Clinical trial NCT03703882
Conditions: Muscular Dystrophy, Duchenne
Keywords: Muscular Dystrophies Musculoskeletal Diseases Neuromuscular Diseases Duchenne muscular dystrophy DMD dystrophin dystrophy Duchenne
Sponsor: Catabasis Pharmaceuticals
Start date: 2018-10-02; Completion date: 2020-09-22
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The PolarisDMD study is a Phase 3, global study to evaluate the efficacy and safety of edasalonexent in pediatric patients with a genetically confirmed diagnosis of DMD. Male patients from 4-7 years of age (up to 8th birthday) will be enrolled.

Edasalonexent is an orally administered small molecule that inhibits NF-kB, which is the key link between loss of dystrophin and disease pathology and plays a fundamental role in the initiation and progression of skeletal and cardiac muscle disease in DMD.

Detailed description:
The study includes a 52-week, randomized, double-blind, placebo-controlled period, followed by a 2-week follow- up. Approximately 125 boys with DMD will be enrolled in this trial, with 2 boys receiving edasalonexent for every 1 boy receiving placebo.

Following completion of the treatment period, patients may elect to continue in a separate open-label extension study.

Arms: arm 1: Edasalonexent 100 mg/kg/day. Capsules taken by mouth three times per day. arm 2: Matching placebo
Interventions: intervention 1: Edasalonexent intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg/kg/day intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
    
 
 
 
 
 
 
Official Title: A Randomized, Double-Blind, Placebo controlled, Global Phase 3 Study of Edasalonexent 
in Pediatric Patients with Duchenne Muscular Dystrophy 
 
NCT Number: NCT03703882 
 
Applicant/MAH: Catabasis Pharmaceuticals Inc. 
 
Version Date: 16 April 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
2 
 
 
 
 
Investigator’s Agreement 
 
This protocol was designed and will be conducted, recorded, and reported in accordance with the Protocol and 
in compliance with the principles of Good Clinical Practice (GCP), and any other applicable regulatory 
requirements.  GCP principles are stated in “Guidance for Good Clinical Practice,” International Council for 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. 
I have read and agree to abide by the requirements of this protocol. 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
Principal Investigator Name (please print or type) 
 
 
 


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Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
5 
1. 
SYNOPSIS 
Name of Sponsor/Company: 
Catabasis Pharmaceuticals, Inc. 
Name of Investigational Product: 
Edasalonexent 
Name of Active Ingredient: 
Edasalonexent 
Title of Study:  
A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric 
Patients with Duchenne Muscular Dystrophy 
Phase of Development: 3 
Objectives:  
Primary 
• 
To assess the efficacy of edasalonexent as measured by change from Baseline (CFB) on North Star 
Ambulatory Assessment (NSAA) Total Score in pediatric patients with Duchenne muscular 
dystrophy (DMD)  
Secondary  
• 
To assess the safety and tolerability of edasalonexent in pediatric patients with DMD  
• 
To assess the effects of edasalonexent on physical function as measured by the 10-meter walk/run 
test (10MWT), time to stand from supine, and the 4-stair climb in pediatric patients with DMD  
Methodology:  
This is a randomized, double-blind, placebo-controlled, Phase 3, multisite study of edasalonexent in pediatric 
patients with DMD.  Approximately 126 patients will be enrolled.   
Eligible patients will be ambulatory boys from ≥4.0 to <8.0 years of age with a confirmed diagnosis of DMD 
who have not used steroids within 24 weeks prior to treatment initiation (Day 1).   
As shown in the figure below, the study includes a 52-week, double-blind, placebo-controlled period 
comparing 1 dose level of edasalonexent with placebo, followed by a 2-week follow-up.  
Following completion of the treatment period and Primary Endpoint evaluation, patients may elect to 
continue in the open-label extension study, pending approval by appropriate ethics committees and regulatory 
authorities.  Patients who choose not to participate should complete the safety follow-up within 2 weeks. 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
6 
CAT-1004-301 – Overview of Study Design 
 
Double-Blind Placebo-Controlled Study 
Following a Screening period to determine eligibility, approximately 126 patients will be randomized 2:1 to 
receive edasalonexent 100 mg/kg/day (administered as approximately 33 mg/kg 3 times per day [TID]) or 
placebo in double-blind fashion daily for 52 weeks.  Randomization will be stratified by Baseline age 
(≤6.0 years or >6.0 years), time to stand from supine (≤5 seconds or >5 seconds), treatment with eteplirsen 
(yes or no), and region (North America or Europe/Asia/Australia).  If siblings are enrolled, they will be 
assigned to the same treatment group. 
Screening procedures should be performed within 4 weeks prior to the start of treatment on Day 1.  At the 
discretion of the Investigator, informed consent, collection of medical history and demographic data, and 
collection of laboratory Screening assessments may be completed remotely by a qualified medical 
professional at an alternative site setting.   
After Screening, eligible patients will complete Baseline procedures and begin receiving study drug 
(edasalonexent or placebo) on Day 1.  Study drug will be orally administered as soft-gel capsules in divided 
doses taken with food containing at least 8 grams of fat.  Patients and their families will be provided with 
written and verbal instructions for study drug administration, and subsequent doses will be administered 
remotely, except for on scheduled site visits as specified in the Schedule of Assessments (SOA).   
Patients will have site visits approximately every 13 weeks with site calls in between as specified in the SOA.  
The efficacy and safety of edasalonexent will be assessed at the timepoints specified in the SOA.   
Efficacy assessments will include:  the NSAA; timed function tests (TFTs) including the 10MWT, time to 
stand from supine, and the 4-stair climb; muscle strength testing; Performance of Upper Limb (PUL) entry 
item assessment; and assessment of health-related physical functioning as measured by the PODCI. 
Safety assessments will include collection of adverse events (AEs), serious adverse events (SAEs), growth 
parameters, vital signs, physical examinations, clinical laboratory testing (including chemistry, hematology, 
and urinalysis), assessment of adrenal function (adrenocorticotrophic hormone [ACTH] and cortisol levels), 
and electrocardiogram (ECG).   
For analysis of pharmacokinetics (PK), blood samples will be obtained for determination of edasalonexent 
and its metabolite concentrations.   
Additionally, blood samples will be drawn to evaluate gene expression, micro-RNA, and protein biomarkers 
that might predict the course of disease and/or responses to treatment. 
Additional cardiac ECG monitoring will be performed via a wearable cardiac monitoring device if approved 
for use in the participating country.  


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
7 
Lateral thoracolumbar spine radiography and dual energy X-ray absorptiometry (DXA) scan will be 
performed if approved by the appropriate governing bodies at each site or country. 
A safety follow-up should occur within 2 weeks of the last dose of study drug for collection of AEs.   
Inclusion / Exclusion Criteria:  
The eligibility criteria are designed to include only patients with an established diagnosis of DMD based on 
clinical, laboratory and genetic findings who are sufficiently well (both in terms of DMD and in terms of 
concomitant illness) to safely participate in study procedures and provide interpretable results.  
Inclusion Criteria 
A patient must meet all the following criteria to be eligible for this study. 
1. Written consent/assent by patient and/or legal guardian as per regional and/or Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) requirements  
2. Diagnosis of DMD based on a clinical phenotype with increased serum creatine kinase (CK) and 
documentation of mutation(s) in the dystrophin gene known to be associated with a DMD phenotype  
3. Male sex by birth 
4. Age ≥4.0 to <8.0 years (at the time of consent) 
5. Able to perform stand from supine without assistance in ≤ 10 seconds  
6. Able to perform the 10MWT and 4-stair climb 
7. Able to swallow placebo capsules at the Screening Visit 
8. Followed by a doctor or medical professional who coordinates Duchenne care on a regular basis and 
willingness to disclose patient's study participation with medical professionals 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study. 
1. Use of corticosteroids within 24 weeks prior to Day 1; use of inhaled, intranasal, and topical 
corticosteroids is permitted 
2. Use of an investigational drug, idebenone, or dystrophin-focused therapy within 4 weeks or a period 
of 5 half-lives duration prior to Day 1 (whichever is longer) or ongoing participation in any other 
therapeutic clinical trial.  Exception: Patients who have received at least 24 weeks of a stable dose of 
eteplirsen prior to Day 1, and expected to continue treatment, will be eligible.  
3. Use of the following within 4 weeks prior to Day 1: immunosuppressive therapy, warfarin, 
phenytoin, S-mephenytoin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, alfentanil, 
pimozide, quinidine, sirolimus, tacrolimus, or paclitaxel 
4. Use of human growth hormone within 3 months prior to Day 1 
5. Documented positive hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency 
virus (HIV) or a known risk factor for hepatitis such as a blood transfusion within 12 weeks prior to 
Day 1 
6. Hemoglobin <10.5 g/dL 
7. Abnormal gamma-glutamyl transferase (GGT) (>laboratory’s upper limit of normal [ULN]) 
8. Other prior or ongoing medical condition, known hypersensitivity to omega-3 fatty acids, physical 
findings, ECG findings, or laboratory abnormality (including but not limited to renal insufficiency or 
impaired hepatic function) that, in the Investigator’s opinion, could adversely affect the safety of the 
patient, make it unlikely that the course of treatment or follow-up would be completed, or impair the 
assessment of study results (e.g., a gastrointestinal condition that would impair fat absorption) 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
8 
9. In the Investigator’s opinion, unwilling or unable for any reason (e.g., attentional or behavioral 
issues) to complete all study assessments and laboratory tests and comply with scheduled visits, 
administration of drug, and all other study procedures 
Note:  Patients may be re-tested or re-screened for eligibility after discussion with the Medical Monitor. 
Number of Patients:  
Approximately 126 patients will be enrolled in a 2:1 ratio to receive edasalonexent or placebo. 
Investigational Product, Dosage and Mode of Administration:  
Edasalonexent 100 mg/kg/day (administered as approximately 33 mg/kg TID).  The Sponsor will supply 
edasalonexent soft-gel capsules at a dose strength of 250 mg for oral administration; 100-mg capsules will be 
available should patients need a smaller size capsule to facilitate swallowing.  An Interactive Web Response 
System (IWRS) will determine each patient’s weight-based dosing; the total daily dose will be within 80% to 
125% of each target dose.  Study drug will be taken with food containing at least 8 grams of fat.  
Duration of treatment:  
The approximate duration of participation for each patient will be 58 weeks, including the 4-week Screening 
period, the 52-week dosing period, and the 2-week follow-up.   
Reference therapy, dosage and mode of administration:  
The Sponsor will supply placebo capsules for oral administration for assessment of swallowing prior to 
initiation of treatment and for administration during the study.  The appearance and administration of placebo 
will be identical to that of the investigational product. 
Criteria for evaluation: 
Efficacy  
The primary efficacy assessment is the NSAA Total Score. 
Secondary efficacy assessments will include the following:  
• 
10MWT 
• 
Stand from supine 
• 
4-stair climb 
Additional efficacy assessments will include the following: 
• 
Muscle strength testing 
• 
PUL entry item assessment  
• 
PODCI Transfer and Basic Mobility scale 
Safety: 
Safety will be evaluated in terms of all treatment-emergent adverse events (TEAEs) and SAEs, as well as 
physical examination, growth parameters, vital signs, clinical laboratory parameters (including chemistry, 
hematology and urinalysis), adrenal function (ACTH and cortisol levels), and ECG.  Data from ECGs will be 
locally read and centrally evaluated.   
Additional Analyses: 
Plasma and urine PK will be evaluated in terms of concentrations of edasalonexent and its metabolites.   
PD evaluations may include gene expression, micro-RNA, and circulating protein biomarkers to evaluate the 
course of disease and/or responses to treatment. 
In addition, deoxyribonucleic acid (DNA) samples may be collected to permit pharmacogenomics analysis 
of potential markers of clinical risk/benefit as well as drug metabolizing enzyme and/or transporter analysis.  


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
9 
To measure heart rate and heart rate variability, additional cardiac monitoring will be performed for 
approximately 48 hours via a wearable cardiac monitoring device if approved for use in the participating 
country. 
To measure bone health, lateral thoracolumbar spine radiography and DXA scan will be performed if 
approved by the appropriate governing bodies at each site or country.  Bone radiography will be locally read 
and centrally evaluated. 
Statistical Methods:  
Analysis Populations: 
The Randomized Population consists of all patients who are randomized into the study.  
The Safety Population will consist of all patients who receive at least 1 dose of study drug.  
The Full Analysis Population for efficacy analyses will be a modified intent to treat (mITT) population and 
will consist of all patients in the Randomized Population who receive at least 1 dose of study drug and 
provide at least 1 valid post Baseline NSAA efficacy assessment.   
The Per Protocol (PP) Population will consist of all patients in the Full Analysis Population who complete the 
study, without any significant protocol violations.   
The PK Population will consist of all patients in the Safety Population who receive at least 1 dose of 
edasalonexent and have at least 1 measured plasma concentration.   
Other analysis populations may be defined in the statistical analysis plan (SAP). 
General Considerations: 
Descriptive characteristics for continuous variables will be summarized using mean, median, standard 
deviation, minimum and maximum values.  For categorical variables, the number and percentage of patients 
(or observations) will be reported.   
Unless otherwise defined for a particular endpoint, a patient’s baseline value is the last measurement prior to 
initiation of study drug. 
Demographics, Baseline characteristics, and DMD-specific medical history will be listed by patient, and 
summarized by treatment group.   
Results of efficacy assessments will be listed by patient, and summarized by treatment group and timepoint as 
applicable.  Descriptive statistics will be calculated for efficacy data as well as for CFB and differences 
between groups as applicable.   
Results of safety assessments will be listed by patient, and summarized by treatment group and timepoint as 
applicable.  Descriptive statistics will be calculated for safety assessments by treatment group and timepoint 
as applicable.  AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
dictionary and will be categorized by system organ class and preferred term.  Abnormal clinical laboratory 
values will be identified as outside (above or below) the normal range and will be evaluated for clinically 
notable abnormalities.  Reference (normal) ranges for laboratory parameters will be included in the clinical 
study report.  Shift tables will be implemented as applicable.  Concomitant medications will be listed by 
treatment and coded using the World Health Organization (WHO) Drug dictionary.  Medical history will be 
listed and coded by patient using the MedDRA® dictionary.  
Results of PK and PD assessments will be listed by patient and summarized by treatment group and timepoint 
as applicable. 
Efficacy Endpoints and Analyses: 
The primary efficacy endpoint will be the CFB in the NSAA Total Score at Week 52.  
The CFB in NSAA Total Score will be analyzed using a mixed-model repeated-measures (MMRM) analysis 
of covariance (ANCOVA), implemented using SAS® Proc Mixed.  The factors in the model will be Baseline 
age (≤6.0 years or >6.0 years), time to stand from supine (≤5 seconds or >5 seconds), region (North America 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
10 
or Europe/Asia/Australia), visit, treatment group, Baseline value, Baseline value by visit, and treatment group 
by visit.   
The primary analysis will test the treatment difference at Week 52 via the MMRM model at the 2-sided 0.05 
level. The primary efficacy analysis will be performed on the Full Analysis Population with exclusions that 
may be defined in the SAP, such as excluding patients receiving treatment with eteplirsen. 
Secondary efficacy endpoints will include the CFB on the following:  
• 
10MWT speed 
• 
Stand from supine speed 
• 
4-stair climb speed 
The secondary efficacy endpoints will be analyzed in a similar manner to the primary efficacy endpoint 
analysis.   
Additional efficacy endpoints will include CFB on the following: 
• 
Muscle strength testing  
• 
PUL entry item assessment 
• 
PODCI Transfer and Basic Mobility scale 
Determination of Sample Size 
Approximately 126 patients will be randomized to either edasalonexent or placebo in a 2:1 ratio.  Based on 
Phase 1/2 data of changes in NSAA in this age group, an effect size of 0.625 is assumed.  With this effect 
size, and assuming a dropout rate of approximately 20%, the study has approximately 80% power to show a 
difference between the treatment groups at a 2-sided type I error rate of 0.05.   


Clinical Trial Protocol:  CAT-1004-301 
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TABLE OF CONTENTS 
SPONSOR’S AGREEMENT .......................................................................................................... 3 
PROCEDURES IN CASE OF EMERGENCY ............................................................................... 4 
1. 
SYNOPSIS ................................................................................................................... 5 
TABLE OF CONTENTS .............................................................................................................. 11 
LIST OF TABLES ........................................................................................................................ 15 
LIST OF FIGURES ....................................................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................... 16 
2. 
INTRODUCTION ...................................................................................................... 18 
2.1. 
Summary of Edasalonexent Nonclinical Data ........................................................... 19 
2.2. 
Summary of Edasalonexent Clinical Experience ....................................................... 20 
2.3. 
Dose Selection Rationale ........................................................................................... 21 
3. 
TRIAL OBJECTIVES ............................................................................................... 22 
3.1. 
Primary ....................................................................................................................... 22 
3.2. 
Secondary ................................................................................................................... 22 
3.3. 
Overall Study Design ................................................................................................. 22 
3.3.1. 
Double-Blind Placebo-Controlled Study Design ....................................................... 23 
3.3.2. 
Study Conduct during the COVID-19 Pandemic ....................................................... 23 
3.3.3. 
Completion of a Patient’s Participation in the Study and Overall Study 
Completion ................................................................................................................. 24 
3.3.3.1. 
Completion of a Patient’s Participation in the Study ................................................. 24 
3.3.3.2. 
Premature Patient Discontinuation from the Study .................................................... 24 
3.3.3.3. 
Overall Study Completion .......................................................................................... 24 
3.4. 
Discussion of Study Design, Including Choice of Control Group ............................. 24 
4. 
PATIENT POPULATION AND SELECTION ......................................................... 27 
4.1. 
Inclusion Criteria ........................................................................................................ 27 
4.2. 
Exclusion Criteria ....................................................................................................... 27 
5. 
TREATMENTS ......................................................................................................... 29 
5.1. 
Treatments Administered ........................................................................................... 29 
5.1.1. 
Double-Blind Placebo-Controlled Treatment ............................................................ 29 
5.1.2. 
Investigational Product(s) Description ....................................................................... 29 
5.1.3. 
Packaging and Labeling ............................................................................................. 29 
5.1.4. 
Storage ........................................................................................................................ 29 


Clinical Trial Protocol:  CAT-1004-301 
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Confidential and Proprietary 
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5.1.5. 
Preparation and Administration ................................................................................. 29 
5.2. 
Dosing Considerations ............................................................................................... 30 
5.2.1. 
Dose Selection Rationale ........................................................................................... 30 
5.2.2. 
Dose Modification or Reduction ................................................................................ 30 
5.2.3. 
Safety Monitoring ...................................................................................................... 30 
5.2.4. 
Treatment Compliance ............................................................................................... 30 
5.2.5. 
Treatment Discontinuation ......................................................................................... 30 
5.3. 
Prior and Concomitant Medications and Therapeutic Procedures ............................. 30 
5.4. 
Method of Assigning Patients to Treatment ............................................................... 31 
5.5. 
Blinding and Randomization ...................................................................................... 31 
5.5.1. 
Blinding and Randomization ...................................................................................... 31 
5.5.2. 
Scheduled Unblinding ................................................................................................ 32 
5.5.3. 
Emergency Unblinding .............................................................................................. 32 
6. 
STUDY ASSESSMENTS .......................................................................................... 33 
6.1. 
Study Schedule of Events ........................................................................................... 33 
6.2. 
Screening and Baseline Assessments and Start of Treatment .................................... 33 
6.3. 
Efficacy Assessments ................................................................................................. 33 
6.3.1. 
North Star Ambulatory Assessment (NSAA) ............................................................ 33 
6.3.2. 
Timed Function Testing ............................................................................................. 34 
6.3.3. 
Muscle Strength Testing ............................................................................................ 34 
6.3.4. 
Performance of Upper Limb (PUL) Scale ................................................................. 34 
6.3.5. 
The Pediatric Outcomes Data Collection Instrument (PODCI) ................................. 35 
6.3.6. 
Assessor Training and Ensuring Compliance with Protocol-Specified Test-
Administration. ........................................................................................................... 35 
6.4. 
Safety Assessments .................................................................................................... 35 
6.4.1. 
Physical Examination and Growth Parameters .......................................................... 36 
6.4.2. 
Vital Signs .................................................................................................................. 36 
6.4.3. 
Clinical Laboratory Tests ........................................................................................... 36 
6.4.4. 
Electrocardiogram ...................................................................................................... 36 
6.4.5. 
Concomitant Medications and Therapies ................................................................... 37 
6.5. 
Pharmacokinetic Assessments ................................................................................... 37 
6.6. 
Pharmacodynamic Assessments ................................................................................. 37 
6.7. 
Cardiac Monitoring .................................................................................................... 37 


Clinical Trial Protocol:  CAT-1004-301 
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Confidential and Proprietary 
13 
6.8. 
Bone Evaluations ....................................................................................................... 38 
6.9. 
Study Drug Acceptability ........................................................................................... 38 
6.10. 
Total Volume of Blood Collected .............................................................................. 38 
7. 
ADVERSE EVENTS AND ADVERSE EVENT REPORTING .............................. 39 
7.1. 
Timeframe for Collection of Adverse Events ............................................................ 39 
7.1.1. 
Adverse Events Occurring Prior to Study Treatment ................................................ 39 
7.1.2. 
Adverse Events Occurring After Study Treatment .................................................... 39 
7.1.3. 
Adverse Events Occurring Following Patient Discontinuation of Treatment ........... 39 
7.2. 
Definitions .................................................................................................................. 39 
7.2.1. 
Definition of an Adverse Event .................................................................................. 39 
7.2.2. 
Definition of a Serious Adverse Event ....................................................................... 40 
7.3. 
Evaluation of Adverse Events/Serious Adverse Events ............................................. 40 
7.3.1. 
Relationship to Study Treatment ................................................................................ 40 
7.3.2. 
Severity Grading of Adverse Event Scoring .............................................................. 40 
7.3.3. 
Outcome ..................................................................................................................... 41 
7.3.4. 
Action Taken Regarding the Investigational Product ................................................ 41 
7.4. 
Recording of Adverse Events/Serious Adverse Events ............................................. 42 
7.5. 
COVID-19 Adverse Events and/or Serious Adverse Events ..................................... 42 
7.6. 
Reporting of Serious Adverse Events ........................................................................ 42 
7.7. 
Follow-up of Adverse Events/Serious Adverse Events ............................................. 43 
7.8. 
Pregnancy Reporting .................................................................................................. 43 
7.9. 
Temporary or Persistent Dose Reductions ................................................................. 43 
7.10. 
Monitoring of Abnormal Laboratory Values ............................................................. 43 
7.11. 
Stopping Rules ........................................................................................................... 44 
7.12. 
Restriction on the Lifestyle of Patients ...................................................................... 44 
8. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ......... 45 
8.1. 
Recording of Data ...................................................................................................... 45 
8.2. 
Data Quality Assurance .............................................................................................. 45 
8.3. 
Data Management ...................................................................................................... 45 
8.4. 
Data Safety Monitoring Board ................................................................................... 45 
9. 
STATISTICAL METHODS AND PLANNED ANALYSES ................................... 47 
9.1. 
General Considerations .............................................................................................. 47 
9.2. 
Determination of Sample Size ................................................................................... 47 


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9.3. 
Analysis Sets .............................................................................................................. 47 
9.4. 
Demographics and Baseline Characteristics .............................................................. 48 
9.5. 
Concomitant Medications .......................................................................................... 48 
9.6. 
Medical History .......................................................................................................... 48 
9.7. 
DMD-Specific Medical History ................................................................................. 48 
9.8. 
Patient Disposition ..................................................................................................... 48 
9.9. 
Study Treatment Usage and Compliance ................................................................... 48 
9.10. 
Efficacy Analyses ....................................................................................................... 48 
9.10.1. 
Primary Efficacy Endpoint ......................................................................................... 49 
9.10.2. 
Secondary Efficacy Endpoints ................................................................................... 49 
9.10.3. 
Controlling for Multiplicity ........................................................................................ 49 
9.10.4. 
Sensitivity Analyses of the Primary and Secondary Efficacy Endpoints .................. 49 
9.10.5. 
Additional Efficacy Endpoints ................................................................................... 49 
9.11. 
Pharmacokinetic Analyses ......................................................................................... 50 
9.12. 
Safety Analyses .......................................................................................................... 50 
9.12.1. 
Physical Examination, Growth Parameters, Electrocardiograms, and Vital Signs .... 51 
9.12.2. 
Clinical Laboratory Tests ........................................................................................... 51 
9.12.3. 
Adverse Events ........................................................................................................... 51 
9.13. 
Pharmacodynamic Analyses ...................................................................................... 51 
9.14. 
Cardiac Monitoring .................................................................................................... 52 
9.15. 
Bone Evaluations ....................................................................................................... 52 
9.16. 
Other Statistical Issues ............................................................................................... 52 
9.16.1. 
Missing or Invalid Data .............................................................................................. 52 
9.16.2. 
Multisite Issues ........................................................................................................... 52 
9.16.3. 
Subgroup Analyses ..................................................................................................... 52 
10. 
SPECIAL REQUIREMENTS AND PROCEDURES ............................................... 53 
10.1. 
Institutional and Ethics Review ................................................................................. 53 
10.2. 
Changes to the Conduct of the Study or Protocol ...................................................... 53 
10.3. 
Investigator’s Responsibilities ................................................................................... 53 
10.3.1. 
Patient Informed Consent ........................................................................................... 53 
10.3.2. 
Case Report Forms ..................................................................................................... 53 
10.3.3. 
Record Retention ........................................................................................................ 54 
10.3.4. 
Monitoring .................................................................................................................. 54 


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10.3.5. 
Study or Site Termination .......................................................................................... 54 
10.3.6. 
Investigational Product Control ................................................................................. 55 
10.3.6.1. 
Receipt of Investigational Product ............................................................................. 55 
10.3.6.2. 
Disposition of Unused Investigational Product .......................................................... 55 
10.3.6.3. 
Product Handling and Complaints Reporting ............................................................ 55 
10.3.7. 
Disclosure of Data ...................................................................................................... 55 
10.3.8. 
Confidentiality and Data Privacy ............................................................................... 55 
11. 
REFERENCES ........................................................................................................... 57 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .................................................................... 60 
APPENDIX 2. POTENTIAL MODIFICATIONS TO THE SCHEDULE OF 
ASSESSMENTS DURING THE COVID-19 PANDEMIC ...................................... 62 
APPENDIX 3. LIST OF CLINICAL LABORATORY ASSESSMENTS ................................ 65 
APPENDIX 4. STUDY DRUG QUESTIONNAIRE ................................................................. 66 
APPENDIX 5. PEDIATRIC OUTCOMES QUESTIONNAIRE (PODCI) ............................... 68 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................. 4 
Table 2: 
Prohibited Prior and Concomitant Medications ......................................................... 31 
 
LIST OF FIGURES 
Figure 1: 
CAT-1004-301 – Overview of Study Design ............................................................ 22 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and terms are used in this study protocol. 
Abbreviation 
Definition 
10MWT  
10-meter walk/run test  
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BID 
twice a day 
BMI 
body mass index 
CA 
Competent Authorities 
CFB 
change from Baseline 
Clast 
last quantifiable plasma concentration 
Cmax 
maximum plasma concentration 
CK 
creatine kinase 
DHA 
docosahexaenoic acid 
DMD 
Duchenne muscular dystrophy 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
DXA 
dual energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ET 
early termination 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GRMD 
golden retriever muscular dystrophy 
HEENT 
head, eyes, ears, nose, throat 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LPS 
lipopolysaccharide  


