development of the IP 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent regulations of IRB or 
appropriate regulatory authorities 


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• 
Failure of the Investigator to comply with the protocol 
• 
Submission of knowingly false information from the research facility to the DSMB, the 
study monitor, IRB or regulatory authorities 
• 
Insufficient adherence to protocol requirements consistent with 21 CFR 312 or the 
European Clinical Trial Directive 2001/20/EC 
 
 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
International Conference on Harmonisation (ICH) E6 on Good Clinical Practice (GCP) as well as 21 
CFR 312.56b and the European Clinical Trial Directive 2001/20/EC which require an Investigator’s 
compliance with these requirements and to promptly secure a plan for compliance or discontinue 
shipment of the IP to the Investigator and end the Investigator’s participation in the study. 
8 TREATMENT OF SUBJECTS 
8.1 
Investigational Products 
 
The Investigational Products (IPs) (casimersen, eteplirsen, and golodirsen injection) are supplied as 
concentrated sterile solutions, which are diluted with 0.9% sodium chloride injection prior to 
administration via an IV infusion. 
 
Casimersen, eteplirsen, and golodirsen injections are sterile, clear, colorless, isotonic, phosphate- 
buffered saline (PBS) solutions supplied in single-use 2-mL glass vials containing 2 mL of casimersen, 
eteplirsen, or golodirsen at a concentration of 50 mg/mL. 
8.1.1 Packaging and Labeling 
Please refer to the Clinical Study Manual of Operations for information on packaging and labeling. The 
label text for the study treatments will comply with applicable regional, national, and local laws and 
regulations and will include at a minimum the contents of the  vial, the appropriate regional cautionary 
statements, lot number, storage conditions, and the name of the Drug Provider (Sarepta Therapeutics, 
Inc.). 
8.1.2 Storage 
 
Store the study treatment at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light and store in 
the original carton until ready for use. 
 
Vials of study treatment must be stored in a secured, limited-access area with appropriate temperature 
recording, controls, and monitoring. Details for study treatment handling, storage and for preparation of 
the diluted study treatment for administration can be found in the study-specific Clinical Study Manual 
of Operations. 
8.2 
Treatments Administered 
 
Eligible subjects will receive a weekly IV infusion of study treatment (30 mg/kg of casimersen, eteplirsen, 
or golodirsen, according to genotype) for up to 48 weeks. Subjects will be transitioned to the Sarepta 
Clinical TransitionProgram/SareptAssist after the study period for continuous weekly drug access while 
study sample analysis is pending. 
 
The dose of casimersen, eteplirsen, or golodirsen will be calculated based on the most recent subject 
weight obtained at the site prior to the current visit. Infusion solutions of casimersen, eteplirsen, or 


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golodirsen are to be prepared by following the steps detailed in the study-specific Clinical Study 
Manual of Operations. 
 
• 
Study treatment will be administered as an IV infusion over a period of approximately 35 
to 60 minutes. Patients are to be closely monitored for at least 1 hour following the 
completion of all infusions. It is recommended that a topical anesthetic cream (e.g. 
lidocaine 2.5%, prilocaine 2.5%, LMX4 cream, or other per the Investigator’s discretion) 
be applied to the infusion site prior to each administration of study treatment. Additional 
administration and IP details are available in the study-specific Clinical Study Manual of 
Operations. 
 
An implanted venous access port may be inserted for study treatment administration at the discretion of 
the Investigator. After study treatment administration and the saline flush, the port may be flushed with 
heparin to heplock the port prior to removal of the infusion line. If study treatment is administered into 
an existing IV line, the line must be flushed with normal saline before and after administration of study 
treatment. 
Subjects will have vital signs measured on infusion days within approximately 30 minutes prior to 
infusion and approximately 5, 30, and 60 minutes after the end of the infusion. At each infusion, 
conconmittant medications and adverse events will be reviewed. 
No other medications may be administered concomitantly during the study treatment infusion. All 
subjects will be observed for at least 1 hour following the end of each infusion.  
The following guidelines for the timing of dosing are to be followed throughout the study: 
 
1. Subjects should receive study treatment once every 7 days starting at the Week 1 Visit. 
2. After the first infusion, a window of ±2 days around the scheduled weekly dosing date 
(referenced back to the first dose at Week 1) is acceptable. 
3. Subjects may not receive 2 separate doses of study treatment within the same 60-hour 
period. 
4. The Principal Investigator is to be contacted in the event of a missed dose. 
 
8.2.1 Dose Modification, Reduction, or Delay 
 
There is no provision for dose alteration in this study. If a subject experiences an AE that requires 
interruption of administration for ≥2 consecutive doses, the Investigator will consult with the DSMB to 
determine whether the subject may resume treatment.  
8.3 
Prior and Concomitant Medications 
 
Oral corticosteroids, including but not limited to prednisolone and prednisone, for treatment of DMD are 
required for boys older than 5 years during the course of this study. Subjects entering the study on 
corticosteroids must have been on a stable dose (or dose equivalent) of oral corticosteroids for at least 12 
weeks prior to the first administration of study treatment at Week 1. If clinically necessary, subjects may 
be allowed to change the corticosteroid compound as long as equivalent dosing is maintained. 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. 
 


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Provided they have been on a stable dose for at least 12 weeks prior to Week 1 and the dose is expected 
to remain constant throughout the study, subjects are allowed to take other medications including: 
• 
Oral ACE inhibitors, including but not limited to perindopril and lisinopril 
• 
Oral β adrenergic 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 preparations such as herbal supplements, vitamins, minerals, and 
homeopathic preparations 
 
Other concomitant medications (excluding other RNA antisense or gene therapy agents) may also be 
taken if, in the opinion of the Investigator, they do not interfere with study assessments and outcomes. 
The Investigator is to contact the DSMB if he/she is unsure of the impact of a concomitant medication 
on study assessments and outcomes. Every attempt should be made to keep the dosage constant 
throughout the treatment period (i.e. through Week 48), although modifications to accommodate 
changes in weight are permitted. 
 
It is recommended that introduction of new physiotherapy interventions during the course of the study 
be avoided unless the best interests of the subject are at stake. Should a contracture develop during the 
course of the study, and it is considered in the best interest of the subject to treat the contracture, then 
any of the following interventions may be used to reduce the contracture, but they must be clearly 
documented: 
• 
Stretching exercises (passive, active, self) 
• 
Night splints 
• 
Contracture control device 
• 
Serial casting 
 
The following therapies are not permitted during the conduct of this study: 
• 
Systemic or oral steroids for non-DMD conditions that, in the Investigator’s opinion, could 
interfere with study assessments and outcomes 
• 
Other 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 
• 
Immunosuppressants (other than oral or systemic corticosteroids, as outlined) 
• 
Systemic aminoglycoside antibiotics (unless discussed and agreed upon with the 
Investigator and the DSMB) 
• 
Statins (unless discussed and agreed upon with the Investigator and DSMB) 
 
8.4 
Treatment Compliance 
 
Treatment compliance will be assessed via compliance with scheduled weekly infusions. 
9 STUDY VISITS 


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The schedule outlining the study assessments and times of assessments is shown in Section 9.9 and all 
procedures are described in detail in Section 10. All assessments scheduled on the same day as study 
treatment administration are to be completed prior to initiation of study treatment infusion. 
 
9.1 
Screening and Baseline (Approximately 8 weeks prior to Week 1) 
 
9.1.1 Informed Consent 
Subjects and/or parent(s)/legal guardian(s) will be invited to review and sign the Informed Consent Form 
(ICF) and assent (if applicable) to participate in this trial prior to the collection of any data and any study 
related procedures. Overall study requirements and details surrounding Screening and Baseline 
assessments are reviewed by the subject and their parent(s)/guardian(s) during this process. Baseline 
measures from subjects will be obtained prior to infusion.  
 
