Clinical trial NCT04336826
Conditions: Nonsene Mutation Duchenne Muscular Dystrophy
Sponsor: PTC Therapeutics
Start date: 2021-12-29; Completion date: 2023-08-07
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate safety, tolerability, and pharmacokinetics (PK) in male children with nmDMD aged ≥6 months to \<2 years treated daily for 24 weeks with orally administered ataluren 10, 10, and 20 milligrams/kilogram (mg/kg) (morning, mid-day, and evening dose, respectively).

Detailed description:
Participants who complete the 24-week treatment period in this study will be offered participation to a follow-up extension period for at least 52 weeks from the date of first administration of ataluren in this parent study.

Arms: arm 1: Participants will receive ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 24 weeks.
Interventions: intervention 1: Ataluren
Intervention descriptions: intervention 1: Ataluren will be administered as per the dose and schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
V4.0 
PTC Therapeutics - Confidential 
Page 1 of 62 
CLINICAL PROTOCOL 
AN OPEN-LABEL STUDY EVALUATING THE SAFETY AND 
PHARMACOKINETICS OF ATALUREN IN CHILDREN FROM 
≥6 MONTHS TO <2 YEARS OF AGE WITH NONSENSE MUTATION 
DUCHENNE MUSCULAR DYSTROPHY 
PTC124-GD-048-DMD 
06 MAY 2022 
VERSION 4.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #: NCT04336826


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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC124-GD 
Therapeutic Area  
Genetic Disorders - Duchenne Muscular Dystrophy 
PTC Therapeutics Substance Identifier 
Ataluren (PTC124) 
IND Number 
068431 
NCT Number 
04336826 
EudraCT Number 
2020-000980-21 
Protocol Number 
PTC124-GD-048-DMD 
Protocol Version 
Version 4.0 
Protocol Version Date 
06 May 2022 
Protocol Phase 
Phase 2 
Protocol Title 
An Open-Label Study Evaluating the Safety and 
Pharmacokinetics of Ataluren in Children From 
≥6 Months to <2 Years of Age with Nonsense 
Mutation Duchenne Muscular Dystrophy 
PTC Clinical Lead 
 
 
PTC Therapeutics, Inc. 
 
100 Corporate Court 
 
South Plainfield, NJ 07080 USA 
 
Tel. (office): 
 
 
Fax.: 
 
 
E-mail:
  
PTC Medical Monitor 
 
 
PTC Therapeutics, Inc. 
 
100 Corporate Court 
 
South Plainfield, NJ 07080 USA 
 
Tel. (office): 
 
 
Fax.: 
 
 
E-mail: 
 
PTC Biostatistician 
 
 
PTC Therapeutics, Inc. 
 
100 Corporate Court 
 
South Plainfield, NJ 07080 USA 
 
Tel. (office): 
 
 
Fax.: 
 
 
E-mail:
 
PTC Study Manager 
 
 
PTC Therapeutics, Inc. 
 
100 Corporate Court 
 
South Plainfield, NJ 07080 USA 
 
Tel. (office): 
 
 
E-mail: 
 


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PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
The Signature Page is located on the last page. 


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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the protocol 
and all applicable regulations. 
 
 
 
 
Principal Investigator Full Name & Signature 
 
Date 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province: 
 
Country: 
 
Phone: 
 
Fax: 
 
E-mail: 
 
 
 
 


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SYNOPSIS 
Name of Sponsor/Company PTC Therapeutics 
Study Number 
PTC124-GD-048-DMD 
Name of Investigational 
Product 
Ataluren (PTC124) 
Title of Study 
An Open-Label Study Evaluating the Safety and 
Pharmacokinetics of Ataluren in Children From ≥6 Months to 
<2 Years of Age with Nonsense Mutation Duchenne Muscular 
Dystrophy 
Proposed Indication 
For the treatment of nonsense mutation Duchenne muscular 
dystrophy (nmDMD) in children <2 years of age 
Number of Study Sites  
≤3 sites 
Trial Phase  
Phase 2 
Study Objectives 
Primary 
• To assess the safety and tolerability of ataluren in 
male children with nmDMD aged ≥6 months to 
<2 years old 
Secondary 
• To assess the pharmacokinetics (PK) of ataluren in 
male children with nmDMD aged ≥6 months to 
<2 years old 
Exploratory 
• To assess changes from baseline in creatine kinase 
(CK) levels 
Study Endpoints 
Primary 
• Overall safety profile of ataluren in terms of type, 
frequency, severity, seriousness, timing, and 
relationship to study therapy of any 
treatment-emergent adverse event (TEAE) during the 
24 weeks of treatment 
Secondary 
• Evaluation of PK parameters after 24 weeks of 
treatment as follows:  
− Area under the concentration curve from a time 
of 0 to 24 hours post first morning dose 
(AUC0-24) and AUC between dose 
interval (AUC0-τ) 
− Tmax 
− Cmax 
− Trough concentration (Plasma concentration pre 
morning dose) (Ctrough) 
Exploratory 
• Change from baseline in CK levels after 24 weeks of 
treatment 
Study Population 
Male subjects with nmDMD aged ≥6 months to <2 years 


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Sample Size 
Up to 10 subjects (minimum of 6 subjects) 
Methodology/Study Design Study 048 is a Phase 2, open-label study to evaluate safety, 
tolerability, and PK of ataluren in male children with nmDMD 
aged ≥6 months to <2 years of age treated TID for 24 weeks 
with orally administered ataluren 10, 10, 20 mg/kg (morning, 
mid-day, and evening dose, respectively). 
Safety evaluations will include TEAEs, serious adverse events 
(SAEs), adverse events (AEs) leading to discontinuation, 
laboratory evaluations, EGCs, vital signs, and physical 
examination.  
The study will include 3 PK profile assessments (baseline, 
Week 4, and end of treatment at Week 24). At these visits, PK 
parameters will be investigated based on blood sampling at 
pre-dose, and 1-, 2-, 3-, and 4-hours post-dose following both 
the morning and mid-day ataluren doses, and immediately 
pre-dose, and 1-, 2-, 3-, 4- and 12- (before the next day 
morning dose) hours post-dose following the evening dose.  
The PK parameters, including AUC0-24 and AUC0-τ, Tmax, Cmax, 
Ctrough will be assessed after each dose. If feasible, apparent 
clearance (CL/F), and T1/2 will also be assessed after each dose. 
 
Main Inclusion Criteria  
1. 
Signed and dated informed consent document 
indicating that the parent(s)/caregivers(s) of the 
subject has been informed of all pertinent aspects of 
the study prior to initiation of any study-related 
procedures. 
2. 
Males ≥6 months to <2 years of age.  
3. 
Body weight ≥7.5 kg 
4. 
Willingness and ability of the subject’s 
parent/caregiver to comply with scheduled visits, 
drug administration plan, study procedures, and study 
restrictions. 
5. 
Diagnosis of Duchenne muscular dystrophy (DMD) 
based on an elevated serum CK and genotypic 
evidence of dystrophinopathy.  
6. 
Documentation of the presence of a nonsense 
mutation of the dystrophin gene as determined by 
gene sequencing confirmed by a PTC 
Therapeutics (PTC) designee is required prior to 
enrollment. 