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP9 
matrix metalloproteinase 9 
MMRM 
mixed-model repeated-measures  
MRI 
magnetic resonance imaging 
MuRF1 
muscle RING finger protein 1 
n 
sample size 
NCS 
not clinically significant 
NF-κB 
nuclear factor kappa light chain enhancer of activated B cells  
NOAEL 
no-observed-adverse-effect level 
NSAA 
North Star Ambulatory Assessment  
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PODCI 
Pediatric Outcomes Data Collection Instrument  
PUL 
Performance of Upper Limb 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDHM 
Study Drug Handling Manual  
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
SOCS3 
suppressor of cytokine signaling 3 
SRM 
Study Reference Manual 
TID 
3 times per day 
TEAE 
treatment emergent adverse event 
TFT 
Timed Function Test 
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION  
The purpose of this multisite, Phase 3 study is to confirm the efficacy and safety of edasalonexent 
(CAT-1004) on ambulatory male pediatric patients with a confirmed diagnosis of Duchenne muscular 
dystrophy (DMD).  The study is a 52-week, double-blind, placebo-controlled study comparing 
100 mg/kg/day of edasalonexent (administered as approximately 33 mg/kg 3 times per day [TID]) 
with placebo.   
Duchenne Muscular Dystrophy 
DMD is a progressively debilitating and ultimately fatal inherited neuromuscular disorder affecting 
approximately 1 in 3,500 to 5,000 live male births worldwide.  It is caused by mutations in the gene 
encoding dystrophin, a critical part of the protein complex that connects the cytoskeletal actin of a 
muscle fiber to the extracellular matrix.  In the absence of dystrophin, the stress of repeated muscle 
contractions damages the sarcolemma resulting in repeated cycles of cellular degeneration, 
progressively failing regeneration, and inflammation (Blake, 2002; Emery, 2002).  Over time, muscle 
is replaced by fibrotic tissue and fat.  Of note, while a lack of dystrophin is the primary cause of 
DMD, it is not sufficient for disease progression, as evidenced by the heterogeneity in disease 
progression among different muscles (Porter, 2003; Hu, 2015). 
Affected children are usually diagnosed between the ages of 3 to 5 years when they begin to show 
lordosis, waddling gait, toe walking, calf hypertrophy, and have difficulty climbing stairs.  By 8 years 
of age, most patients are losing the ability to rise from the floor and climb stairs, have an increasingly 
labored gait, and often fall while walking.  By 10 to 14 years of age, most are wheelchair-dependent.  
Upper limb, cardiac, and diaphragmatic muscles continue to progressively weaken during 
adolescence, and patients often require ventilation support in their teens.  In recent years, use of 
ventilation support and glucocorticoids have increased life span by several years (Kohler, 2009); 
however, DMD still has an early mortality rate of 100%.   
There is no cure for DMD and those drug treatments that have recently been approved for the disease, 
i.e., ataluren, which received conditional approval in the European Union, and eteplirsen 
(Exondys51™), which received accelerated approval in the United States, demonstrate limited 
efficacy and are appropriate for only a subset of patients.  Current standard of care guidelines include 
the administration of glucocorticoids (Birnkrant, 2018a; Birnkrant, 2018b), which can delay the time 
to respirator dependence and the onset of scoliosis, and improve performance on measures of clinical 
function in patients with DMD (Manzur, 2009).  However, they do not fully ameliorate symptoms or 
halt disease progression.  Moreover, their use is often limited by numerous side effects, including 
growth inhibition, delay of pubertal changes, weight gain, behavioral changes, osteoporosis resulting 
in fractures, Cushingoid facies and habitus, cataracts, and myopathy, a particularly serious concern 
for patients with DMD (Manzur, 2009; Schakman, 2009; Hanaoka, 2012).   
Thus, even though there are a handful of treatment options available, those options are inadequate and 
a significant need remains for safer and more effective treatments for patients affected by this fatal 
disease. 
Rationale for Edasalonexent as a Potential Therapy for the Treatment of DMD 
Edasalonexent, an orally administered small molecule containing covalently linked salicylic acid and 
docosahexaenoic acid (DHA), synergistically leverages the ability of both compounds to 
intracellularly inhibit activated nuclear factor kappa light chain enhancer of activated B cells 


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(NF-κB) to reduce NF-κB-mediated inflammation and muscle degeneration and facilitate muscle 
regeneration (Kopp, 1994; Yin, 1998; Cai, 2004; Zwart, 2010).  Following its cellular uptake, 
edasalonexent is hydrolyzed into its constituents by endogenous fatty acid amide hydrolase (FAAH), 
simultaneously delivering salicylic acid and DHA to key intracellular targets where they significantly 
inhibit activated NF-κB. 
In vitro, edasalonexent inhibits NF-κB and downstream cytokines known to be increased in DMD 
(Vu, 2016).  Edasalonexent inhibits lipopolysaccharide (LPS)-stimulated pro-inflammatory gene 
expression (TNFα, IL-6, IL-1β, SOCS3, MMP9) in RAW264.7 macrophages and this effect is greater 
than that produced by DHA or the combination of DHA and salicylic acid.  In addition, studies in 
mouse C2C12 myotubes showed that edasalonexent blocks cytokine-induced reductions in MyoD to 
a greater degree than dexamethasone and blunts cytokine-induced upregulation of MuRF1 and 
MMP9, both of which promote the degradation of key intracellular proteins and the extracellular 
matrix (Cai, 2004; Li, 2009).  These data are consistent with selective inhibition of activated NF-κB 
by edasalonexent having a more positive and favorable effect on muscle degeneration and 
regeneration than that produced by the concomitant NF-κB inhibition and activation of the 
glucocorticoid receptor by glucocorticoids.  
In vivo, edasalonexent inhibits NF-κB, and has positive effects in the mdx and golden retriever 
muscular dystrophy (GRMD) models of DMD.  Edasalonexent reduced LPS-stimulated release of 
TNFα levels in normal mice, and reduced muscle inflammation and muscle fiber degeneration, 
preserved muscle mass, and increased the number of regenerating fibers per field in the mdx mouse 
model of muscular dystrophy (Hammers, 2016).  Moreover, a single treatment with edasalonexent 
inhibited basal NF-κB p65 deoxyribonucleic acid (DNA) binding as well as LPS-stimulated NF-κB 
p65 activity and induction of TNFα protein in the GRMD dog model.  Similarly, administration of 
CAT-1041, a closely related analog of edasalonexent that differs only in the omega-3 fatty acid 
moiety, significantly improved muscle endurance, increased muscle mass, and reduced fibrosis in the 
mdx mouse, and improved pulmonary function in the GRMD model of DMD. 
By reducing inflammation and muscle degeneration while simultaneously facilitating muscle 
regeneration, pharmacological inhibition of NF-κB with edasalonexent has the potential to provide 
disease-modifying benefits to patients of all mutations beyond those afforded by glucocorticoids, but 
without their negative side effects, which are largely independent of their anti-inflammatory 
properties (Schacke, 2004; Newton, 2007).   
2.1. 
Summary of Edasalonexent Nonclinical Data 
In nonclinical studies, edasalonexent demonstrated reduction of NF-κB activation in vitro and in vivo, 
and disease-modifying effects in 2 established animal models of DMD, the mdx mouse and the 
GRMD models.  To support single- and repeat-dose oral administration in healthy subjects, 
edasalonexent has been assessed in a series of nonclinical studies including safety pharmacology, 
genotoxicity, and general toxicity studies in rats and dogs, with durations of repeat dose oral 
administration up to 6 and 9 months, respectively.   
Detailed information on all edasalonexent nonclinical studies conducted to date can be found in the 
Investigator’s Brochure. 


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2.2. 
Summary of Edasalonexent Clinical Experience 
Edasalonexent was evaluated in three Phase 1 studies in adults (Donovan, 2017). Across the 
3 studies, 79 adult subjects received single doses of edasalonexent up to 6000 mg and multiple doses 
up to 4000 mg/day for 14 days (~100 and 67 mg/kg/day, respectively), with no identified safety 
concerns.  Single-dose exposures of 2000 mg (~33 mg/kg) edasalonexent significantly reduced 
ex vivo LPS-stimulated NF-κB activity and NF-κB p65 DNA binding, while 14 days of dosing with 
edasalonexent reduced basal expression of NF-κB target genes in patients with type 2 diabetes with 
mild inflammation.   
Edasalonexent is currently being evaluated in ambulatory boys with DMD from ≥4 to <8.0 years of 
age at enrollment who are not receiving corticosteroids in a multipart, Phase 1/2 clinical study, 
CAT-1004-201.  Phase 1, which has been completed, was a 1-week, open-label study to assess the 
safety and pharmacokinetics (PK) of 3 sequential ascending doses (33, 67, or 100 mg/kg/day 
administered as 17 mg/kg twice daily [BID], 33 mg/kg BID, or 33 mg/kg TID) of edasalonexent 
under low- or high-fat conditions.  Results from Phase 1 indicate that 7 days of treatment with 
edasalonexent at doses up to 100 mg/kg/day were safe and generally well tolerated. There were no 
serious adverse events (SAEs), discontinuations, or dose reductions, and the most common adverse 
events (AEs) were gastrointestinal, primarily mild diarrhea.  Pharmacokinetic data collected showed 
daily exposures projected to be within the range observed in adults (on a mg/kg basis), with only 
modest differences between dosing after a high- or low-fat meal at the 67 mg/kg/day dose.  
Importantly, clinical exposure at 100 mg/kg/day was 4 times lower than exposures at the 
no-observed-adverse-effect level (NOAEL) in the 13-week postnatal day (PND) 21 rat study, and 
2 times lower than those at the NOAEL in the 13-week dog study.  
Phase 2, which has also been completed, included patients from Phase 1 as well as additional patients 
(total N = 31) and was a randomized, placebo-controlled study to evaluate the efficacy, safety, PK, 
and PD of the 2 higher doses edasalonexent (67 and 100 mg/kg/day) over 12 weeks.  Both doses were 
safe and generally well tolerated.  There were no dose-dependent safety findings and, as in Phase 1, 
the majority of AEs were mild in nature and the most common treatment-related AEs were 
gastrointestinal, primarily mild and transient diarrhea.  There were no treatment-related SAEs, drug 
discontinuations, or dose reductions, nor were there any concerning trends in chemistry, hematology, 
coagulation, or adrenal function assessments.  Edasalonexent plasma exposures were consistent with 
those observed in Phase 1.  The 100 mg/kg/day dose level demonstrated numerical improvement 
versus placebo across multiple efficacy measures, though not statistically significant.  The 
67 mg/kg/day dose group had mixed efficacy results compared with both the 100 mg/kg/day dose 
group and placebo, which in each case were not statistically significant.   
In the open-label extension, which is currently ongoing, all patients (including those who received 
placebo in Phase 2) were to receive open-label edasalonexent at dose levels of 67 or 100 mg/kg for up 
to 124 weeks.  Based on results from Phase 2 and the recommendation of the Data Safety Monitoring 
Board (DSMB), all patients in the 67 mg/kg/day dose group were switched to the 100 mg/kg/day dose 
group (which was already ongoing at the time the Phase 2 results were analyzed).   
In an interim analysis conducted with all data through December 31, 2017, patients on edasalonexent 
at 100 mg/kg/day over 60 weeks of treatment showed a slower decline in timed function test speeds 
(10-meter walk/run test [10MWT], 4-stair climb, and time to stand) and North Star Ambulatory 
Assessment (NSAA) when compared to declines in the prior off-treatment control period.  In addition 
to the muscle function assessments, supportive changes in measures of muscle health were observed, 


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consistent with positive edasalonexent treatment effects.  Four muscle enzymes (creatine kinase, 
alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase) were significantly 
lower compared to Baseline following 12 weeks of edasalonexent treatment and at later time points, 
consistent with a slowing of muscle degeneration and an improvement in muscle integrity.  A 
composite of magnetic resonance imaging (MRI) T2 rates of change in five lower leg muscles was 
also significantly improved through 48 weeks of 100 mg/kg/day edasalonexent treatment compared to 
the off-treatment control period, consistent with a reduction of inflammation in the muscle. 
Improvements were also seen in rates of change in both soleus and vastus lateralis magnetic 
resonance spectroscopy (MRS) fat fraction through 48 weeks of edasalonexent treatment compared to 
the off-treatment control period, consistent with a reduction of fat in the muscle.  Edasalonexent 
remained well tolerated and no safety signals were observed. The most common adverse events, 
gastrointestinal, were typically mild and transient.  Based on emerging safety and efficacy data, all 
patients moved to 133 mg/kg/day (33/33/67 mg/kg in 3 divided doses) in the open-label extension. 
As of June 2018, 32 pediatric patients had received up to 112 weeks of active dosing with 
edasalonexent at doses up to 133 mg/kg/day, with a total combined exposure of over 45 years, with 
no safety concerns.  More detailed information on clinical studies and potential clinical risks of 
edasalonexent can be found in the Investigator’s Brochure.   
2.3. 
Dose Selection Rationale 
Selection of the 100 mg/kg/day dose of edasalonexent for this Phase 3 study is supported by interim 
results from the ongoing Phase 1/2 study of edasalonexent in same aged boys with DMD 
(CAT-1001-201), which showed: 
• The plasma exposure of edasalonexent at the NOAEL in the 26-week rat study (2000 
mg/kg/day) is approximately 4-fold higher than that expected with the anticipated clinical 
dose utilized in CAT-1004-201 of 100 mg/kg/day.  The plasma exposure of edasalonexent 
at the NOAEL in the 13-week and 9-month dog studies (1000 mg/kg/day) is 
approximately 2-fold higher, than that expected with the anticipated clinical dose for this 
study of 100 mg/kg/day. 
• Treatment with edasalonexent at doses of 67 mg/kg/day for up to 47 weeks, at 
100 mg/kg/day for up to 84 weeks, and at 133 mg/kg/day for up to 32 weeks was safe and 
generally well tolerated with no dose-dependent safety findings, treatment-related SAEs, 
drug discontinuations, or dose reductions, and no concerning trends in chemistry, 
hematology, coagulation, or adrenal function assessments. 
• Treatment with 100 mg/kg/day edasalonexent resulted in numerical improvements across 
multiple efficacy measures compared to placebo.  In contrast, the 67 mg/kg/day dose 
group had mixed efficacy results compared with both the 100 mg/kg/day dose group and 
placebo.  Compared to declines in the prior off-treatment control period, patients on 100 
mg/kg/day edasalonexent showed a slower decline in timed function test speeds and 
NSAA scores over 60 weeks of treatment. 


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3. 
TRIAL OBJECTIVES 
3.1. 
Primary 
• To assess the efficacy of edasalonexent as measured by change from Baseline (CFB) on 
NSAA Total Score in pediatric patients with DMD  
3.2. 
Secondary 
• To assess the safety and tolerability of edasalonexent in pediatric patients with DMD  
• To assess the effects of edasalonexent on physical function as measured by the 10MWT, 
time to stand from supine, and the 4-stair climb in pediatric patients with DMD  
3.3. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 3, multisite study of edasalonexent in 
pediatric patients with DMD.  Approximately 126 patients will be enrolled.   
Eligible patients will be ambulatory boys ≥4.0 to <8.0 years of age with a confirmed diagnosis of 
DMD who have not used steroids within 24 weeks prior to treatment initiation (Day 1).  In regions 
where eteplirsen is approved or there is an established access program, patients who have received at 
least 24 weeks of treatment with eteplirsen prior to Day 1 will be eligible for the study. 
As shown in Figure 1, this is a 52-week, double-blind, placebo-controlled study comparing one dose 
level of edasalonexent with placebo.   
Following completion of the treatment period and Primary Endpoint evaluation, patients may elect to 
continue in the open-label extension study, pending approval by appropriate ethics committees and 
regulatory authorities.  Patients who choose not to participate should complete the safety follow-up 
within 2 weeks of the last dose of study drug. 
Figure 1: 
CAT-1004-301 – Overview of Study Design 
 


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3.3.1. 
Double-Blind Placebo-Controlled Study Design 
As shown in Figure 1, following a Screening period to determine eligibility, approximately 
126 patients will be randomized 2:1 to receive edasalonexent 100 mg/kg/day (administered as 
approximately 33 mg/kg TID) or placebo in double-blind fashion daily for 52 weeks.  The exact 
capsule count per dose will be provided.  Randomization will be stratified by Baseline age (≤6.0 years 
or >6.0 years), time to stand from supine (≤5 seconds or >5 seconds), treatment with eteplirsen (yes 
or no), and region (North America or Europe/Asia/Australia). If siblings are enrolled, they will be 
assigned to the same treatment group. 
All Screening procedures will be performed within 4 weeks prior to the start of treatment (Day 1).  At 
the discretion of the Investigator, informed consent, collection of medical history and demographic 
data, and collection of laboratory Screening assessments may be completed remotely by a qualified 
medical professional at an alternative site setting.   
After Screening, eligible patients will complete Baseline procedures and begin receiving study drug 
(edasalonexent or placebo) on Day 1.  Study drug will be orally administered as soft-gel capsules in 
divided doses taken with food containing at least 8 grams of fat as detailed in Section 5.1.1.  Patients 
and their families will be provided with written and verbal instructions for study drug administration, 
and subsequent doses will be administered remotely, except for on scheduled site visits as specified in 
the Schedule of Assessments (SOA) in Appendix 1.  Nutritional guidance will be provided at 
Baseline.  Patient compliance with nutritional guidance will be confirmed throughout treatment.   
Efficacy and safety will be assessed at site visits at the timepoints specified in the SOA in 
Appendix 1.  Efficacy assessments will include: the NSAA; timed function tests (TFTs) including the 
10MWT, time to stand from supine, and the 4-stair climb; muscle strength testing; the Performance of 
Upper Limb (PUL) scale; and assessment of physical functioning as measured by the PODCI.   
Safety assessments will include collection of AEs, SAEs, growth parameters (height and weight), 
vital signs, physical examinations, clinical laboratory testing (including chemistry, hematology, and 
urinalysis), assessment of adrenal function (adrenocorticotrophic hormone [ACTH] and cortisol 
levels), and electrocardiogram (ECG).  To measure heart rate and heart rate variability, additional 
cardiac monitoring will be performed for approximately 48 hours via a wearable cardiac monitoring 
device if approved for use in the participating country. To measure bone health, lateral spine 
radiography and dual energy X-ray absorptiometry (DXA) scan will be performed if approved by the 
appropriate governing bodies at each site or country. 
For analysis of PK, blood and urine samples will be obtained for determination of edasalonexent and 
its metabolite concentrations.  Blood samples will be drawn for analysis of PD. 
To assess acceptability and palatability of edasalonexent, caregivers will complete a study drug 
questionnaire. 
A safety follow-up should occur within 2 weeks of the last dose of study drug for collection of AEs. 
3.3.2. 
Study Conduct during the COVID-19 Pandemic  
Ensuring the safety of patients is paramount especially during a pandemic so modifications have been 
made to the original study procedures and schedule of assessments to reduce the patient’s risk or 
exposure to COVID-19 while ensuring the integrity of the study. Changes to the study visit schedule 
which should be considered, or deemed necessary per the local situation at each site during the 


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COVID-19 pandemic are captured in Appendix 2. Patients may not be able to come on-site for visits 
as specified in Appendix 1 or patients may be able to come on-site for visits however for a reduced 
amount of time to minimize risk or exposure to COVID-19, so considerations for modifying the 
schedule of assessments are captured in Appendix 2.        
Investigators must document how restrictions or institutional requirements during the COVID-19 
pandemic led to the changes in study conduct and duration of those changes and indicate which 
patients were impacted and how those patients were impacted.    
3.3.3. 
Completion of a Patient’s Participation in the Study and Overall Study Completion 
3.3.3.1. 
Completion of a Patient’s Participation in the Study 
The length of a patient’s participation in the study will be from the time the informed consent form is 
signed through the Week 52 visit.  A patient will be considered to have completed the study when 
they have completed the Week 52 assessments.  Patients who do not participate in the open-label 
extension study will be considered to have completed the study after they complete the safety follow-
up.  
3.3.3.2. 
Premature Patient Discontinuation from the Study 
Parents/guardians and patients (as applicable according to site and regional regulations) are free to 
withdraw consent and/or discontinue participation in the study at any time, without prejudice to 
further treatment.  A patient’s participation in the study may also be discontinued at any time at the 
discretion of the Investigator, Medical Monitor, or Sponsor. 
The reasons indicated in Section 5.2.5 for withdrawing a patient from treatment may also be 
justifiable reasons for the Investigator, Medical Monitor, or Sponsor to remove a patient from the 
study.  Patients also may be discontinued from the study if the study is terminated by the Sponsor (see 
Section 10.3.5). 
Patients who are prematurely withdrawn from the study (i.e., those who leave the study prior to 
completing the Week 52 assessments) will be asked to complete an early termination (ET) visit prior 
to their last dose of study drug and are not permitted to re-enroll in the study.   
Post-study SAEs will be reported according to Section 7.6.  A patient will be considered discontinued 
due to an AE if they discontinued due to any AE, regardless of whether the AE is considered related 
to investigational product.  If the patient withdraws from the study due to an AE, the Investigator 
should arrange for the patient to be followed appropriately until the AE has resolved or stabilized (in 
the opinion of the Investigator). 
At the end of the patient’s participation in the study, the Investigator will document the reason(s) for 
study discontinuation in the electronic case report form (eCRF). 
3.3.3.3. 
Overall Study Completion 
The study will be considered complete when the last patient has completed their last assessment. 
3.4. 
Discussion of Study Design, Including Choice of Control Group 
This is a Phase 3 study to evaluate the efficacy, safety, PK, and PD of edasalonexent in ambulatory, 
male, pediatric patients with a confirmed diagnosis of DMD.  This is a randomized, double-blind, 


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placebo-controlled study in which patients will receive either edasalonexent or placebo daily for 
52 weeks.  
The rationale for the dose levels and dosing regimen used in the study is provided in Section 2.3. 
Population 
The study’s eligibility criteria are designed to include only patients with an established diagnosis of 
DMD who are sufficiently well (both in terms of DMD and in terms of concomitant illness) to safely 
participate in study procedures and provide interpretable results.  Diagnostic criteria will include 
demonstration of a classic DMD clinical phenotype, increased serum creatine kinase (CK), and the 
presence of a mutation in the dystrophin gene consistent with DMD. 
Eligible patients will be ambulatory boys ≥4.0 to <8.0 years of age.  These gender and age criteria are 
intended to facilitate enrollment (as DMD is much more common in boys), and ensure that the 
enrolled patients will be able to complete the timed function tests included in the study as efficacy 
assessments.  In addition, eligible patients must have not used steroids within the 24 weeks prior to 
initiation of study treatment (Day 1).  It is important to evaluate the effects of edasalonexent in the 
absence of concomitant steroid use since the positive effects of glucocorticoids are thought to be at 
least partially mediated by their anti-inflammatory action via modulation of NF-κB, and 
edasalonexent is proposed to work through the same pathway (but without the negative side effects).  
While it is also important to evaluate the efficacy and safety of edasalonexent in the absence of other 
disease-modifying therapies, recent nonclinical data have shown that administration of edasalonexent 
in combination with eteplirsen results in increased dystrophin expression and does not reveal any 
increased risk.  Therefore, patients who have received at least 24 weeks of treatment with eteplirsen 
prior to Day 1 will be eligible for the study.   
For detailed information on prohibited concomitant medications, please refer to Section 5.3.   
To minimize the risk for practice effects (which could mask potential treatment effects), decrease the 
heterogeneity of the patient population with respect to disease state, and ensure that patients are not at 
high risk for imminent loss of ambulation, patients will be required to do the following to enroll:  
stand from supine in ≤10 seconds, and complete the 10MWT and 4-stair climb. 
It is strongly recommended that all patients receive annual vaccinations for influenza virus. 
Safety Monitoring 
The safety measures used in this study are standard and reflect appropriate monitoring of pediatric 
patients receiving an investigational drug.  Although no adrenal abnormalities have been observed in 
the Phase 1/2 study, CAT-1004-201 (see the Investigator’s Brochure), since weight loss and adverse 
effects on adrenal glands were observed in 13-week juvenile rat toxicology studies at plasma 
exposures higher than anticipated in humans, monitoring of adrenal function will be included in this 
study as a precaution.  In addition to monitoring by the Investigators, sub-Investigators and Medical 
Monitors, a DSMB will provide oversight of the study. 
Efficacy 
The selection of efficacy endpoints was based on consideration of the primary clinical manifestations 
of DMD, namely a progressive loss of muscle strength and the associated impact of this loss on 
function.  The potential effects of edasalonexent on muscle strength and function are assessed by 


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means of widely used and accepted measures of these constructs including NSAA, TFTs, muscle 
strength testing, PUL entry item assessment, and the PODCI Transfer and Basic Mobility scale.   


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4. 
PATIENT POPULATION AND SELECTION 
4.1. 
Inclusion Criteria 
A patient must meet all the following criteria to be eligible for this study. 
1. Written consent/assent by patient and/or legal guardian as per regional and/or Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) requirements  
2. Diagnosis of DMD based on a clinical phenotype with increased serum creatine kinase (CK) 
and documentation of mutation(s) in the dystrophin gene known to be associated with a DMD 
phenotype  
3. Male sex by birth 
4. Age ≥4.0 to <8.0 years (at the time of consent) 
5. Able to perform stand from supine without assistance in ≤10 seconds  
6. Able to perform the 10MWT and 4-stair climb 
7. Able to swallow placebo capsules at the Screening Visit 
8. Followed by a doctor or medical professional who coordinates Duchenne care on a regular 
basis and willingness to disclose patient's study participation with medical professionals 
4.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study. 
1. Use of corticosteroids within 24 weeks prior to Day 1; use of inhaled, intranasal, and topical 
corticosteroids is permitted 
2. Use of an investigational drug, idebenone, or dystrophin-focused therapy within 4 weeks or a 
period of 5 half-lives duration prior to Day 1 (whichever is longer) or ongoing participation in 
any other therapeutic clinical trial.  Exception: Patients who have received at least 24 weeks of 
a stable dose of eteplirsen prior to Day 1, and expected to continue treatment, will be eligible.  
3. Use of the following within 4 weeks prior to Day 1: immunosuppressive therapy, warfarin, 
phenytoin, S mephenytoin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, alfentanil, 
pimozide, quinidine, sirolimus, tacrolimus, or paclitaxel 
4. Use of human growth hormone within 3 months prior to Day 1 
5. Documented positive hepatitis B surface antigen, hepatitis C antibody, or human 
immunodeficiency virus (HIV) or a known risk factor for hepatitis such as a blood transfusion 
within 12 weeks prior to Day 1 
6. Hemoglobin <10.5 g/dL 
7. Abnormal gamma glutamyl transferase (GGT) (>laboratory’s upper limit of normal [ULN]) 
8. Other prior or ongoing medical condition, known hypersensitivity to omega 3 fatty acids, 
physical findings, ECG findings, or laboratory abnormality (including but not limited to renal 
insufficiency or impaired hepatic function) that, in the Investigator’s opinion, could adversely 
affect the safety of the patient, make it unlikely that the course of treatment or follow up 


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would be completed, or impair the assessment of study results (e.g., a gastrointestinal 
condition that would impair fat absorption) 
9. In the Investigator’s opinion, unwilling or unable for any reason (e.g., attentional or 
behavioral issues) to complete all study assessments and laboratory tests and comply with 
scheduled visits, administration of drug, and all other study procedures 
Note:  Patients may be re-tested or re-screened for eligibility after discussion with the Medical 
Monitor. 


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5. 
TREATMENTS 
5.1. 
Treatments Administered 
5.1.1. 
Double-Blind Placebo-Controlled Treatment 
Eligible patients will be randomly assigned 2:1 to receive either edasalonexent 100 mg/kg/day 
(administered as approximately 33 mg/kg TID) or placebo in double-blind fashion daily for 52 weeks.  
The exact capsule count per dose will be provided.  All doses of study drug will be orally 
administered in divided doses with food containing at least 8 grams of fat.  Nutritional guidance will 
be provided at Baseline.  Patient compliance with the nutritional guidance will be confirmed 
throughout treatment.  The acceptability and palatability of edasalonexent will be explored in this 
study; data will be collected from patients and caregivers. 
5.1.2. 
Investigational Product(s) Description 
Description of edasalonexent capsules: 
• 100-mg capsules (Size 3 oval) containing 100 mg edasalonexent formulated with the 
following excipients: polysorbate-80, glyceryl monooleate (type 40), PEG-400, and dl-
alpha-tocopherol, with imprint “####” using black iron oxide ink   
• 250-mg capsules (Size 7.5 oval) containing 250 mg edasalonexent formulated with the 
following excipients: polysorbate-80, glyceryl monooleate (type 40), PEG-400, and dl-
alpha-tocopherol, with imprint “####” using black iron oxide ink   
Description of placebo capsules: 
• Placebo 100-mg match capsules (Size 3 oval) containing the following excipients:  
polysorbate-80, glyceryl monooleate (type 40), PEG-400, and dl-alpha-tocopherol, with 
imprint “####” using black iron oxide ink 
• Placebo 250-mg match capsules (Size 7.5 oval) containing the following excipients:  
polysorbate-80, glyceryl monooleate (type 40), PEG-400, and dl-alpha-tocopherol, with 
imprint “####” using black iron oxide ink 
5.1.3. 
Packaging and Labeling 
The investigational products described in Section 5.1.2 will be provided to the site by the Sponsor or 
designee.  Refer to the Study Drug Handling Manual (SDHM) for additional details.  The Sponsor or 
designee will provide the Investigator with packaged investigational product labeled in accordance 
with country-specific regulatory requirements. 
5.1.4. 
Storage 
The investigational products must be stored refrigerated at 2°C to 8°C (36°F to 46°F) at the site.  
Single bottles dispensed to patients may be stored at up to 25°C (77°F; controlled room temperature) 
for up to 30 days.  Refer to the SDHM for additional details. 
5.1.5. 
Preparation and Administration 
Refer to the SDHM for additional details.   