If there are changes to the study that affect the consent or assent, parents and or the subject will be 
reconsent/assented at their next visit. 
9.1.2 Screening 
The screening evaluations will take place over two visits to allow time for assessement of all available 
criteria before the subject undergoes sedation. 
9.1.2.1 Screening Day 1 
The following assessments will occur at this visit: 
• 
Informed Consent 
• 
Assent, if applicable 
• 
Medical history 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Weight 
 
The following blood lab work will occur at this visit: 
• 
Hepatitis B, C and HIV 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehydrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
• 
Genotyping of DMD, if not previously done 
The following urine lab work will occur at this visit: 


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• 
Urinalysis 
9.1.2.2 Screening Day 2 
The following will be assessed at this visit: 
• 
Adverse Events 
• 
Concommitant Medications  
• 
ECHO 
• 
ECG 
• 
Bayley scale of Infant Development (6 to 36 months of age) 
• 
100M – ambulant subjects (3.5 years until non-ambulant) 
• 
NSAA (3 years to non-ambulant) 
• 
Active-seated – non ambulant subjects (5 years and older) 
• 
Pulmonary functional test (PFT) (10 years and older) 
• 
Timed functional tests for (ambulant subjects 3 years and older) 
• 
Pediatric Outcomes Data Collection Instruments (PODCI, ages 2-17) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extermity 
Report (ages 18+) 
• 
Assessment of inclusion and exclusion criteria 
• 
Height 
 
9.1.3 Baseline  
The baseline visit should occur 3-5 weeks after screening is completed and will occur over two days. 
9.1.3.1 Day 1 
The following assessments will occur at this visit: 
• 
Confirmation of eligibility 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Height 
• 
Weight 
• 
ECG 
• 
Bayley scale of Infant Development (6 to 36 months of age) 
• 
100M – ambulant subjects (3.5 years until non-ambulant) 
• 
NSAA (3 years to non-ambulant) 
• 
Active-seated – non ambulant subjects (5 years and older) 
• 
Pulmonary functional test (PFT) (10 years and older) 
• 
Timed functional tests for (ambulant subjects 3 years and older) 
• 
Pediatric Outcomes Data Collection Instruments (PODCI, ages 2-17) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extermity 


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Report (ages 18+) 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
9.1.3.2 Day 2 
A baseline open muscle biopsy will be performed in one gastrocnemius muscle or alternate muscle.  (Note 
that the rationale and methods of muscle biopsy site selection and performance for this and subsequent 
biopsies are discussed in Section 10.2.1). If in the discretion of the principal investigator, an implanted 
venous access port needs to be placed prior to infusion, this placement may occur at the same time as the 
muscle biopsy. RNAseq analysis will be completed on tissue from this muscle biopsy. 
If in the opinion of the Principal Investigator, a PORT placement is indicated, all attempts will be made to 
have this  occur during this same sedation event (see Section 8.2 for full details), but if it is not feasible, a 
separate visit will be scheduled to place the port. 
9.2 
Week 1 
Week 1 should occur within 4 weeks of the Baseline Functional Assessment Visit. If the Week 1 visit is > 
4 weeks after Baseline, the subject is required to repeat the Baseline functional assessments to reconfirm 
eligibility. 
Infusion with the study drug will begin at Week 1 and will occur weekly through the week 48 visit. For 
details regarding the infusion, please see Section 8.2. 
The following assessments will occur at this visit: 
• 
Confirmation of eligibility 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Weight 


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• 
Infusion 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
9.3 
Week 4 (+/- 1 week) 
The following assessments will occur at this visit: 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Weight 
• 
Infusion 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 


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9.4 
Week 8 (+/- 1 week) 
The following assessments will occur at this visit: 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Brief Physical Exam 
• 
Vital Signs 
• 
Weight 
• 
Infusion 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
 
9.5 
Weeks 12 and 36 (Functional Assessment Visits) (+/- 1 week) 
The following assessments will occur at this visit: 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Height 
• 
Weight 
• 
ECG 
• 
Bayley scale of Infant Development (6 to 36 months of age) 
• 
100M – ambulant subjects (3.5 years until non-ambulant) 
• 
NSAA (3 years to non-ambulant) 
• 
Active-seated – non ambulant subjects (5 years and older) 
• 
Pulmonary functional test (PFT) (10 years and older) 


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• 
Timed functional tests for (ambulant subjects 3 years and older) 
• 
Pediatric Outcomes Data Collection Instruments (PODCI, ages 2-17) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extermity 
Report (ages 18+) 
• 
Infusion 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
 
9.6 
Weeks 16, 20, 28, 32, 40 and 44 (+/- 1 week) 
The following assessments will occur at this visit: 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Brief Physical Exam 
• 
Vital Signs 
• 
Weight 
• 
Infusion 
 
9.7 
Week 24 (Functional Assessment Visit) (+/- 1 week) 
The following assessments will occur at this visit: 
• 
Study drug infusion 
• 
Medical history 
• 
Adverse Events 
• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 


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• 
Height 
• 
Weight 
• 
ECHO 
• 
ECG 
• 
Bayley scale of Infant Development (6 to 36 months of age) 
• 
100M – ambulant subjects (3.5 years until non-ambulant) 
• 
NSAA (3 years to non-ambulant) 
• 
Active-seated – non ambulant subjects (5 years and older) 
• 
Pulmonary functional test (PFT) (10 years and older) 
• 
Timed functional tests for (ambulant subjects 3 years and older) 
• 
Pediatric Outcomes Data Collection Instruments (PODCI, ages 2-17) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extermity 
Report (ages 18+) 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
 
9.8 
Week 48 (or Early Termination Visit, if more than 28 days after a Functional Assessment 
Visit) (+/- 1 week) 
 
Early termination assessments are the same as Week 48 assessments. An Early Termination visit is 
required if the patient discontines more that 28 days after a Functional Assessment visit (Week 12, 24 or 
36) The evaluations will take place over two visits. 
 
 
9.8.1 Day 1 
 
The following assessments will occur at this visit: 
• 
Medical history 
• 
Adverse Events 


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• 
Concommitant Medications 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Height 
• 
Weight 
• 
Infusion 
• 
ECHO 
• 
ECG 
• 
Bayley scale of Infant Development (6 to 36 months of age) 
• 
100M – ambulant subjects (3.5 years until non-ambulant) 
• 
NSAA (3 years to non-ambulant) 
• 
Active-seated – non ambulant subjects (5 years and older) 
• 
Pulmonary functional test (PFT) (10 years and older) 
• 
Timed functional tests for (ambulant subjects 3 years and older) 
• 
Pediatric Outcomes Data Collection Instruments (PODCI, ages 2-17) 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extermity 
Report (ages 18+) 
The following blood lab work will occur at this visit: 
• 
Complete Metabolic Panel (CMP) 
• 
Amylase 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Complete Blood Count (CBC)/Differential 
• 
Coagulation Measures 
• 
Uric Acid 
• 
Lactate dehudrogenase (LDH) 
• 
C-reactive Protein (CRP) 
• 
Creatine Kinase (CK) 
• 
Cystatin C 
 
The following urine lab work will occur at this visit: 
• 
Urinalysis 
 
9.8.2 Day 2 
 
A post-treatment open muscle biopsy will be performed in one gastrocnemius muscle.  (Note that the 
rationale and methods of muscle biopsy site selection and performance for this and subsequent biopsies are 
discussed in Section 10.2.1). RNAseq analysis will be completed on tissue from this muscle biopsy. 
Subjects should have the muscle biopsy performed following the Week 48 infusion and functional 
assessments. The biopsy at Week 48 must occur within 2 weeks after the Week 48 visit and  at least 48 
hours after the most recent infusion. 