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Main Exclusion Criteria 
1. 
Subject who is participating in any drug or device 
clinical investigation (or whose sibling is currently 
participating in a blinded portion of another ataluren 
study) or received an investigational drug within 
3 months prior to the Screening Visit or who 
anticipate participating in any other drug or device 
clinical investigation or receiving any other 
investigational drug within the duration of this study. 
2. 
Expectation of a major surgical procedure during the 
study period. 
3. 
Prior or ongoing medical condition, medical history, 
physical findings, or laboratory abnormality that, in 
the Investigator’s opinion, will adversely affect the 
safety of the subject, or will make it unlikely that the 
course of study drug administration or follow-up will 
be completed, or will impair the assessment of study 
results. 
4. 
Known hypersensitivity to any of the ingredients or 
excipients of the study drug (polydextrose, 
polyethylene glycol 3350, poloxamer 407, mannitol 
25C, crospovidone XL10, hydroxyethyl cellulose, 
vanilla, colloidal silica, or magnesium stearate). 
5. 
Ongoing use of the following drugs: 
a. 
Systemic aminoglycoside therapy and/or 
intravenous vancomycin. 
b. 
Coumarin-based anticoagulants (eg, warfarin), 
phenytoin, tolbutamide, or paclitaxel. 
c. 
Inducers of UGT1A9 (eg, rifampicin), or 
substrates of OAT1 or OAT3 (eg, ciprofloxacin, 
adefovir, oseltamivir, aciclovir, captopril, 
furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin).  


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Study Treatment 
All subjects will receive 10, 10, 20 mg/kg ataluren TID in the 
morning, at mid-day, and in the evening, respectively, for 
24 weeks. 
Study Drug Description: Ataluren will be provided as white to 
off-white granules for oral suspension. The granules for oral 
suspension are packaged in aluminum foil, child-resistant 
sachets and supplied in dose strengths containing 125 or 250 mg 
of the active drug substance.  
Study Drug Storage and Preparation:  
Entire content of the sachets: Study drug sachets should be 
stored at labeled storage conditions until time of reconstitution. 
For administration, the powder in the sachet may be mixed with 
water, milk (skim, 1% fat, 2% fat, whole milk, chocolate milk, 
or lactose free milk), breast milk, fruit juice, or fruit punch, or in 
semi-solid food (yogurt, pudding, or applesauce). 
For subjects with body weight <10 kg, a NeoMed oral dosing 
syringe (12 mL) will be used to administer an aliquot of a 
25 mg/mL concentration suspension in water or milk, including 
breast milk. Ataluren remains stable for up to 1 hour at ambient 
temperature in the NeoMed oral syringe.  
For subjects with body weight ≥10 kg, the full contents of each 
sachet should be well-mixed with at least 30 mL (1 ounce) of 
liquid, or 3 tablespoons of semi-solid food. Please reference the 
dosing instructions for further information.  
The constituted ataluren suspension may be kept for up to 
24 hours under refrigeration or 3 hours at room temperature. 
Treatment Duration 
This study includes a 4-week screening period followed by 
24 weeks of treatment with ataluren.  
PTC will ensure that subjects who complete the 24-week 
treatment period are offered participation to a follow-up 
extension period for at least 52 weeks from the date of first 
administration of ataluren in this parent study. The subjects 
who roll over into the extension study will be followed-up for 
long-term safety and efficacy as an exploratory endpoint. 
Safety Monitoring 
Subjects will be monitored closely for AEs, vitals, and 
laboratory and electrocardiogram abnormalities during the 
study.  
Serious Adverse Event 
Reporting 
All SAEs should be reported via the SAE report form to PTC 
within 24 hours of becoming aware of the event(s). 


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Pharmacokinetic Sampling Blood sampling for PK will occur at baseline, Week 4, and end 
of treatment at Week 24.  
On each of these days, blood samples for ataluren PK 
assessments will be collected immediately pre-dose and at 1-, 2-, 
3-, and 4-hours post-dose following both the morning and 
mid-day doses, and immediately pre-dose and 1-, 2-, 3-, 4- and 
12 (before the next day morning dose) hours post-dose 
following the evening dose. 
Blood/plasma partition will be determined at baseline, Week 4, 
and end of treatment at Week 24. Blood samples will be 
collected at 2.5 hours and 4.5 hours post morning dose. 
Statistical Methods 
All subjects who receive ≥1 dose of ataluren will be included in 
the safety analyses. All subjects who receive ≥1 dose of 
ataluren and have at least 1 PK concentration datum will be 
included in the PK population. 
Subject characteristics at study entry will be summarized with 
frequency tables for categorical variables and with descriptive 
statistics, as appropriate, for quantitative variables. 
Frequencies of TEAEs will be tabulated by Medical Dictionary 
of Regulatory Activities System Organ Class, Preferred Term, 
severity, timing, outcome of the event, relationship to study 
drug, and seriousness. 
Timing of Assessments 
See Schedule of Assessments (Table 2, Section 7.1) 


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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................2 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................3 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE............................................4 
SYNOPSIS 5 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Investigational Product ...............................................................................................17 
1.2. 
Nonclinical Findings ...................................................................................................18 
1.3. 
Risk/Benefit Assessment ............................................................................................18 
1.3.1. 
Clinical Studies ...........................................................................................................18 
1.3.2. 
Risk-Benefit Conclusion .............................................................................................20 
2. 
STUDY OBJECTIVE AND ENDPOINTS ................................................................21 
2.1. 
Objectives ...................................................................................................................21 
2.1.1. 
Primary Objective .......................................................................................................21 
2.1.2. 
Secondary Objective ...................................................................................................21 
2.1.3. 
Exploratory Objective .................................................................................................21 
2.2. 
Endpoints ....................................................................................................................21 
2.2.1. 
Primary Endpoint ........................................................................................................21 
2.2.2. 
Secondary Endpoint ....................................................................................................21 
2.2.3. 
Exploratory Endpoints ................................................................................................21 
3. 
STUDY DESIGN .......................................................................................................22 
3.1. 
Overall Design ............................................................................................................22 
3.2. 
Scientific Rationale for Study Design ........................................................................22 
3.3. 
Justification of Dose ...................................................................................................22 
4. 
STUDY POPULATION .............................................................................................23 
4.1. 
Overview .....................................................................................................................23 
4.2. 
Inclusion Criteria ........................................................................................................23 
4.3. 
Exclusion Criteria .......................................................................................................23 
4.4. 
Strategies for Recruitment and Retention ...................................................................24 
5. 
STUDY INTERVENTION ........................................................................................25 


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5.1. 
Study Intervention Administration .............................................................................25 
5.1.1. 
Study Intervention Description ...................................................................................25 
5.1.2. 
Dosing and Administration .........................................................................................25 
5.1.2.1. 
Dose and Dosing Regimen .........................................................................................25 
5.1.2.2. 
Dose Adjustments and Modifications .........................................................................25 
5.1.2.3. 
Schedule of Drug Administration ...............................................................................25 
5.1.2.4. 
Instructions for Delays in Dosing ...............................................................................26 
5.1.2.5. 
Overdose Precautions .................................................................................................26 
5.1.2.6. 
Hydration ....................................................................................................................26 
5.1.3. 
Formulation .................................................................................................................27 
5.1.4. 
Packaging and Labeling ..............................................................................................27 
5.1.5. 
Study Drug Preparation and Storage ..........................................................................27 
5.1.6. 
Study Drug Accountability .........................................................................................28 
5.2. 
Measures to Minimize Bias: Randomization and Blinding ........................................28 
5.3. 
Study Intervention and Compliance ...........................................................................28 
5.4. 
Concomitant Therapy .................................................................................................29 
5.4.1. 
Concomitant Use of Corticosteroids ...........................................................................29 
5.4.2. 
Concomitant Use of Systemic Aminoglycoside Therapy and/or Intravenous 
Vancomycin ................................................................................................................29 
5.4.3. 
Coumarin-Based Anticoagulants ................................................................................30 
5.4.4. 
Inducers of UGT1A9 or Substrates of OAT1, OAT3, or OATP1B3 .........................30 
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................32 
6.1. 
Discontinuation of Study Intervention ........................................................................32 
6.2. 
Participant Discontinuation/Withdrawal from the Study............................................32 
6.2.1. 
Collection of Data from Withdrawn Subjects.............................................................32 
6.2.2. 
Subject Replacement ..................................................................................................32 
6.2.3. 
Subject Follow-Up ......................................................................................................33 
7. 
STUDY ASSESSMENTS AND PROCEDURES......................................................34 
7.1. 
Schedule of Events and Study Parameters ..................................................................34 
7.1.1. 
Screening (Visit 1) ......................................................................................................37 
7.1.2. 
Baseline/ Start of Treatment (Visit 2) .........................................................................37 
7.1.3. 
Treatment Phase (Visits 3-4) ......................................................................................37 