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5.2. 
Dosing Considerations 
5.2.1. 
Dose Selection Rationale 
See Section 2.3 for details on dose rationale. 
5.2.2. 
Dose Modification or Reduction 
Temporary or persistent dose reductions may be made for safety or tolerability at any time during the 
study.  Refer to Section 7.9 for additional details. 
5.2.3. 
Safety Monitoring 
Safety will be monitored on an ongoing basis by the Investigator, Medical Monitor, and Sponsor.  In 
addition, the DSMB will review relevant study data (as defined in the DSMB charter) to decide on 
the continuation, termination, or modification of the trial (also see Section 8.4).   
5.2.4. 
Treatment Compliance  
Throughout the study, patients and their parents/caregivers will complete a diary documenting 
investigational product administration, and diet compliance.  Upon completion of data entry, the 
database will undergo a quality review to ensure acceptable accuracy and completeness.  In addition, 
site calls, which will occur throughout the study as noted in the SOA (Appendix 1), will include a 
compliance check on investigational product administration and diet.  Detailed information regarding 
the study-specific dietary requirements and the process for monitoring compliance to the diet are 
provided in the Study Reference Manual (SRM). 
5.2.5. 
Treatment Discontinuation 
A patient’s study treatment may be discontinued at any time at the patient’s/parent/legal guardian’s 
request or at the discretion of the Investigator, Medical Monitor or Sponsor.  The following may be 
justifiable reasons for the Investigator, Medical Monitor or Sponsor to discontinue a patient from 
treatment: 
• The patient experiences an intolerable or unacceptable AE 
• The patient is unable to comply with the requirements of the protocol 
• The patient participates in another investigational study without the written authorization 
of the Sponsor 
Discontinuation of treatment does not imply withdrawal from the study.   
Patients who discontinue treatment prematurely will be asked to complete the early termination visit 
prior to their last dose of study drug as noted in the SOA in Appendix 1.   
5.3. 
Prior and Concomitant Medications and Therapeutic Procedures 
In general, disease-modifying drugs, investigational drugs, immunosuppressive therapy, and drugs 
with narrow therapeutic indices metabolized by CYP3A4, CYP2C8, CYP2C9, and CYP2C19 are 
prohibited for at least 4 weeks prior to Day 1 and during the study (Table 2).  Recent nonclinical data 
have shown that administration of edasalonexent in combination with eteplirsen results in increased 
dystrophin expression and does not reveal any increased risk.  In regions where eteplirsen is approved 


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or there is an established access program, patients who have received at least 24 weeks of treatment 
with eteplirsen prior to Day 1 will be eligible for the study.   
Throughout the study, Investigators may prescribe concomitant medications or treatments deemed 
necessary to provide adequate supportive care to patients.   
Treatment with corticosteroids is prohibited within 24 weeks prior to Day 1 and during the study 
(Table 2).   
All medications should be taken as prescribed, per Investigator judgment, even when blood samples 
are planned to be drawn.  In addition, all concomitant medications, including supplements must be 
recorded in the source documentation and in the eCRF.   
Note:  Annual vaccination for influenza is strongly recommended for all patients. 
Table 2: 
Prohibited Prior and Concomitant Medications 
Medication 
Prohibited within 
24 weeks prior to Day 1 
Prohibited within 
4 weeks prior to Day 1a 
Initiation prohibited 
throughout the study 
Corticosteroids b 
X 
X 
X 
Deflazacort (Emflaza™) 
X 
X 
X 
Ataluren (Translarna™) 
 
X 
X 
Idebenone (Raxone®) 
 
X 
X 
Other investigational drugs 
 
X 
X 
Immunosuppressive therapy 
 
X 
X 
Warfarin, phenytoin, 
S mephenytoin, cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, alfentanil, pimozide, 
quinidine, sirolimus, tacrolimus, 
paclitaxel 
 
X 
X 
 Eteplirsen (Exondys 51™) c 
 
 
X 
a 
If 5 half-lives of the drug is >4 weeks, drug is prohibited for 5 half-lives prior to Day 1. 
b       Use of inhaled, intranasal, and topical corticosteroids is permitted. 
c       Use of eteplirsen is permitted if on a stable dose for at least 24 weeks prior to Day 1. 
5.4. 
Method of Assigning Patients to Treatment 
During the study, patients will be randomly assigned in a 2:1 ratio to receive edasalonexent or 
placebo in double-blind fashion.   
5.5. 
Blinding and Randomization 
5.5.1. 
Blinding and Randomization 
Approximately 126 patients will be randomized 2:1 to receive edasalonexent or placebo in double-
blind fashion daily for 52 weeks.  Randomization will be stratified by Baseline age (≤6.0 years or 
>6.0 years), time to stand from supine (≤5 seconds or >5 seconds), treatment with eteplirsen (yes or 
no), and region (North America or Europe/Asia/Australia). 


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If siblings are enrolled, only one sibling will be included in the Randomized Population, the second 
sibling will be assigned to the same treatment group as the randomized sibling (see Section 9.3).  If 
both siblings meet the inclusion/exclusion criteria, the sibling to be included in the Randomized 
Population will be the first sibling randomized. 
5.5.2. 
Scheduled Unblinding 
After completion of the study, patients, monitors, Investigators, study center personnel, and the 
Sponsor will remain blinded to treatment assignments until results from the study are available.   
5.5.3. 
Emergency Unblinding 
Prior to scheduled unblinding (see Section 5.5.2), if an emergency where the identity of the 
investigational product must be known by the Investigator to provide appropriate medical treatment 
occurs, the Investigator will be allowed to unblind using the Interactive Web Response System 
(IWRS).  Before doing this, the Investigator should make every effort to discuss the situation with the 
Medical Monitor. 
The treatment assignment should only be unblinded when knowledge of the treatment assignment 
will impact the clinical management of the patient.  Every reasonable attempt should be made to 
complete the final treatment assessment procedures prior to unblinding, as knowledge of the 
treatment assignment could influence patient assessment.   


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6. 
STUDY ASSESSMENTS 
6.1. 
Study Schedule of Events 
The SOA for the study is provided in Appendix 1. 
The modified SOA for this study during the COVID-19 pandemic is provided in Appendix 2. 
6.2. 
Screening and Baseline Assessments and Start of Treatment 
Once written informed consent, and when appropriate, written assent is obtained, patients will be 
screened for eligibility for entry into the study based on the inclusion and exclusion criteria detailed 
in Sections 4.1 and 4.2.  A full medical/surgical history will be obtained, including information 
relating to any prior or existing medical conditions/surgical procedures that may be relevant to the 
patient’s experience in the study.  Demographic data and DMD-specific medical history information 
will also be recorded.  Patients will undergo a full physical examination, including vital signs (see 
Sections 6.4.1 and 6.4.2), safety labs, a 12-lead ECG tracing will be obtained, and body weight will 
be measured.  Additional cardiac monitoring will be performed via a wearable cardiac monitoring 
device to measure heart rate and heart rate variability if approved for use in the country.  The 
laboratory assessments shown in Appendix 3 will be performed.   
Screening assessments should be completed within 4 weeks of Day 1. 
At Baseline, patient eligibility for the study will be reconfirmed and the patient will be randomized.  
Patients will undergo a full physical examination.  Height and body weight will be measured and 
body mass index (BMI) will be calculated.  Any AEs or changes in concomitant medications since 
Screening will be recorded.  Patients will undergo Baseline efficacy evaluations as specified in 
Appendix 1, and blood samples will be drawn for safety, ACTH/cortisol, biomarkers and gene 
expression.  Bone evaluations (spine radiography and DXA scan) will be performed if approved by 
the appropriate governing bodies at each site or country.  Patients and their families will be provided 
with written and verbal instructions for study drug administration.  Nutritional guidance will also be 
given and study drug will be dispensed. 
6.3. 
Efficacy Assessments 
Efficacy will be assessed at the timepoints specified in Appendix 1.  
6.3.1. 
North Star Ambulatory Assessment (NSAA) 
The NSAA is a clinician-reported outcome instrument designed to measure ambulatory function in 
males with DMD (Scott, 2012).  During this assessment, patients are asked to perform 17 different 
functional activities, including a 10MWT, rising from supine, rising from a sit to stand, standing on 
1 leg, e.g., climbing and descending a step, rising from the floor, lifting the head, standing on heels, 
and jumping.  The NSAA has undergone detailed psychometric evaluations based on traditional 
(reliability and validity) and modern (Rasch analysis) methods, and has been included in international 
clinical trials (Kinali, 2009).  In addition, 36-month longitudinal data are available in patients with 
DMD (Mazzone, 2011; Pane, 2014b).  The NSAA will be administered by trained evaluators; every 
effort will be made to have the same evaluator perform all assessments for a given child at the same 
time of day.  Completion of this test is expected to take approximately 20-30 minutes. 


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Additional details on the performance of the NSAA are provided in the Clinical Evaluator Manual. 
6.3.2. 
Timed Function Testing  
TFTs will include the 10MWT and the stand from supine (as measured in the NSAA) as well as the 
4-stair climb.  These tests have been used as clinical trial endpoints in DMD and have shown 
response to therapeutic intervention with steroids (Mendell, 1989; Griggs, 1990; Beenakker, 2005; 
Manzur, 2009).  TFTs will be performed by trained evaluators; every effort will be made to have the 
same evaluator perform all assessments for a given child at the same time of day.  Completion of 
TFTs is expected to take approximately 10 minutes. 
Additional details on the performance of the TFTs is provided in the Clinical Evaluator Manual. 
6.3.3. 
Muscle Strength Testing 
Muscle strength testing will include assessment of knee extension and elbow flexion.  Muscle testing 
will be performed using a hand-held dynamometer.  Knee myometry will be performed while the 
patient is in a sitting position.  Elbow myometry will be performed while the patient is positioned 
supine.  Muscle testing will be performed by trained evaluators; every effort will be made to have the 
same evaluator perform all assessments for a given child at the same time of day.  Completion of each 
muscle test is expected to take approximately 10-15 minutes, for a total of 20-30 minutes.   
Additional details on the assessment of muscle strength are provided in the Clinical Evaluator 
Manual. 
6.3.4. 
Performance of Upper Limb (PUL) Scale 
The PUL was specifically designed by an international Clinical Outcomes Group consisting of 
clinicians, scientists, patient advocacy groups and industries representative to assess upper limb 
function in ambulant and non-ambulant DMD patients (Mercuri, 2012; Mayhew, 2013b).  The PUL is 
made up of a 6-point entry item (based on the modified Brooke Upper Extremity Scale) to define the 
starting functional level, and 22 items subdivided into shoulder level (6 items), middle level (9 items) 
and distal level (7 items) dimension (Pane, 2018).  Loss of full overhead reach occurs at median age 
9.6 with some boys losing the ability as early as age 5 or 6 (McDonald, 2018).  Patients will perform 
the PUL entry item assessment as specified in Appendix 1.  Based on the age of patients in this study, 
most patients will score a 6 on the 6-point entry item assessment.  Those patients who score a 6 on the 
6-point entry item assessment will not be required to perform the additional items.  Patients who 
score below a 6 on the 6-point entry item assessment will perform a subset of the PUL battery 
including the shoulder level dimension and supination, consisting of 7 items with a maximum score 
of 14.  In boys with DMD, the PUL has robust internal reliability, validity, and hierarchical 
scalability (Mayhew, 2013a), excellent interobserver and intra-observer reliability (Pane, 2014a), and 
is sensitive to changes over time (Seferian, 2015) and in response to steroid treatment (Pane, 2015).  
It may be most suitable for DMD patients 5 years of age and above.  Completion of the 6-point entry 
item assessment is expected to take approximately 5 minutes. Completion of the battery of PUL 
assessments is expected to take approximately 20 minutes.  
Additional details on the PUL scale are provided in the Clinical Evaluator Manual. 


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6.3.5. 
The Pediatric Outcomes Data Collection Instrument (PODCI) 
The PODCI is a well-validated tool for assessment of health-related functioning in children, and has 
been used in a study of boys with DMD (Henricson, 2013).  It is designed to be completed by the 
parent/caregiver of children aged 10 or younger, contains 86 questions, takes approximately 
20-30 minutes to complete, and provides information on the following 6 scales:  
• Upper Extremity and Physical Function Scale:  Measures difficulty encountered in 
performing daily personal care and student activities. 
• Transfer and Basic Mobility Scale:  Measures difficulty experienced in performing routine 
motion and motor activities in daily activities. 
• Sports and Physical Functioning Scale:  Measures difficulty or limitations encountered in 
participating in more active activities or sports.   
• Pain/Comfort Scale:  Measures the level of pain experienced during the past week. 
• Happiness Scale:  Measures overall satisfaction with personal looks and sense of 
similarity to friends and others of own age. 
• Global Functioning Scale:  A general combined scale calculated from the first 4 scales 
listed above. 
Parents/caregivers will complete the PODCI listed in Appendix 5 at timepoints listed in Appendix 1. 
6.3.6. 
Assessor Training and Ensuring Compliance with Protocol-Specified Test-
Administration. 
The following efficacy assessments will be administered by trained evaluators:  NSAA, TFTs, muscle 
strength testing, and PUL.  To help ensure proper and consistent test administration across 
evaluators/sites, all evaluators will undergo training on the proper administration of these assessments 
prior to the study.  As part of this training, therapists will administer each assessment to boys with 
DMD who are not participating in the study; test administrations will be videotaped, reviewed for 
adherence and inter-rater consistency, and feedback will be provided as applicable. 
To help ensure proper and consistent test administration over the course of the study, administration 
of NSAA, TFTs, and muscle strength testing may be videotaped and reviewed for each patient at 
Screening and Week 52 and may also be required at Baseline as specified in Appendix 1. 
Additional information on the training and monitoring of the administration of these tests is provided 
in the Clinical Evaluator Manual.  
6.4. 
Safety Assessments 
Safety will be assessed for all enrolled patients from Screening through the safety follow-up, as 
specified in Appendix 1.  Safety parameters include physical examinations, growth parameters, vital 
signs, clinical laboratory tests (including chemistry, hematology, urinalysis, and tests for adrenal 
function), ECGs, and concomitant medication monitoring as described in Section 6.4.5 and AEs as 
described in Section 7.  A list of all required clinical laboratory assessments is provided in 
Appendix 3.   


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6.4.1. 
Physical Examination and Growth Parameters 
The physical examinations will include an assessment of the patient’s general appearance; skin; head, 
ears, eyes, nose, throat (HEENT); lymph nodes; heart; lungs; abdomen; extremities/joints; and 
neurological and mental status.  Physical examinations should be performed by the same person when 
possible.  Height and weight will be measured at the timepoints specified in Appendix 1 and BMI 
will be calculated. 
6.4.2. 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be measured at the 
timepoints specified in Appendix 1.  Systolic and diastolic blood pressure (preferably assessed on the 
same arm each time) will be measured only after the patient is positioned in a semi-supine position 
and resting for at least 5 minutes.   
6.4.3. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for clinical laboratory evaluations (see Appendix 3 for a 
complete list of analytes). 
The clinical laboratory tests to be done at Screening include hematology with differential, chemistry, 
and urinalysis.   
Blood samples for ACTH and cortisol will be obtained at Baseline before initiation of treatment.   
Chemistry, hematology, and ACTH/cortisol assessments done during the treatment period will be 
performed in the morning when possible.   
A central laboratory will provide collection supplies, arrange collection, and perform analysis of 
clinical laboratory evaluations indicated in Appendix 3.  Using the central laboratory for unscheduled 
clinical laboratory evaluations and repeat testing is recommended.  Procedures for the handling and 
shipment of all central laboratory samples will be included in the Laboratory Manual.  Specimens 
will be appropriately processed by the central laboratory facility and laboratory reports will be made 
available to the Investigator in a timely manner to ensure appropriate clinical review. 
The enrolling Investigator is responsible for reviewing and signing all laboratory reports unless the 
patient is transferred to another site for all subsequent visits.  The clinical significance of each value 
outside of reference range will be assessed by the Investigator and documented as either not clinically 
significant (NCS) or clinically significant.  All clinically significant values require a comment and the 
out-of-range value or the overlying diagnosis (or value if the diagnosis is unknown) must be captured 
as an AE. 
Clinical laboratory reports will serve as source documents. 
6.4.4. 
Electrocardiogram 
The 12-lead ECGs will be performed only after the patient is positioned supine, resting, and quiet for 
a minimum of 5 minutes.  If findings are abnormal, the Investigator is responsible for indicating 


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whether the ECG tracing is NCS or clinically significant.  In addition, ECGs will be centrally 
evaluated.   
6.4.5. 
Concomitant Medications and Therapies 
Concomitant medications and therapies are to be assessed at all visits.  Reasonable efforts will be 
made to determine all treatments (pharmacological and non-pharmacological) received by the patient.   
A medication/therapy is considered concomitant if it is taken/administered at any time from 
Screening through the final study evaluation. 
Data on pharmacological and non-pharmacological treatments will be recorded on an eCRF page, to 
include:  drug name/name of procedure, dose, route, regimen, start date, stop date, and indication.  At 
each study visit, the parent or caregiver will be asked about any additional treatments or any changes 
in regimen or dosages since the last visit.  Indications for any new medications or therapies during the 
study period will be recorded as an AE. 
Patients and their parents/caregivers will be contacted by the site between scheduled visits to assess 
concomitant medications and AEs (as indicated in Appendix 1). 
For detailed information on prohibited concomitant medications please refer to Section 5.3.   
6.5. 
Pharmacokinetic Assessments 
Samples for determination of edasalonexent and its metabolite concentrations will be drawn at 
selected visits as detailed in Appendix 1.  
In addition to the PK analyses described, any of the collected PK plasma and urine samples from 
study patients may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, or to assess other actions of study 
drug with plasma constituents. 
6.6. 
Pharmacodynamic Assessments 
Blood samples will be obtained at selected visits as indicated in Appendix 1.  Assessments may 
include: 
• Circulating protein biomarkers to evaluate course of disease and/or response to treatment 
• DNA, RNA (ribonucleic acid), and micro-RNA samples may be collected and used for 
pharmacogenomic analyses that might predict the course of disease and/or responses to 
treatment as well as analysis of drug metabolizing enzyme and/or transporters. 
Details of blood collection procedures will be provided in the Laboratory Manual.   
6.7. 
Cardiac Monitoring 
Patients with DMD are known to have resting tachycardia even in the age range in this clinical study 
(Thomas, 2012).  Additionally, decreases in heart rate variability have been observed (Thomas, 
2015).  Since decreases in heart rate to age-normative values were observed in a previous clinical 
study (CAT-1004-201), measures of heart rate and variability will be collected for approximately 48 
hours via a wearable cardiac monitoring device if approved for use in the participating country. In 
addition, the results from the patient’s last cardiac assessment should be documented as part of 


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medical history. Prospective cardiac assessments performed should also be documented as part of 
ongoing procedures. 
6.8. 
Bone Evaluations 
Patients with DMD have a deficiency of bone mineral density and increased incidence of bone 
fractures which becomes more severe when taking corticosteroids.  Patients who use corticosteroids 
have over two times as many fractures as steroid naïve patients (King, 2007).  Fractures that occur in 
lower extremities can lead to early loss of ambulation.  Bone evaluations will be performed through 
lateral thoracolumbar spine radiography and DXA scan.  In Germany, bone assessment will not be 
performed until the respective approvals from the German Federal Office for Radiation Protection 
(Bundesamt für Strahlenschutz) become available.  A qualified medical professional will review the 
results of the lateral thoracolumbar spine radiography and DXA scan and designate the findings as 
normal or abnormal; if abnormal, the Investigator will indicate whether the scans are NCS or 
clinically significant.  In addition, bone radiography will be centrally evaluated.  
6.9. 
Study Drug Acceptability 
To evaluate the acceptability and palatability of edasalonexent, caregivers will complete the study 
drug questionnaire listed in Appendix 4  at timepoints indicated in Appendix 1.  
6.10. 
Total Volume of Blood Collected 
The total number of venipunctures and the total volume of blood collected during the study will be 
limited to that needed for safety monitoring, PK, and PD measurement.  Refer to the SRM and/or 
laboratory manual for the collection preparation and procedures as well as the estimated total volume 
of blood to be collected during the study.  The total blood volume collected from each patient for the 
entire study is within the guidelines set forth by the World Health Organization (WHO) (Howie, 
2011). 


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7. 
ADVERSE EVENTS AND ADVERSE EVENT REPORTING 
At each study visit, patients will be evaluated for new AEs and the status of existing AEs.  The 
Investigator may elicit symptoms using an open-ended question, followed by appropriate questions 
that clarify the patient’s verbatim description of AEs or change in concomitant medications.  The 
enrolling Investigator is responsible for safety oversight of data for all visits unless the patient is 
transferred to another site for all subsequent visits.  All AEs from the time of signing the informed 
consent through follow-up will be recorded on the eCRF. 
7.1. 
Timeframe for Collection of Adverse Events 
7.1.1. 
Adverse Events Occurring Prior to Study Treatment 
All AEs that occur between the time informed consent is provided and the patient’s receipt of the first 
dose of investigational product will be considered pretreatment AEs. 
7.1.2. 
Adverse Events Occurring After Study Treatment 
All AEs that occur from the time of the administration of the first dose of investigational product 
through the end of the safety follow-up will be considered treatment-emergent AEs (TEAEs).  
7.1.3. 
Adverse Events Occurring Following Patient Discontinuation of Treatment 
For patients who prematurely discontinue study treatment (see Section 5.2.5), but who are not 
withdrawn from the study, AEs will continue to be recorded until the patient completes the study (see 
Section 3.3.3.1 for definition of patient completion).  See Section 7.6 for reporting requirements after 
the patient completes the study. 
7.2. 
Definitions 
7.2.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation patient, which does not 
necessarily have a causal relationship with the investigational product (active or placebo drug, 
biologic, or device).  An AE can, therefore, be any unfavorable and unintended symptom, sign, 
disease or condition, or test abnormality, whether considered related to the investigational product. 
Adverse events include: 
• Symptoms described by the patient or signs observed by the Investigator or medical staff 
• Test abnormalities (laboratory tests, ECG, X-rays, etc.) that result in an alteration in 
medical care (diagnostic or therapeutic) 
Adverse events do not include: 
• Changes that are characteristic of disease progression in Duchenne 
Abnormalities present at Baseline are considered AEs only if they reoccur after resolution or they 
worsen during the study. 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
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40 
7.2.2. 
Definition of a Serious Adverse Event 
Seriousness of an AE serves as a guide for defining regulatory reporting obligations.  An SAE is any 
AE that results in any of the following: 
Death:  The patient died as the result of the event. 
Life-threatening event:  Any AE that places the patient, in the view of the Investigator, at immediate 
risk of death from the AE as it occurred, i.e., does not include an AE that had it occurred in a more 
severe form, might have caused death. 
Required or prolonged inpatient hospitalization:  The AE resulted in an initial inpatient 
hospitalization or prolonged an existing hospitalization of the patient.  Note:  Planned hospital 
admissions, or surgical procedures for an illness or disease that existed before the administration of 
the study treatment or before the patient was enrolled in the study, will not be captured as SAEs 
unless they occur at a time other than the planned date. 
Persistent or significant disability/incapacity:  An AE that results in a substantial disruption of a 
person’s ability to conduct normal life functions. 
Congenital anomaly/birth defect:  A congenital anomaly/birth defect that occurs in the offspring of a 
patient exposed to the investigational product. 
Important medical events:  An AE that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
7.3. 
Evaluation of Adverse Events/Serious Adverse Events 
7.3.1. 
Relationship to Study Treatment 
Assessment of the association between the AE and study drug exposure is important for regulatory 
reporting.  For each AE/SAE, the Investigator will determine whether there is a reasonable possibility 
that the AE may have been caused by the study drug according to the following categories: 
Not Related:  The AE is clearly not related to study drug. 
Unlikely Related:  There is no evidence of a causal relationship between study drug and the AE; 
although such relationship cannot be ruled out. 
Possibly Related:  There is some evidence supporting the possibility of a causal relationship between 
study drug and the AE. 
Related:  There is strong evidence that there is a causal relationship between study drug and the AE. 
A relationship to the investigational product must be given for each AE/SAE recorded, even if there 
is only limited information at the time.  The Investigator may change his/her opinion of causality in 
light of follow-up information, amending the AE/SAE report accordingly. 
7.3.2. 
Severity Grading of Adverse Event Scoring 
Note that severity is not the same as “seriousness,” which is defined in Section 7.2.2.   


Clinical Trial Protocol:  CAT-1004-301 
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41 
The Investigator will grade the severity of all AEs/SAEs as mild, moderate, or severe, based on the 
following definitions (developed from Clinical Data Interchange Standards Consortium [CDISC] 
Study Data Tabulation Model [SDTM] standard terminology v3.1.1): 
Mild:  An AE that is usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of daily living. 
Moderate:  An AE that is usually alleviated with specific therapeutic intervention.  The event 
interferes with usual activities of daily living, causing discomfort, but poses no significant or 
permanent risk of harm to the research participant. 
Severe:  An AE that interrupts usual activities of daily living, or significantly affects clinical status, or 
may require intensive therapeutic intervention. 
7.3.3. 
Outcome 
Outcome describes the status of the AE.  The Investigator will provide information regarding the 
patient outcome of each AE. 
Possible results of an AE outcome are defined as follows: 
Fatal:  The termination of life as a result of an AE. 
Not recovered/not resolved:  The patient has not recuperated or the AE has not improved. 
Recovering/resolving:  The patient is recuperating or the AE is improving. 
Recovered/resolved:  The patient has recuperated or the AE has resolved. 
Recovered with sequelae/resolved with sequelae:  The AE has resolved, but the patient has been left 
with symptoms or pathology. 
Unknown:  Not known, not observed, not recorded, or refused. 
7.3.4. 
Action Taken Regarding the Investigational Product 
The Investigator will be required to provide the action taken regarding investigational product (e.g., 
active, comparator) in response to the AE according to the following categories: 
Dose not changed:  No change in administration of the investigational product. 
Dose reduced:  Reduction in the frequency, strength or amount of investigational product 
administered. 
Drug (investigational product) interrupted:  Temporary interruption (termination) in administration of 
the investigational product. 
Drug (investigational product) withdrawn:  Administration of the investigational product terminated 
(no further dosing). 
Not applicable:  Determination of a value is not relevant in the current context. 
Unknown:  Not known, not observed, not recorded, or refused. 