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9.9 
Schedule of Events 
Table 6 
 
 
 
 
 
 
Study Period
Baselineg
(3-5 weeks after 
Screening)
Week #
1a
4
8
12
16
20
24
28
32
36
40
44
48/
ETb,e
Visit #
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Informed consent/Assentf
X
Assess Inclusion/Exclusion Criteria
X
Confirm Eligbility
X
X
Medical History
Adverse Events
Concomitant Medications 
Study Treatment
Port Placement
Xf
Muscle Biopsy
X
Xh
RNAseq
X
X
Full Physical Exam 
X
X
X
X
X
X
X
X
Brief Physical Exam
X
X
X
X
X
X
X
Vital Signsc
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
ECHO
X
X
X
ECG
X
X
X
X
X
X
Antibody testing Hep. B, C and HIV
X
CMP
X
X
X
X
X
X
X
X
X
Amylase
X
X
X
X
X
X
X
X
X
GGT
X
X
X
X
X
X
X
X
X
CBC/Diff
X
X
X
X
X
X
X
X
X
Coagulations
X
X
X
X
X
X
X
X
X
Uric Acid
X
X
X
X
X
X
X
X
X
Lactate dehydrogenase (LDH)
X
X
X
X
X
X
X
X
X
C-reactive Protein (CRP)
X
X
X
X
X
X
X
X
X
Creatine Kinase (CK)
X
X
X
X
X
X
X
X
X
Cystatin C
X
X
X
X
X
X
X
X
X
Genotyping for DMD  mutation, if not 
previously done
X
Urinalysis
X
X
X
X
X
X
X
X
X
Bayley Scale of Infant Development
X
X
X
X
X
X
100 M
X
X
X
X
X
X
NSAA
X
X
X
X
X
X
Active Seated
X
X
X
X
X
X
Timed Function Tests
X
X
X
X
X
X
PFT
X
X
X
X
X
X
PODCI
X
X
X
X
X
X
PROMIS
X
X
X
X
X
X
g. All assessments that are to occur on the same day as an infusion will be completed prior to the infusion. 
h. The week 48 muscle biopsy must occur withing 2 weeks of the week 48 visit and at least 48 hours post the most recent 
infusion. 
e. Visit will occur over multiple days
a. Week 1 should occur within 4 weeks of the Baseline Functional Assessment Visit. If the Week 1 visit is > 4 weeks after Baseline, 
the subject is required to repeat the Baseline functional assessments to reconfirm eligibility.
d. If there are changes to the study that affect the consent or assent, parents and or the subject will be reconsented/assented at 
their next visit.
f. A PORT will be placed per Principal Investigator discretion.
TREATMENT WITH CASIMERSEN, ETEPLIRSEN, OR GOLODIRSEN STUDY TIMELINE
Screeningg
b. Early termination assessments are the same as Week 48 assessments. An Early Termination visit is required if the patient 
discontinues more that 28 days after a Functional Assessment visit (Week 12, 24 or 36)
c. During infusion visits, vitals will be measured approximately 30 minutes prior to infusion and approximately 5, 30,  and 60 
minutes after the end of the infusion. At all other visits, vitals will be measured only once. 
Approximately 8 Weeks
 prior to Week 1
Treatment Period
Continuous (Weekly)
Once Weeklyg
1
Continuous (Weekly)
Once Weekly
Continuous (Weekly)


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9.10 Muscle and Strength Test Schedule 
Table 7 
  
 
10 STUDY PROCEDURES 
10.1 Safety Assessments 
10.1.1 Adverse Events 
 
The collection of adverse events is described in Section 11. 
 
10.1.2 Clinical Laboratory Evaluations 
 
The following routine clinical laboratory tests will be performed at the time points specified in Section 
9. Safety samples will be collected analyzed by an accredited central laboratory: 
 
Hematology: 
White blood cells (WBC), hemoglobin, hematocrit, platelets, red blood cells 
(RBCs), neutrophils, lymphocytes, monocytes, eosinophils, basophils, and 
any abnormal cells 
Coagulation: 
Prothrombin time, international normalized ratio (INR), and activated 
partial thromboplastin time (aPTT) 
Chemistry: 
Complete Metabolic Panel [CMP,  including: sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen (BUN), creatinine, glucose, calcium, 
total protein, albumin, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and alkaline phosphatase)], amylase, 
gamma-glutamyl transferase (GGT), uric acid, lactate dehydrogenase 
(LDH), C-reactive protein (CRP), creatine kinase (CK), and serum cystatin 
C 
Immunology: 
Hepatitis B, C and HIV 
Urine: 
Urinalysis (including: specific gravity, pH, cytology, hemoglobin, protein, 
glucose, and ketones) 
* For subjects taking drugs that potentially induce GGT synthesis through the cytochrome P450 system, the 
clinically significant range will be estimated at two times the levels obtained from the baseline screening test. 
 
6 mos - 3 yrs 3 - 3.5 yrs
3.5 - 4.9 yrs 5 - 9.9 yrs
10 yr Until
Non-Ambulant
Non-
Ambulant
Bayley
Timed Functional 
Tests
NSAA
100 meter
ACTIVE
PFTs
Number of 
Assessments
1
3
3
4
5
3


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Any value outside of the current reference ranges for the laboratory performing the test will be flagged 
on the laboratory results. The Investigator will determine whether abnormal assessment results are 
clinically significant (CS) or not clinically significant (NCS). Clinical significance is defined as any 
variation in assessment results that has medical relevance resulting in an alteration in medical care. If 
clinically significant deterioration from Baseline levels is noted, the Investigator will continue to 
monitor the subject with additional assessments until: 
 
• 
Values have reached normal range and/or Baseline levels 
 
10.1.3 Electrocardiogram 
 
Twelve-lead ECGs will be obtained at the time points specified in Section 9. ECGs will be performed 
at a consistent time of day throughout the study. ECGs will be performed only after the subject is in 
the supine position, resting, and quiet for a minimum of 15 minutes. The ECG will be manually 
reviewed and interpreted by medically qualified personnel according to pre-specified criteria. The 
Investigator will review the results and determine if the findings are clinically significant. 
 
10.1.4 Echocardiogram 
 
A standard 2-dimensional (2D) ECHO will be obtained at the time points specified in Section 9. ECHOs 
will be performed at a consistent time of day throughout the study. The ECHO will be reviewed and 
interpreted by medically qualified personnel according to pre-specified criteria. Ejection fraction (EF) 
will be noted. The Investigator will review the results of the ECHO report and determine if the findings 
are clinically significant. 
 
10.1.5 Vital Signs, Weight, and Height 
 
Vital signs (blood pressure, heart rate, respiration, and temperature) and weight will be measured at the 
time points specified in Section 9. 
 
For infusion visits, vital signs are to be collected within approximately 30 minutes prior to infusion 
and approximately 5, 30, and 60 minutes after the end of the infusion. All assessments will be 
performed after subjects have remained seated for 5 minutes. Heart rate and respiratory rate are to be 
measured over 1 minute. 
 
Temperature is to be recorded in degrees Celsius (°C). 
 
Weight is to be recorded in kilograms. If a subject’s weight varies by more than 10% from the prior 
visit, the subject is to be re-weighed to confirm the result, and an explanation of the change must be 
documented. 
Height will be measured at the time points specified in Section 9. Height is to be measured with shoes 
off. If standing height cannot be obtained, height is to be calculated using the following equation30: 
 
Height (cm) = 4.605U + 1.308A + 28.003 
 
where U is the length of the ulna in centimeters measured using an anthropometer or calipers, and A 
is the subject’s age in years. 


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10.1.6 Adverse Events 
Adverse Events will collected by the Investigator or qualified staff at the time points specified in Section 
9. 
 
10.1.7 Medical History 
 
A full medical history will be conducted by the Investigator or qualified study staff at the time points 
specified in Section 9. Special attention will be paid to any fracture history.   
 
10.1.8 Physical Examination 
 
Physical examinations, full and brief, will be conducted at the time points specified in Section 9. 
Physical examinations will be performed by the Investigator or qualified study staff.  
10.1.8.1 Full Physical Exam 
Full physical examinations will include examination of general appearance, head, eyes, ears, nose, and 
throat (HEENT), heart, chest, abdomen, skin, lymph nodes, extremities, musculoskeletal, and 
neurological systems.  
10.1.8.2 Brief Physical Exam 
Brief physical examinations will include examination of general appearance, HEENT, heart, chest, 
abdomen, and skin. 
 