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7.1.4. 
End of Treatment/Early Termination (Visit 5) ...........................................................37 
7.1.5. 
Post-treatment Follow-Up/End of Study (Visit 6) ......................................................38 
7.1.6. 
Unscheduled Visits .....................................................................................................38 
7.2. 
Eligibility Procedures .................................................................................................38 
7.2.1. 
Informed Consent .......................................................................................................38 
7.2.2. 
Medical History ..........................................................................................................38 
7.2.3. 
Demographic Information ..........................................................................................38 
7.3. 
Safety Assessments .....................................................................................................38 
7.3.1. 
Physical Examination .................................................................................................38 
7.3.2. 
Clinical Laboratory Assessments (hematology, biochemistry, urinalysis) ................39 
7.3.3. 
Confirmatory Gene Sequencing .................................................................................39 
7.3.4. 
Pharmacokinetic Assessment ......................................................................................39 
7.3.5. 
Weight, Height, and Body Mass Index .......................................................................40 
7.3.6. 
Vital Signs ..................................................................................................................40 
7.3.7. 
Electrocardiogram .......................................................................................................40 
7.3.8. 
Adverse Events/Serious Adverse Events ....................................................................40 
7.3.9. 
Concomitant Medications ...........................................................................................40 
7.4. 
Study Drug Administration Procedures ......................................................................40 
7.4.1. 
Study Drug Administration .........................................................................................40 
7.5. 
Laboratory Procedures/ Sample Preparation, Handling, Storage and 
Shipment .....................................................................................................................41 
7.5.1. 
Blood Collection Summary ........................................................................................41 
7.6. 
Adverse Events and Serious Adverse events ..............................................................41 
7.6.1. 
Definition of Adverse Events .....................................................................................41 
7.6.2. 
Definition of Serious Adverse Events ........................................................................42 
7.6.3. 
Unexpected Adverse Events .......................................................................................43 
7.6.4. 
Eliciting Adverse Event Information ..........................................................................43 
7.6.5. 
Recording Nonserious Adverse Events and Serious Adverse Events ........................43 
7.6.6. 
Describing Adverse Event Relationship to Study Drug .............................................44 
7.6.7. 
Grading of Severity of Adverse Events ......................................................................45 
7.6.8. 
Adverse Event Reporting ............................................................................................45 
7.6.9. 
Serious Adverse Event Reporting ...............................................................................46 
7.6.10. 
Reporting Pregnancy ..................................................................................................46 


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7.6.11. 
PTC Therapeutics Adverse Event Reporting Requirement ........................................47 
7.6.12. 
Describing Outcome of Adverse Event ......................................................................47 
7.6.13. 
Follow-up of Unresolved Adverse Events ..................................................................47 
8. 
STATISTICAL METHODS AND DATA ANALYSIS ............................................48 
8.1. 
Statistical Methods ......................................................................................................48 
8.2. 
Sample Size Determination ........................................................................................48 
8.3. 
Statistical Significance ................................................................................................48 
8.4. 
Population for Analyses ..............................................................................................48 
8.5. 
Specific Planned Statistical Analyses .........................................................................48 
8.5.1. 
Subject Disposition and Baseline Characteristics .......................................................48 
8.5.2. 
Use of Concomitant Medication and Supportive Therapy .........................................48 
8.5.3. 
Primary Variables – Safety .........................................................................................49 
8.5.4. 
Secondary Variables - PK Parameters ........................................................................49 
8.5.4.1. 
PK Analysis Methods .................................................................................................50 
8.5.5. 
Other Variables ...........................................................................................................50 
8.5.5.1. 
Vital Signs and Physical Examination ........................................................................50 
8.5.5.2. 
Laboratory Values ......................................................................................................50 
8.5.5.3. 
Electrocardiogram .......................................................................................................50 
8.5.6. 
Treatment Administration and Drug Compliance ......................................................50 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................51 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................51 
9.1.1. 
Informed Consent Process ..........................................................................................51 
9.1.2. 
Study Discontinuation and Closure ............................................................................51 
9.1.3. 
Confidentiality and Privacy ........................................................................................52 
9.1.4. 
Clinical Monitoring ....................................................................................................52 
9.1.5. 
Ethical Conduct of the Study ......................................................................................52 
9.1.6. 
Study Discontinuation and Closure ............................................................................53 
9.1.7. 
Quality Assurance and Quality Control ......................................................................53 
9.1.8. 
Institutional Review Board/Independent Ethics Committee ......................................53 
9.1.9. 
Data Handling and Record Keeping ...........................................................................54 
9.1.10. 
Case Report Forms .....................................................................................................54 
9.1.11. 
Protocol Deviations ....................................................................................................54 


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9.1.12. 
Publication and Data Sharing Policy ..........................................................................55 
9.2. 
Additional Considerations ..........................................................................................56 
9.3. 
Protocol Amendment History .....................................................................................56 
9.3.1. 
Amendment 1: 29 April 2021 (Version 2.0) ...............................................................56 
9.3.2. 
Amendment 2: 01 July 2021 (Version 3.0) ................................................................60 
9.3.3. 
Amendment 3: 06 May 2022 (Version 4.0) ................................................................60 
10. 
REFERENCES ...........................................................................................................61 
 
LIST OF TABLES 
Table 1: 
Suggested Daily Dosing .............................................................................................26 
Table 2: 
Schedule of Assessments ............................................................................................35 
Table 3: 
Summary of Estimated Total Blood Volume by Assessment and Visit .....................41 
Table 4: 
Relationship of Study Drug to Adverse Event ...........................................................44 
Table 5: 
Grading of Adverse Event Severity ............................................................................45 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events ..................................45 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
6MWD 
6-minute walk distance 
AE 
Adverse event 
AUC0-τ 
Area under the plasma concentration curve between dose interval 
AUC0-24 
Area under the plasma concentration curve from time zero following the 
morning dose up to hour 24 
BCRP 
Breast cancer resistant protein 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ctrough 
Trough concentration (Plasma concentration pre morning dose) 
CK 
Creatine Kinase 
CL/F 
Apparent clearance 
CRF (eCRF) 
Case Report Form (electronic CRF) 
CRO 
Contract Research Organization 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
CYP 
Cytochrome P450 
DMD 
Duchenne muscular dystrophy 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good clinical practice 
HDL 
High-density lipoprotein 
HR 
Heart rate 
IB 
Investigator brochure 
ICH 
International Conference on Harmonization  
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDL 
Low-density lipoprotein 
mRNA 
Messenger ribonucleic acid 
MedDRA 
Medical Dictionary for Regulatory Activities 
NeoMed syringe 
Neonatal oral syringe 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
OAT 
Organic anion transporter 
OATP 
Organic anion transporting polypeptide 
PIP 
Pediatric investigation plan 
PK 
Pharmacokinetics 
PTC124 
Ataluren 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SmPC 
Summary of Product Characteristics 