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Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary 
43 
any safety alert notifications for onward submission to their local IRB/IEC as required.  All reports 
sent to Investigators will be blinded. 
The Investigator must continue to follow the patient until the SAE has resolved or until the condition 
becomes chronic in nature, stabilizes (in the case of persistent impairment) or the patient dies.  Within 
24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., patient 
discharge summary or autopsy reports) to contacts above via fax or e-mail.  If it is not possible to 
access the EDC system, refer to the procedures outlined above for initial reporting of SAEs.   
7.7. 
Follow-up of Adverse Events/Serious Adverse Events 
All AEs/SAEs documented at a previous visit/contact that are designated as not recovered/not 
resolved or recovering/resolving will be reviewed by the Investigator at subsequent visits/contacts. 
All AEs will be followed until the parameter returns to its Baseline status, resolution of AE, 
completion of the patient’s participation, agreement is reached between the Investigator and Sponsor 
that the event no longer requires follow-up, or study termination, whichever occurs first.  SAEs will 
be followed until resolution, the condition stabilizes, or the Investigator and Medical Monitor agree 
that follow-up is no longer necessary.  Rules for AE/SAE follow-up apply to all patients, including 
those withdrawn prematurely to the extent allowed by the patient’s consent.  The Investigator will 
ensure that follow-up includes further investigations consistent with appropriate medical management 
and patient consent to elucidate the nature and/or causality of the AE/SAE. 
7.8. 
Pregnancy Reporting 
Not applicable for this study. 
7.9. 
Temporary or Persistent Dose Reductions 
Temporary or persistent dose reductions may be made for safety or tolerability reasons in the 
judgment of the Principal Investigator.  If at any time after initiation of treatment the patient 
experiences a clinically significant AE indicative of drug intolerance, the patient will undergo clinical 
assessment as soon as reasonably possible.  The Principal Investigator should discuss any potential 
dose modifications or reduction with the Medical Monitor.   
7.10. 
Monitoring of Abnormal Laboratory Values 
Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are common in 
patients with DMD, so exclusion of patients with abnormal Baseline values is not feasible.  Patients 
with abnormal GGT will be excluded.   
During the study, liver function tests will be monitored, including ALT, AST, GGT, alkaline 
phosphatase, glutamate dehydrogenase, and bilirubin.  If increases in ALT or AST are noted, the 
relationship of these to CK will be determined, as well as to GGT and measures of liver synthetic 
function.  Trends in these parameters will be monitored.  Safety alert flags for the Investigator and 
Medical Monitor will include an alert for increases in ALT >150 U/L with stable or decreased CK, as 
well as for total bilirubin, glutamate dehydrogenase, or GGT parameters greater than the ULN.   
Additional information on safety alert flags will be included in the Laboratory Manual.   


Clinical Trial Protocol:  CAT-1004-301 
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7.11. 
Stopping Rules 
Either the Investigator or Medical Monitor may stop dosing in individual patients based on 
tolerability or AEs. 
7.12. 
Restriction on the Lifestyle of Patients 
Not applicable. 


Clinical Trial Protocol:  CAT-1004-301 
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8. 
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT 
8.1. 
Recording of Data 
The Investigator must provide the Sponsor or its designee direct access to each patient’s source 
documents.  Source documents may include, but are not limited to, the following original documents, 
data, and records where information is first recorded. 
• Hospital records 
• Medical histories and narrative statements relating to the patient’s progress 
• Clinical and office charts (electronic or paper) 
• Operative reports 
• Laboratory notes/reports 
• Project-specific worksheets (e.g., for study visits), including all worksheets developed 
specifically for this study 
• X-ray, MRI, and computed tomography (CT) reports 
• Cardiac ultrasound, echocardiogram 
Required data for this study will be captured using eCRFs via EDC unless otherwise specified in this 
document, below. 
Clinical data that are not recorded on the eCRF will be captured and transferred to the Sponsor or its 
designee. 
8.2. 
Data Quality Assurance 
The eCRFs will be reviewed by the Sponsor’s clinical monitor or designee for completeness and 
accuracy.  Source document verification will be performed.  The data will also be reviewed internally 
by the Sponsor’s Data Management department or its designee and, if necessary, the investigational 
sites will be queried for corrections and/or clarifications.  Upon completion of data entry and 
reconciliation, all EDC user access privileges will be changed to read only.  Upon completion of data 
entry, the database will undergo a quality review to ensure acceptable accuracy and completeness.   
8.3. 
Data Management 
The format and content of the eCRF will be approved by the Sponsor or its designee prior to the start 
of the study.  The Sponsor or its designee will be responsible for database creation, data entry if 
applicable, and management of data from sources other than the clinical database (e.g., laboratory 
data).  Once all patients have completed all study visits, the database will be cleaned, locked, 
unblinded and the statistical analysis will be performed. 
8.4. 
Data Safety Monitoring Board 
External oversight for this trial will be provided by a DSMB, which will include physicians 
experienced in treating DMD and a biostatistician experienced in clinical trials.  The primary 


Clinical Trial Protocol:  CAT-1004-301 
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46 
responsibility of the DSMB is to protect the safety and welfare of patients participating in this clinical 
trial and to ensure the integrity of the clinical trial.   
Specifically, for this study, the DSMB will be responsible for examining accumulated safety data, 
PK, and compliance data to make recommendations concerning the continuation, termination, or 
modification of the trial based on the safety of the interventions under study throughout the study.  
The DSMB will meet with a frequency as defined in the DSMB charter. 
Further information regarding the DSMB review process will be provided in the DSMB charter. 


Clinical Trial Protocol:  CAT-1004-301 
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47 
9. 
STATISTICAL METHODS AND PLANNED ANALYSES 
9.1. 
General Considerations 
A Statistical Analysis Plan (SAP), in compliance with the International Council for Harmonisation 
(ICH) and Food and Drug Administration’s Guidance for Industry: “Statistical Principles for Clinical 
Trials”, will be written and finalized prior to database lock and unblinding providing greater detail on 
the statistical analysis methodology. 
All eCRF data, as well as any outcomes derived from the data, will be displayed in data listings.   
Descriptive characteristics for continuous variables will be summarized using mean, median, standard 
deviation, minimum and maximum values.  For categorical variables, the number and percentage of 
patients (or observations) will be reported.  
Unless otherwise defined for a particular endpoint, a patient’s baseline value is the last measurement 
prior to initiation of study drug. 
9.2. 
Determination of Sample Size 
Approximately 126 patients will be enrolled and assigned to either edasalonexent or placebo in a 
2:1 ratio.  Based on Phase 1/2 data of changes in NSAA in this age group, an effect size of 0.625 is 
assumed.  With this effect size, and assuming a dropout rate of approximately 20%, the study has 
approximately 80% power to show a difference between the treatment groups at a 2-sided type I error 
rate of 0.05.   
The number of enrolled patients on eteplirsen should not exceed their representation in the Duchenne 
population. 
9.3. 
Analysis Sets  
The following are the analysis populations for this study: 
Randomized Population:  The Randomized Population consists of all patients who are randomized 
into the study.  
Note: If a randomized patient has a sibling assigned to the same treatment group, the non-randomized 
sibling (i.e., the sibling assigned to the same treatment as the randomized sibling) will not be included 
in the randomized population (see Section 5.5.1).   
Safety Population:  The Safety Population will consist of all patients who receive at least 1 dose of 
study drug.  This will include the set of patients who were assigned the same treatment as their 
randomized sibling.   
Full Analysis Population:  The Full Analysis Population for efficacy analyses will be a modified 
intent to treat (mITT) population and will consist of all patients in the Randomized Population who 
receive at least 1 dose of study drug, and provide at least 1 valid post Baseline NSAA efficacy 
assessment.   
Per Protocol Population:  The Per Protocol (PP) Population will consist of all patients in the Full 
Analysis Population who complete the study, without any significant protocol violations.   


Clinical Trial Protocol:  CAT-1004-301 
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48 
PK Population:  The PK Population will consist of all patients in the Safety Population who receive at 
least 1 dose of edasalonexent and have at least 1 measured plasma concentration.   
Other analysis populations may be defined in the SAP.   
9.4. 
Demographics and Baseline Characteristics 
Demographics, including age at Baseline considered as a continuous variable, frequency of age by 
year, age at Baseline (≤6.0 years or >6.0 years) and Baseline characteristics, including time to stand 
from supine (≤5 seconds or >5 seconds) treatment with eteplirsen (yes or no), and region (North 
America or Europe/Asia/Australia) will be listed by patient, and summarized by treatment group and 
overall.   
9.5. 
Concomitant Medications 
Concomitant medications will be listed by treatment and coded using the WHO Drug dictionary.  
9.6. 
Medical History 
Medical history will be listed and coded by patient using the Medical Dictionary for Regulatory 
Activities (MedDRA®) dictionary Version 21.0. 
9.7. 
DMD-Specific Medical History 
DMD-specific medical history, including age at symptom onset and diagnosis, will be listed by 
patient, and summarized by treatment group and overall.   
9.8. 
Patient Disposition 
All patients who sign the informed consent will be included in a summary(s) of patient disposition.  
The number of patients randomized, and the number and percentage of patients discontinuing and 
completing treatment, will be presented.  The number of patients discontinuing before study 
completion (including reason for discontinuation), and the number of patients completing the study 
will be presented as well.  The number and percentage of patients in the various analysis populations 
will be presented separately. 
9.9. 
Study Treatment Usage and Compliance 
For the Safety Population, treatment duration, number of administrations, and compliance will be 
summarized by treatment group and overall.   
9.10. 
Efficacy Analyses 
Results of efficacy assessments will be listed by patient, and summarized by treatment group and 
timepoint, as applicable.  For the TFTs, both the times to complete in seconds and their speed (i.e., 
the reciprocals) will be tabulated (in the case of the 10MWT, in units of 10 meters per second; in the 
case of the stand from supine and 4-stair climb in units of task per second).  Descriptive statistics will 
be calculated for quantitative efficacy data as well as for the CFB, and differences between groups as 
applicable. 


Clinical Trial Protocol:  CAT-1004-301 
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9.10.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the CFB in the NSAA Total Score at Week 52. 
The CFB in NSAA Total Score will be analyzed using a mixed-model repeated-measures (MMRM) 
analysis of covariance (ANCOVA), implemented using SAS® Proc Mixed.  The factors in the model 
will be Baseline age (≤6.0 years or >6.0 years), time to stand from supine (≤5 seconds or >5 seconds), 
region (North America or Europe/Asia/Australia), visit, treatment group, Baseline value, Baseline 
value by visit, and treatment group by visit. 
The primary analysis will test the treatment difference at Week 52 via the MMRM model at the two-
sided 0.05 level.  Details of the MMRM model will be provided in the SAP. The primary analysis 
will be performed on the Full Analysis Population with exclusions that may be defined in the SAP, 
such as excluding patients receiving treatment with eteplirsen. 
9.10.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be the CFB to Week 52 on the 10MWT, stand from supine, 
and 4-stair climb. 
The Baseline values and CFB in each will be summarized by treatment group and timepoint using 
descriptive statistics.  The CFB will be analyzed using the same MMRM ANCOVA model as 
described above for the primary efficacy endpoint. The secondary efficacy analyses will be performed 
on the Full Analysis Population with exclusions that may be defined in the SAP, such as excluding 
patients receiving treatment with eteplirsen. 
9.10.3. 
Controlling for Multiplicity 
The method for controlling the overall Type I Family-wise error rate at the two-sided 0.05 level will 
be provided in the SAP. 
9.10.4. 
Sensitivity Analyses of the Primary and Secondary Efficacy Endpoints 
Sensitivity analyses of the primary and secondary efficacy endpoints will be specified in the SAP.   
While the MMRM analysis represents the primary method for incorporating patients with missing 
data (i.e., observed case analyses), a multiple imputation method for addressing missing data will be 
applied using the primary and secondary analysis methods.   
Additional details on the methods to assess the impact of missing data will be provided in the SAP. 
9.10.5. 
Additional Efficacy Endpoints 
Additional efficacy endpoints will include CFB on the following endpoints: 
• Muscle strength testing  
• PUL entry item assessment 
• PODCI Transfer and Basic Mobility scale 
The analysis methods for these endpoints will be defined in the SAP.  Additional efficacy endpoints 
may also be defined in the SAP. 


Clinical Trial Protocol:  CAT-1004-301 
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9.11. 
Pharmacokinetic Analyses 
Serial plasma concentration time data collected for edasalonexent and its metabolites will be analyzed 
using non-compartmental methods for all patients with evaluable data.  Actual sample and dosing 
times will be used for pharmacokinetic analyses. Pharmacokinetic parameters, as data permit, will be 
reported for individual patients and summarized using descriptive statistics by visit. Trough 
concentrations will be summarized separately, along with other single time-point plasma 
concentration data by visit. Exploratory PK-PD analyses may be performed as deemed necessary. 
In addition to non-compartmental analyses or when the data do not lend to a non-compartmental 
approach, pharmacokinetic data will be analyzed using non-linear mixed-effects modeling approach 
for population pharmacokinetic analyses. For population PK analyses, data from this clinical study 
will be pooled with data from other clinical studies with extensive and/or sparse sampling. The 
population PK analyses will characterize the inter- and intra-subject variability in pharmacokinetic 
parameters and evaluate the effect of covariates such as but not limited to, demographics (e.g., age, 
body weight, race), disease status on oral clearance and volume. Exploratory population PK-PD 
analyses may also be performed to evaluate and characterize exposure-response relationships. 
As an exploratory analysis, urine samples will be analyzed in terms of concentrations of 
edasalonexent and/or metabolites. 
Raw and derived data will be summarized using descriptive statistics and presented graphically, as 
appropriate.  Plasma PK parameters will be estimated from plasma concentration-versus-time data 
using noncompartmental analyses.   
The following noncompartmental PK parameters will be calculated from plasma samples: 
• Area under concentration time curve from time 0 to time of last quantifiable concentration 
(AUClast) 
• Area under concentration time curve from time 0 to 4 hours post dosing (AUC0-4) 
• Maximum plasma concentration (Cmax) 
• Last quantifiable plasma concentration (Clast) 
• Time of Cmax (Tmax) 
• Time of Clast (Tlast) 
• Time between the time of dosing and time of appearance of plasma concentration (Tlag) 
The detailed methodology will be described in the SAP. 
9.12. 
Safety Analyses 
Safety will be assessed using the incidence of treatment-emergent AEs and SAEs, physical 
examination findings, growth parameters, vital signs, clinical laboratory evaluations, and ECGs.   
Results of all safety assessments will be listed by patient, and summarized by treatment group and 
timepoint as applicable.  
These safety analyses will be compared qualitatively between groups; however, there will be no 
inferential statistical comparisons between groups. 


Clinical Trial Protocol:  CAT-1004-301 
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51 
9.12.1. 
Physical Examination, Growth Parameters, Electrocardiograms, and Vital Signs 
Physical examination (general appearance, skin, HEENT, etc.) abnormal results will be summarized.  
Physical examination results will also be summarized in a shift table from Baseline. 
Growth parameters (height, weight, BMI) will be compared to age-normative percentiles. 
ECG results will be summarized at each timepoint, and also using shift tables from Baseline. 
Vital signs (temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure), and 
changes from Baseline in vital signs, will be summarized descriptively at Baseline and other study 
timepoints.  Data listings will be provided. 
9.12.2. 
Clinical Laboratory Tests 
Values at all study timepoints and changes from Baseline to post Baseline timepoints in clinical 
chemistry, hematology and urinalysis results will be summarized descriptively.  Shift tables from 
Baseline to each timepoint and from Baseline to each patient’s final visit will be produced by cohort 
and overall.   
Abnormal clinical laboratory values will be identified as outside (above or below) the normal range 
and will be evaluated for clinically notable abnormalities.  Reference (normal) ranges for laboratory 
parameters will be included in the clinical study report.   
9.12.3. 
Adverse Events 
Adverse events will be coded using the MedDRA® dictionary and will be categorized by system 
organ class (SOC) and preferred term.  
An overall summary of TEAEs will include the number and percentage of patients in each cohort and 
overall reporting: 
• Any TEAEs 
• Treatment-related TEAEs 
• Severe TEAEs 
• Serious TEAEs, including any events resulting in death 
• Treatment-related serious TEAEs 
• TEAEs (and treatment-related TEAEs) leading to discontinuation of study drug 
TEAEs will be summarized by SOC and preferred term, with each patient counted only once for each 
AE reporting level.  TEAEs will also be summarized by SOC, preferred term, and severity and by 
SOC, preferred term, and relatedness.  The most severe occurrence of a TEAE, as well as the most 
extreme relationship of the TEAE to the study procedures or treatment, will be used in tabulations of 
severity and relatedness in cases of multiple occurrences of the same TEAE.   
9.13. 
Pharmacodynamic Analyses 
Pharmacodynamic analyses may include evaluation of gene expression as well as circulating protein 
and micro-RNA biomarkers that help inform target engagement and efficacy.  These will be assessed 
at the times specified in Appendix 1.  Blood samples will also be collected at times specified in 


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Appendix 1  for pharmacogenomic studies that might predict the course of disease and/or response to 
treatment as well as analysis of drug metabolizing enzyme and/or transporters.   
9.14. 
Cardiac Monitoring 
Measures of cardiac autonomic dysfunction, including heart rate variability, will be measured at the 
times specified in Appendix 1. Results will be summarized by treatment group and timepoint as 
applicable.  
The detailed analyses will be provided in the SAP. 
9.15. 
Bone Evaluations 
Lateral thoracolumbar spine radiography scans and DXA scans will be performed at the times 
specified in Appendix 1. Bone radiography will be locally read and centrally evaluated. 
Results will be summarized by treatment group and timepoint as applicable.  
The detailed analyses will be provided in the SAP. 
9.16. 
Other Statistical Issues 
9.16.1. 
Missing or Invalid Data 
For the primary and secondary efficacy analyses, the MMRM analyses will be observed case 
analyses.  Multiple imputation will be used as a sensitivity analysis to address missing data (see 
Section 9.10.4); additional methods will be specified in the SAP.  
If a patient is not able to complete a TFT, a value of 0 tasks/second will be assigned. 
If a patient initiates corticosteroid therapy or discontinues study treatment, all observations from a 
patient after these events will be censored from the primary and secondary efficacy analyses.  
Sensitivity analyses which incorporate these observations will be defined in the SAP. 
9.16.2. 
Multisite Issues   
Summary statistics for the primary and secondary efficacy endpoints will be presented by 
investigative site. 
9.16.3. 
Subgroup Analyses 
The SAP will address analyses of additional subgroups. 


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10. 
SPECIAL REQUIREMENTS AND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
ICH/Good Clinical Practice (GCP) guideline.  These requirements are stated in the ICH Guideline 
Topic E6 entitled “Guideline for Good Clinical Practice”. 
10.1. 
Institutional and Ethics Review 
This protocol and a patient informed consent form, participant-facing information sheets, and any 
proposed advertising materials, must be reviewed and approved by an IRB/IEC, applicable regulatory 
authorities, and host institution(s) for written approval (where applicable) before enrollment of 
patients and release of investigational product.  Documentation of IRB/IEC approval and the 
approved consent form must be received by the Sponsor or its designee prior to obtaining the 
patient’s informed consent.  These documents will also be submitted to and approved by the above 
parties for all substantial amendments to the original approved documents, where applicable. 
10.2. 
Changes to the Conduct of the Study or Protocol 
Any changes in the study protocol, such as changes in the study design, objectives or endpoints, 
inclusion and exclusion criteria, and/or procedures (except to eliminate an immediate hazard) will be 
implemented only after the mutual agreement of the Investigator and the Sponsor or designee.  All 
protocol changes must be documented in protocol amendment(s).  Protocol amendment(s) must be 
signed by the Investigator and approved by the IRB/IEC and Competent Authorities (CA), if 
applicable, prior to implementation.  Any changes in study conduct that result from a pending 
amendment will be considered protocol deviations until required IRB/IEC/CA approvals are granted.  
Documentation of IRB/IEC/CA approval (as applicable) must be returned to the Sponsor or designee.  
10.3. 
Investigator’s Responsibilities 
10.3.1. 
Patient Informed Consent 
Investigators must adhere to GCP, which includes ethical principles that have their origin in the 
Declaration of Helsinki, when developing the patient informed consent form and when obtaining 
consent from the patient.  Written informed consent from the parent or legal guardian of the patient 
(and written assent for pediatric patients as per regional and/or IRB/IEC requirements) is required 
prior to enrollment in the study.  It is the responsibility of the Investigator to document the consent 
process within the source documents and obtain consent using an IRB-/IEC-approved consent form. 
10.3.2. 
Case Report Forms 
Copies of pertinent records relevant to the study, including all source documents, will be made 
available to the Sponsor or its designee on request with due precaution towards protecting the privacy 
of the patient. 
Data will be entered by the site onto the eCRFs in the EDC system.  Unless explicitly directed, blank 
data fields are not acceptable.  Any erroneous entries made on the eCRFs should be corrected.  
Changes made to the data after initial entry into the eCRF will be captured via an electronic audit 
trail, and should include the reason for change.  Incomplete entries or entries needing additional 
explanation will be highlighted or queried to the Investigator for clarification. 


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10.3.3. 
Record Retention 
The enrolling Investigator is responsible for oversight and maintenance of the study records and 
patient source documents unless the patient is transferred to another site for all subsequent visits.  
These records must be readily available for audit or inspection. 
The Investigator must retain study records for at least 2 years after the last marketing approval has 
been granted, or at least 2 years have elapsed since the formal discontinuation of clinical program.  
However, these documents should be retained for a longer period, if required by other applicable 
requirements (e.g., applicable local regulatory requirement) or by an agreement with the Sponsor or 
its designee.  The Investigator should contact the Sponsor or its designee prior to any record 
destruction. 
Patient records or other source data must be kept for the maximum period of time mandated by the 
hospital, institution, or private practice, but not less than 15 years. 
If off-site archiving is used, all records should be retrieved and made available for review at the time 
of an audit or regulatory authority inspection. 
10.3.4. 
Monitoring 
A representative of the Sponsor or its designee will visit the Investigator periodically for the purpose 
of monitoring the progress of this study in accordance with the protocol, GCP, and local regulations.  
Noncompliance with the protocol, GCP, and local regulations will be documented and corrective 
actions implemented, as necessary.  It is the responsibility of the Investigator to be present or 
available for consultation during monitoring visits.  During these routine visits, all data pertaining to a 
patient’s participation in this clinical investigation must be made available to the monitor. 
Monitoring during the COVID-19 pandemic is subject to Investigator and/or local restrictions. It is 
possible that after local restrictions are lifted, monitoring may resume with more intense pace to clean 
all data accumulated during the pandemic.   
At any time prior to, during, or after completion of the clinical study, an audit may be performed by 
the Sponsor or its designee or a representative of a national regulatory agency may choose to inspect 
a study site.  Investigators should notify the Sponsor or its designee upon notification of inspection by 
a representative of a national regulatory agency.  A Sponsor or designee representative will be 
available to assist in the preparation for study site inspections.  All pertinent study data should be 
made available for verification, audit, or inspection purposes. 
10.3.5. 
Study or Site Termination 
If the Sponsor, the Investigator, or regulatory authorities discover any conditions during the study that 
indicate that the study or study site should be terminated, this action may be taken after appropriate 
consultation between the Sponsor and the Investigator.  The Sponsor has the right to terminate the 
participation of either an individual site or the study at any time, for any reason, which may include 
the following: 
• The incidence and severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Patient enrollment is unsatisfactory 


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• Data recording is inaccurate or incomplete. 
• Investigator(s) does not adhere to the protocol or applicable regulatory guidelines in 
conducting this study 
• Submission of knowingly false information from the study site to the Sponsor or 
regulatory authorities 
In the event that the study is terminated early, the Sponsor will provide specific guidance to 
investigational sites regarding the end-of-study procedures. 
10.3.6. 
Investigational Product Control 
10.3.6.1. Receipt of Investigational Product 
A proof of receipt, which details the quantity and description of the investigational product, will 
accompany the shipment from the Sponsor or designee to the Investigator.  The site must 
acknowledge each shipment of investigational product in the IWRS system once received. The 
Investigator must ensure that the investigational product is maintained in a controlled location, with 
limited access, and under adequate storage conditions (as described in Section 5.1.4). 
10.3.6.2. Disposition of Unused Investigational Product 
All unused investigational products must be maintained under adequate storage conditions in a 
limited-access area.  If any unused material is remaining upon completion of the study, the material 
will be returned to the Sponsor or destroyed only after the following has been completed: 
• Accountability has been performed by a representative of the Sponsor. 
• Approval to return or destroy unused Investigational Product.  Refer to the SDHM for 
further details. 
10.3.6.3. Product Handling and Complaints Reporting 
If there are any issues during the study related to the quality of the Investigational Product, the 
clinical site pharmacist or pharmacy designee should contact the Sponsor. 
10.3.7. 
Disclosure of Data 
All details related to the disclosure and publication of study data will be addressed in the 
Investigator’s study contract.   
10.3.8. 
Confidentiality and Data Privacy    
Personal data recorded on all documents will be regarded as strictly confidential and will be handled 
and stored in accordance with the General Data Protection Regulation (GDPR 25May2018) in 
European Union Member States.  
Sponsor affirms the patient's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is more stringent). Sponsor requires the Investigator 
to permit sponsor representatives (monitor) and when necessary, representatives from regulatory 
authorities, to review and/or copy any medical records relevant to the study in accordance with local 
laws (any copies of patients’ records must be duly anonymised to protect patients’ confidentiality).  


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Should direct access to medical records require a waiver or authorisation separate from the patient’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. Representative of the sponsor may be required to have access 
to patient’s medical records for quality assurance purposes but patients should be reassured that their 
confidentiality will be respected at all times.  
Representative of sponsor must maintain the confidentiality of all patient’s data and will not disclosed 
information by which patients may be identified to any third party other than those directly involved 
in the treatment and organization for which the patient has given explicit consent for data transfer. 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
 
Screen a 
BL b 
Double Blind, Placebo-Controlled Treatment (Weeks 1 - 52) 
Safety F/U c 
Study Week(s) 
-4 - 0 
0 
6 
13 
19 
26 
32 
39 
45 
52/ETd  
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
Site Visit e  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Site Call e, f 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Med History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization g 
 
X 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Weight  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Height 
 
X 
 
 
 
X 
 
 
 
X 
 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
AEs/Con Medsh  
X 
Continuous 
12-Lead ECGi  
X 
 
 
 
 
X 
 
 
 
X 
 
Cardiac Monitoring j 
X 
 
 
 
 
X 
 
 
 
X 
 
Hematology/Chemistry k 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
ACTH/Cortisol k  
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
X 
 
DNA Sample l 
 
X 
 
 
 
 
 
 
 
 
 
Biomarkers, Gene Expression k 
 
X 
 
X 
 
X 
 
X 
 
X 
 
NSAA, Stand from Supine, 10MWT, 
4-Stair Climb, Muscle Strength m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
PUL n 
 
X 
 
 
 
X 
 
 
 
X 
 
Videotape Functional Assessments o 
X 
X 
 
 
 
 
 
 
 
X 
 
PODCI p 
 
X 
 
 
 
 
 
 
 
X 
 
Lateral Spinal Radiography, DXA q 
 
X 
 
 
 
 
 
 
 
X 
 
Study Drug Questionnaire 
 
 
 
 
 
X 
 
 
 
 
 
Nutritional Guidance r 
 
X 
 
 
 
 
 
 
 
 
 
Drug Dispensation  
 
X 
 
X 
 
X 
 
X 
 
 
 
Drug Accountability 
 
 
 
X 
 
X 
 
X 
 
X 
 
PK (plasma and urine) s 
 
 
 
X 
 
X 
 
 
 
X 
 
 
a Per Investigator’s discretion, informed consent, medical history/demographic data and lab assessments may be completed remotely by a qualified medical professional. 
b The first day of study drug is “Day 1”; unless otherwise specified, all assessments should be completed within a 4 week window prior to Day 1. 
c Safety follow-up should occur within 2 wks. after last dose of study drug.  Patients continuing in the open-label extension study are not required to perform the safety follow-up. 
d If patient discontinues treatment early, patient will be asked to return for early termination (ET) visit prior to their last dose of study drug.  Functional assessments performed 
within 6 weeks of discontinuing treatment do not need to be repeated at the ET visit.  If the ET visit occurs after drug has been discontinued, certain assessments may be omitted 
per Sponsor discretion. 