10.1.9 Concomitant Medications and Therapies 
 
The PI will encourage participants to maintain the medication and supplements they are on at enrollment 
through the course of the study.  Subjects on aspirin or drugs that could affect coagulation will continue 
their medication as indicated.  Several investigations show that preoperative aspirin ingestion and 
intravenous heparin therapy can be administered safely without concerns about the risk of postoperative 
bleeding and should not lead to modification or cessation of such therapy. 
 
10.2 Efficacy Assessments 
10.2.1 Functional Assessments 
Details about how each assessment is performed is provided in the Clinical Evaluator Manual. 
10.2.1.1 Bayley Scales of Infant Development 
The Bayley Scales of Infant & Toddler Development – 3rd edition is a standardized, norm-reference 
assessment of infant and toddler development.   It is intended for use between the ages of 1 to 2 months, 
inclusive (to be used only if age of enrollment is 1 to 36 months).   It can also be used as a developmental 
checklist in older children with developmental delay, such as boys with Duchenne Muscular 
Dystrophy.   It has five domains of development (cognitive, receptive and expressive communication and 
gross and fine motor).   
 
 


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10.2.1.2 North Star Ambulatory Assessment (NSAA) 
 
The NSAA will be performed at the time points specified in Section 9. The NSAA is a clinician-
administered scale that rates subject performance on various functional activities31. For subjects older 
than 3 years old, the NSAA will be administered as long as the subject remains ambulant. 
During this assessment, subjects will be asked to perform 17 different functional activities, including a 
10 m walk/run, rising from a sit to stand, standing on 1 leg, climbing a box step, descending a box step, 
rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. 
Subjects will be graded as follows: 2 = achieves goal without any assistance; 1 = modified method but 
achieves goal independent of physical assistance from another person; and 0 = unable to achieve goal 
independently. A revised scored is provided for children from 36 to 60 months. 
10.2.1.3 100-Meter Walk / Run Test (100M) 
 
The 100M will be performed at the time points specified in Section 9 starting at ages 3.5 years until 
nonambulant. In the 100-metre Walk/Run Time test the subject is asked to complete 4 laps on a 25 m 
track, for a total of 100 meters as quickly as safely possible. If the subject is able to run, he is 
encouraged to do so. The total time spent to complete the task is recorded. 
10.2.1.4 ACTIVE-Seated Test 
 
The ACTIVE-Seated Test will be performed at the time points specified in Section 9 for subjects 5 years 
and older.  
10.2.1.5 Pulmonary Functional Testing (PFT): 
 
The PFT will be performed at the time points specified in Section 9 in subjects 10 years and older. The 
PFT involves assessing maximal lung function with both a spirometer and respiratory pressure meter. 
The Forced Vital Capacity (FVC) is reported on the subject’s CRF.  
10.2.1.6 Timed Functional Test 
Timed functional tests will be conducted in subjects 3 years and older. 
10.2.1.6.1 Time 4-Step Test 
 
The Timed 4-Step Test will be performed at the time points specified in Section 9. Timed 4-stair climb 
quantifies the time required for the patient to ascend and descend four standard stairs (6” height for each 
step). 
10.2.1.6.2 10-meter Walk Run (10MWR) 
 
The 10MWR will be performed at the time points specified in Section 9. The time it takes the subject 
to move will be recorded. 
10.2.1.6.3 Rise Time 
 
Rise Time will be recorded at the time points specified in Section 9. The time it takes the subject to rise 
from supine will be recorded. 
 
 


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10.2.2 Quality of Life Assessment: PODCI 
 
Quality of life will be evaluated for subjects at the time points specified in Section 9using the PODCI, a 
parent-reported measure of quality of life for children with acute or chronic illnesses. The PODCI has 
been used to evaluate health-related quality of life in subjects with DMD32, 33. The 86-item instrument 
generates 8 scales including upper extremity and physical function scale, transfer and basic mobility 
scale, sports/physical functioning scale, pain/comfort scale, treatment expectations scale, happiness 
scale, satisfaction with symptoms scale, and global functioning scale32, 34. 
10.2.3 Quality of Life Assessment: PROMIS 
The Patient-Reported Outcomes Measurement Information System (PROMIS) is a collection of patient-
reported measures assessing various domains of physical, mental, and social health.  PROMIS tools 
were developed in collaboration with NIH and are considered psychometrically-sound instruments 
created to be relevant across conditions and symptoms.  The PROMIS Upper Extremity questionnaire 
assesses self-reported performance of 16 upper extremity tasks with higher scores indicating higher 
function with a maximum  score of 80 points. 
10.2.4 Muscle Biopsy 
 
Upon qualification for the study based on Screening and Baseline assessments, all subjects will undergo 
two muscle biopsies at Baseline and Week 48.  
The Baseline muscle biopsy may be obtained as soon as eligibility is confirmed (i.e. Baseline assessment 
is complete and genotype is confirmed), prior to the first dose of study treatment. The first dose of study 
treatment must be within 4 weeks of the Baseline Functional Assessment visit. Muscle biopsy surgery 
must be performed within the 4-week window between the Baseline Functional Assessment visit and 
Week 1. Subjects will not begin to receive study treatment until after the Baseline muscle biopsy has 
been performed. 
 
The Baseline muscle biopsy will be obtained from one gastrocnemius muscle and the subsequent 
muscle biopsy will be obtained from the contralateral muscle. A previously unbiopsied alternative 
upper leg muscle may be used if the gastrocnemius has been biopsied previously. If an alternative 
muscle is used, the same contralateral muscle will be biopsied at the subsequent muscle biopsy. 
The Biopsy at Week 48 must occur within 2 weeks after the week 48 visit  and at least 48 hours after 
the most recent infusion. 
 
All analyses related to quantification of dystrophin protein will be performed at the conclusion of the 
study. 
 
Tissue samples may be stored for a maximum of 15 years and may be used for research at a later time 
(Long term follow-up). 
10.2.4.1 RNAseq Analysis 
The efficiency of splicing alteration will be assessed by RNA Sequencing (RNA-Seq).  Data will be 
analyzed to establish DMD mRNA copy number, and the exon-exon junction frequency quantified, with 
normalization to exon junction read values from exon junctions in regions distinct from the targeted exon. 
10.3 Additional Assessments 
10.3.1 Genotype Confirmation 
If a subject does not have a previously acceptable genetic report stating their mutation, blood will be 
collected to send out for genetic mutation analysis of DMD.  


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11 ADVERSE EVENTS AND SAFETY REPORTING 
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 subject 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 End of Study visit (or early termination from the 
study) will be recorded in each individual subject’s CRF. For subjects who prematurely discontinue the 
study (see Section 7.5), AEs will continue to be recorded until 28 days after the last study treatment 
infusion.  
11.2 Definition of Adverse Events 
 
11.2.1 Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a clinical trial participant, which does not necessarily 
have a causal relationship with the investigational drug. An AE can, therefore, be any unfavorable and 
unintended symptom, sign, disease, condition, or test abnormality that occurs during or after 
administration of an IP whether or not considered related to the IP. Adverse events include: 
 
• 
Symptoms described by the subject 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 Screening 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 subject died as the result of the event. 
 
• 
Life-threatening event: Any AE that places the subject, in the view of the Sponsor-
Investigator, 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 insubject hospitalization: The AE resulted in hospitalization or 
prolonged an existing hospitalization. Since hospitalization may be part of the study, only 
hospitalizations that are longer than expected based on Investigator judgment, will be 
considered prolonged hospitalizations. 
 
• 
Persistent or significant disability/incapacity: An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
 


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• 
Congenital anomaly/birth defect: A congenital anomaly/birth defect that occurs in the 
offspring of a subject exposed to the IP. 
 
• 
Important medical events: An AE that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
11.3 Classification of Adverse Events 
 
Each AE whether serious or non-serious will be classified by the Investigator according to the 
following rules and definitions. 
 