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Abbreviation or 
Specialized Term 
Explanation 
SUSAR 
Serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
VAMS 
Volumetric absorptive microsampling 
 


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1. 
INTRODUCTION 
1.1. 
Investigational Product 
Ataluren (also known as PTC124) is a novel, orally bioavailable, small-molecule drug being 
developed for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD).  
A nonsense mutation in DNA results in a premature stop codon within the corresponding 
messenger ribonucleic acid (mRNA) that causes disease by terminating translation before a 
functional protein is generated. Duchenne muscular dystrophy (DMD) is a rare, X-linked genetic 
muscle disorder that is debilitating, progressive, and ultimately fatal . Duchenne muscular 
dystrophy is caused by a mutation in the dystrophin gene. Dystrophin is a 427 kDa structural 
protein present at the muscle sarcolemma that provides stability to the muscle and is expressed in 
skeletal, respiratory, and cardiac muscle, . Dystrophin acts as a shock absorber during muscle 
contraction by linking the actin of the contractile apparatus to the layer of connective tissue that 
surrounds each fiber .  
Dystrophin mutations disrupt the connection with the actin cytoskeleton and connective tissue 
resulting in chronic muscle damage, inflammation, and eventual replacement of muscle fibers by 
fat and fibrotic tissue resulting in progressive and irreversible loss of muscle function . The 
culmination of muscle function loss leads to early death; the average life expectancy of DMD 
patients is about 25 years of age. 
Approximately 10% to 15% of boys with DMD have the disease due to a nonsense mutation in 
the dystrophin gene , resulting in a premature stop codon in the dystrophin mRNA. 
Consequently, ribosomal translation of nonsense codon-containing mRNA results in premature 
termination of translation before a full-length, functional protein is generated. 
To date, no medications cure or reverse the effects of DMD. The goal of current interventions is 
to help slow or stabilize disease progression, prolong patients’ ability to manage activities of 
daily living, and to delay the onset of subsequent deterioration. Recent clinical guidelines 
recommend treatment with glucocorticoids, which address the inflammatory component of the 
disease, and have beneficial effects on prolonging ambulation and muscle and respiratory 
function .  
The progressive and irreversible effects of nmDMD underscore the importance of early 
intervention with treatments that have the potential to slow physical deterioration and delay the 
natural course of this fatal disease. While treatment with corticosteroids target the inflammatory 
component of the disease, additional treatments are needed to address the loss of dystrophin, the 
underlying cause of the disease. Because of the role of the dystrophin protein, dystrophin 
restoration therapy would be expected to stabilize or slow disease progression in patients with 
DMD. 


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1.2. 
Nonclinical Findings 
The mechanism by which ataluren restores dystrophin has been established in comprehensive 
preclinical studies and supported in clinical evaluations. Ataluren promotes ribosomal 
readthrough of mRNA containing premature stop codons, resulting in production of a functional 
protein . In reporter assays, as well as in nonclinical models of genetic disease, ataluren 
demonstrates the ability to specifically and selectively enable ribosomal readthrough of mRNA 
containing a premature stop codon, inducing production of protein that localizes to the 
appropriate cellular location and is functionally active . Ataluren does not promote readthrough 
of normal stop codons, does not alter mRNA levels, and does not affect the process of nonsense-
mutation-mediated mRNA decay. In vitro and in vivo studies in nmDMD have shown that 
ataluren can restore production of the missing dystrophin protein. 
In support of administering ataluren to children from 6 months to 2 years of age, a 3-month 
juvenile dog study was performed (Test Facility Study 9001126). The administration of ataluren 
by once daily oral gavage for 3 months at doses of 125, 250, and 500 mg/kg/day (up to steady 
state systemic exposures equivalent to the steady state area under the concentration curve [AUC] 
in patients) was well tolerated in juvenile beagle dogs when dosed from post-natal day 7 to 
post-natal day 97. Cytoplasmic alteration of the brown adipose tissue, considered likely 
ataluren-related and nonadverse, was observed in 1 male at 125 mg/kg/day, 2 males at 
500 mg/kg/day, and 1 female each at 125 and 250 mg/kg/day. Following the 3-month recovery 
period, the cytoplasmic alteration of brown adipose tissue was not present, suggesting recovery 
of the change. No other ataluren-related macroscopic or organ weight changes were observed. 
Based on these results, the no-observed-adverse-effect level was considered to be 
500 mg/kg/day. 
Nonclinical safety pharmacology and toxicology studies, including the completed juvenile 
toxicology study, indicate that ataluren has an acceptable safety profile. Findings pose a low 
human safety risk, and the overall program supports chronic administration of ataluren for the 
treatment of nmDMD in patients as young as neonates. 
1.3. 
Risk/Benefit Assessment 
1.3.1. 
Clinical Studies 
The clinical efficacy and safety of ataluren for the treatment of nmDMD were assessed in 
2 randomized, double-blind, placebo-controlled, 48-week studies (PTC124-GD-007-DMD 
[NCT00592553] [Study 007] and PTC124-GD-020-DMD [NCT01826487] [Study 020]). 
Study 007 was a Phase 2b, international, multicenter, randomized, double-blind, 
placebo-controlled, dose-ranging study of ataluren in 174 male subjects ≥5 years old with 
nmDMD. Subjects were randomized 1:1:1 to receive placebo, low-dose level of ataluren (10, 10, 
20 mg/kg), or high-dose level of ataluren (20, 20, 40 mg/kg) TID for a duration of 48 weeks. At 
the end of Week 48, the mean change from baseline in 6-minute walk distance (6MWD) was 
approximately 30 meters greater in subjects treated with low-dose ataluren than in subjects 
treated with placebo, while there was no difference between high-dose ataluren and placebo in 
change in 6MWD over 48 weeks. Plasma concentrations were dose-proportional and 
well-maintained over time. Ataluren was well tolerated at both the low- and high-dose levels. 


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None of the subjects prematurely discontinued treatment because of adverse events (AEs), and 
no ataluren-related serious adverse events (SAEs) were reported. 
Study 020 was a Phase 3, international, multicenter, randomized, double-blind, 
placebo-controlled efficacy and safety study of ataluren in ambulatory males ≥7 to ≤16 years old 
with nmDMD. A total of 230 subjects were randomized (1:1) to receive placebo or ataluren 
10, 10, 20 mg/kg TID. Ataluren-treated subjects experienced clinical benefit as measured by 
numerically favorable differences versus placebo across all efficacy endpoints. The difference 
between the ataluren and placebo arms in mean change in observed 6MWD from baseline to 
Week 48 was 15.4 meters favoring ataluren. In a subgroup analysis of subjects with baseline 
6MWD ≥300 to <400 meters, the Week 48 treatment difference in mean change in 6MWD was 
47.2 meters (p=0.007). Ataluren was well tolerated and slowed the decline in physical 
functioning in subjects with nmDMD. 
Small increases in mean serum creatinine, blood urea nitrogen (BUN), and cystatin C, changes in 
lipid profile (increased triglycerides and cholesterol), and hypertension with use of concomitant 
systemic corticosteroids were reported for some subjects in clinical studies. Monitoring serum 
creatinine, BUN, and cystatin C, total cholesterol, low-density lipoprotein (LDL), high-density 
lipoprotein (HDL), triglycerides, and resting systolic and diastolic blood pressure (BP) in 
subjects receiving ataluren concomitantly with corticosteroids is recommended every 6 to 
12 months, or more frequently as needed based on the subject’s clinical status 
(Ataluren, SmPC 2019). 
Data from Studies 007 and 020 supported conditional marketing authorization of ataluren for the 
treatment of nmDMD in ambulatory subjects aged ≥5 years in Europe on 31 Jul 2014. 
Subsequently, the indication was extended to ≥2 years of age based on pharmacokinetic (PK) 
extrapolation from study PTC124-GD 030-DMD (Study 030). 
Study 030 was a Phase 2, open-label study of ataluren safety, PK, and pharmacodynamics in 
14 male subjects with nmDMD, aged ≥2 to <5 years. Ataluren was administered at 10, 10, 20 mg 
TID for 52 weeks. The PK analysis demonstrated ataluren exposures similar to that observed in 
older subjects. Improvements were seen in physical functioning across all assessments. Ataluren 
was well tolerated by all subjects. The treatment-emergent adverse events (TEAEs) classified as 
possibly related to ataluren were rash, flatulence, nausea, and vomiting and were all classified as 
mild in severity, except for 2 occurrences of vomiting that were classified as moderate. No 
subjects experienced an SAE or prematurely discontinued study drug due to a TEAE. 
This study (Study 048) is designed to evaluate the safety and pharmacokinetics of ataluren 
exposure in male children ≥6 months to <2 years old with nmDMD. Ataluren has been 
administered to subjects with nmDMD as young as 2 years of age. There were no obvious 
differences in the activity or safety profiles of ataluren in children relative to adults. Given that 
ataluren, in children <5 years old, has demonstrated an ataluren PK profile that is similar to that 
observed in older subjects, has shown improvements in physical functioning assessments, and 
exhibited a favorable safety profile, the benefit-risk profile of ataluren is positive. Hence, the 
study design and the importance of confirming a similar PK profile, and the safety and 
tolerability in children ≥6 months to <2 years old results in a positive risk/benefit. 