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e Weeks 6-19 should be conducted within the study week with a ±4-day window.  Weeks 26-54 have a ±10-day window. 
, f Per Investigator discretion, site calls may occur by telephone or use of other technology. 
g Randomization occurs after Screening assessments have been completed and eligibility is confirmed. 
h AEs and concomitant medication/therapy will be assessed at all visits and during site calls. 
i ECGs will be performed predose at all timepoints. At Week 26, ECG will per performed predose and 2 hours postdose (+/-15 min). 
j Cardiac monitoring will be performed for approximately 48 hours remotely via a wearable cardiac monitoring device if approved for use in the participating country. 
k Blood samples will be drawn in the morning when possible.  
l DNA sample may be collected at Baseline for drug metabolizing enzyme and/or transporter analysis as well as pharmacogenomic analysis of potential markers of clinical 
risk/benefit. 
m Assessments should be performed in the order listed and in the morning when possible.  Time to stand from supine and 10MWT will be recorded as measured in the NSAA.  
n The PUL 6-point entry item scale will be performed at all timepoints.  If a patient scores a 6 on the PUL entry item scale, no further PUL testing is required for the visit. 
o  Videotaping at Baseline is required if Screening video did not pass QC.   
p PODCI will be performed when feasible. 
q These assessments should be collected within 2 months prior to Day 1. In Germany, bone assessment will not be performed until the respective approvals from the German 
Federal Office for Radiation Protection (Bundesamt für Strahlenschutz) become available. 
r Patient compliance with the nutritional guidance will be confirmed throughout the trial. 
s Urine PK collection will be performed at Week 13.  Plasma PK collection will be performed predose at Week 13 and Week 52.  At Week 26 plasma PK collection will be 
performed predose, 1 hour (+/- 5 min), 2 hours (+/-15 min), and 4 hours (+/- 15 min) postdose.


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APPENDIX 2. POTENTIAL MODIFICATIONS TO THE SCHEDULE OF 
ASSESSMENTS DURING THE COVID-19 PANDEMIC 
At the time of the COVID-19 pandemic, all enrolled patients had completed at least Week 26 so 
the implementation of alternative means to complete study assessments is intended for Week 39 
and Week 52 only.  
If the Investigator is able to perform the scheduled visit without impact to the safety of the 
patients and their families because of the COVID-19 pandemic, the Investigator should perform 
study assessments on site according to Appendix 1.   
If the Investigator is unable or unwilling to perform the scheduled Week 52 visit within window 
without impact to the safety of the patients and their families because of the COVID-19 
pandemic, the Investigator, along with the patient/caregiver may decide to conduct the visit out 
of window (but in no case should the projected target date be changed by more than 2 months).    
The COVID-19 pandemic has impacted study sites variably, so individual situations at each site 
may impact the capabilities of sites to perform certain study assessments.  The purpose of 
Appendix 2 is to outline considerations for sites to perform study procedures either on site or 
remotely by using alternative approaches to collect study assessments.  While some study 
assessments can be performed remotely, it is acknowledged that others are not feasible to be 
conducted remotely. 
As the top priority is safety, assessing for AE and concomitant medications is the highest priority 
to continue, which will occur remotely at intervals specified in Appendix 1.  Based on the safety 
profile of edasalonexent to date, and consideration that all patients in this study have been on 
study drug for 6 months, other safety assessments, including physical examinations, chemistry 
and hematology labs and urinalysis can be deferred for six-month intervals if not feasible given 
the COVID-19 pandemic.   
The next priority is study integrity, which requires continued administration of study drug and 
efficacy assessments.  Drug dispensation can take place according to local site procedures, 
including secured, temperature-controlled shipments to the patients’ homes.  Study drug 
accountability can be assessed remotely as well.   
Remote collection of efficacy measurements may occur if not feasible on site. Efficacy 
measurements collected remotely will be administered and monitored by trained evaluators. 
Additional details on the remote collection of efficacy measurements are provided in the Remote 
Efficacy Assessment Clinical Evaluator Manual developed for Duchenne clinical trials during 
the COVID-19 pandemic.  Functional assessments may be limited by the remote testing 
environment.  
Some study assessments from Appendix 1 may be not included in Appendix 2 due to the 
Sponsor’s assessment of patient safety vs. criticality during the COVID-19 pandemic.   
In the situation where the Investigator is able to perform study procedures on site but requires 
prioritization of study assessments to minimize patient time on site or exposure to certain 
locations within the study location, the Investigator should prioritize according to the outline 


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below. If a prioritized assessment cannot be performed, that does not preclude other assessments 
for the specific Visit in Appendix 1 if feasible and without additional risk.  
 
• Week 39 Visit: performed on-site, priorities listed below 
− Assess AE and Concomitant Medications 
− Measure weight (to re-supply study drug), perform study drug accountability, re-
supply Study Drug 
− Perform Primary and Secondary Efficacy Assessments (NSAA, TFTs, PUL) 
− Physical examination and vital signs 
− Lab assessments:  chemistry, hematology, UA and PK (drawn at the same time) 
• Week 39 Visit: on-site visit is cancelled, priorities listed below 
− Reconsent/assent for remote efficacy assessments  
− Assess AE and Concomitant Medications 
− Measure weight by home scale (to re-supply study drug), assess drug 
accountability as appropriate, re-supply Study Drug via courier service 
− Perform Primary and Secondary Efficacy Assessments (NSAA, TFTs, PUL) 
remotely requires videotaping. More detail can be found in the Remote Efficacy 
Assessment Clinical Evaluator Manual 
• Week 52 Visit: performed on-site, priorities listed below 
− Assess AE and Concomitant Medications 
− Perform Primary and Secondary Efficacy Assessments (NSAA, TFTs, PUL) 
− Physical examination and vital signs, including height and weight 
− Lab assessments:  chemistry, hematology, UA and PK and biomarkers (drawn at 
the same time) 
− ECG 
− PODCI (if time limitations, provide and collect at next opportunity) 
− DXA and lateral spine films (recognizing that traveling to other parts of the clinic 
or hospital) may not be conducive at this time) 
• Week 52 Visit: on-site visit is cancelled, priorities listed below 
− Reconsent/assent for remote efficacy assessments  
− Assess AE and Concomitant Medications 
− Perform Primary and Secondary Efficacy Assessments (NSAA, TFTs, PUL) 
remotely requires videotaping. More detail can be found in the Remote Efficacy 
Assessment Clinical Evaluator Manual 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary  
64 
− Measure weight by home scale and height as feasible.  
− Perform drug accountability as appropriate 
− Lab assessments:  chemistry, hematology, UA to be considered via local labs but 
defer to Investigators’ judgement and interval since most recent assessments 
− PODCI (provide electronically and collect at next opportunity 
 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary  
65 
APPENDIX 3. LIST OF CLINICAL LABORATORY ASSESSMENTS  
For timing of laboratory assessments, see Schedule of Assessments in Appendix 1   
Clinical Safety Assessments 
Clinical Chemistry 
Urinalysis 
Hematology 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Creatine kinase  
Calcium 
Phosphorus 
Glucose 
Blood urea nitrogen 
Creatinine 
Uric Acid 
Lactate dehydrogenase 
Total bilirubin (direct if above ULN) 
Alkaline phosphatase 
AST 
ALT 
GGT 
Cystatin C 
Cortisol (AM) 
ACTH 
Glutamate dehydrogenase 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
RBCs 
WBCs 
Epithelial cells 
Bacteria 
Casts 
Crystals 
WBC count 
RBC count 
Hemoglobin 
Hematocrit 
MCV, MCH, and MCHC 
Platelet count 
WBC differential (% and 
absolute) 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
 
 
ACTH=adrenocorticotropic hormone; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
GGT=gamma-glutamyl transferase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; RBC=red blood cell; ULN=upper level of normal; WBC=white blood cell 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary  
66 
APPENDIX 4.    STUDY DRUG QUESTIONNAIRE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Patient Initials 
|  
|  
|  
| 
        Patient Study ID 
 |__|__|__| - |__ |__|__| 
 
STUDY DRUG QUESTIONNAIRE          
Protocol CAT-1004-301 
 
 
 
 
 
09Jul2018 
 
 
Patient Initials ________           Subject ID: _______ - _______          Date: _________________ 
 
 
This questionnaire should be completed by the caregiver of the patient. Please circle the answer that most 
closely reflects the patient’s opinion of the study drug. Circle only one answer per question.  
 
1. The taste and aftertaste (a taste that remains in your mouth after swallowing) of the study drug 
capsules are acceptable: 
 
 
 
 
 
2. The smell of the study drug capsules is acceptable: 
 
 
 
 
 
3. The size and shape of the study drug capsules are acceptable: 
 
1 
2 
3 
4 
5 
Strongly Agree 
Agree 
Neither Agree Nor 
Disagree 
Disagree 
Strongly Disagree 
1 
2 
3 
4 
5 
Strongly Agree 
Agree 
Neither Agree Nor 
Disagree 
Disagree 
Strongly Disagree 
1 
2 
3 
4 
5 
Strongly Agree 
Agree 
Neither Agree Nor 
Disagree 
Disagree 
Strongly Disagree 


Clinical Trial Protocol:  CAT-1004-301 
16 April 2020 
Confidential and Proprietary  
68 
APPENDIX 5.   PEDIATRIC OUTCOMES QUESTIONNAIRE (PODCI) 
 
 


 
 
 
Pediatric 
Outcomes Questionnaire 
 
 
 
 
Developed by: 
American Academy of Orthopaedic Surgeons® 
Pediatric Orthopaedic Society of North America 
American Academy of Pediatrics 
Shriner’s Hospitals 
 
To be completed by the parent for children 2 – 10 years old 
 
 
 
 
 
Based on the Version 2.0 Pediatrics-Parent/Child Outcomes Intrument 
 
 
Also commonly referred to as the PODCI ("Pediatric Outcomes Data Collection Instrument") 
 
 
Revised, renumbered, reformatted August 2005 
 


 
Pediatric Outcomes Instrument: Page 2 of 8 
Pediatric Health Assessment (parent-reported) 
 
FOR OFFICE USE ONLY 
 
Clinic ID  
 
 
First six letter of patient’s last name   
 
 
Physician ID 
 
 
Office Chart #  
 
 
 
Diagnosis & ICD-9 Code*  
Procedure & CPT Code 
CPT Date  
Side of body 
procedure was 
performed on:  
Primary DX  
DX  
 
ICD-9  
Tx  
 
ICD-9  
 
□ Right     □ Left  
□ Both      □ N/A  
Secondary DX  
DX  
 
ICD-9  
Tx  
 
ICD-9  
 
□ Right     □ Left  
□ Both      □ N/A  
Secondary DX  
DX  
 
ICD-9  
Tx  
 
ICD-9  
 
□ Right     □ Left  
□ Both      □ N/A  
Secondary DX  
DX  
 
ICD-9  
Tx  
 
ICD-9  
 
□ Right     □ Left  
□ Both      □ N/A  
Secondary DX  
DX  
 
ICD-9  
Tx  
 
ICD-9  
 
□ Right     □ Left  
□ Both      □ N/A  
 
 


 
Pediatric Outcomes Instrument: Page 3 of 8 
Pediatric Health Assessment (parent-reported) 
 
 
Today’s Date 
 
 / 
 
 / 
 
Thank you for completing this questionnaire!  
 
This questionnaire will help us to better understand your 
general health and any problems related to bone and muscle 
conditions.  
 
Your completion of this questionnaire is completely voluntary 
and your responses will be held in the strictest confidence.  
 
Please answer every question. Some questions may look 
like others, but each one is different.  
 
There are no right or wrong answers. If you are not sure how 
to answer a question, just give the best answer you can. You 
can make comments in the margin. We do read all your 
comments, so feel free to make as many as you wish.  
Your Child's Birth Date   
/  
 
/ 
 
Your Child's Social Security Number ___________________ 
Your Social Security Number ______________________ 
 


 
Pediatric Outcomes Instrument: Page 4 of 8 
Pediatric Health Assessment (parent-reported) 
 
 
Some kind of problems can make it hard to do many activities, such as eating, bathing, school work, and playing 
with friends. We would like to find out how your child is doing. (Circle one response on each line.)  
 
During the last week was it easy or hard for your child to:  
 
 
 
Easy 
A little 
hard 
Very 
hard 
Can't do 
at all 
Too young for 
this activity 
1. 
Lift heavy books? 
1 
2 
3 
4 
5 
2. 
Pour a half gallon of milk? 
1 
2 
3 
4 
5 
3. 
Open a jar that has been opened 
before? 
1 
2 
3 
4 
5 
4. 
Use a fork and spoon? 
1 
2 
3 
4 
5 
5. 
Comb his/her hair?  
1 
2 
3 
4 
5 
6. 
Button buttons?  
1 
2 
3 
4 
5 
7. 
Put on his/her coat? 
1 
2 
3 
4 
5 
8. 
Write with a pencil? 
1 
2 
3 
4 
5 
 
 
9.  On average, over the last 12 months, how often did your child miss school (preschool, day care, camp, etc.) 
because of his/her health?  
 
1. Rarely 
2. Once a month 
3. Two or three times a month 
4. Once a week 
5. More than once a week 
6. Does not attend school, etc. 
 
During the last week  how happy has your child been with: (Circle one response on each line.)  
 
 
 
Very 
happy 
Somewhat 
happy 
Not sure 
Somewhat 
unhappy 
Very 
unhappy 
Child is 
too young 
10. 
How he/she looks? 
1 
2 
3 
4 
5 
6 
11. 
His/her body? 
1 
2 
3 
4 
5 
6 
12. 
What clothes or shoes he/she can 
wear? 
1 
2 
3 
4 
5 
6 
13. 
His/her ability to do the same things 
his/her friends do? 
1 
2 
3 
4 
5 
6 
14. 
His/her health in general? 
1 
2 
3 
4 
5 
6 
 


 
Pediatric Outcomes Instrument: Page 5 of 8 
Pediatric Health Assessment (parent-reported) 
During the last week, how much of the time: 
(Circle one response on each line.) 
 
 
 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of the 
time 
15. 
Did your child feel sick and tired? 
1 
2 
3 
4 
16. 
Were your child full of pep and energy?  
1 
2 
3 
4 
17. 
Did pain or discomfort interfere with your 
child's activities? 
1 
2 
3 
4 
 
 
During the last week, has it been easy or hard for your child to:  
 
 
 
 
(Circle one response on each line.)  
 
 
 
 
 
 
Easy 
A little hard 
Very hard 
Can't do 
at all 
Too young for 
this activity 
18. 
Run short distances? 
1 
2 
3 
4 
5 
19. 
Bicycle or tricycle? 
1 
2 
3 
4 
5 
20. 
Climb three flights of stairs?  
1 
2 
3 
4 
5 
21. 
Climb one flight of stairs? 
1 
2 
3 
4 
5 
22. 
Walk more than a mile? 
1 
2 
3 
4 
5 
23. 
Walk three blocks? 
1 
2 
3 
4 
5 
24. 
Walk one block? 
1 
2 
3 
4 
5 
25. 
Get on and off a bus? 
1 
2 
3 
4 
5 
 
 
26.  How often does your child need help from another person for walking and climbing? (Circle one response.)  
 
1    Never 
2    Sometimes 
3    About half the time 
4    Often 
 5    All the time 
 
 
27.  How often does your child use assistive devices (such as braces, crutches, or wheelchair) for walking and 
climbing? (Circle one response.)  
 
1    Never 
2    Sometimes 
3    About half the time 
4    Often 
 5    All the time 
 
 
During the last week, has it been easy or hard for your child to: 
(Circle one response on each line.)   
 
 
Easy 
A little hard 
Very hard 
Can't do 
at all 
Too young for 
this activity 
28. 
Stand while washing his/her hands and face 
at a sink? 
1 
2 
3 
4 
5 
29. 
Sit in a regular chair without holding on? 
1 
2 
3 
4 
5 
30. 
Get on and off a toilet or chair? 
1 
2 
3 
4 
5 
31. 
Get in and out of bed? 
1 
2 
3 
4 
5 
32. 
Turn door knobs? 
1 
2 
3 
4 
5 
33. 
Bend over from a standing position and pick 
up something off the floor? 
1 
2 
3 
4 
5 


 
Pediatric Outcomes Instrument: Page 6 of 8 
Pediatric Health Assessment (parent-reported) 
 
34. How often does your child need help from another person for sitting and standing? (Circle one response.)  
 
1    Never 
2    Sometimes 
3    About half the time 
4    Often 
 5    All the time 
 
 
35. How often does your child use assistive devices (such as braces, crutches, or wheelchair) for sitting and 
standing? (Circle one response.) 
 
1    Never 
2    Sometimes 
3    About half the time 
4    Often 
 5    All the time 
 
 
36. Can your child participate in recreational outdoor activities with other children the same age?  
(For example: bicycling, tricycling, skating, hiking, jogging)  (Circle one response.)  
 
1    Yes, easily 
2    Yes, but a little hard 
3    Yes, but very hard 
4    No 
 
If you answered “no” to Question 36 above, was your child's activity limited by: (Circle yes to all that apply)  
 
 
 
Yes 
37. Pain? 
1 
38. General Health? 
1 
39. Doctor or parent instructions? 
1 
40. Fear the other kids won’t like him/her? 
1 
41. Dislike of recreational outdoor activities? 
1 
42. Too young? 
1 
43. Activity not in season? 
1 
 
 
44. Can your child participate in pickup games or sports with other children the same age?  
(For example: tag, dodge ball, basketball, soccer, catch, jump rope, touch football, hop scotch)   
(Circle one response.)  
 
1    Yes, easily 
2    Yes, but a little hard 
3    Yes, but very hard 
4    No 
 
If you answered “no” to Question 44 above, was your child's activity limited by: (Circle yes to all that apply)  
 
 
 
Yes 
45  Pain? 
1 
46. General Health? 
1 
47. Doctor or parent instructions? 
1 
48. Fear the other kids won’t like him/her? 
1 
49. Dislike of pickup games or sports? 
1 
50. Too young? 
1 
51. Activity not in season? 
1 
 
 


 
Pediatric Outcomes Instrument: Page 7 of 8 
Pediatric Health Assessment (parent-reported) 
52.  Can your child participate in competitive level sports with other children the same age? 
(For example: hockey, basketball, soccer, football, baseball, swimming, running [track or cross country], 
gymnastics, or dance) (Circle one response.)  
 
1    Yes, easily 
2    Yes, but a little hard 
3    Yes, but very hard 
4    No 
 
If you answered “no” to Question 52 above, was your child's activity limited by: (Circle yes to all that apply)  
 
 
 
Yes 
53. Pain? 
1 
54. General Health? 
1 
55. Doctor or parent instructions? 
1 
56. Fear the other kids won’t like him/her? 
1 
57. Dislike of pickup games or sports? 
1 
58. Too young? 
1 
59. Activity not in season? 
1 
 
 
60. How often in the last week did your child get together and do things with friends? (Circle one response.)  
 
1    Often 
2    Sometimes 
3    Never or rarely 
 
If you answered “sometimes” or “never or rarely” to Question 60 above, was your child's activity limited by: 
(Circle yes to all that apply)  
 
 
Yes 
61. Pain? 
1 
62. General Health? 
1 
63. Doctor or parent instructions? 
1 
64. Fear the other kids won’t like him/her? 
1 
65. Friends not around? 
1 
 
 
66. How often in the last week did your child participate in gym/recess? (Circle one response.)  
 
1    Often 
2    Sometimes 
3    Never or rarely 
4    No gym or recess 
 
If you answered “sometimes” or “never or rarely” to Question 63 above, was your child's activity limited by: 
(Circle yes to all that apply)  
 
 
Yes 
67. Pain? 
1 
68. General Health? 
1 
69. Doctor or parent instructions? 
1 
70. Fear the other kids won’t like him/her? 
1 
71. Dislike of gym/recess? 
1 
72. School not in session? 
1 
73. Does not attend school? 
1 
 
74.  Is it easy or hard for your child to make friends with children his/her own age? (Circle one response.)  
 
1  Usually easy 
2    Sometimes easy 
3    Sometimes hard 
4    Usually hard 


 
Pediatric Outcomes Instrument: Page 8 of 8 
Pediatric Health Assessment (parent-reported) 
75. How much pain has your child had during the last week? (Circle one response.)  
 
1  None 
2    Very mild 
3   Mild 
4   Moderate 
5   Severe 
6   Very severe 
 
 
76. During the last week, how much did pain interfere with your child's normal activities  (including at home, 
outside of the home, and at school)?  (Circle one response.)  
 
1    Not at all 
2    A little bit 
3    Moderately 
4    Quite a bit 
 5    Extremely 
 
 
 
What expectations do you have for your child's treatment? 
As a result of my child's treatment, I expect my child: 
(Circle one response on each line.) 
 
 
 
Definitely 
yes 
Probably 
yes 
Not sure 
Probably 
not 
Definitely 
not 
77. 
To have pain relief. 
1 
2 
3 
4 
5 
78. 
To look better. 
1 
2 
3 
4 
5 
79. 
To feel better about himself/herself. 
1 
2 
3 
4 
5 
80. 
To sleep more comfortably. 
1 
2 
3 
4 
5 
81. 
To be able to do activities at home. 
1 
2 
3 
4 
5 
82. 
To be able to do more at school. 
1 
2 
3 
4 
5 
83. 
To be able to do more play or 
recreational activities (biking, walking, 
doing things with friends).  
1 
2 
3 
4 
5 
84. 
To be able to do more sports. 
1 
2 
3 
4 
5 
85. 
To be free from pain or disability as an 
adult.  
1 
2 
3 
4 
5 
 
 
86.  If your child had to spend the rest of his/her life with his/her bone and muscle condition as it is right now, 
how would you feel about it? (Circle one response.)  
 
1    Very satisfied 
2    Somewhat satisfied 
3    Neutral  
4    Somewhat dissatisfied 
 5    Very dissatisfied 
 


Clinical Trial Protocol CAT-1004-301 
Summary of Changes 
 
 
 
 
 
 
           16 April 2020  
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 
Study of Edasalonexent in Pediatric Patients with Duchenne 
Muscular Dystrophy 
Protocol Number: 
CAT-1004-301 
Original Version Date: 
09 July 2018 
Amendment: 
 1 
Summary and Rationale for Changes 
The following information summarizes the changes captured in Amendment 1 reflective of 
study conduct during the COVID-19 pandemic:  
• 
As patients may not be able to come on-site for visits or for a reduced amount of time, 
modifications have been made to the original study procedures and schedule of 
assessments to reduce the patient’s risk or exposure to COVID-19 for Week 39 and 
Week 52 study visits. These include: 
o Allowance for the Week 52 visit to be conducted out of the visit window (but 
in no case should the projected target date be changed by more than 2 months). 
o Ability to perform study procedures either on site or remotely by using 
alternative approaches to collect study assessments. 
o As the top priority is safety, assessing for AE and concomitant medications is 
the highest priority to continue, which will occur remotely at intervals. 
o Based on the safety profile of edasalonexent to date, and consideration that all 
patients in this study have been on study drug for 6 months, other safety 
assessments, including physical examinations, chemistry and hematology labs 
and urinalysis can be deferred for six-month intervals if not feasible. 
o Drug dispensation can take place according to local site procedures, including 
secured, temperature-controlled shipments to the patients’ homes 
o A prioritized list of assessments has been included in Appendix 2 of the 
protocol. 
 
• 
Clarification that post the COVID-19 pandemic, clinical monitoring may resume with 
more intense pace to clean all data accumulated.   
 
 

SAP_001.pdf: 
 
 
 
    
 
 
 
 
 
 
Official Title: A Randomized, Double-Blind, Placebo controlled, Global Phase 3 Study of Edasalonexent 
in Pediatric Patients with Duchenne Muscular Dystrophy 
 
NCT Number: NCT03703882 
 
Applicant/MAH: Catabasis Pharmaceuticals Inc. 
 
Version Date: 05 OCT 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Confidentiality 
This document is confidential and proprietary property of Catabasis Pharmaceuticals, Inc. and to be used only as 
authorized by Catabasis Pharmaceuticals, Inc. No part is to be reproduced, disclosed to others, or quoted without 
prior written authorization from Catabasis Pharmaceuticals, Inc. 
STATISTICAL ANALYSIS PLAN 
Protocol CAT-1004-301 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
GLOBAL PHASE 3 STUDY OF EDASALONEXENT IN PEDIATRIC 
PATIENTS WITH DUCHENNE MUSCLAR DYSTROPHY 
Protocol Number: 
(Version Date) 
CAT-1004-301 
16 APR 2020 
Name of Test Drug: 
Edasalonexent (CAT-1004) 
Phase: 
3 
Methodology: 
Randomized, Double-blind, Placebo-controlled 
Sponsor: 
Catabasis Pharmaceuticals, Inc. 
100 High Street, 28th Floor 
Boston, MA 02110 
Tel:
 
Fax:
  
Sponsor Representative: 
, M.D., Ph.D. 
Chief Medical Officer 
Sponsor Representative: 
 
, MHP 
Vice President, Clinical Operations 
Document Date: 
05 OCT 2020 
Document Version: 
5.0 
 
PI
PI
PI
PI


Signature:
Email:
Clinical Trial Protocol: CA T-1004-301 
05 October 2020 
SIGNATURE PAGE 
Protocol Title: 
Sponsor: 
Protocol Number: 
Document DateN ersion: 
Cytel, Inc. Author: 
 
Cytel, Inc. 
675 Massachusetts Avenue 
Cambridge, MA 02139 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, GLOBALPHASE3 STUDY OF 
EDASALONEXENT IN PEDIATRIC PATIENTS 
WITH DUCHENNE MUSCLARDYSTROPHY 
Catabasis Pharmaceuticals, Inc. 
100 High Street, 28th Floor 
Boston, MA 02110 
Tel: 
 
Fax:
 
CAT-1004-301 
05 OCT2020 
Sig 
Date: -----------------
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the _planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
All changes to the planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
, M.D., Ph.D. 
Chief Medical Officer 
Cat-ab-asis Ph-armaceuticals, Inc. 
100 High Street, 28th Floor 
Boston, MA 02110 
Tel:
 
Fax: 
 
Confidential and Proprietary 
2 
PI
PI
PI
PI
PI
PI
PI
PI
PI


Clinical Trial Protocol:  CAT-1004-301 
05 October 2020 
 
 
Confidential and Proprietary  
 
 
 
3 
TABLE OF CONTENTS 
Section                                                                                                                 Page 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ........................................... 9 
1. 
INTRODUCTION ..................................................................................... 9 
1.1. 
Objectives of Statistical Analysis .............................................................. 9 
1.2. 
Summary of Changes ................................................................................. 9 
1.2.1. 
Summary of SAP Version 2 Changes from Version 1 .............................. 9 
1.2.2. 
Summary of SAP Version 3 Changes from Version 2 .............................. 9 
1.2.3. 
Summary of SAP Version 4 Changes from Version 3 ............................ 10 
1.2.4. 
Summary of SAP Version 5 Changes from Version 4 ............................ 10 
2. 
STUDY DESIGN..................................................................................... 11 
2.1. 
Synopsis of Study Design ........................................................................ 11 
2.2. 
Randomization Methodology................................................................... 11 
2.3. 
Unblinding ............................................................................................... 12 
2.4. 
Study Procedures ..................................................................................... 12 
2.5. 
Efficacy Estimands .................................................................................. 15 
2.5.1. 
Primary Objective Estimand .................................................................... 15 
2.5.2. 
Secondary Objective Estimands .............................................................. 15 
2.6. 
Efficacy Endpoints ................................................................................... 16 
2.6.1. 
Primary Efficacy Endpoint ...................................................................... 16 
2.6.2. 
Secondary Efficacy Endpoints ................................................................. 17 
2.6.3. 
Additional Efficacy Endpoints ................................................................. 17 
2.6.4. 
Safety Endpoints ...................................................................................... 20 
2.6.5. 
Additional Endpoints ............................................................................... 20 
3. 
PATIENT POPULATIONS..................................................................... 21 
3.1. 
Population Definitions ............................................................................. 21 
3.2. 
Protocol Deviations .................................................................................. 21 
4. 
STATISTICAL METHODS .................................................................... 23 
4.1. 
Sample Size Justification ......................................................................... 23 
4.2. 
General Statistical Methods and Data Handling ...................................... 23 
4.2.1. 
General Methods ...................................................................................... 23 
4.2.2. 
Computing Environment .......................................................................... 23 