11.3.1 Relationship to Investigational Product 
 
For each AE, the Investigator will determine 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 study treatment 
Possibly/probably related: 
The event could be related/is likely to be related to the study 
treatment 
Definitely related: 
The event is clearly related to the study treatment 
 
11.3.2 Relationship to Study Procedures 
 
For each AE the Investigator will determine whether there is a reasonable possibility that the AE may 
have been caused by the study procedures according to the categories below: 
 
Unrelated: 
The event is clearly not related to the study procedures 
Possibly/probably related: 
The event could be related/is likely to be related to study 
procedures 
Definitely related: 
The event is clearly related to the study procedures 
11.3.3 Relationship to Underlying Disease 
 
For each AE the Investigator will determine whether there is a reasonable possibility that the AE may 
be related to the underlying disease according to the categories below: 
 
Unrelated: 
The event is clearly not related to the underlying disease 
Possibly/probably related: 
The event could be related/is likely to be related to the 
underlying disease 


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Definitely related: 
The event is clearly related to the underlying disease 
 
Events of disease progression may be considered AEs, based on the Investigator’s discretion. 
 
11.3.4 Severity of Adverse Events 
 
Note that severity is not the same as “seriousness,” which is defined in Section 11.2.2 and which serves 
as a guide for defining regulatory reporting obligations. 
 
The Investigator will assess the severity of all AEs as Mild, Moderate, or Severe, based on the following 
definitions: 
 
Mild: 
The event does not interfere with the subject’s usual activities. 
Moderate: 
The event interferes with the subject’s usual activities. 
Severe: 
The event prevents the subject from undertaking their usual activities and requires 
therapeutic intervention or cessation of the study treatment. 
 
11.3.5 Outcome 
 
Outcome describes the status of the AE. The Investigator will provide information regarding the subject 
outcome of each AE. 
 
11.3.6 Action Taken Regarding the Investigational Drug Product 
 
The Investigator will provide information regarding the action taken with respect to the study treatment in 
response to the AE. 
 
11.3.7 Expectedness of an Adverse Event 
The expectedness of all AEs will be determined according to the most recent versions of the 
Investigator’s Brochures for casimersen and the prescribing information for eteplirsen and golodirsen. 
 
11.3.8 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected unexpected serious adverse reactions (SUSARs) will be handled by appropriate Study 
Sponsor or designee personnel and reported within the required timelines in an unblinded fashion 
to regulatory authorities and IRB per the requirements of the concerned competent authorities.  
 
11.3.9 Adverse Event Reporting 
 
Only Treatment Emergent Adverse Events (TEAEs) will be summarized in reports. Non-emergent events 
will be recorded in data listings. For all AE tables, the number and percent of subjects reporting AEs 
(grouped by the Medical Dictionary for Regulatory Activities [MedDRA] System Organ Class [SOC] 
and Preferred Term [PT]) will be summarized by treatment group. In general, tables will have events 
categorized into all TEAEs and treatment-related TEAEs.  Treatment-related TEAEs will be defined as 
those that the Investigator considers possibly/probably or definitely related to the study treatment. 
 


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Multiple occurrences of the same AE (at the PT level) in the same subject will be counted only once in 
frequency tables. If a subject experiences multiple episodes of the same event with different 
relationship/severity, the event with the strongest relationship and maximum severity to study treatment 
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 
• 
Deaths 
 
In addition, all SAEs regardless of their treatment-emergent status will be summarized by SOC and PT. 
 
The following listings will be produced: 
• 
Non-treatment emergent AEs 
• 
All TEAEs 
• 
AEs leading to discontinuation 
• 
SAE 
11.4 Recording Adverse Events 
 
All AEs/SAEs experienced from the time of informed consent/assent to the last follow-up visit will be 
recorded within each subject’s CRF. For patients who prematurely discontinue from the study (Section 
7.6), AEs will continue to be recorded until 28 days after the last study treatment infusion. 
Information should include: a concise description of the event; date of event onset and resolution; 
determination of seriousness, severity, corrective treatment, outcome, and relationship to IP or study 
procedure or underlying disease; and any action taken will be recorded. Resolution occurs when the 
subject has returned to his Baseline state of health or further improvement or worsening of the event is 
not expected. 
 
Whenever possible, a diagnosis will be recorded as an AE, rather than symptoms or isolated laboratory 
abnormalities related to that diagnosis. Several symptoms or laboratory results that are related to the 
same diagnosis can thus be part of the same AE.  
A medical or surgical procedure is not an AE; rather the condition leading to the procedure should be 
recorded as the AE. Similarly, death is not an AE, but is rather the outcome of the AE(s) that resulted in 
death. If the AE(s) leading to death are not known, then death must be reported as an AE. All AEs will 
be followed until the resolution of AE, completion of the subject’s study participation, or study 
termination, whichever occurs first. SAEs will be followed until resolution or until the condition 
stabilizes or returns to Baseline status. 
 
11.5 Safety Reporting 
 
The investigator or his designee will report all serious adverse events according to the following: 
 
DSMB: The Investigator or his/her designee will report SAEs to the DSMB within the below timeframe:  


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o Any serious adverse event that is fatal or life-threatening and possibly, probably, or 
definitely related to one of the investigational products, regardless of expectedness, will 
be reported to the DSMB within 5 business days of initial receipt of the information.  
o Any serious adverse event that is unexpected and possibly, probably, or definitely related 
with the use of one of the investigational products (SUSAR), but is not fatal or life-
threatening, will be reported within 5 business days of initial receipt of the information.   
 
FDA: The Investigator or his/her designee will report SAEs to their FDA Investigator-Initiated IND 
within the below timeframe: 
o Any serious adverse event that is fatal or life-threatening and unexpected and possibly, 
probably, or definitely associated with the use of one of the investigational products 
(SUSAR) will be reported as soon as possible, but in no case later than 7 calendar days 
after initial receipt of the information.  
o Any serious adverse event that is unexpected and possibly, probably, or definitely 
associated with the use of one of the investigational products (SUSAR), but is not fatal 
or life-threatening, will be reported as soon as possible, but in no case later than 15 
calendar days after initial receipt of the information. 
o If, after further evaluation, an unexpected serious adverse event that is initially 
considered not to be associated with the use of one of the investigational products is 
subsequently determined to be associated, then the event will be reported as soon as 
possible, but in no case later than 15 calendar days after the determination is made. 
 
IRB: The Investigator or his/her designee will report SAEs to the IRB within the below timeframe: 
o Any serious adverse event that is unexpected and possibly, probably, or definitely related 
will be reported to the IRB within 5 business days of initial receipt of the information. 
 
Sarepta: The Investigator or his/her designee will report SAEs to Sarepta within the below timeframe: 
o Any serious adverse event that is unexpected and possibly, probably, or definitely related 
(SUSAR) will be reported to Sarepta within 24 hours of initial receipt of the information. 
All follow-up information on SUSARs will be reported to Sarepta within 24 hours of 
initial receipt of the information.  
o All other serious adverse events and Special Situation listings will be reported to Sarepta 
monthly, regardless of expectedness, relatedness, or if they meet the definition for 
unanticipated problems to the clinical trial.  
 
Sarepta will be responsible for submitting expedited reports to their respective FDA INDs and 
NDAs, as applicable, all ex-US regulatory authorities, and to Investigators in ongoing studies 
of casimersen, eteplirsen or golodirsen. 
 
Changes in the FDA reporting schedule will be permitted only where, under the FDA IND regulations 
[21 CFR 312(c) (3)], changes in this reporting schedule have been approved by the FDA and are reflected 
in the protocol.  Nationwide Children's Hospital will be responsible for reporting to their Investigator-
Initiated FDA IND for the product.  
 


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Relevant follow-up information will be submitted concurrently to the FDA, IRB, DSMB, and Sarepta, 
as applicable, as soon as the information is available and will be identified as such, i.e., "Follow-up IND 
Safety Report.”  
 
If a serious adverse event occurs after the end of a clinical trial, the event will be reported to the FDA, 
IRB, DSMB  and Sarepta according to the criteria and timelines defined above for reporting SAEs during 
the trial.  
 