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Known and potential risks associated with ataluren: The potentiation of aminoglycoside renal 
toxicity is a clearly documented risk for ataluren. Other potential risks include long-term 
cardiovascular effects including changes in lipid profile, hypertension with use of concomitant 
systemic corticosteroids, renal toxicity, hepatic toxicity, hibernoma, and general malignancies. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ataluren is 
provided in the Investigator’s Brochure (IB). 
1.3.2. 
Risk-Benefit Conclusion  
Any benefit of ataluren depends on the presence of a nonsense mutation. Participants in this 
study have the potential for direct, early benefit from treatment with ataluren. This theoretical 
early benefit justifies the known and potential risks as detailed in the SmPC and ataluren IB. 
Substantial nonclinical and clinical safety experience provides appropriate risk-benefit 
information that supports the conduct of this study. This information is detailed in the ataluren 
IB. The potential risks (real and theoretical) have been weighed against the expected benefits for 
the children enrolled in the clinical study. It is believed that the balance of risks versus expected 
benefits will be positive for the clinical study. 


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2. 
STUDY OBJECTIVE AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of ataluren in male 
children with nmDMD aged ≥6 months to <2 years old. 
2.1.2. 
Secondary Objective 
The secondary objective of this study is to assess the PK of ataluren in male children with 
nmDMD aged ≥6 months to <2 years old. 
2.1.3. 
Exploratory Objective 
The exploratory objective of this study is to assess changes from baseline in creatine kinase (CK) 
levels. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint of this study is the overall safety profile of ataluren in terms of type, 
frequency, severity, seriousness, timing, and relationship to study therapy of any TEAE during 
the 24 weeks of treatment.  
2.2.2. 
Secondary Endpoint 
The secondary endpoint of this study is the evaluation of PK parameters after 24 weeks of 
treatment as follows: 
• AUC from a time of 0 to 24 hours post first morning dose (AUC0-24) and AUC 
between dose interval (AUC0-τ) 
• Tmax 
• Cmax 
• Ctrough (concentration prior to the morning dose) 
2.2.3. 
Exploratory Endpoints 
• Change from baseline in CK levels after 24 weeks of treatment 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
Study 048 is a Phase 2, open-label study to evaluate safety, tolerability, and PK of ataluren in 
male children with nmDMD aged ≥6 months to <2 years of age treated TID for 24 weeks with 
orally administered ataluren 10, 10, 20 mg/kg (morning, mid-day, and evening dose, 
respectively). 
3.2. 
Scientific Rationale for Study Design 
At the request of the European Medicines Agency, Paediatric Committee, and as agreed upon by 
PTC Therapeutics (PTC), Study 048 is being conducted as part of a Paediatric Investigation Plan 
(PIP) as PIP Study 7. 
Translarna was granted a conditional marketing authorization on 31 July 2014 for the treatment 
of nmDMD in ambulatory patients aged 5 years and older. On 23 July 2018, the expansion of the 
indication to include patients aged ≥2 to <5 years old with nmDMD was approved on the basis of 
comparable pharmacokinetics and consistency with the known safety profile of ataluren in 
PTC124-GD-030-DMD (Study 030 - PIP Study 6). 
Study 048 is designed to evaluate the safety, tolerability, and PK of ataluren in male children 
aged ≥6 months to <2 years old with nmDMD. 
3.3. 
Justification of Dose 
Participants in the study will be administered ataluren 10, 10, 20 mg/kg (morning, mid-day, and 
evening dose, respectively), orally or via a neonatal oral syringe (NeoMed syringe). Dosing is 
based on body weight, a common practice in pediatric studies that reduces variability in exposure 
by accommodating differences in subject size across the span of ages of the subjects who will 
participate in the clinical study. 
The schedule of drug administration was derived directly from Phase 1 PK modeling and from 
Phase 2 exposure information. The intent of administering 2 smaller doses at 6-hour intervals 
during the day and a larger dose at a 12-hour interval overnight (eg, at 7:00 AM, 1:00 PM, and 
7:00 PM) is to optimally sustain target plasma concentrations while minimizing total exposures. 
This schedule is likely to fit well with daily patterns of living for subjects, thus enhancing 
compliance. As confirmation of that premise, compliance with ataluren dosing in Phase 2 and 
Phase 3 testing has been excellent.  
In clinical studies of ataluren in nmDMD, ataluren has been studied most extensively at the 
10, 10, 20 mg/kg dose level. In the Phase 2b, randomized, double-blinded, placebo-controlled 
study of ataluren in nmDMD (Study 007), 57 subjects received ataluren 10, 10, 20 mg/kg for 
48 weeks with a favorable risk-benefit at this dose level . Ataluren has been conditionally 
approved at a dose of 10, 10, 20 mg/kg for the treatment of nmDMD. Based on the collective 
clinical experience with ataluren 10, 10, 20 mg/kg, this dose level will be evaluated in male 
children ≥6 months to <2 years old with nmDMD.  


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4. 
STUDY POPULATION 
4.1. 
Overview 
The study will include up to 10 subjects (minimum of 6 subjects) selected according to the 
following inclusion and exclusion criteria.  
4.2. 
Inclusion Criteria 
1. Signed and dated informed consent document indicating that the parent(s)/caregiver(s) of 
the subject has been informed of all pertinent aspects of the study prior to initiation of 
any study-related procedures. 
2. Males ≥6 months to <2 years of age. 
3. Body weight ≥7.5 kg.  
4. Willingness and ability of the subject’s parent(s)/caregiver(s) to comply with scheduled 
visits, study drug administration plan, study procedures, and study restrictions.  
5. Diagnosis of DMD based on an elevated serum CK and genotypic evidence of 
dystrophinopathy. 
6. Documentation of the presence of a nonsense mutation of the dystrophin gene as 
determined by gene sequencing confirmed by a PTC designee is required prior to 
enrollment.  
4.3. 
Exclusion Criteria 
1. Subject who is participating in any drug or device clinical investigation or whose sibling 
is currently participating in a blinded portion of another ataluren study or received an 
investigational drug within 3 months prior to the Screening Visit or who anticipate 
participating in any other drug or device clinical investigation or receiving any other 
investigational drug within the duration of this study. 
2. Expectation of a major surgical procedure during the study period. 
3. Prior or ongoing medical condition, medical history, physical findings, or laboratory 
abnormality that, in the investigator’s opinion, will adversely affect the safety of the 
subject, or will make it unlikely that the course of study drug administration or follow-up 
will be completed, or will impair the assessment of study results. 
4. Known hypersensitivity to any of the ingredients or excipients of the study drug 
(polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone 
XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate). 
5. Ongoing use of the following drugs: 
a. Systemic aminoglycoside therapy and/or intravenous (IV) vancomycin. 
b. Coumarin-based anticoagulants (eg, warfarin), phenytoin, tolbutamide, or paclitaxel. 
c. Inducers of UGT1A9 (eg, rifampicin), or substrates of OAT1 or OAT3 
(eg, ciprofloxacin, adefovir, oseltamivir, aciclovir, captopril, furosemide, bumetanide, 
valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin). 