Clinical Trial Protocol:  CAT-1004-301 
05 October 2020 
 
 
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4 
Section                                                                                                                 Page 
4.2.3. 
Methods of Pooling Data ......................................................................... 23 
4.2.4. 
Adjustments for Covariates...................................................................... 23 
4.2.5. 
Multiplicity .............................................................................................. 23 
4.2.6. 
Subgroups ................................................................................................ 24 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up ............................................. 24 
4.2.8. 
Missing, Unused, and Spurious Data ....................................................... 24 
4.2.9. 
Visit Windows ......................................................................................... 24 
4.2.10. 
Early Termination Visit ........................................................................... 25 
4.2.11. 
Baseline .................................................................................................... 25 
4.3. 
Interim Analyses ...................................................................................... 25 
4.4. 
Patient Disposition ................................................................................... 25 
4.5. 
Demographic and Baseline Characteristics ............................................. 25 
4.6. 
Concomitant Medications ........................................................................ 26 
4.7. 
Medical History ....................................................................................... 26 
4.8. 
DMD-Specific Medical History ............................................................... 26 
4.9. 
Treatment Exposure and Compliance ...................................................... 26 
4.10. 
Efficacy Evaluation .................................................................................. 29 
4.10.1. 
Primary Efficacy Analysis ....................................................................... 29 
4.10.2. 
Secondary Efficacy Analyses .................................................................. 30 
4.10.3. 
Additional Efficacy Analyses .................................................................. 30 
4.10.4. 
Sensitivity Analyses for the Primary Efficacy Endpoint ......................... 31 
4.10.5. 
Sensitivity Analyses for the Secondary Efficacy Endpoints.................... 32 
4.10.6. 
Multiple Imputation Methods .................................................................. 32 
4.10.7. 
Supportive Analyses on Primary and Secondary Efficacy Endpoints ..... 34 
4.10.8. 
Subgroup Analyses on Primary and Secondary Efficacy Endpoints ....... 37 
4.11. 
Pharmacokinetic Analyses ....................................................................... 37 
4.12. 
Pharmacodynamic Analyses .................................................................... 37 
4.13. 
Safety Analyses ........................................................................................ 37 
4.13.1. 
Adverse Events ........................................................................................ 38 
4.13.2. 
Physical Examination and Growth Parameters ........................................ 39 
4.13.3. 
Laboratory Data ....................................................................................... 40 


Clinical Trial Protocol:  CAT-1004-301 
05 October 2020 
 
 
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5 
Section                                                                                                                 Page 
4.13.4. 
Vital Signs ................................................................................................ 40 
4.13.5. 
Electrocardiogram .................................................................................... 40 
4.13.6. 
Cardiac Monitoring .................................................................................. 41 
4.13.7. 
Bone Evaluation ....................................................................................... 41 
4.13.8. 
Prior and Concomitant Medications and Therapeutic Procedures ........... 41 
5. 
COVID-19 ASSESSMENTS AND RELATED ANALYSES ................ 43 
5.1. 
COVID-19 Site-Level Assessments ........................................................ 43 
5.2. 
COVID-19 Patient-Level Listings ........................................................... 43 
5.3. 
COVID-19 Analyses ................................................................................ 45 
6. 
CHANGES TO PLANNED ANALYSES ............................................... 46 
7. 
REFERENCES ........................................................................................ 47 
8. 
CLINICAL STUDY REPORT APPENDICES ....................................... 48 
APPENDIX 1: SAMPLE MMRM CODE .................................................................. 49 
APPENDIX 2: SAMPLE MULTIPLE IMPUTATION CODE ................................. 50 
APPENDIX 3: PODCI SCORING ALGORITHM .................................................... 53 
 
LIST OF IN-TEXT TABLES 


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Table                                                                                                                     Page 
Table 1: Schedule of Assessments ............................................................................... 13 
Table 2: Estimand for the Primary Objective .............................................................. 15 
Table 3: Estimands for the Secondary Objectives ....................................................... 15 
Table 4: Early Termination Visit Window Algorithm ................................................. 25 
Table 5: Random Number Seeds for Multiple Imputation .......................................... 32 
Table 6: PODCI Scoring Algorithm ............................................................................ 56 
 
LIST OF IN-TEXT FIGRURES 
Figure                                                                                                                    Page 
Figure 1 Overview of Study Design............................................................................. 11 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
10MWT 
10-meter walk/run test 
ACTH 
Adrenocorticotrophic hormone 
AE 
Adverse events 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Class 
BMI 
Body mass index 
CDC 
Centers for disease control and prevention 
CFB 
Change from Baseline 
CIs 
Confidence intervals  
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical study report 
DMD 
Duchenne muscular dystrophy 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
FAP 
Full Analysis Population 
HEENT 
Head, ears, eyes, nose, and throat 
kg 
Kilogram 
LS-means 
Least-squares means 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 
MNAR 
Missing not at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-model repeated-measures 
NSAA 
North Star Ambulatory Assessment 
OC 
Observed Case 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PP 
Per Protocol  
PT 
Preferred Term 
PUL 
Performance of Upper Limb 
RNA 
ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SOC 
System organ class 


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Abbreviation 
Definition 
TEAE 
Treatment-Emergent Adverse Event 
TFT 
Timed function test 
WHO 
World Health Organization 


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INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1. 
INTRODUCTION 
This statistical analysis plan provides the pre-specification and details for the statistical analyses 
outlined within protocol CAT-1004-301 entitled “A Randomized, Double-Blind, Placebo-
Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne 
Muscular Dystrophy” Protocol Amendment 1 dated 16APR2020. 
1.1. 
Objectives of Statistical Analysis 
The primary objective of this Phase 3 study is to assess the efficacy of edasalonexent as 
measured by change from Baseline (CFB) on the North Star Ambulatory Assessment (NSAA) 
Total Score in pediatric patients with Duchenne muscular dystrophy (DMD). 
Secondary objectives include assessing the safety and tolerability of edasalonexent and 
assessing the effects of edasalonexent on physical function as measured by the 10-meter 
walk/run test (10MWT), time to stand from supine, and the 4-stair climb in pediatric patients 
with DMD. 
Additional efficacy assessments will include muscle strength testing, Performance of Upper 
Limb (PUL) entry item assessments, and the Pediatric Outcomes Data Collection Instrument 
(PODCI) Transfer and Basic Mobility scale. 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer these study objectives. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Summary of Changes 
1.2.1. 
Summary of SAP Version 2 Changes from Version 1  
The following is a summary of the changes made in version 2.0 of the SAP (dated 30 JAN 
2020) relative to version 1.0 (dated 24 OCT 2019).  
• Based on FDA feedback the efficacy endpoint: CFB multivariate rank sum score at 
Week 52 was changed from a secondary efficacy endpoint to an additional efficacy 
endpoint. The method for controlling for multiplicity for the primary and secondary 
efficacy endpoints was updated accordingly.  
• Methods for addressing mis-categorization in the randomization strata were included.  
1.2.2. 
Summary of SAP Version 3 Changes from Version 2  
The following is a summary of the changes made in version 3.0 of the SAP (dated 31AUG 
2020) relative to version 2.0 (dated 30 JAN 2020).  


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• The algorithms for estimating treatment exposure and compliance were updated and 
clarified. 
• Methods for assessing the impact of COVID-19 were included.  
• The method for calculating the total NSAA score when individual NSAA items are 
missing for reasons unrelated to patient’s abilities to complete measures was updated. 
• Additional analyses of the NSAA endpoint were included. 
• The muscle strength testing algorithm was updated.  
• Additional summaries of adverse events were included.  
• Additional details were added to the protocol deviations section. 
• The CFB multivariate rank sum score exploratory endpoint was modified to only include 
patients with non-missing Week 52 CFB scores for all 5 of the component endpoints and 
the analysis was clarified that this is a Week 52 endpoint only. The corresponding 
analysis was modified to an analysis of covariance (ANCOVA). 
• The PODCI analyses was changed from a mixed-model repeated measures (MMRM) to 
an ANCOVA as it is only assessed at Week 52 post-baseline. A sensitivity analysis for 
the PODCI endpoint was added.  
• Additional minor updates and clarifications were also performed.  
1.2.3. 
Summary of SAP Version 4 Changes from Version 3  
The following is a summary of the changes made in version 4.0 of the SAP (dated 28SEP2020) 
relative to version 3.0 (dated 31AUG 2020).  
• Updates to the COVID-19 listings 
• Minor updates and edits for clarity.  
1.2.4. 
Summary of SAP Version 5 Changes from Version 4  
The following is a summary of the changes made in version 5.0 of the SAP (dated 05OCT2020) 
relative to version 4.0 (dated 28SEP2020).  
• Updates to the Per Protocol Population definition to address study drug compliance 
assessment issues due to COVID-19 pandemic. 
 
 
 
 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 3, multisite study of 
edasalonexent in pediatric patients with DMD. 
Eligible patients will be ambulatory boys aged >=4.0 to <8.0 years with a confirmed diagnosis 
of DMD who have not use steroids within 24 weeks prior to treatment start (Day 1). In regions 
where eteplirsen is approved or there is an established access program, patients who have 
received at least 24 weeks of treatment with eteplirsen prior to Day 1 will be eligible. 
As shown in Figure 1, following a 4-week screening period to determine eligibility, 
approximately 126 patients will be randomized 2:1 to receive edasalonexent 100 mg/kg/day or 
placebo in a double-blind fashion daily for 52 weeks. Randomization will be stratified by 
baseline age (<=6.0 vs. >6.0 years), baseline time to stand from supine (<=5 vs. >5 seconds), 
treatment with eteplirsen (yes vs. no), and region (North America vs. Europe/Asia/Australia). 
Note that if siblings are enrolled, they will be assigned to the same treatment group. 
Randomized patients (and enrolled siblings who are not randomized) will complete Baseline 
procedures and begin receiving study drug (edasalonexent or placebo) on Day 1. During the 
treatment period, patients will have site visits approximately every 13 weeks with site calls in 
between as specified in the Schedule of Assessments (Table 1). For those patients who do not 
enter the extension study, a safety follow-up should occur within 2 weeks of the last dose of 
study drug for collection of adverse events (AEs).  
The length of a patient’s participation in the study will be from the time of informed consent 
through the Week 52 visit. A patient will be considered to have completed the study when they 
have completed the Week 52 assessments. Patients who do not participate in the open-label 
extension study will be considered to have completed the study after they complete the safety 
follow-up. 
Figure 1 Overview of Study Design 
 
2.2. 
Randomization Methodology 
Patients will be randomized 2:1 to receive edasalonexent or placebo in a double-blind fashion. 
Randomization will be stratified by Baseline age (<=6.0 vs. >6.0 years), baseline time to stand 


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from supine (<=5 vs. >5 seconds), treatment with eteplirsen (yes vs. no), and region (North 
America vs. Europe/Asia/Australia). Note that if siblings are enrolled, they will be assigned to 
the same treatment group. 
Any mis-categorization of a patient’s randomization strata (i.e., a patient being assigned to an 
incorrect randomization strata relative to their actual study data) will be presented in a listing. 
Analyses by strata (i.e., see Section 4.10.8) will be based on the randomization strata values.  
2.3. 
Unblinding 
After completion of the study, patients, monitors, Investigators, study center personnel, and the 
Sponsor will remain blinded to treatment assignments until results from the study are available. 
2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1.


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Table 1: Schedule of Assessments 
 
 
Screen a 
BL b 
Double Blind, Placebo-Controlled Treatment (Weeks 1 - 52) 
Safety 
F/U c 
Study Week(s) 
-4 - 0 
0 
3 
6 
13 
19 
26 
32 
39 
45 
52/ET d 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Site Visit e 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Site Call e,f 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Med History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization g 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Weight  
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Physical Examination 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
AEs/Con Meds/Change in Function h 
X 
Continuous 
12-Lead ECG i 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Cardiac Monitoring j 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Hematology/Chemistry k 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
ACTH/Cortisol k 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis  
X 
 
 
 
 
 
X 
 
 
 
X 
 
DNA Sample l 
 
X 
 
 
 
 
 
 
 
 
 
 
Biomarkers, Gene Expression k 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
NSAA, Stand from Supine, 10MWT,   
4-Stair Climb, Muscle Strength, PUL l 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Videotape Functional Assessments m 
X 
X 
 
 
 
 
 
 
 
 
X 
 
PODCI n 
 
X 
 
 
 
 
 
 
 
 
X 
 
Lateral Spinal Radiography, DXA o 
 
X 
 
 
 
 
 
 
 
 
X 
 
Nutritional Guidance p 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug Dispensation  
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Drug Accountability 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Plasma PK q 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
a  Per Investigator’s discretion, informed consent, medical history/demographic data and lab assessments may be completed remotely by a qualified medical professional. 


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b  The first day of study drug is “Day 1”; unless otherwise specified, all assessments should be completed within a 4 week window prior to Day 1. 
c  Safety follow-up should occur within 2 weeks after the last dose of study drug. Patients continuing into the open-label extension study are not required to perform the safety 
follow-up. 
d  If patient discontinues treatment early, patient will be asked to return for early termination (ET) visit prior to their last dose of study drug. Functional assessments performed 
within 6 weeks of discontinuing treatment do not need to be repeated at the ET visit. If the ET visit occurs after drug has been discontinued, certain assessments may be omitted 
per Sponsor discretion. 
e  Weeks 6-19 should be conducted within the study week with a ±4-day window. Weeks 26-54 have a ±10-day window. 
f  Per Investigator discretion, site calls may occur by telephone or use of other technology. 
g  Randomization occurs after Screening assessments have been completed and eligibility is confirmed. 
h  AEs and concomitant medication/therapy will be assessed at all visits and during site calls. 
i  ECGs will be performed predose at all timepoints. At Week 26, ECG will per performed predose and 2 hours postdose (+/-15 min). 
j  Cardiac monitoring will be performed for approximately 48 hours remotely via a wearable cardiac monitoring device if approved for use in the participating country. 
k  Blood samples will be drawn in the morning when possible. 
l  A DNA sample may be collected at Baseline for drug metabolizing enzyme and/or transporter analysis as well as pharmacogenomic analysis of potential markers of clinical 
risk/benefit. 
m  These assessments should be performed in the order listed and in the morning when possible. Time to stand from supine and 10MWT will be recorded as measured in the 
NSAA. 
n  The PUL 6-point entry item scale will be performed at all timepoints. If a patient scores a 6 on the PUL entry item scale, no further PUL testing is required for the visit. 
o  Videotaping at Baseline is required if Screening video did not pass QC. 
p  PODCI will be performed when feasible. 
q  These assessments should be collected within 2 months prior to Day 1. In Germany, bone assessment will not be performed until the respective approvals from the German 
Federal Office for Radiation Protection (Bundesamt für Strahlenschutz) become available. 
r  Patient compliance with the nutritional guidance will be confirmed throughout the trial. 
s  Urine PK collection will be performed at Week 13. Plasma PK collection will be performed predose at Week 13 and Week 52. At Week 26 plasma PK collection will be 
performed predose, 1 hour, 2 hours (+/-15 min), and 4 hours postdose. 
 


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2.5. 
 Efficacy Estimands 
The estimands corresponding to the primary and secondary efficacy objectives are provided in 
Sections 2.5.1 and 2.5.2, respectively.  
2.5.1. 
Primary Objective Estimand 
The estimand corresponding to the primary objective for this study is shown in Table 2.  
Table 2: Estimand for the Primary Objective 
Objective 
Efficacy of edasalonexent - NSAA Total Score 
Estimand 
The expected effect in patients if all patients had adhered to the 
treatment regimen and did not take any corticosteroid therapy or 
discontinue treatment. 
Population 
Full Analysis Population (FAP) 
Variable 
Change from baseline at Week 52 on NSAA Total Score 
Intercurrent Events 
Treatment discontinuation or initiating corticosteroid therapy or any 
approved Duchenne therapy: The study is interested in the treatment 
effect assuming that patients remained on their treatment regimen 
throughout the study, without initiating corticosteroid therapy or any 
approved Duchenne therapy. 
Population-level 
Summary 
The population summary for the primary estimand is the mean 
difference in the Week 52 change from baseline on the North Star 
Ambulatory Assessment Total Score between the edasalonexent and 
the placebo treatment groups using the model described in Section 
4.10.1. This summary is computed using the FAP as defined in 
Section 3.1  
 
2.5.2. 
Secondary Objective Estimands 
The estimands corresponding to the secondary objectives are shown in Table 3. 
Table 3: Estimands for the Secondary Objectives 
Objective 
Efficacy of edasalonexent - 10MWT 
Population 
FAP 
Variable 
Change from baseline at Week 52 on the 10MWT speed. 
Intercurrent 
Events 
Treatment discontinuation or initiating corticosteroid therapy or any 
approved Duchenne therapy: The study is interested in the treatment 
effect assuming that patients remained on their treatment regimen 
throughout the study, without initiating corticosteroid therapy or any 
approved Duchenne therapy. 


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Population-level 
Summary 
The population summary for the estimand is the mean difference in the 
Week 52 change from baseline on the 10MWT speed between the 
edasalonexent and the placebo treatment groups. This summary is 
computed using the FAP as defined in Section 3.1. 
Objective 
Efficacy of edasalonexent - Stand from Supine Speed 
Population 
FAP 
Variable 
Change from baseline at Week 52 on the stand from supine speed. 
Intercurrent 
Events 
Treatment discontinuation or initiating corticosteroid therapy or any 
approved Duchenne therapy: The study is interested in the treatment 
effect assuming that patients remained on their treatment regimen 
throughout the study, without initiating corticosteroid therapy or any 
approved Duchenne therapy. 
Population-level 
Summary 
The population summary for the estimand is the mean difference in the 
Week 52 change from baseline on the stand from supine speed between 
the edasalonexent and the placebo treatment groups. This summary is 
computed using the FAP as defined in Section 3.1.  
Objective 
Efficacy of edasalonexent - 4-Stair Climb 
Population 
FAP 
Variable 
Change from baseline at Week 52 on the 4-Stair climb speed. 
Intercurrent 
Events 
Treatment Discontinuation or initiating corticosteroid therapy or any 
approved Duchenne therapy: The study is interested in the treatment 
effect assuming that patients remained on their treatment regimen 
throughout the study, without initiating corticosteroid therapy or any 
approved Duchenne therapy. 
Population-level 
Summary 
The population summary for the estimand is the mean difference in the 
Week 52 change from baseline on the 4-Stair Climb speed between the 
edasalonexent and the placebo treatment groups. This summary is 
computed using the FAP as defined in Section 3.1.  
 
2.6. 
Efficacy Endpoints 
2.6.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the CFB in the NSAA Total Score at Week 52. 
The NSAA is a clinician-reported outcome instrument designed to measure ambulatory function 
in males with DMD. During this assessment, patients are asked to perform 17 different 
functional activities, including a 10MWT, rising from sit to stand, standing on one leg, climbing 
and descending a step, stand from supine, lifting the head, standing on heels, and jumping. To 
optimize standardization and consistency of testing, study procedures must be performed by 
trained evaluators only, with every effort made to have the same clinical evaluator perform all 
assessments for a given patient, in the same order, at the same time of day, preferably in the 
morning. Completion of this test is expected to take approximately 20-30 minutes.  


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Each function activity will be scored as 0 (unable to achieve independently), 1 (modified 
method but achieves goal independent of physical assistance from another), or 2 (no obvious 
modification of activity) or “Not Scored”. If the NSAA test was performed and any of the 
individual items are scored as “not scored” (i.e., for reasons unrelated to the patients physical 
capabilities), the corresponding total score will be set to missing. The sum of these 17 scores 
will be used to form an ordinal total score (range 0 – 34). 
2.6.2. 
Secondary Efficacy Endpoints 
The 3 secondary efficacy endpoints are: 
• The CFB in the 10MWT speed at Week 52  
• The CFB in the stand from supine speed at Week 52 
• The CFB in the 4-stair climb speed at Week 52 
The 10MWT measures time to walk a distance of 10 meters. The stand from supine and 4-stair 
climb tests measure the amount of time taken to complete those tasks. To optimize 
standardization and consistency of testing, study procedures must be performed by trained 
evaluators only, with every effort made to have the same clinical evaluator perform all 
assessments for a given patient, in the same order, at the same time of day, preferably in the 
morning. Completion of timed function tests (TFTs) is expected to take approximately 10 
minutes. 
For all TFTs, both the times to complete (seconds) and the speed of completing the tests (i.e., 
calculated as the reciprocals of the time to complete; speed=1/time) will be provided. If there 
are any patients not able to complete the test (reason not done = “subject physically unable to 
complete test”), a value of 0 will be assigned for the reciprocal test (i.e., speed; in units of task 
per second). For the “time to complete” endpoints, a value of 12 seconds will be imputed.  
Additionally, for the 3 TFTs, the time will be set to 12 seconds and the speed to 0 if the TFT 
assessment meets the following TFT grading criteria (i.e., each of the TFTs is “graded”): 
• 10MWT: a Grade of 1 or 2 (from a 6-point scale) 
1=Unable to walk independently 
2=Unable to walk independently but can walk with knee-ankle foot orthoses or support 
from a person 
• Stand from Supine: a Grade of 1 or 2 (from a 6-point scale) 
1 = Unable to stand from supine, even with use of a chair 
2 = Assisted Gowers – requires furniture for assist in arising from supine to full upright 
posture (no time to be recorded) 
• 4-Stair Climb: a Grade of 1 (from a 6-point scale)  
1 = Unable to climb 4 standard stairs (no time recorded) 
2.6.3. 
Additional Efficacy Endpoints 
Additional efficacy endpoints include CFB on the following: 
• Muscle strength testing 
• PUL entry item assessment 


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• PODCI Transfer and Basic Mobility Scale 
• CFB multivariate rank sum score  
2.6.3.1. 
Muscle Strength Testing 
Muscle strength testing will include assessment of knee extension and elbow flexion (in 
kilograms), and will be performed using a hand-held dynamometer. Knee myometry will be 
performed while the patient is in a sitting position. Elbow myometry will be performed while 
the patient is positioned supine.  
Muscle testing will be performed by trained evaluators; every effort will be made to have the 
same evaluator perform all assessments for a given patient at the same time of day. Completion 
of each muscle test is expected to take approximately 10-15 minutes, for a total of 20-30 
minutes.  
Multiple assessments are taken on the right and left knee and right and left elbow. The following 
is the algorithm for determining the patients elbow (knee) scores: 
• For both the left and right elbow (separately) the peak score (i.e., maximum value) will 
be used as the value for the patient.  
• The average of the maximum right elbow score and maximum left elbow score will be 
the elbow score for that visit. 
• The same algorithm is used for the knee 
As such, at each scheduled timepoint, there will be an elbow flexion and knee flexion endpoint 
for the muscle testing (units of kilogram (kg)). 
2.6.3.2. 
Performance of Upper Limb (PUL) Entry Item Assessment 
The PUL (PUL 2.0; Pane (2018)) was specifically designed to assess upper limb function in 
ambulant and non-ambulant DMD patients. The PUL is made up of a 6-point entry item 
assessment to define starting functional level, and 22 items subdivided into shoulder level (6 
items), middle level (9 items), and distal level (7 items) dimension. Loss of full overhead reach 
occurs at median age 9.6 years with some boys losing the ability as early as age 5 or 6.  
Patients will perform the PUL entry item assessment; based on the age of patients in this study, 
most patients are expected to score a 6 on the scale of 0 – 6 and will not be required to perform 
the additional items.  
Patients who score below a 6 on the entry item assessment will perform a subset of the PUL 
battery including the shoulder level dimension and supination, consisting of 7 items with a 
maximum score of 14. Completion of the 6-point entry item assessment is expected to take 
approximately 5 minutes. Completion of the battery of PUL assessments is expected to take 
approximately 20 minutes. Any missing items on the entry item assessment or the subset of the 
PUL battery will be considered a zero for the purposes of deriving the overall score.  
The following endpoints will be analyzed from the PUL assessments 
• Item 1 and Item 2 (Summed): this is the sum of Items 1 and 2: 
o Item 1: Shoulder abduction both arms above head “Raise your arms out to the 
side and above your head– try and keep straight elbows” a 0 – 2 point scale 


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o Item 2: Raise both arms to shoulder height (elbows at shoulder height) “Raise 
your arms to shoulder level” a 0 – 2 point scale 
• PUL Total Score: The PUL total score is a sum of items 1 -7. Each of the 7 items has a 
score range from 0 – 2 with a higher score indicating better function. The PUL total 
score ranges from 0 – 14 with a higher score indicating better functioning.  
For patients who score a “6” on Item A (and are not required to perform PUL items 1 – 7), the 
following data imputation will be performed: 
• Items 1 and 2 be imputed with a value of 2 
• Items 3, 4, 5, 6, 7 will not be imputed, items will remain missing. 
• The PUL Total Score will be not be imputed, the score will be missing.  
Due to this missing data issue, the analysis of the PUL Total Score will be performed on the 
subset of FAP patients who did not score a “6” on Item A. The analysis of Items 1 and 2 (i.e., 
where scores are imputed for patients who score a “6” on Item A) will be performed on the 
FAP.  
2.6.3.3. 
Pediatric Outcomes Data Collection Instrument (PODCI) 
The PODCI is an assessment of health-related functioning in children, and is designed to be 
completed by the parent/caregiver of children aged 10 or younger (Henricson, 2013). It contains 
86 questions, takes approximately 20-30 minutes to complete, and provides information on the 
following 6 scales: 
• Upper Extremity and Physical Function Scale – measures difficulty encountered in 
performing daily personal care and student activities 
• Transfer and Basic Mobility Scale – measures difficulty experienced in performing 
routine motion and motor activities in daily activities 
• Sports and Physical Functioning Scale – measures difficulty or limitations encountered 
in participating in more active activities or sports 
• Pain/Comfort Scale – measures the level of pain experienced during the past week 
• Happiness Scale – measures the overall satisfaction with personal looks and sense of 
similarity to friends and others of own age 
• Global Functioning Scale – a general combined scale calculated from the first 4 scales 
listed above. 
For each of the first five scales, the average of the scores in the questions is calculated and 
standardized on a 0 to 100 scale, where higher numbers represent a positive value. The global 
functioning scale is an average of the first four subscales (i.e., excluding the “Happiness 
Scale”). The details of the PODCI scoring are provided in Appendix 3: PODCI Scoring 
Algorithm. 
2.6.3.4. 
Multivariate Rank Sum Score Endpoint 
This multivariate rank sum score endpoint is designed to assess the effect of edasalonexent 
versus placebo across multiple endpoints using a non-parametric rank-based approach. For 
Week 52, the endpoint is the sum of the ranks of the following Week 52 CFB scores: NSAA, 


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10MWT speed, stand from supine speed, 4-stair climb speed, and PODCI transfer and basic 
mobility scale. 
The multivariate rank sum score at Week 52 will be derived using the method described in 
O'Brien (1984). Specifically, for each patient i, the overall rank score is given by: 
Rii = rij1 + rij2 + rij3 + rij4 + rij5  
where:  
i = an indicator for a specific patient 
j = an indicator for a treatment group 
rij1 = patient i’s rank of the Week 52 CFB in NSAA score at Week 52 
rij2 = patient i’s rank of the Week 52 CFB in 10MWT speed score at Week 52 
rij3 = patient i’s rank of the Week 52 CFB in Stand from Supine Speed score at Week 52 
rij4 = patient i’s rank of the Week 52 CFB in 4-stair Climb Speed at Week 52 
rij5 = patient i’s rank of the Week 52 CFB in the PODCI Transfer and Basic Mobility 
Scale score at Week 52 (described in Section 2.6.3.3) 
In determining ranks, if there are ties, the average value of the ranks that would have been 
assigned to all observations with the same value will be used.  
Only patients with non-missing values for each of these 5 Week 52 CFB scores will be included 
in the analysis.  
The patient’s baseline rank sum score will be used a covariate for some of the rank-based 
analyses. This is defined as the sum of the ranks across the 5 endpoints using the baseline value 
(using the methodology described above).  
2.6.4. 
Safety Endpoints 
Safety will be evaluated in terms of all treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs), as well as physical examination, growth parameters (height and weight), 
vital signs, clinical laboratory parameters (including chemistry, hematology and urinalysis), 
adrenal function (adrenocorticotrophic hormone (ACTH) and cortisol levels), and 
electrocardiogram (ECG). Data from ECGs will be locally read and centrally evaluated. Cardiac 
monitoring and bone evaluations will also be performed. 
2.6.5. 
Additional Endpoints 
To access acceptability and palatability of edasalonexent, caregivers will complete a study drug 
questionnaire, these results will be presented in a listing and the following questions will be 
summarized by treatment group. 
1) The taste and aftertaste (a taste that remains in your mouth after swallowing) of the study 
drug capsules are acceptable. 
2) The smell of the study drug capsules is acceptable. 
3) The size and shape of the study drug capsules are acceptable: 
These 3 questions are measured on a 1 (strongly agree) to 5 (strongly disagree) point scale. The 
frequency of each response category will be summarized. 