Should a serious adverse event deemed possibly, probably or definitely related to one of the 
investigational products occur during administration, the product will be discontinued, appropriate 
treatment will be given under medical supervision and the subject will be examined as frequently as 
necessary thereafter until symptoms cease or stabilize. 
 
11.5.1 Serious Adverse Event Reporting: Content and Format 
The serious adverse event report will include, but need not be limited to: (1) the date of the event; (2) 
designation of the report as an initial report or a follow-up report, identification of all safety reports 
previously filed for the clinical protocol concerning a similar adverse event, and an analysis of the 
significance of the adverse event in light of previous similar reports; (3) clinical site; (4) the Principal 
Investigator; (5) FDA’s Investigational New Drug (IND) application number; (6) Drug name; (7) route of 
administration, e.g., intramuscular; (8) dosing schedule; (9) a complete description of the event; (10) relevant 
clinical observations; (11) relevant clinical history; (12) relevant tests that were or are planned to be 
conducted; (13) date of any treatment of the event; and (14) the suspected cause of the event.  
This report will be sent to the IRB, FDA, DSMB  and Sarepta according to regulatory requirements 
described in section Safety Reporting. 
 
11.5.2 Special Situations 
All occurences of pregnancy, overdose, medication error, and accidental or occupational exposure with 
study treatment (regardless of whether an AE or SAE has occurred) must be reported to the DSMB within 
24 hours of notification and to Sarepta on monthly line listings.  
11.5.2.1 Pregnancy 
If the female partner of a treated male subject becomes pregnant, the male subject must notify the 
Investigator within 24 hours of learning of the pregnancy. The Investigator must make every effort to ensure 
that the pregnant female is aware of the need to notify her healthcare provider regarding her male partner’s 
participation in this clinical trial and his potential exposure to casimersen, eteplirsen or golodirsen. 
The study site must complete a pregnancy form within 24 hours of learning of the pregnancy and send to the 
DSMB. The study site will make every effort to follow the pregnancy until outcome is known. 
11.5.2.2 Overdose 
An overdose is defined as administration of a dose that is >10% higher than the assigned dose per the 
protocol. 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 DSMB or designee within 24 hours.  
 
 
 
 


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Medication Error 
Medication Error is any preventable incident that may cause or lead to inappropriate study treatment use 
or patient harm, while the study drug is in the control of the healthcare professional, or in certain cases, 
the patient. Such incident may be due to health-care professional practice, product labeling, packaging 
and preparation, procedures for administration, and systems, including the following: prescribing, order 
communication, dispensing, nomenclature, compounding, distribution, administration, education, 
monitoring, and use. 
 
Accidental/Occupational Exposure 
Accidental/Occupational Exposure is the unintentional exposure to a study treatment as a result of one’s 
professional or non-professional occupation, or accidental exposure to a nonprofessional to whom 
exposure was not intended (eg, study drug given to wrong patient). 
11.5.2.3 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. 
11.5.3 Responsibilities of the Investigator 
 
The responsibilities of the Investigator include but are not limited to the following: 
• 
Monitor and record all AEs 
• 
Determine seriousness, severity, and relationship to IP and/or study procedure and/or underlying 
disease 
• 
Determination of the onset and end date of each event 
• 
Report SAEs to the DSMB, IRB, FDA (Investigator-Initiated IND) and Sarepta within the 
timelines outlined in Section 11.5.1.  
• 
Report follow-up information on SAEs within the timelines outlined in Section 11.5.  
• 
Ensure source documentation for all AEs are accurate and complete 
• 
Ensure that the study is conducted as defined in this document 
 
11.5.4 Responsibilities of Sarepta 
Notification of SUSARs to Sarepta’s FDA INDs and NDAs, as applicable, all ex-US regulatory 
authorities and Investigators in ongoing studies of casimersen, eteplirsen, and golodirsen 
12 DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT 
12.1 Recording of Data 
Clinical data for this study will be captured in an electronic format. Electronic data capture (EDC) will be 
built by the Nationwide Children’s Hospital Research Information. The Investigator, or personnel 
delegated by the Investigator, will perform primary data collection/perform assessments based on the 
protocol design and captured in source documentation. All required study information must be recorded 
on the appropriate CRF screens/forms using the CRF Completion Guidelines for the study. A CRF must 
be completed for each subject 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. 


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12.2 Quality Assurance 
The CRFs will be reviewed at regular intervals by a clinical monitor per the agreed upon Monitoring Plan 
against the source documentation for identification and clarification of any discrepancies. Automated and 
manual quality checks will be in place to identify discrepancies, such as missing data, protocol deviations, 
out-of-range data, other data inconsistencies and compliance. Requests for data clarification or correction 
will be documented as electronic queries within the CRF and for the Investigator or study coordinator to 
resolve. All changes to the CRFs will be tracked in an electronic audit trail. Site Study Files will be 
reviewed for compliance throughout the study. 
 
Audits may be carried out by the IIS Supporter’s representatives, and inspections may be performed by 
IRBs or regulatory authorities before, during, or after the study. The Investigator will allow and assist 
the IIS Supporter’s representatives and any regulatory agency to have direct access to all study records, 
CRFs, subject medical records and other source documentation, IP dispensing records and IP storage 
area, study facilities, and any other source documentation. 
 
The Investigator must make study files and data accessible to the study monitor, to other authorized 
representatives of the IIS Supporter, and to the appropriate regulatory authority inspectors such as the 
United States Food and Drug Administration (US FDA). 
12.3 Retention of Study Documents 
 
At study completion, all CRF data will be copied onto a compact disc (CD) and provided to the 
Investigator for retention in the Study Files. The supporting Site Study Files must be retained by the 
Investigator for a period of 3 years after the investigation is discontinued and regulatory authorities are 
notified. 
 
However, these documents must be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the IIS Supporter. No study documents will be destroyed or 
moved to a new location without prior written approval from the IIS Supporter. If the Investigator 
relocates, retires, or withdraws from the clinical study for any reason, all records that are required to be 
maintained for the study are to be transferred to an agreed-upon designee. 
Subject 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 must be retrieved and made available for review at the time of an 
audit or regulatory authority inspection. 
12.4 Essential Study Documents 
Essential study documents are among the critical documents required before study enrollment is to occur. 
Essential documents, as well as supplemental information such as the Investigator’s Brochure or package 
insert for each product (as applicable), final protocol, as specified in the Clinical Operations Manual 
and/or Regulatory Binder, must be kept on-site in a designated study site file. 
 
The study site files will also contain, including but not limited to, subject accountability records, drug 
accountability (receipt/dispensing) records, Study Sponsor/Investigator correspondence, IRB 
correspondence, deviations, biological sample records, and SAE and Investigational New Drug (IND) 
safety reports/Safety Alert Letters/SUSARs. 
 


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13 STUDY REPORTS 
13.1 Final Study Report 
The final study report will include data through the final study visit and the safety follow-up phone call 
approximately 28 days after the last infusion of study drug.  
13.2 Annual Study Report 
Within 60 days after the one-year anniversary of the date on which the investigational new drug (IND) 
application went into effect, and after each subsequent anniversary until the trial is completed, the 
Principal Investigator will submit information set forth as follows:  
 
(a) Clinical Trial Information. This will be a brief summary of the status of the trial in progress or 
completed during the previous year. The summary will include the following information for the trial: (1) 
the title and purpose of the trial; (2) clinical site; (3) the Principal Investigator; (4) clinical protocol 
identifiers, NCH IRB protocol numbers, and the FDA IND application number; (5) participant population 
(such as disease indication and general age group); (6) the total number of participants planned for 
inclusion in the trial; the number entered into the trial to date; the number whose participation in the trial 
was completed; and the number who dropped out of the trial with a brief description of the reasons; (7) 
the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully 
completed, and (8) if the trial has been completed, a brief description of any study results. 
  