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4.4. 
Strategies for Recruitment and Retention 
A minimum of 6 male subjects will be enrolled. Subjects will be recruited from 
dystrophinopathy populations who receive care or are referred for evaluation at the 
investigational site. Subjects who have siblings with nmDMD who have a history of ataluren 
exposure or a nmDMD treatment plan may be eligible for this study. The principal investigator 
or sub-investigator will discuss the possibility of participation directly with subject’s 
parent(s)/caregiver(s) in the clinic. Participant’s sibling cannot be participating in the blinded 
portion of another ataluren study at the time of subject’s enrollment in this study. 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures. 
PTC will have an opportunity to review in advance and approve the content of any study 
recruitment materials provided to potential study subjects’ parent(s) or caregiver(s).  


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5. 
STUDY INTERVENTION 
5.1. 
Study Intervention Administration  
Ataluren will be the only study medication administered in this open-label study. 
Ataluren will be supplied to the investigational site(s) by PTC for appropriate distribution to the 
subject’s parent(s)/caregiver(s). 
5.1.1. 
Study Intervention Description 
Ataluren will be provided as white to off-white granules for oral suspension.  
5.1.2. 
Dosing and Administration 
Subjects in the study will be administered ataluren 10, 10, 20 mg/kg (morning, mid-day, and 
evening dose, respectively), orally or via a NeoMed syringe. Dosing will be based on body 
weight, a common practice in pediatric studies that reduces variability in exposure by 
accommodating differences in subject size across the span of ages of the subjects who will 
participate in the clinical study. The subject’s parent(s)/caregiver(s) will be provided a Study 
Drug Administration Record (dosing sheet) to document daily subject compliance. 
5.1.2.1. 
Dose and Dosing Regimen 
Dosing of ataluren will be on a milligram of drug per kilogram of subject body weight at 
baseline (Visit 2). A subsequent weight-based dose adjustment may be necessary over time (see 
Section 5.1.2.2 ). All subjects will receive approximately 10, 10, 20 mg/kg ataluren TID in the 
morning, at mid-day, and in the evening, respectively, for 24 weeks. Ataluren will be 
administered orally immediately after preparation.  
The amount of study drug administered to each subject, any missed doses, and the reason for 
noncompliance will be recorded in the source documents and electronic Case Report Form 
(eCRF). 
5.1.2.2. 
Dose Adjustments and Modifications 
Because of changes in subject body weight over time, a weight-based dose adjustment may be 
necessary. Weight will be re-assessed at Week 12 and ataluren dosing adjusted accordingly. 
5.1.2.3. 
Schedule of Drug Administration 
Ataluren administration will begin at baseline (Visit 2) and continue for up to 24 weeks. 
As noted in Table 1, three ataluren doses should be taken per day; the first dose in the morning, 
the second dose during the middle of the day (mid-day), and the third dose in the evening. 
Ideally each dose should be taken within ~30 minutes after a meal (eg, ~7:00 AM after breakfast, 
~1:00 PM after lunch, and ~7:00 PM after dinner). Intervals for dosing should be ~6 hours 
(±1 hour) between morning and mid-day doses, ~6 hours (±1 hour) between mid-day and 
evening doses, and ~12 hours (±1 hour) between evening doses and the morning dose on the next 
day. While it is realized that variations in dosing schedule may occur in the outpatient setting, the 
prescribed regimen (including dosing intervals and the relationship of dosing to meals) should be 
followed closely on the day preceding PK sample collection in the clinic. 


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Table 1: 
Suggested Daily Dosing 
Dose Designation 
Preceding Meal 
Example Dose Times 
Morning 
Breakfast 
~7:00 AM - 0700 hours (±1 hour) 
↑ 
6 hours 
↓ 
Mid-day 
Lunch 
~1:00 PM - 1300 hours (±1 hour) 
↑ 
6 hours 
↓ 
Evening 
Dinner 
~7:00 PM - 1900 hours (±1 hour) 
↑ 
12 hours 
↓ 
Next Day Morning 
 
~7:00 AM - 0700 hours (±1 hour) 
5.1.2.4. 
Instructions for Delays in Dosing 
Dosing delays will be handled as follows: 
1. If there is a delay in the administration of ataluren of <3 hours after the morning or 
mid-day doses or <6 hours after the evening dose, the planned dose is to be taken with no 
changes to the subsequent dose schedules. 
2. If there is a delay in the administration of ataluren of >3 hours after the morning or 
mid-day doses or >6 hours after the evening dose, the planned dose is not to be taken and 
subjects are to resume their usual dosing schedule. 
5.1.2.5. 
Overdose Precautions  
For any subject experiencing an overdose (administration of a study drug dose >4 times the 
highest intended total daily dose level for this protocol [ie, >160 mg/kg/day]), observation for 
any symptomatic side effects should be instituted, and vital signs and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects should be 
initiated. Pending the acquisition of sufficient human experience with the drug, use of gastric 
lavage or induction of emesis is not specifically recommended nor contraindicated. 
The PTC medical monitor must be contacted if an overdose occurs. Under applicable 
regulations, overdosing may be considered an SAE and should be reported accordingly (see 
Section 7.6.2  and Section 7.6.8). 
5.1.2.6. 
Hydration 
Dehydration is a condition that occurs when the body loses too much water and other fluids that 
it needs to work normally. Dehydration is usually caused by severe diarrhea and vomiting, but it 
may also be caused by not drinking enough water or other fluids, sweating too much, fever, 
urinating too much, or taking certain medicines. Signs and symptoms include thirst, dry mouth, 
headache, fatigue, dark-colored urine, urinating less than normal, sunken eyes or cheeks, dry and 
cool skin, dizziness, fainting, muscle cramps, rapid heartbeat, and rapid breathing. Dehydration 
can be severe, especially in young children and older adults. Because of the potential risk of 
renal dysfunction during periods of dehydration in subjects receiving study drug, it is important 