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3. 
PATIENT POPULATIONS 
3.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
• Randomized Population: all patients who are randomized into the study with patients to 
be analyzed based on the study treatment they were randomized to. 
• Safety Population: all patients who receive at least one dose of study drug with patients 
to be analyzed based on the actual study treatment received. 
• Full Analysis Population (FAP): all patients in the Randomized Population who receive 
at least one dose of study drug and provide at least one non-missing post-Baseline 
NSAA efficacy assessment.  
o Note that the FAP will exclude patients on eteplirsen at randomization and 
patients will be analyzed based on the study treatment they were randomized to.  
• Per Protocol (PP) Population: all patients in the FAP who complete the 52-week 
treatment period of the study without any significant protocol deviations with patients to 
be analyzed based on the study treatment they were randomized to. 
The set of patients in the Per Protocol population may be updated due to study drug 
compliance information which will not be collected until after database lock and 
unblinding due to the COVID-19 pandemic, see Section 3.2.    
note: the variable to determine a patient completing the 52-week treatment period is 
from the End of Study eCRF page “Did subject complete the study?” = Yes. 
The FAP will be the primary population for the analysis of efficacy parameters. The Safety 
Population is the primary population for the analysis of safety endpoints. 
Note that if siblings are enrolled, only one sibling will be included in the Randomized 
Population. This is to avoid having siblings being randomized to different study medications, 
increasing the risk a subject will inadvertently take incorrect study medication. The second 
sibling will be assigned to the same treatment group as the randomized sibling. If both siblings 
meet the inclusion/exclusion criteria, the sibling to be included in the Randomized Population 
will be the first sibling randomized, both siblings will be included in the Safety Population (see 
Section 3.1). The sibling not included in the Randomized Population will have their data 
presented in the listings and will be included in some of the sensitivity analyses. 
3.2. 
Protocol Deviations 
At the discretion of the sponsor, significant protocol deviations as determined by a review of the 
data prior to unblinding of the study may result in the removal of a patient’s data from the Per 
Protocol Population. The sponsor, or designee, will be responsible for producing the final 
protocol deviation file (formatted as a Microsoft Excel file), in collaboration with Cytel and the 
data monitoring group as applicable; this file will include a description of the protocol deviation, 
and clearly identify whether or not this deviation warrants exclusion from the Per Protocol 
Population. This file will be finalized prior to database unblinding.  
All protocol deviations will be summarized by category and presented in the data listings. The 
following are the protocol deviation categories: 


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• Eligibility 
• Inclusion/Exclusion criteria 
• Informed consent deviation 
• Laboratory 
• Other 
• Outside protocol window 
• Procedure or labs not done 
• Restricted concomitant medication change 
• Study drug 
• Study drug dosing 
• Study procedures 
• Subject non compliance 
• Visit not done 
• Visit window 
Note: Due to the impact of the COVID-19 pandemic on study sites and patients, drug 
accountability may be incomplete for some patients at the time of database lock and the 
timeframe for resolution may not be near term or indeed possible. This impacts the assessment 
of study drug compliance. If, after database lock and unblinding, additional drug accountability 
information is provided such that a patient’s overall study drug compliance is determined to be 
less than 80%, then the Per Protocol population will be updated to exclude this patient (i.e., if 
the patient has not previously been excluded from the Per Protocol population). This set of 
patients (i.e., patients with less than 80% study drug compliance identified after database lock 
and unblinding) will be provided in the CSR.    
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
Approximately 126 patients will be randomized to either edasalonexent or placebo in a 2:1 ratio. 
Based on Phase 1/2 data of changes in NSAA in this age group, an effect size of 0.625 is 
assumed. With this effect size, and assuming a dropout rate of approximately 20%, the study has 
approximately 80% power to show a difference between the treatment groups at a 2-sided type I 
error rate of 0.05. 
Based on an underlying standard deviation estimate of 4.8 in the change from baseline in NSAA 
score (derived from the phase 2 study data) this would equate to a treatment difference of 3.0, 
which would be considered a clinically meaningful change.  
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage within 
each category (with a category for missing data) of the parameter will be presented. For 
continuous variables, the mean, median, standard deviation, minimum and maximum values will 
be presented. Unless otherwise defined for a particular endpoint, a patient’s Baseline value is 
defined as the last non-missing measurement prior to the initiation of study drug. The first day 
of study drug is “Day 1”. 
Formal statistical hypothesis testing will be performed on the primary and secondary efficacy 
endpoints (Section 2.5.1), with all tests conducted at the 2-sided, 0.05 level of significance. 
Summary statistics will be presented, as well as confidence intervals (CIs) on selected 
parameters, as described in the sections below. 
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software 
(Version 9.4), unless otherwise noted. Medical History and adverse events will be coding using 
the current Medical Dictionary for Regulatory Activities (MedDRA) version. Concomitant 
medications will be coded using the most current version of the World Health Organization 
(WHO) Drug Reference List.  
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates 
Statistical models will adjust for the stratification variables as covariates. 
4.2.5. 
Multiplicity 
The following multiplicity adjustment approach will be used to strongly control the overall Type 
I error rate at 0.05 (two-sided) for the primary endpoint and three secondary endpoints.  
A hierarchical testing procedure will be used for the secondary endpoints. At each step the test 
for treatment effect will be considered statistically significant if the p-value is less than or equal 


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to 0.05 and all previous tests also meet this level of significance. The testing hierarchy is as 
follows: 
1. Primary endpoint: CFB in the NSAA Total Score at Week 52 
2. Secondary endpoint: CFB in the Stand from Supine Speed at Week 52 
3. Secondary endpoint: CFB in the 10MWT Speed at Week 52  
4. Secondary endpoint: CFB in the 4-Stair Climb Speed at Week 52 
This method provides strong control of the family-wise error rate at the 2-sided 0.05 level.  
4.2.6. 
Subgroups 
Primary and secondary efficacy analyses will be performed within each of the following 
subgroups based on the FAP: 
• Baseline Age (<= 6.0 years old vs. > 6.0 years old) 
• Baseline Time to Stand from Supine (<=5 seconds vs. >5 seconds) 
• Region (North America vs. Europe/Asia/Australia) 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
Patients who withdrew from the study will not be replaced. 
4.2.8. 
Missing, Unused, and Spurious Data 
For the primary and secondary efficacy endpoint analyses, an MMRM using observed case 
analysis represents the primary method for handling missing data (as described in Sections 
4.10.1 and 4.10.2). Multiple sensitivity analyses on the primary and secondary endpoints which 
utilize alternative methods of handling missing data are being performed as described in 
Sections 4.10.4 and 4.10.5. 
Additionally, the following missing data conventions are being applied: 
• For all TFTs, as described in Section 2.6.2, If there are any patients not able to complete the 
test (reason not done = “subject physically unable to complete test”), a value of 0 will be 
assigned for the speed of the TFT (i.e., speed in units of task per second). For the time to 
complete endpoints, a value of 12 seconds will be imputed.  
Additionally, as described in Section 2.6.2, if the TFT has a grade of 1 or 2 for 10MWT or 
stand from supine, or a grade of 1 for the 4-stair climb, the speed will be set to 0 and the 
time set to 12 seconds.  
• As described in Section 3.1, if siblings are enrolled, only one sibling will be included in the 
Randomized Population. Sensitivity analyses for all efficacy variables will be performed 
with the both siblings’ values to be used (as described in Sections 4.10.1 and 4.10.2).  
4.2.9. 
Visit Windows 
Screening takes place in the 4-week interval prior to first day of study drug (Day 1). Week 6 – 
19 visits should be conducted with the study week with a ±4-day window. Week 26 – 54 visits 
have a ±10-day window. 
Safety follow-up should occur within 2 weeks after the last dose of study drug.  


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However, visits which occur outside the windows will still be included in the analysis for that 
visit.  
4.2.10. 
Early Termination Visit 
If a patient has an Early Termination visit, the assessments from that visit will be mapped to a 
scheduled visit using the algorithm presented in Table 4. Note that if the subject has already had 
the corresponding scheduled visit, the early termination visit data will not be included in 
summary statistics, but will be included in listings. The listings will show the visit as “Early 
Termination”, not the corresponding mapped visit.  
Table 4: Early Termination Visit Window Algorithm 
Study Day of Early Termination 
Visit 
Visit mapping 
2 – 136 
Week-13 Visit 
137 – 227 
Week-26 Visit 
228 – 318 
Week-39 Visit 
319 – 364 
Week-52 Visit 
note: The first day of study drug is “Day 1”.  
4.2.11. 
Baseline 
A patient’s baseline value will be most recent non-missing value occurring prior to initiation of 
study drug. In most cases this will be the value assessed at the Baseline visit. If the Baseline 
value is missing, the next most recent non-missing value will be used (i.e., in most cases this 
will be the Screening visit value).  
4.3. 
Interim Analyses 
No interim analyses were planned for this study. 
4.4. 
Patient Disposition 
All patients who sign the informed consent will be included in a summary of patient disposition. 
The number of patients screened, randomized, and dosed in each treatment group will be 
presented. The number and percentage of patients discontinuing and completing treatment, the 
number of patients discontinuing before study completion (including reason for 
discontinuation), and the number of patients completing the study will be presented as well.  
The number and percentage of patients in the various analysis populations will be presented 
separately. 
The above information will also be provided in a by-patient listing. 
4.5. 
Demographic and Baseline Characteristics 
Demographics, including age at Baseline are considered as a continuous variable, frequency of 
age by year, age at Baseline (<=6.0 vs. >6.0 years) and Baseline characteristics, including time 
to stand from supine (both as a continuous and dichotomous variable: <=5 vs. >5 seconds), 
treatment with eteplirsen (yes vs. no), and region (North America vs. Europe/Asia/Australia) 
will be summarized by treatment group and overall, and also listed by patient for the Safety 


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Population. Baseline NSAA score will also be summarized. No inferential statistical 
comparisons between groups will be performed. 
Note that age (in years) will be derived to the tenths place from the date of birth to the date of 
randomization. For the patients who do not have a date of birth provided (e.g., patients from 
Germany) the baseline age will be calculated via the years and months old provided at screening 
plus the time from the screening visit to the date of randomization. 
4.6. 
Concomitant Medications  
Concomitant medications will be listed by treatment and coded using the most current version 
of the WHO Drug Reference List.  
4.7. 
Medical History 
Medical History will be listed and coded by patient using the MedDRA version 21.0. 
4.8. 
DMD-Specific Medical History 
DMD-specific medical history, including age at symptom onset and diagnosis, will be listed by 
patient, and summarized by treatment group and overall for the Safety Population. 
4.9. 
Treatment Exposure and Compliance 
Throughout the study, patients and their parents/caregivers will complete a diary documenting 
study drug administration and diet compliance. For the Safety Population, treatment duration, 
number of administrations, and compliance (summarized by assessing capsule count) will be 
summarized by treatment group and overall. 
Treatment Duration: Treatment Duration will be the number of days from the patient’s first dose 
until their Week 52 visit. If the patient discontinued from the study and did not have a Week 52 
visit the subject’s Early Termination visit will be used (note: if the subject does not have an 
early termination visit, the last visit will be used). 
The patient’s date of first dose is determine by the study drug administration at baseline: 
• If for the baseline visit the “first dose of the day administered in clinic” = “No” (i.e., 
variable EX. EXPERF= “N”) then the date of first dose is the date in the field 
EX.EXSTDAT (i.e., the “Date of study drug administration). 
• Otherwise the date of first dose is the date of the baseline visit. 
Expected Average Daily Dose: The expected number of capsules that a patient is to take each 
day is specified at each visit that the patient receives new study medication (e.g., Baseline, 
Week 13, Week 26, and Week 39, but there may be distribution at unscheduled visits as well). 
The daily total of capsules is broken up into morning/afternoon/evening administration. The 
exact capsule count per dose and the capsule dose strength (i.e., 250 mg or 100 mg) will be 
provided through the IXRS based on the patient weight at each study visit. 
The periods are: 
• 1st day patient takes study medication to the day before the Week 13 visit 
• Week 13 to the day before the Week 26 visit 
• Week 26 to the day before the Week 39 visit 


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• Week 39 to the day of the Week 52 visit. 
Please note the following potential modifications to these periods: 
• If the patient discontinues the study early, the corresponding period will end at the date 
of the early termination visit.  
• If the patient has an unscheduled visit where study drug is dispensed the periods will be 
updated to account for this visit. The following is an example of the update to the 
algorithm where the patient had an unscheduled visit between the Week 26 and Week 39 
visits.  
o 1st day patient takes study medication to the day before the Week 13 visit 
o Week 13 to the day before the Week 26 visit 
o Week 26 to the day before the Unscheduled Visit where study drug was 
dispensed. 
o Unscheduled Visit where study drug was dispensed to the day before the Week 
39 visit. 
o Week 39 to the day of the Week 52 visit. 
 
For each study drug administration period, the daily dose (mg/day) is calculated as:  
Daily Dose (mg/day) = expected number of capsules per day  capsule strength  
(note: Capsule strength is either 250mg or 100mg). 
The average daily dose is calculated by taking the average across the patient’s different dosing 
periods weighted by the number of days in the period.  
As such the algorithm is: 
Average daily dose (mg/day) =  
{Daily dose for 1st day patient takes study medication to the day before Week 13 Period  # of 
days in this period +  
 Daily dose for Week 13 to the day before the Week 26 visit  # of days in this period +  
 Daily dose for Week 26 to the day before the Week 39 visit  # of days in this period + 
 Daily dose for Week 39 to the day before the Week 52 visit  # of days in this period} 
 / {Total # of days summed across these periods}. 
 
Please note the following potential modifications to the algorithm: 
• If the patient discontinues the study early, the corresponding period will end at the date 
of the early termination visit.  
• If the patient has an unscheduled visit where study drug is dispensed the periods will be 
updated to account for this visit. The following is an example of the update to the 
algorithm where the patient had an unscheduled visit between the Week 26 and Week 39 
visits.  
o 1st day patient takes study medication to the day before the Week 13 visit 


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o Week 13 to the day before the Week 26 visit 
o Week 26 to the day before the Unscheduled Visit where study drug was 
dispensed. 
o Unscheduled Visit where study drug was dispensed to the day before the Week 
39 visit. 
o Week 39 to the day of the Week 52 visit. 
Actual Number of Capsules: The number of capsules taken will be based on the “number of 
used units” from the IXRS data which is provided for each study kit. The total number of 
capsules taken by a patient will be the sum of the “number of used units” across the study.  
Note: the following modification to the IXRS data will be applied. If the following holds: 
• Is the Kit present at the Site = “No” 
• Date returned by subject = “Missing” 
• Discrepancy reason is not “Damaged by Subject”  
Then the number of used units will be set to 90. (note: in these situations, the convention was 
for the site pharmacy to set the “Used Units” to 0 and the “Missing Unit” to 90).  
 
Planned Number of Capsules:  
Planned Number of Capsules =  
{# of Capsules for 1st day patient takes study medication to the day before Week 13 Period  # 
of days in this period +  
 # of Capsules for Week 13 to the day before the Week 26 visit  # of days in this period +  
 # of Capsules for Week 26 to the day before the Week 39 visit  # of days in this period + 
 # of Capsules for Week 39 to the day before the Week 52 visit  # of days in this period}. 
 Please note the following potential modifications to the algorithm: 
• If the patient discontinues the study early, the corresponding period will end at the date 
of the early termination visit.  
• If the patient has an unscheduled visit where study drug is dispensed the periods will be 
updated to account for this visit. The following is an example of the update to the 
algorithm where the patient had an unscheduled visit between the Week 26 and Week 39 
visits.  
o 1st day patient takes study medication to the day before the Week 13 visit 
o Week 13 to the day before the Week 26 visit 
o Week 26 to the day before the Unscheduled Visit where study drug was 
dispensed. 
o Unscheduled Visit where study drug was dispensed to the day before the Week 
39 visit. 
o Week 39 to the day of the Week 52 visit. 
 


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Percent Compliance:  Percent Compliance calculated as: 
Percent Compliance = 100 Actual Number of Capsules / Planned Number of Capsules. 
 
4.10. 
Efficacy Evaluation 
The FAP is used as the primary population, and the PP and Randomized Populations will be 
used for sensitivity analyses as described for each efficacy analysis below.  
Efficacy endpoints will be listed by patient, and summarized by treatment group and time point, 
as applicable. For the timed function tests, both the times to complete (seconds) and their speed 
(i.e. the reciprocals) will be tabulated. In the case of the 10MWT, units will be 10 meters per 
second. In the case of the stand from supine and the 4-stair climb, units will be task per second. 
Descriptive statistics will be calculated for quantitative efficacy data as well as for the CFB, and 
differences between treatment groups as applicable. 
Summary statistics for the primary and secondary efficacy endpoints will be presented by 
investigative site and overall. 
If a patient initiates corticosteroid therapy or discontinues study treatment, all observations from 
that patient after these events will be censored from the efficacy analyses. 
4.10.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the CFB in the NSAA Total Score at Week 52. NSAA Total 
Scores and the CFB values will be summarized by treatment group and time point using 
descriptive statistics.  
If a patient initiates corticosteroid therapy or discontinues study treatment, all observations from 
that patient after these events will be censored from the primary efficacy analyses. 
The primary efficacy endpoint analysis will be an MMRM ANCOVA. The MMRM model will 
include: 
• CFB in the NSAA Total Score as the dependent variable 
• Variables in the Model  
Visit (a categorical variable) 
 
Treatment (edasalonexent or placebo) 
Treatment  Visit 
Region (North America vs. Europe/Asia/Australia) 
Region  Visit 
Baseline age (as a continuous variable), 
Baseline Age  Visit 
Baseline time to stand from supine (as a continuous variable) Baseline time to Stand  Visit 
Baseline NSAA score (as a continuous variable) 
Baseline NSAA score  Visit 
• Patient as a random effect.  
The primary efficacy analysis will test the difference between the edasalonexent versus placebo 
at Week 52 using this MMRM model.  
Sample SAS code for the primary efficacy analysis is provided in APPENDIX 1: Sample 
MMRM Code.  
Descriptive summary statistics including number of patients, mean, standard error, least-square 
means (LS means), LS means differences, along with the p-values and corresponding 95% CIs 


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will be provided. Specifically, the primary efficacy endpoint hypothesis test of no treatment 
difference between edasalonexent and placebo is based on the least-squares means (LS-means) 
difference and corresponding p-value from the Week 52 visit. The results for the treatment 
difference for the other visits will also be provided to assess the consistency of treatment effect 
over different visits. 
The repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured covariance structure to model the within-patient errors. A Kenward-
Roger approximation will be used for the denominator degrees of freedom. If there is a 
convergence problem due to the unstructured covariance matrix, a compound symmetry 
covariance structure will be used to model the within-patient variance; if the compound 
symmetric covariance structure fails to converge, a variance components approach will be 
applied.  
The primary efficacy endpoint analysis is an observed case analysis, with no imputation of 
missing data. 
Descriptive summary statistics will be provided for each of the 17 NSAA items at each of the 
scheduled assessment timepoints.  
4.10.2. 
Secondary Efficacy Analyses 
The TFT secondary efficacy endpoints are: 
• CFB in 10MWT Speed at Week 52 
• CFB in Stand from Supine Speed at Week 52  
• CFB in 4-stair Climb Speed at Week 52 
Descriptive statistics will be calculated for the speed and time to complete the TFT secondary 
efficacy endpoints as well as all CFB values by treatment group and time point.  
The secondary efficacy endpoint analyses for these endpoints will be an MMRM ANCOVA, 
using the methodology described for the primary efficacy endpoint analysis (Section 4.10.1). 
The difference being that, instead of baseline NSAA as a covariate, the corresponding baseline 
secondary efficacy endpoint value will be used.  
As described in Section 2.6.2, if there are any patients not able to complete the test (reason not 
done = “subject physically unable to complete test”), a value of 0 will be assigned for the 
reciprocal test (i.e., speed in units of task per second).  
4.10.3. 
Additional Efficacy Analyses 
Additional efficacy endpoints include CFB on the following: 
• Muscle strength testing: 2 endpoints: elbow flexion (i.e., average of the left and right 
elbows), knee extension (average of the left and right knees). If either the left or right 
value is missing the value will be the non-missing score.  
Note: values which are indicated as not being valid as determined by a response of “No” 
to “Was test valid? (i.e. representative of child’s true function)” for these assessments 
will not be included in the analysis (but will be presented in listings).  


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These additional efficacy endpoints will be analyzed using an MMRM ANCOVA, in a 
manner similar to that described in Section 4.10.1 with the corresponding baseline 
muscle strength endpoint replacing baseline NSAA as a covariate. 
• PUL endpoints: This includes the PUL Total Score, and the sum of individual items 1 
and 2 (note these 2 items are imputed for patients who scored a “6” on Item A as defined 
in Section 2.6.3.2).  
The sum of individual items 1 and 2, and PUL total score endpoints will be analyzed 
using an MMRM ANCOVA, in a manner similar to that described in Section 4.10.1 with 
the corresponding baseline PUL score replacing baseline NSAA as a covariate. 
PODCI Transfer and Basic Mobility Scale: This additional efficacy endpoint will be 
analyzed using an ANCOVA. The ANCOVA model will include CFB in the PODCI 
Transfer and Basic Mobility Scale at Week 52 as the dependent variable, treatment and 
region (North America vs. Europe/Asia/Australia) as factors, and baseline age (as a 
continuous variable), baseline time to stand from supine (as a continuous variable), and 
baseline PODCI Transfer and Basic Mobility Scale score (as a continuous variable) as 
covariates. 
As an additional analysis of the PODCI Transfer and Basic Mobility Scale endpoint, the 
analysis above will be repeated subset to the subgroup of patients with the same 
caregiver completing the form at both baseline and Week 52 (i.e., from the PODCI 
eCRF page “Who completed this form?” with responses of: Caregiver, Father, Mother). 
Note that summary statistics will be provided for the additional POCDI scales at each 
scheduled timepoint.  
CFB multivariate rank sum score: The analysis for this Week 52 endpoint will be an 
ANCOVA, The ANCOVA model will include Week 52 CFB multivariate rank sum 
score as the dependent variable, treatment and region (North America vs. 
Europe/Asia/Australia) as factors, and baseline age (as a continuous variable), baseline 
time to stand from supine (as a continuous variable), and the corresponding rank sum of 
the score at baseline will be used (as described in Section 2.6.2).  
4.10.4. 
Sensitivity Analyses for the Primary Efficacy Endpoint 
The following sensitivity analyses of the primary and secondary efficacy endpoints will be 
performed to assess the robustness of the analyses across endpoints:  
a) The primary efficacy endpoint analysis performed on the PP population 
The primary efficacy endpoint analysis, as defined in Section 4.10.1 will be performed using 
the PP Population 
b) The primary efficacy endpoint analysis performed on the Randomized population 
The primary efficacy endpoint analysis, as defined in Section 4.10.1 will be performed using 
the Randomized Population (note: this includes randomized patients on eteplirsen) 
c) ANCOVA on the primary efficacy endpoint using MAR, MNAR, and OC 
The primary efficacy endpoint, the CFB in the NSAA Total Score at Week 52 will be 
analyzed by an ANCOVA model. The ANCOVA model will include CFB in the NSAA 
Total Score at Week 52 as the dependent variable, treatment and region (North America vs. 
Europe/Asia/Australia) as factors, and baseline age (as a continuous variable), baseline time 


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to stand from supine (as a continuous variable), and baseline NSAA score (as a continuous 
variable) as covariates.  
Three different methods of addressing missing data will be performed: 
1) Missing at Random (MAR) Missing data will be imputed using the MAR algorithm 
described in Section 4.10.6.1.  
2) Missing Not at Random (MNAR) Missing data will be imputed using the MNAR 
algorithm described in Section 4.10.6.2.  
3) OC (Observed Case) this ANCOVA will be performed on non-missing data.  
These analyses will be performed on the FAP.  
d) Observed Week 52 MMRM 
The primary efficacy endpoint analysis will be repeated (i.e., as described in Section 4.10.1) 
subset to those patients who had a non-missing CFB value at Week 52. 
e) MMRM with multiple imputation assuming MAR 
The primary efficacy endpoint analysis will be repeated (i.e., as described in 4.10.1) with 
missing data imputed based on a Missing at Random (MAR) pattern as described in 
4.10.6.1. 
f) MMRM with multiple imputation assuming MNAR 
The primary efficacy endpoint analysis will be repeated (i.e., as described in 4.10.1) with 
missing data imputed based on a Missing Not at Random (MNAR) pattern as described in 
4.10.6.2 
g) Including siblings 
The primary efficacy endpoint analysis will be repeated (i.e., as described in 4.10.1) 
including the siblings in the FAP.  
4.10.5. 
Sensitivity Analyses for the Secondary Efficacy Endpoints 
The sensitivity analyses for the primary efficacy endpoint as defined in Section 4.10.4 will be 
applied to the secondary endpoints.  
4.10.6. 
Multiple Imputation Methods 
As part of the sensitivity analysis, the missing CFB primary and secondary efficacy endpoints 
will be imputed using multiple imputation (MI) for each of the scheduled assessment visits (i.e., 
Weeks 13, 26, 39, and 52). Both an MAR and MNAR method will be applied.  
The following random number seeds will be used for each endpoint/multiple imputation; these 
seeds were randomly generated.  
Table 5: Random Number Seeds for Multiple Imputation 
Endpoint 
Random Number Seed 
MAR 
MNAR 
NSAA 
29068 
24158 


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10MWT Speed 
52987 
60804 
Stand from Supine Speed 
69440 
21531 
4-stair Climb Speed 
36875 
55339 
 
Imputation distribution:  
The imputation distribution for the missing change from baseline endpoints will be a normal 
distribution. Although the change from baseline values are integers for the primary change from 
baseline in NSAA endpoint, imputed values will be rounded to 1 decimal place when used in the 
analysis. For the change from baseline secondary endpoints (i.e., TFT reciprocal of seconds 
endpoints) the imputed values will be rounded to 4 decimal places (i.e., the ten-thousandth 
place).  
4.10.6.1. Multiple Imputation Assuming MAR 
Imputation algorithm: 
Missing post-baseline change from baseline values will be imputed via multiple imputation (MI) 
assuming MAR for each scheduled assessment visit. 
Fifty imputed datasets will be created. Each of the imputed datasets will be analyzed via the 
specified primary or secondary efficacy endpoint analysis. The results across the multiple 
imputed data sets will be combined using SAS Proc MIANALZYE (sample SAS code for 
primary analysis provided in APPENDIX 2: Sample Multiple Imputation Code). 
The following are the set of variables to be used in the multiple imputation model: 
• Treatment group (edasalonexent or placebo) 
• Region (North America vs. Europe/Asia/Australia) 
• Baseline age (continuous variable) 
• Baseline time to stand from supine (continuous variable) 
• Baseline value for the endpoint being imputed (continuous variable) 
• Previous change scores (e.g., for the Week 52 CFB imputation, the CFB scores at Weeks 13, 
26, and 39 will be included)  
The imputations will be performed using monotone linear regression imputation methods which 
will impute the patients’ missing post-baseline change scores at each of the scheduled 
assessment visits in the study.  
If the missing data does not follow a monotonic pattern, a sequential approach to imputing the 
data via a Markov chain Monte Carlo (MCMC) method to produce a monotone missing data 
pattern will be applied using the MCMC impute=monotone option in Proc MI (SAS System). 
Following the method described in Smith (2017) the non-monotonic data imputation will be 
performed “by” the categorical treatment variable (note: the categorical variable Region will not 
be included in the non-monotonic imputation). Then the monotone linear regression imputation 
methods will be applied.  