(b) Progress Report and Data Analysis. Information obtained during the previous year's clinical and non-
clinical investigations, including: (1) a narrative or tabular summary showing the most frequent and most 
serious adverse experiences by body system; (2) a summary of all serious adverse events submitted 
during the past year; (3) a summary of serious adverse events that were expected or considered to have 
causes not associated with the use of the gene transfer product such as disease progression or concurrent 
medications; (4) if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death; and (5) a brief description of any information obtained that is 
pertinent to an understanding of the gene transfer product’s action, including, for example, information 
about dose-response, information from controlled trials, and information about bioavailability.  
  
(c) A copy of the updated clinical protocol including a technical and non-technical abstract. 
 
13.3 Data and Safety Monitoring Plan 
 
13.3.1 The Data Safety Monitoring Plan 
A Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to review participant safety 
and study progress for the “48-Week, Open Label, Study to Evaluate the Efficacy and Safety of 
Casimersen, Eteplirsen and Golodirsen in Subjects with Duchenne Muscular Dystrophy carrying eligible 
DMD duplications " study.  
 
The activities and composition of this committee will be detailed in the DSMB Charter, which will be 
ratified during the initial DSMB meeting, which will occur prior to the commencement of dosing of the 
patients.  


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13.3.1.1 DSMB Membership 
The DSMB membership consists of 3-4 persons completely independent of the investigator who have no 
financial, scientific, or other conflicts of interest with the trial. Current or past collaborators of Dr. 
Flanigan must note any significant conflict of interest before their eligibility to serve on the DSMB is 
approved.  
 
The DSMB will include experts in or representatives of the fields of: 
 
• 
Pediatric Neurology and Neuromuscular Diseases 
• 
Muscular Dystrophy Clinical Care 
• 
Clinical Research and Clinical Trials 
• 
Pulmonology 
• 
Complex Care 
 
Individuals invited to serve on the DSMB as either voting or non-voting members must disclose any 
potential conflicts of interest, whether real or perceived.  Conflicts of interest can include professional, 
proprietary, and miscellaneous interests as described in the NIH Grant Policy Statement and 45 CFR Part 
94.  Potential conflicts that develop during a member’s tenure on a DSMB must also be disclosed.  Written 
documentation attesting to an absence of conflict of interest is required.  
 
14.1.2 DSMB Responsibilities 
Responsibilities of the DSMB are to:  
• 
Review the research protocol, informed consent documents and plans for data and safety 
monitoring; 
• 
Evaluate the progress of the trial, including periodic assessments of data quality and 
timelines, participant recruitment, accrual and retention, participant risk versus benefit, 
trial site performance, and other factors that can affect study outcome; 
• 
Consider factors external to the study when relevant information becomes available, such 
as scientific or therapeutic developments that may have an impact on participant safety or 
the ethics of the trials; 
• 
Review study performance, make recommendations and assist in the resolution of 
problems reported by the Principal Investigator; 
• 
Protect the safety of the study participants; 
• 
Review safety data to determine whether to recommend dose escalation; 
• 
Ensure the confidentiality of the trial data and the results of monitoring; and  
• 
Assist by commenting on any problems with study conduct, enrollment, and sample size 
and/or data collection. 
 
An additional responsibility of the non-voting Sarepta member is to provide additional or relevant safety 
information occurring in other Sarepta clinical trials using these three products that is relevant and 
pertinent to the safety of the participants in this NCH clinical trial.  
13.4 Safety Reporting and Meetings 
Reports describing the status of the study will be prepared by the Principal Investigator’s staff and sent to 
the DSMB before every meeting, every 6 months beginning with the first infusion, or at the DSMB’s 
request.  
 
A meeting (either by teleconference or webcast) with the DSMB will be scheduled prior to study 
initiation and reports will be submitted prior to a scheduled meeting for review by the DSMB. 


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Reports will include the following: 
• 
A brief narrative of the study status, including the target enrollment, current and projected time to 
completing enrollment. Any significant events and/or difficulties should be briefly described in 
this narrative. 
• 
A brief narrative for each participant describing gender, age, race and ethnicity and other relevant 
demographic characteristics. The narrative for each participant should briefly describe his/her 
study status (i.e., dose level, visit number, adverse event information); 
• 
A timeline outlining the study progress relative to visit number for each participant, as well as 
time points for each SAE. A total for Adverse Events (AEs) for each participant should be 
included.  
• 
A summary of AEs by severity levels; 
• 
A listing of AE details grouped by participant; 
• 
A listing of SAE details grouped by participant; 
• 
A summary of TEAEs by Sytem Organ Class, Preferred Term, and Maximum Severity 
• 
A listing of deaths 
• 
A summary of clinically significant laboratory test results 
 
 


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14 STATISTICAL CONSIDERATIONS 
 Analysis for both efficacy and safety will be occur for each subject. 
14.1 General Considerations 
 
This section describes the rules, conventions, statistical analysis, and presentation of data for this study.  
 
All available data will be included in data listings and tabulations. No imputation of values for missing 
data will be performed. Percentages of subjects with AEs or laboratory abnormalities will be based on 
non-missing values. 
 
All data collected in this study will be presented using summary tables and subject data listings. 
Summary statistics for raw and change from Baseline data of continuous variables will minimally 
include n, mean, standard deviation (SD), minimum, median, and maximum. For categorical variables, 
frequencies and percentages will be presented. Graphical displays will be provided as appropriate. 
 
Endpoints will be assessed primarily using simple descriptive statistics and/or inferential statistics. 
Baseline will generally be defined as the last available value before dosing. 
14.2 Determination of Sample Size 
The sample size for this study was based on the availability of subjects with these unusual mutations for 
this open label study, and not on power estimates of effect size. 
14.3 Analysis Sets: 
Three analysis sets will be considered:  
 
Efficacy Analysis Set: All patients who are enrolled in this study and receive at least 1 dose of 
study treatment, and at least one post-baseline measurements. 
 
Safety Analysis Set: All patients who are enrolled in the study and receive at least 1 dose of study 
treatment. 
14.3.1 Efficacy Analyses   
Change from Baseline in the dystrophin protein levels by Western blot and dystrophin intensity levels 
determined by immunofluorescence will be based on a 1-sample permutation t-test.  
14.3.1.1 Analyses of the Primary Efficacy Endpoint 
The population for the primary endpoint analysis will be all patients who receive at least one dose of any 
type of study drug, and who has both Baseline and Week 48 dystrophin expression quantified by Western 
blot in muscle biopsy tissue. The change from Baseline at Week 48 in dystrophin level (as percent 
normal) by Western blot will be analyzed by 1-sample permutation test, assuming the treatment effects 
are similar for the three types of study drug. Note that the 1-sample permutation test is an exact test and 
the smallest two-sided p value with sample size of 5 and 6 are 0.0625 and 0.03125, respectively. Hence 
the sample size needs to be at least 6 for rejecting the null hypothesis of no treatment effect.  
Sensitivity analysis may be performed to assess the impact of assay results outside of the limits of 
quantification on the conclusion of treatment effects, using different imputation methods. For the 
calculation of average assay value, if there are assay results outside of the limits of quantification, 
different imputation methods will be used. Values less than the lower limit of quantification (LLOQ) will 


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be imputed using one of 3 methods: as 0, as 0.24 (level immediately below the LLOQ), and as the actual 
measured value, even if those values are below the LLOQ.  Values greater than the upper limit of 
quantification (ULOQ) will be imputed using one of 2 methods: as 4.01 (level immediately above the 
ULOQ), and as the actual measured value, even if those values are above the ULOQ.  If there are both 
values less than LLOQ and values greater than ULOQ, then there will be 6 imputation methods.  Of them, 
the primary analysis will be based on the actual measured value for values less than LLOQ and based on 
the actual measured value for values greater than ULOQ.  Analyses based on other imputation methods 
will be considered sensitivity analyses.   
 