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to encourage study subjects to maintain adequate hydration throughout the study. Frequent 
sipping or drinking of water is recommended to prevent dehydration. Subjects should be 
adequately hydrated prior to receiving potentially nephrotoxic agents such as aminoglycosides or 
vancomycin, and hydration status should be carefully monitored throughout the administration of 
these agents. Investigators should be particularly vigilant with subjects who are experiencing 
nausea, vomiting, diarrhea, or fever, or who have laboratory evidence of dehydration. 
During the course of the study, breastfeeding and milk formula are allowed as part of a normal 
alimentation regime. 
5.1.3. 
Formulation 
Ataluren is manufactured under current good manufacturing procedures conditions. 
The formulation includes matrix and suspending agents, surfactants, and various excipients that 
aid in the manufacturing process. 
5.1.4. 
Packaging and Labeling 
Ataluren granules for oral use will be packaged in aluminum foil, child-resistant sachets 
(packets) and supplied in dose strengths containing 125 or 250 mg of the active drug substance. 
Sachets and cartons will be affixed with color-coded labels to indicate dosage strength 
(125 mg - yellow, 250 mg - pink). 
Labels will be provided in appropriate languages as required by each country in which the study 
is conducted. The content of the labeling will be in accordance with local regulatory 
specifications and requirements. 
5.1.5. 
Study Drug Preparation and Storage  
Sachets of study drug will be shipped at labeled storage conditions and stored at room 
temperature (15 to 30°C [59 to 86°F]). Upon receipt at the study site, study drug(s) will be stored 
in a safe and secure area with restricted access and stored at room temperature 15 to 30°C 
(59 to 86°F).  
The available stability data from representative samples support the use of the drug product for 
48 months when stored at room temperature. The stability of the clinical study samples or 
representative samples will be monitored to support the clinical study.  
Ataluren Suspension in a NeoMed Oral Syringe: Ataluren, suspended in either milk or water, 
remains stable for up to 1 hour at ambient temperature in the NeoMed oral syringe. 
Entire content of the sachets: Study drug sachets should be stored at labeled storage conditions, 
away from the reach of children until time of reconstitution. For administration, the powder in 
the sachet may be mixed with water, milk (skim, 1% fat, 2% fat, whole milk, chocolate milk, or 
lactose free milk), breast milk, fruit juice, or fruit punch, or in semi-solid food (yogurt, pudding, 
or applesauce). The number of sachets to be taken for a dose should be separated from the total 
number of sachets dispensed for the subject. 
For subjects with body weight <10 kg, a NeoMed oral dosing syringe (12 mL) will be used to 
administer an aliquot of a 25 mg/mL concentration suspension in water or milk, including breast 
milk. Ataluren remains stable for up to 1 hour at ambient temperature in the NeoMed oral 
syringe. 


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For subjects with body weight ≥10 kg, the full contents of each sachet should be well-mixed with 
at least 30 mL (1 ounce) of liquid, or 3 tablespoons of semi-solid food. The prepared dose should 
be mixed well before administration. The amount of the liquid or semi-solid food can be 
increased based on subject preference. Please reference the dosing instructions for further 
information. 
The constituted ataluren suspension may be kept for up to 24 hours under refrigeration or 3 hours 
at room temperature. 
The clinic staff will instruct each subject’s parent(s)/caregiver(s) on the specific number of 
sachets to be taken from each kit at each dose and will provide detailed oral directions regarding 
drug preparation. In addition, detailed written drug mixing and dosing instructions will be 
provided to the subject’s parent(s)/caregiver(s) when drug supplies are dispensed. The clinic staff 
should attempt to follow-up with the parent(s)/caregiver(s) regarding the drug preparation and 
dosing procedures within an appropriate interval (eg, 1 week) after initiation of study treatment. 
5.1.6. 
Study Drug Accountability 
Upon receipt of the study drug(s), the investigator or designee will maintain accurate records of 
study drug delivery to the study center, the inventory at the study center, the use by each subject, 
the reconciliation of all study drug(s) received from the sponsor, and the return to the sponsor’s 
or its designated depot/vendor of unused study drug(s).  
Study personnel must ensure that all study drug supplies are temperature monitored and kept in a 
secure locked area with access limited to authorized personnel. This study product must not be 
used outside the context of this protocol. Under no circumstances should the investigator or site 
personnel supply study product to other investigators or clinics; or allow the supplies to be used 
other than as directed by this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by PTC or its designee, including, but not limited to, the date 
received, lot number, amount received, and the disposition of all study drug. Current 
reconciliation and dispensing records must also be maintained that include the date and amount 
of drug dispensed, and subject’s assigned study number. 
Unused clinical supplies must be returned to PTC or its designated depot/vendor after the study 
is completed. Accountability must be verified by the site monitor prior to return. Records 
documenting the date of study drug shipped, relevant sachet numbers, and amount shipped 
should be kept in the investigator site study file. 
5.2. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study.  
5.3. 
Study Intervention and Compliance 
Subject’s parent(s)/caregiver(s) should return all remaining study drug (all unused sachets and 
drug kits) to the study site at Week 4 (Visit 3), Week 12 (Visit 4), and end of treatment (EOT) at 
Week 24 (Visit 5). The dosing sheet provided to subject’s parent(s)/caregiver(s) will serve as a 
source document for subject compliance and will help the investigator determine how much 
unused drug should be returned upon study completion.   


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5.4. 
Concomitant Therapy 
Other than the study drug, any treatments (including prescription and non-prescription drugs, 
health foods, herbal remedies, or self-prescribed drugs) that are taken by or given to a subject 
during the screening period, during study drug administration, and for 4 to 6 weeks after 
discontinuation of study drug are considered concomitant medications.  
To the extent possible, administration of any treatment other than the study drug is to be 
minimized during the study period. The subject’s parent(s)/caregiver(s) are discouraged from 
providing “health supplements” (eg, creatine, glutamine, coenzyme Q), herbal remedies, growth 
hormone, or self-prescribed drugs, at any time during the study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any other drug(s) must take into account subject safety, the medical need, the 
potential for drug interactions, the possibility for masking symptoms of a more relevant 
underlying event, and whether use of a concomitant medication would compromise the outcome 
or integrity of the study. 
The subject’s parent(s)/caregiver(s) will be instructed about the importance of informing the 
clinic staff of the subject’s use of any drugs or remedies (whether prescribed, over the counter, or 
illicit) before and during the course of the study. Information regarding all concomitant 
medications will be collected and documented in the concomitant medication page of the eCRF 
and in the source documents by the clinic staff. Concomitant therapies will be recorded, 
reviewed, and updated at each visit. 
Any new concomitant therapy or modification of an existing therapy can be linked to an AE. 
A corresponding AE Form is to be completed to account for the change in therapy, except in 
some cases, such as therapy used for prophylaxis and dose modification for a chronic condition. 
5.4.1. 
Concomitant Use of Corticosteroids 
Although it is recognized that corticosteroid use has demonstrated benefit in DMD patients , 
because of their potential to influence changes in BP measurements and cholesterol and 
triglyceride levels, corticosteroid use is strongly discouraged in this study in order to minimize 
potential confounding effects on the interpretation of study results. If the investigator deems it 
necessary for the benefit of the subject to continue use of a corticosteroid during the study, a 
stable and standardized regimen must be maintained for at least 30 days prior to randomization, 
and throughout the duration of the study.  
5.4.2. 
Concomitant Use of Systemic Aminoglycoside Therapy and/or Intravenous 
Vancomycin 
Ataluren should not be co-administered with IV aminoglycosides. Cases of decreased renal 
function were observed in a clinical study of subjects with nonsense mutation cystic fibrosis 
receiving concomitant ataluren and IV aminoglycosides (as described in the Ataluren IB). 