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Note: if the multiple imputation model does not converge or produce estimates (i.e., due to over-
specification) the set of imputation variables may be modified. 
4.10.6.2. MMRM with Multiple Imputation Assuming MNAR 
Imputation algorithm: 
For this imputation the monotonic missing post-baseline change from baseline scores will be 
imputed via multiple imputation assuming MNAR for each scheduled assessment visit (i.e., 
Weeks 13, 26, 39, and 52).  
The imputation of monotonic missing scores in the edasalonexent treatment group will be based 
on the distribution in the placebo group. This method assumes that the trajectory of withdrawals 
from the edasalonexent treatment arm follows the distribution of the placebo patients. The 
MNAR option in Proc MI (SAS system) will be used to impute the placebo distribution as 
described (Yuan, 2014).  
Fifty imputed datasets will be created. Each of the imputed datasets will be analyzed via the 
same model as the primary efficacy endpoint analysis (see Section 4.10.1). The results across 
the multiple imputed data sets will be combined using SAS Proc MIANALZYE (details 
provided in APPENDIX 2: Sample Multiple Imputation Code).  
The set of variables for this MNAR multiple imputation model is the same set as defined for the 
MAR multiple imputation (Section 4.10.6.1), with the exception of Treatment group, which is 
not included in the MNAR imputation (i.e., the placebo distribution is used to impute the data). 
The imputations will be performed using monotone linear regression imputation methods which 
will impute the patients’ missing post-baseline change scores at each of the scheduled visits in 
the study (i.e., Weeks 13, 26, 39, and 52).  
If the missing data does not follow a monotonic pattern, a sequential approach to imputing the 
data via an MCMC method to produce a monotone missing data pattern will be applied using 
the MCMC impute=monotone option in Proc MI (SAS System). Following the method 
described in Smith (2017) the non-monotonic data imputation will be performed “by” the 
categorical treatment variable (note: the categorical variable Region will not be included in the 
non-monotonic imputation). Then the monotone linear regression imputation methods will be 
applied. 
Note: if the multiple imputation model does not converge or produce estimates (i.e., due to over-
specification) the set of imputation variables may be modified. 
4.10.7. 
Supportive Analyses on Primary and Secondary Efficacy Endpoints 
The following analyses will be performed to support the primary endpoint analyses. These 
analyses will be performed on the FAP.  
• NSAA Categorical Change from Baseline: The percentage of patients with a change 
from baseline in NSAA Total Score at Week 52 will be compared between the treatment 
groups. The following categories for change from baseline in NSAA will be considered 
o Improvement: ≥ 0, ≥ 1, ≥ 2, ≥ 3, ≥ 4 
o Decline: ≤ 0, ≤ -1, ≤ -2, , ≤ -3 , ≤ -4, , ≤ -5  


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The difference between the treatment groups will be compared by a chi-square test, 
except for the scenarios where, in either group, there are only 5 patients or less in the 
numerator (or, conversely, N-5 patients or more) in which case a Fisher’s exact test will 
be used.  
Additionally, a Kolmogorov–Smirnov test for differences in the change from baseline in 
NSAA Total Score between treatment groups will be performed.  
 
• Increase in function in Week 52 NSAA Items: For each of the 17 NSAA items, the 
number and percent of patients with an increase in function will be summarized. A 
patient is defined as having an increase in function if the baseline items score is <2 and 
the post-baseline value is greater than the baseline value. Patients with a baseline item 
score of 2 or a missing Week 52 NSAA item value are excluded from the analysis.  
For each item, the percentages, odds ratio (with 95% CI), and a p-value comparing the 
treatment group difference in proportions will be presented.  
For the Overall NSAA increase in function, the overall odds ratio, 95% CI, and p-value 
will be estimated from a generalized estimating equations (GEE) model with treatment 
and NSAA item as class variables in the model, increase in NSSA item (i.e., a 
dichotomous variable) as the dependent variable, baseline item score as a covariate, and 
subject as the repeated term with an exchangeable working correlation matrix. 
The patient count and percent of number of Week 52 NSAA items which increased in 
function will be presented (i.e., the “count” is the number of NSAA items with a 
baseline score <2 and the post-baseline value is greater than the baseline value. The 
percent is the “count” divided by the number of NSAA items with a baseline score <2 
and non-missing Week 52 value).  
 
• Preservation of function in Week 52 NSAA Items: For each of the 17 NSAA items, the 
number and percent of patients with preservation of function will be summarized. A 
patient is defined as having a preservation of function if the baseline items score is >0 
and the post-baseline value is >0. Patients with a baseline item score of 0 or a missing 
Week 52 NSAA item value are excluded from the analysis.  
For each item, the percentages, odds ratio (with 95% CI), and a p-value comparing the 
treatment group difference in proportions will be presented.  
For the Overall NSAA increase in function, the overall odds ratio, 95% CI, and p-value 
will be estimated from a generalized estimating equations (GEE) model with treatment 
and NSAA item as class variables in the model, NSSA item score >0 (i.e., a 
dichotomous variable) as the dependent variable, baseline item score as a covariate, and 
subject as the repeated term with an exchangeable working correlation matrix. 
The patient count and percent of number of Week 52 NSAA items with preserved 
function will be presented (i.e., the “count” is the number of NSAA items with a 
baseline score >0 and the post-baseline value is >0. The percent is the “count” divided 
by the is the number of NSAA items with a baseline score >0 and non-missing Week 52 
value).  
 


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• Worsening of function in Week 52 NSAA Items: For each of the 17 NSAA items, the 
number and percent of patients with a worsening of function will be summarized. A 
patient is defined as having a worsening of function if the baseline items score is >0 and 
the post-baseline value is less than the baseline value. Patients with a baseline item score 
of 0 or a missing Week 52 NSAA item value are excluded from the analysis.  
For each item, the percentages, odds ratio (with 95% CI), and a p-value comparing the 
treatment group difference in proportions will be presented.  
For the Overall NSAA worsening in function, the overall odds ratio, 95% CI, and p-
value will be estimated from a generalized estimating equations (GEE) model with 
treatment and NSAA item as class variables in the model, worsening of function (i.e., a 
dichotomous variable) as the dependent variable, baseline item score as a covariate, and 
subject as the repeated term with an exchangeable working correlation matrix. 
The patient count and percent of number of Week 52 NSAA items with worsening 
function will be presented (i.e., the “count” is the number of NSAA items with a 
baseline score >0 and the post-baseline value is less than the baseline value. The percent 
is the “count” divided by the is the number of NSAA items with a baseline score >0 and 
non-missing Week 52 value).  
• Loss in function in Week 52 NSAA Items: For each of the 17 NSAA items, the number 
and percent of patients with a loss of function will be summarized. A patient is defined 
as having a loss of function if the baseline items score is >0 and the post-baseline value 
is 0. Patients with a baseline item score of 0 or a missing Week 52 NSAA item value are 
excluded from the analysis.  
For each item, the percentages, odds ratio (with 95% CI), and a p-value comparing the 
treatment group difference in proportions will be presented.  
For the Overall NSAA loss in function, the overall odds ratio, 95% CI, and p-value will 
be estimated from a generalized estimating equations (GEE) model with treatment and 
NSAA item as class variables in the model, loss of function (i.e., a dichotomous 
variable) as the dependent variable, baseline item score as a covariate, and subject as the 
repeated term with an exchangeable working correlation matrix. 
The patient count and percent of number of Week 52 NSAA items with loss of function 
will be presented (i.e., the “count” is the number of NSAA items with a baseline score 
>0 and the post-baseline value is 0. The percent is the “count” divided by the is the 
number of NSAA items with a baseline score >0 and non-missing Week 52 value).  
 
• Gain of function in Week 52 NSAA Items: For each of the 17 NSAA items, the number 
and percent of patients with a gain in function will be summarized. A patient is defined 
as having a gain in function if the baseline items score is 0 and the post-baseline value is 
> 0 (i.e., a score of 1 or 2). Patients with a baseline item score of 1 or 2 or a missing 
Week 52 NSAA item value are excluded from the analysis (i.e., this analysis is based on 
the items with a baseline score of 0).  
For each item, the percentages, odds ratio (with 95% CI), and a p-value comparing the 
treatment group difference in proportions will be presented.  
For the Overall NSAA gain of function, the overall odds ratio, 95% CI, and p-value will 
be estimated from a generalized estimating equations (GEE) model with treatment and 


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NSAA item as class variables in the model, gain of function (i.e., a dichotomous 
variable) as the dependent variable, baseline item score as a covariate, and subject as the 
repeated term with an exchangeable working correlation matrix. 
The patient count and percent of number of Week 52 NSAA items with a gain in 
function will be presented (i.e., the “count” is the number of NSAA items with a 
baseline score of 0 and the post-baseline value is >0. The percent is the “count” divided 
by the is the number of NSAA items with a baseline score of 0 and non-missing Week 
52 value).  
 
• NSAA Items: Change from Baseline: For each NSAA item at each scheduled visit, the 
change from baseline will be summarized and the two treatment groups will be 
compared using CMH test on change from baseline score controlling for baseline NSAA 
item score.  
4.10.8. 
Subgroup Analyses on Primary and Secondary Efficacy Endpoints 
Subgroup analyses of the primary and secondary endpoints will be performed in the same 
manner as the primary analysis within each of the following subgroups based on the FAP: 
• Baseline Age (<= 6.0 years old and > 6.0 years old) 
• Baseline Time to Stand from Supine (<=5 seconds and >5 seconds) 
• Region (North America and Europe/Asia/Australia). 
The MMRM model for the previous treatment with eteplirsen subgroup will be the same as the 
main model. The MMRM model for the other subgroups will be the same as the main model, 
excluding the subgroup as a factor. If particular subgroups have two few observations (patients) 
to provide a meaningful MMRM analysis, then descriptive statistics only will be presented for 
those particular subgroups. 
Note that these analyses will be performed on the randomization strata. 
4.11. 
Pharmacokinetic Analyses 
Pharmacokinetic (PK) analyses will be described in a separate analysis plan. 
4.12. 
Pharmacodynamic Analyses 
Pharmacodynamic (PD) analyses may include evaluation of gene expression as well as 
circulating protein and micro- ribonucleic acid (RNA) biomarkers that help inform target 
engagement and efficacy. These assessments and blood samples will be collected at the times 
specified in Table 1.  
Descriptive statistics will be presented by treatment group for applicable PD endpoints and will 
be included as an appendix to the CSR (note: PD data may not be available at the time of 
database lock). 
4.13. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population. Results of all safety assessments 
will be listed by patient, and summarized by treatment group and time point as applicable. These 
safety analyses will be compared qualitatively between treatment groups; however, there will be 


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no inferential statistical comparisons between groups (except for specific analyses, noted 
below).  
4.13.1. 
Adverse Events 
Adverse events will be coded using the MedDRA dictionary and displayed in tables and listings 
using System/Organ/Class (SOC) and Preferred Term (PT). 
Analyses of adverse events will be performed for those events that are considered TEAEs, 
where treatment emergent is defined as any adverse event with onset after the administration of 
study medication through the end of the study (Week 52 visit) or any event that was present at 
Baseline but worsened in intensity or was subsequently considered drug-related by the 
investigator through the end of the study.  
If the start date of an AE is partially or completely missing, then the date will be compared as 
far as possible with the date of the randomization. The AE will be assumed to be treatment 
emergent if it cannot be definitively shown that the AE did not occur or worsen during the post-
randomization period (worst case approach).  
The following general rules will be used: 
• If the start day is missing, but the start month and year are complete, an AE will only be 
excluded as being on-study if the start month/year is before the month/year of 
randomization or if the stop date is before randomization.  
• If the start day and month are missing, but the start year is complete, an AE will only be 
excluded as being on-study if start year is before the year of randomization or if the stop 
date is before randomization.  
• If the start date is completely missing, an AE will be considered on-study unless the stop 
date is before randomization. 
TEAE summaries will include the number and percentage of patients in each treatment group 
and overall. Summaries will include patients with: 
• Any TEAEs 
• Treatment-related TEAEs (Related, Possibly related) 
• Maximum Severity of TEAEs 
• Serious TEAEs, including any events resulting in death 
• Treatment-related serious TEAEs 
• TEAEs (and treatment-related TEAEs) leading to discontinuation of study drug 
TEAEs are summarized by patient incidence rates, therefore, in any tabulation, a patient 
contributes only once to the count for a given adverse event (SOC or preferred term). TEAEs 
will also be summarized by SOC, PT, and severity and by SOC, PT, and relatedness. The most 
severe occurrence of a TEAE, as well as the most extreme relationship of the TEAE to the study 
procedure or treatment, will be used in tabulations of severity and relatedness in cases of 
multiple occurrences of the same TEAE. 
Additionally, the prevalence of common treatment-related TEAEs will be summarized by 
treatment group and overall across the treatment period stratified into 4-week intervals. A 
common treatment-related TEAE is one which occurs in over 10% of the patients in either 
treatment group. The objective of this analysis is to determine the time course of the incidence 
of these TEAEs. The following are the 13 4-week intervals: 


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1) Baseline – Week 4 (i.e., Day 1 – Day 28) 
2) Week 5 – Week 8 (i.e., Day 29 – Day 56)  
3) Week 9 – Week 12 (i.e., Day 57 – Day 84)  
4) Week 13 – Week 16 (i.e., Day 85 – Day 112)  
5) Week 17 – Week 20 (i.e., Day 113 – Day 140)  
6) Week 21 – Week 24 (i.e., Day 141 – Day 168)  
7) Week 25 – Week 28 (i.e., Day 169 – Day 196)  
8) Week 29 – Week 32 (i.e., Day 197 – Day 224)  
9) Week 33 – Week 36 (i.e., Day 225 – Day 252)  
10) Week 37 – Week 40 (i.e., Day 253 – Day 280)  
11) Week 41 – Week 44 (i.e., Day 281 – Day 308)  
12) Week 45 – Week 48 (i.e., Day 309 – Day 336)  
13) Week 49 – Week 52 (i.e., Day 337 – Day 364)  
For each interval, the percentage of patients with the treatment-related TEAE in the interval will 
be presented. For each interval, the denominator for the percentage will be the number of 
patients who were in the study for any part of that period (i.e., patients who discontinued from 
the study prior to the start of the interval will be excluded). For each related TEAE, a patient 
will be included in the numerator if any of the following criteria are met: 
• The start date of the TEAE is in the interval 
• The stop date of the TEAE is in the interval 
• The start date of the TEAE is before the interval and the stop date is after the interval  
• The start date of the TEAE is before the interval and TEAE is ongoing 
Note: For this prevalence TEAE analysis, if the start day and/or month of the AE is missing, 
a value of 01 for the day and January for the month will be used. If the stop day and/or 
month of the AE is missing, December will be used for the month and the last day of the 
month will be used for the day. 
All adverse events occurring on study will be listed in patient data listings. 
By-patient listings also will be provided for the following: patient deaths; serious adverse 
events; and adverse events leading to discontinuation of study drug. 
4.13.2. 
Physical Examination and Growth Parameters 
Physical examination (general appearance; skin; head, ears, eyes, nose, and throat [HEENT]; 
etc.) results will be summarized in a shift table from Baseline, and abnormal results will also be 
summarized. 
Growth Parameters (height, weight, body mass index [BMI]) will be summarized by age-
normative z-scores. The age-normative height, weight, and BMI scores will be based on a 
Centers for Disease Control and Prevention (CDC) SAS macro which calculates the percentiles 
and z-scores for a child’s sex and age. 
The CDC SAS macro is found here (date accessed: 08Sep2019): 


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https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
These summaries will be performed on the Safety Population. 
4.13.3. 
Laboratory Data 
Values at all study time points and changes from Baseline to post-Baseline time points in 
clinical chemistry, hematology and urinalysis results will be summarized descriptively.  
Abnormal clinical laboratory values will be identified as outside (above or below) the normal 
range and will be evaluated for clinically notable abnormalities.  
All laboratory data and normal ranges will be provided in data listings. A subset listing will be 
presented for all abnormal laboratory values (i.e., values which are indicated as being notable or 
critical low/high). 
The following abbreviations for flags in the central lab database. 
• L: Reference Low  
• NL: Notable Low  
• CL: Critical Low  
• R: Rechecked Value 
• H: Reference High  
• NH: Notable High  
• CH: Critical High 
 
In addition, to assess decreases in creatine kinase (CK), the change from baseline in CK will be 
assessed at each scheduled assessment visit using a non-parametric signed rank test (for a 
within-group comparison) and a Wilcoxon rank sum test for the comparison of edasalonexent 
versus placebo. 
4.13.4. 
Vital Signs  
The actual value and change from Baseline will be summarized for vital signs (temperature, 
heart rate, respiratory rate, and systolic and diastolic blood pressure) descriptively at Baseline 
and other study time points.  
By-patient listings of vital sign measurements will also be provided. 
4.13.5. 
Electrocardiogram 
ECG results will be summarized descriptively, including the number and percent of patients 
with normal, abnormal, and clinically significant abnormal results at Baseline and each study 
time point.  
In addition, an ANCOVA model including CFB in various ECG parameters at Week 52 (i.e., 
corrected QT [Bazett and Fridericia], RR interval, PR interval, QRS duration, Heart Rate) as the 
dependent variable, treatment as a fixed effect, and baseline ECG parameter value, will be used 
to assess the treatment difference in the ECG parameters at Week 52.  
Treatment group differences in heart rate will be compared via an MMRM ANCOVA model 
with treatment, baseline heart rate, visit, visittreatment (interaction term), and baseline heart 


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ratetreatment (interaction term) as fixed effects and patient as a random effect. In this model, 
visit is a categorical variable, treatment is a dichotomous variable, and baseline heart rate is a 
continuous variable. This analysis will be performed on the Safety Population.  
This repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured covariance structure to model the within-patient errors. A Kenward-
Roger approximation will be used for the denominator degrees of freedom. If there is a 
convergence problem due to the unstructured covariance matrix, a compound symmetry 
covariance structure will be used to model the within-patient variance; if the compound 
symmetric covariance structure fails to converge, a variance components approach will be 
applied. 
All ECG data for each patient will be provided in data listings. 
4.13.6. 
Cardiac Monitoring 
Measures of cardiac autonomic dysfunction, including heart rate variability, will be measured at 
Screening, Week 26, and Week 52. Cardiac monitoring will be performed for approximately 48 
hours remotely via a wearable cardiac monitoring device if approved for use in the participating 
country. Cardiac monitoring data analysis methods will be provided in a separate analysis plan. 
4.13.7. 
Bone Evaluation 
Lateral thoracolumbar spine radiography scans and Dual-energy X-ray absorptiometry (DXA) 
scans will be performed at Baseline and Week 52. In Germany, bone assessment will not be 
performed until the respective approvals from the German Federal Office for Radiation 
Protection become available. Bone radiography will be locally read and centrally evaluated. 
Bone evaluation data analysis methods will be provided in a separate analysis plan. 
4.13.8. 
Prior and Concomitant Medications and Therapeutic Procedures 
Prior and concomitant medications and therapeutic procedures will be coded using the WHO 
Drug dictionary. Results will be tabulated by Anatomic Therapeutic Class (ATC; level 4) and 
preferred term. 
Prior medications are those that started and stopped before exposure to study medication (i.e., 
date of first dose); concomitant medications are all medications taken during the study period, 
including those started before but on going at first dose. Where a medication start date is 
partially or fully missing, and it is unclear as to whether the medication is prior or concomitant, 
it will be assumed that it is concomitant. 
The use of concomitant medications will be included in a by-patient data listing and 
summarized in a table. The use of prior medications and therapeutic procedures will be included 
in by-patient data listing. 
Additionally, a by-patient listing of concomitant medications that started or stopped during the 
treatment period will be created, specifically indicating the following: 
• Treatment Group 
• Patient ID: 
• Medication Name/Preferred Term/ATC Term Modification: 
• Indication 


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• Start/Stop Date (ongoing) 
• Dose (unit) 
• Frequency/Route 
The determination of a medication starting or stopping with the treatment period will be based 
on the following:  
• Date of First Exposure to Treatment ≤ Date of medication start date ≤ Date of Last 
Exposure to Treatment 
(i.e., ADCM.TRTSDT ≤  ADCM. ASTDT ≤ ADCM.TRTEDT) 
The following general rules will be used for partially missing medication start dates: 
o If the start day is missing, but the start month and year are complete, the medication 
will be considered as having started during the treatment period if the month/year is 
between the treatment start/stop month/year values (inclusive). 
o If the start day and month are missing, but the start year is complete, the medication 
will be considered as having started during the treatment period if the year is 
between the treatment start/stop year values (inclusive).  
o If the start date is completely missing, the medication will not be considered as 
having started in the treatment period. 
 
• Date of First Exposure to Treatment ≤ Date of medication stop date ≤ Date of Last 
Exposure to Treatment 
(i.e., ADCM.TRTSDT ≤  ADCM. AENDT ≤ ADCM.TRTEDT) 
The following general rules will be used for partially missing medication stop dates: 
o If the stop day is missing, but the stop month and year are complete, the medication 
will be considered as having stopped during the treatment period if the month/year is 
between the treatment start/stop month/year values (inclusive). 
o If the stop day and month are missing, but the stop year is complete, the medication 
will be considered as having stopped during the treatment period if the year is 
between the treatment start/stop year values (inclusive).  
o If the stop date is completely missing, the medication will not be considered as 
having stopped in the treatment period. 
 
Note: Here ADCM refers to the ADaM concomitant medications dataset. The words 
after “ADCM.” indicate variables in the ADaM concomitant medications dataset. 


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5. 
COVID-19 ASSESSMENTS AND RELATED ANALYSES 
The following sections describe the COVID-19 related assessments collected and additional 
analyses to address the potential impact of COVID-19. 
  
 
5.1. 
COVID-19 Site-Level Assessments 
The following site-level information will be listed for each site impacted by COVID-19.  
• Site Number 
• Site Name 
• Trial Activities Impacted by COVID: Yes, No 
• Site Closed to Research: Yes/No 
• Start/Stop Dates of Closure 
• Site Open but Limited Capacity: Yes, No, NA 
• Start/Stop Dates at Limited Capacity 
This information will be collected by the sponsor and provided in an excel spreadsheet for 
incorporation into the database. Only sites impacted by COVID-19 will be included. 
5.2. 
COVID-19 Patient-Level Listings 
The following data will be listed to provide patient-level information on which assessments 
were impacted by COVID-19.  
• Patient ID 
• Visit Week 
• Reason for Impact: This information will be collected via discussions with the site (and 
provided by the sponsor for incorporation into the database) examples of the responses 
will include: 
o Patient Discretion due to COVID 
o Site closed due to COVID 
o Travel Restrictions due to COVID 
o Reduced Capacity due to COVID 
• Out of window visit:  
o Yes, No 
A visit will be considered out of window if the difference between the date of visit and 
the scheduled date is outside of the  10 day window. The scheduled dates for the Week 
26, 39, and 52 visits, are 182, 273, and 364 days from the patient’s date of 
randomization, respectively. For this determination the date of NSAA assessment will be 


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used. If that date is missing, the date of the visit (i.e., from the DOV SAS dataset) will be 
used.  
• Remote Visit:  
o Yes, No 
This will be determined by the “Telehealth Contact” variable in the Date of Visit eCRF 
page (i.e., Telehealth Contact value of “Yes” = Remote Visit = “Yes”; Telehealth 
Contact value of “No” = Remote Visit = “No”). Note for Week 26 this information will 
be provided in the spreadsheet (i.e., the “Remote Visit” Column).  
• Re-supply Study Drug:  
o Yes, No 
This will be determined by the “Re-supply Study Drug” variable in the Date of Visit 
eCRF page. Note for Week 26 this information will be provided in the spreadsheet (i.e., 
the “Re-supply” column). 
• Safety Lab:  
o Yes, No 
This will be determined by the “Safety Labs” variable in the Date of Visit eCRF page. 
Note for Week 26 this information will be provided in the spreadsheet (i.e., the “Safety 
Labs” column).  
• Local Lab:  
o Yes, No 
This will be determined by the SAS variable LB.LOCALYN (i.e., from the eCRF 
Central Laboratory page “Were local labs used for this visit?”). Note for Week 26 this 
information will be provided in the spreadsheet (i.e., the “Local Labs” column). 
• Height Collected, Weight Collected: 
o Yes, No 
If the patient’s height (weight) is non-missing for this visit, the value will be “Yes”, 
“No” otherwise 
• Remote Efficacy:  
o Yes, No 
This will be determined by the “Remote Efficacy” variable in the Date of Visit eCRF 
page; a value of “Yes” indicates a response of “Remote”, a value of “No” indicates 
“Site”. Note there is no remote efficacy at Week 26 (i.e., for Week 26 Remote Efficacy 
= “No” should be populated in the listing).  
• NSAA Performed, 10 MWT Performed, 4SC Performed, TTS Performed, Muscle 
Strength Performed: 
o Yes, No 


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These variables will be determined by the “was the test performed variables” listed 
below: 
Assessment  
SAS Variable 
NSAA Performed 
MK_NSAA. MKPERF  
10 MWT Performed 
MK_TFT.WT_MKPERF  
4SC Performed 
MK_TFT.SCT_MKPERF 
TTS Performed 
MK_TFT.RFS_MKPERF  
Muscle Strength Performed 
MK_MST. MKPERF 
PODCI Performed 
QS_PODCI.QSPERF 
• PE Collected, ECG Collected, PK Collected, Biomarkers Collected, Cardiac Monitoring 
Performed, DXA Performed, Spine Films Performed: 
o Yes, No 
These variables will be determined by the “was the test performed variables” listed 
below: 
Assessment  
SAS Variable 
PE Collected 
PE.PEPERF  
ECG Collected 
EG.EGPERF  
PK Collected 
PC_BL.PCPERF 
Biomarkers Collected 
PC_PD.PCPERF 
Cardiac Monitoring Performed 
FA_CM. FAPERF 
DXA Performed 
PR_DXA. PROCCUR 
Spine Films Performed 
PR_LSR.PROCCUR 
There is also a comment field.  
Only assessments impacted by COVID-19 will be included.  
5.3. 
COVID-19 Analyses 
The primary and secondary efficacy analysis (Sections 4.10.1 and 4.10.2) will be repeated for 
the following two sensitivity analyses (i.e., a total of 8 new analyses: 2 sensitivity analyses 
across the primary and 3 secondary endpoints).  
1) Excluding all remote efficacy assessments 
2) Excluding all assessments which occurred during the time period the patient’s site was 
closed.  


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6. 
CHANGES TO PLANNED ANALYSES 
The following are changes to the planned analyses as specified in the 16APR2020 version of the 
protocol: 
• The MMRM model for the primary and secondary endpoint analyses was updated to 
include baseline covariate by study visit interaction terms and the Baseline age and 
Baseline time to stand are continuous variables (as specified in Section 4.10.1). 
• An additional endpoint was added, the CFB rank sum score at Week 52. This endpoint is 
designed to assess the effect of edasalonexent versus placebo across multiple endpoints 
using a non-parametric rank-based approach. The endpoint is the sum of the ranks of the 
following Week 52 CFB scores: NSAA, 10MWT speed, stand from supine speed, 4-stair 
climb speed, and PODCI transfer and basic mobility scale. 
 
 


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7. 
REFERENCES 
American Academy of Orthopaedic Surgeons (1997). Pediatric Orthopaedic Society of North 
America. American Academy of Pediatrics. Shriners Hospitals. Scoring Algorithms for 
Pediatrics Outcomes Data Collection Instrument. 2.0 ed. 
Henricson, E., R. Abresch, et al. (2013). "The 6-minute walk test and person-reported outcomes 
in boys with duchenne muscular dystrophy and typically developing controls: longitudinal 
comparisons and clinically-meaningful changes over one year." PLoS Curr 5. 
O'Brien (1984). "Procedures for Comparing Samples with Multiple Endpoints." (Biometrics 
40): 1079-1087. 
Pane, M., G. Coratti, et al. (2018). "Upper limb function in Duchenne muscular dystrophy: 24 
month longitudinal data." PLOS ONE 13(6): e0199223. 
Smith, C., Kosten S. (2017). "Multiple Imputation: A Statistical Programming Story." 
PharmaSUG: 2017 - Paper SP2001. 
Yuan, Y. (2014). "Sensitivity Analysis in Multiple Imputation for Missing Data." SUGI paper: 
SAS270-2014. 
 
 
 
 
 


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8. 
CLINICAL STUDY REPORT APPENDICES 
The set of tables and listings along with the corresponding shells will be provided in a separate 
document.