Imputation method for values of dystrophin expression determined by Western blot outside of the 
limits 
 
Imputation 
type 
Treat 
value<=LLOQ as 
Treat value>=ULOQ 
as 
Analysis type 
1 
As measured 
As measured 
Main analysis 
2 
0 
As measured 
Sensitivity analysis 
3 
0.24 
As measured 
Sensitivity analysis 
4 
As measured 
4.01 
Sensitivity analysis 
5 
0 
4.01 
Sensitivity analysis 
6 
0.24 
4.01 
Sensitivity analysis 
Descriptive statistics on primary efficacy endpoint will be provided for different treatment groups.  
14.3.1.2 Analyses of the Secondary Efficacy Endpoints 
The change from Baseline Week 48 in the expression of dystrophin as measured by immunofluorescent 
signal intensity and percent dystrophin positive fibers (PDPF) in muscle tissue sections will be analyzed 
similarly, in all patients who receive at least one dose of any type of study drug, and who has both 
measurements at both Baseline and Week 48. Descriptive statistics on primary efficacy endpoint will 
be provided for different treatment groups. 
 
A 10 percent increase in dystrophin positive fibers defined as fibers with 30 percent of the circumference 
positive for dystrophin will be used as the threshold for continuation of study drug and pursuit of 
insurance authorization to transition the subjects out of the Clinical TransitionProgram/SareptAssist. 
14.3.1.3 Analyses of Additional Efficacy Endpoints 
Listing and descriptive summary statistics may be provided for additional efficacy endpoints.  
 
 
 


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14.3.2 Safety Analysis 
All  subjects who are enrolled in the study and receive at least 1 dose of study treatment (casimersen, 
eteplirsen, or golodirsen) will be included in the safety analysis set. 
The safety and tolerability of casimersen, eteplirsen, and golodirsen will be assessed through a review 
and evaluation of: 
 
• 
Treatment emergent adverse events (TEAEs) will be summarized by the Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT) by treatment 
group. 
• 
Non-emergent events will be recorded in the data listings. For all AE tables, the number and 
percentage of subjects reporting AEs will be grouped by SOC and PT.  
 
Multiple occurrences of the same AE (at the PT level) in the same subject will be counted only once in 
the frequency tables. If a subject experiences multiple episodes of the same event with different 
relationship/severity, the event with the strongest relationship or maximum severity to study treatment 
will be used to summarize AEs by relationship and severity. 
 
Descriptive statistics for ECG, ECHO, vital signs, and safety laboratory parameters will be generated. 
Summary statistics for each parameter at specific time points, as well as the change from Baseline to that 
time point, will also be displayed. All safety data will be presented in the data listings. Safety analyses 
will be descriptive in nature. All safety data will be presented in the data listings. 
 
14.3.2.1 Physical Examination, Vital Signs, Weight, and Height 
 
Vital signs, weight, and height will be presented by treatment group and visit, summarizing the actual 
values and change from Baseline to each visit for each parameter using descriptive statistics. Frequency 
tables of predefined change abnormal in vital sign values will be generated. 
 
Results from physical examinations will be presented in subject data listings. 
 
14.3.2.2 Clinical Laboratory Tests 
 
Clinical chemistry, hematology, coagulation, and urinalysis will be presented by treatment group and 
visit, summarizing the actual values and change from Baseline to each visit for each parameter using 
descriptive statistics for each continuous, and frequency tables for each discrete parameter. Frequency 
tables of predefined abnormal changes of  select laboratory parameter values will be generated. 
 
 
14.3.2.3 Electrocardiograms 
 
The actual value and change from Baseline to each visit will be presented by treatment group and visit, 
summarizing the actual values and change from Baseline to each visit for each parameter using 
descriptive statistics. Shift and frequency tables of predefined abnormal change of  select ECG parameter 
values will be generated. 
 


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14.3.2.4 Echocardiograms 
 
The actual value and change from Baseline to each visit will be summarized by treatment group for each 
ECHO for EF. 
14.3.2.5 Overdoses 
 
 Overdoses will be presented in data listings as defined in Section 11.5.2.2. 
14.3.2.6 Prior and Concomitant Medications and Physiotherapeutic Interventions 
 
All prior and concomitant medications, as well as physiotherapeutic interventions, will be presented in 
data listings. 
14.3.2.7 Additional Analysis 
Additional analyses may be conducted by data listings and descriptive summary.  
14.4 Statistics 
14.4.1 Disposition, Demographics, and Baseline Characteristics 
 
The number and percentage of subjects completing or prematurely discontinuing the study will be 
summarized. Reasons for premature discontinuation will also be summarized. 
 
Demographic characteristics including age (years), race, ethnicity, and Baseline characteristics  
including height (cm), weight (kg), and body mass index (kg/m2) will be summarized. Demographic 
data and Baseline characteristics will be presented in data listings.  
 
14.4.2 Medical History 
 
Medical history will be presented in data listings. 
14.4.3 Concomitant Medications and Therapies 
 
Concomitant medications, changes in dosage of concomitant medications, and concomitant therapies 
will be reviewed and recorded at each visit from the time the parent(s)/guardian(s) sign(s) the informed 
consent and the subject signs the assent form (if applicable). Information on any physiotherapeutic 
intervention must be collected in detail for this study. 
14.4.4 Dosing and Compliance 
 
The cumulative exposure to study treatment, including the total volume of drug administered (mL), 
total number of infusions received, and the cumulative amount of drug received, will be summarized by 
treatment group. Dosing information will be provided in a data listing. 
14.4.5 Protocol Deviations 
 
A listing of protocol deviations will be provided. This deviation listing will be based on  review of 
study data prior to locking the database and will include the nature of the deviation (e.g., 
inclusion/exclusion, prohibited therapies). 
14.4.6 Other Statistical Issues  
Additional analyses may be conducted.  


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


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15.1.5 Confidentiality 
15.1.5.1 Data 
 
All information regarding the nature of the proposed investigation that is provided to the Investigator by 
the DSMB, the DSMB’s designee, or the study monitor, with the exception of information that is 
required by law or regulations to be disclosed to the IRB, the subject’s parent(s) or legal guardian(s) or 
the appropriate regulatory authority, must be kept in confidence by the Investigator in accordance with 
current Health Insurance Portability and Accountability Act (HIPAA) standards and/or European 
standards. 
 
15.1.5.2 Subject Confidentiality 
 
The anonymity of participating subjects will be maintained to the extent required by applicable laws and 
in accordance with current HIPAA standards. Subjects may be referenced by their initials and an 
assigned subject identification number on the CRFs and other data collected by the Study Sponsor. The 
Investigator must maintain all documents related to the study that identify the subject (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, or the study monitor. 
 
 
15.2 General Information 
The Investigator should be familiar with and refer, as needed, to Safety Alert Letters, the Clinical Study 
Operations Manual, Laboratory Manual, 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. Sharing of the study data must follow the stipulations in the agreement with the IIS 
Supporter or other Third Parties. 
 
15.4 Product Handling and Complaints Reporting 
If there are any issues during the course of the study related to the quality of the IP, theInvestigator, 
clinical site pharmacist or pharmacy designee should contact the DSMB or designated contract research 
organization (CRO). 
 


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16  LIST OF REFERENCES 
1. 
Zaharieva IT, Calissano M, Scoto M, et al. Dystromirs as serum biomarkers for monitoring 
the disease severity in Duchenne muscular Dystrophy. PloS one 2013;8:e80263. 
2. 
Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for 
Duchenne muscular dystrophy. Ann Neurol 2012;71:304-313. 
3. 
Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for 
Duchenne muscular dystrophy: 21 years experience in Wales (UK). European journal of 
human genetics : EJHG 2013;21:1049-1053. 
4. 
Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in duchenne muscular dystrophy: 
data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD 
STARnet). J Pediatr 2009;155:380-385. 
5. 
McDonald CM, Widman LM, Walsh DD, Walsh SA, Abresch RT. Use of step activity 
monitoring for continuous physical activity assessment in boys with Duchenne muscular 
dystrophy. Arch Phys Med Rehabil 2005;86:802-808. 
6. 
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Nationwide Children’s Hospital 
Clinical Protocol 
Duplications of DMD exons 45, 51, or 53 
IND: 141894 
 
 
 
63  
Protocol v6.0 (20Apr2021) 
 
 
CONFIDENTAL  
 
 
 
 
 
 
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