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In subjects who require treatment for serious infections, investigators should substitute other 
antibiotics for systemic aminoglycosides when clinically appropriate. If IV aminoglycosides or 
other nephrotoxic antibiotics (eg, vancomycin) are administered, study drug must be interrupted 
during the course of these antibiotics. Subjects requiring IV aminoglycoside or vancomycin 
therapy should be closely monitored in an appropriate setting, such as a hospital. In subjects 
receiving potentially nephrotoxic agents such as IV aminoglycosides or vancomycin, antibiotic 
drug levels and serum creatinine and BUN should be followed closely. The antibiotic trough 
level and creatinine and BUN should be measured within 24 to 48 hours of administration of the 
first antibiotic dose, and further antibiotic dosing should be based on these results. Trough levels 
should be measured at intervals during antibiotic treatment. Creatinine and BUN should be 
measured prior to initiating IV aminoglycoside or vancomycin therapy and at least twice a week 
during the course of treatment. 
5.4.3. 
Coumarin-Based Anticoagulants  
As the primary route of ataluren metabolism is via glucuronidation by UGT1A9, clinically 
significant interactions between ataluren and co-administered drugs metabolized by cytochrome 
P450 (CYP) enzymes are unlikely. In particular, ataluren is not an inhibitor of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, and does not have induction 
potential on the major CYP enzymes. Based on in vitro studies, ataluren is also not expected to 
be an inhibitor or a substrate of p-gp mediated transport. 
As an added measure of safety, investigators should pay specific attention to use of drugs that are 
known substrates of this enzyme, particularly when such drugs may have a low therapeutic 
index. 
Drugs that are metabolized by CYP2C8 or CYP2C9 that have low therapeutics indices 
(in particular, paclitaxel for CYP2C8 and coumarin anticoagulants [eg, warfarin], phenytoin, or 
tolbutamide for CYP2C9) may be of particular concern. Coumarin anticoagulants are cleared by 
CYP2C9 and increases in plasma concentrations of coumarin anticoagulants may result in 
serious clinical consequences. For subjects who require anticoagulation during the study, use of 
an alternative form of anticoagulation (eg, fractionated heparin) should be considered. Phenytoin 
is metabolized by CYP2C9 and concomitant use with ataluren may be of potential concern. For 
subjects who require anticonvulsant therapy during the study, use of alternative anticonvulsant 
drugs should be considered. 
The metabolism of losartan to its active metabolite may, in part, be mediated by CYP2C9. 
However, concomitant use of losartan and inhibitors of CYP2C9 have not been examined. 
Because this drug does not have a narrow therapeutic window, the potential for mild to moderate 
changes in activity does not require a dose modification. 
5.4.4. 
Inducers of UGT1A9 or Substrates of OAT1, OAT3, or OATP1B3 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and breast cancer resistant protein 
(BCRP). Caution should be exercised when ataluren is co-administered with drugs that are 
inducers of UGT1A9 (eg, mycophenolate mofetil, rifampicin), or inhibitors of BCRP 
(eg, cyclosporine). 


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In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
(OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3). Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 
(eg, oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, 
pravastatin, rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration 
of these drugs. 


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6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
6.1. 
Discontinuation of Study Intervention 
If after appropriate consideration of study drug interruption/modification and consultation with 
the PTC medical monitor, it is not appropriate for a subject to continue with study treatment, 
then study drug should be permanently discontinued. After permanent discontinuation of study 
drug for a safety concern, and if the initial event was reported as a SAE, then a follow-up SAE 
report form should be completed. In the case of a treatment discontinuation due to an event that 
is not an SAE, the PTC medical monitor should be notified. In addition, details regarding the 
reasons for discontinuation and the AEs leading to the discontinuation should be recorded in the 
source documents and in the appropriate Case Report Form (CRF). The Early Termination (ET) 
Visit CRF should be completed and appropriate follow-up, ie, at ~4 weeks as per protocol or 
until recovery from or stabilization of the AE, whichever comes last. 
6.2. 
Participant Discontinuation/Withdrawal from the Study 
All subjects who receive ataluren should remain in the study whenever possible. However: 
1. The subject’s parent(s)/caregiver(s) has the right to withdraw consent and discontinue 
ataluren at any time. 
2. If the subject’s condition substantially worsens after initiating ataluren, the subject will 
be carefully evaluated by the investigator. The subject will be withdrawn from treatment 
if continuing would place them at risk.  
3. The investigator may withdraw the subject from ataluren, if, in the investigator’s clinical 
judgment, it is not in the subject’s best interest to continue.  
4. In the event the subject becomes significantly noncompliant with ataluren administration, 
study procedures, or study requirements, the subject should be withdrawn from ataluren 
when the circumstances surrounding noncompliance increase risk to the subject or are 
anticipated to substantially compromise the interpretation of study results.  
5. This study may be discontinued by the relevant regulatory authority, Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and/or PTC at any time. 
6.2.1. 
Collection of Data from Withdrawn Subjects 
The date ataluren is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the eCRF. The PTC medical monitor (or designee) should be informed 
via e-mail of when a subject discontinues study drug. 
When ataluren is discontinued (regardless of the reason), the investigator is expected to capture 
all of the evaluations required at the EOT or follow-up and any additional evaluations should be 
completed that may be necessary to ensure that the subject is free of untoward effects. The 
subject should be encouraged to seek appropriate follow-up for any continuing health problems. 
6.2.2. 
Subject Replacement 
Subjects will only be replaced, if necessary, to meet study objectives. 


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6.2.3. 
Subject Follow-Up 
Investigators will make every effort to obtain follow-up assessments within 4 weeks ±7 days 
from the date of the last ataluren treatment for all subjects withdrawing from study treatment 
prematurely.  


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Schedule of Events and Study Parameters 
Subjects may be in the study for up to 4 weeks prior to receiving study drug at the baseline visit 
(Visit 2) and for 4 weeks ±7 days after last study drug administration (Visit 5). 
The timing and types of procedures and assessments for this study are specified below in 
Table 2. 


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Table 2: 
Schedule of Assessments 
Study Period 
Screeninga 
Baseline/ 
Start of 
Treatmentb 
Treatment Phase 
EOT/ETc 
Post- 
Treatment 
Follow-Up/ 
EOSd 
Visit 
Visit 1 
Visit 2e 
Visit 3e 
Visit 4 
Visit 5e 
Visit 6 
Week 
- 
Week 0 
Week 4 
Week 12 
Week 24 
Week 28 
Visit Window (days) 
(-28 to -1) 
0 
±7 
±7 
±7 
±7 
Eligibility 
 
 
 
 
 
 
Informed Consentf 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
Physical Examinationg 
X 
X 
X 
X 
X 
 
Clinical Labsh 
X 
X 
X 
X 
X 
 
Blood Sample for Gene 
Sequencingi 
X 
 
 
 
 
 
Height/Weightj/BMI 
X 
X 
X 
X 
X 
 
Vitals (HR and BP)k 
X 
X 
X 
X 
X 
 
ECGl 
X 
X 
X 
 
X 
 
AE/SAE Monitoring 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsm 
X 
X 
X 
X 
X 
X 
PK Blood Sampling (VAMS)n 
 
X 
X 
 
X 
 
Blood/Plasma Partition Samplingo 
 
X 
X 
 
X 
 
Study Drug Administration 
 
 
 
 
 
 
Dispense Drug 
 
X 
 
X 
 
 
Unused Drug Return/Compliance 
 
 
X 
Xp 
X 
 
Abbreviations: AE, adverse event; BMI, body mass index; BP, blood pressure; CL/F, apparent clearance; Ctrough, trough concentration (plasma concentration pre 
morning dose); ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; ET, early termination; HR, heart rate; PK, pharmacokinetic; SAE, serious 
adverse event; VAMS, volumetric absorptive microsampling 
a Screening procedures must take place within 28 days of baseline (Visit 2).  
b Any screening procedure completed within and including 14 days of baseline (Visit 2) can serve as baseline assessment and does not need to be repeated at 
Visit 2. 
c Subjects who terminate the study early are to complete all assessments required for EOT/ET (Visit 5) prior to leaving the study and will be contacted by phone 
4 weeks from the final dose of study medication for the post-treatment follow-up/EOS (Visit 6). 
d Post-treatment follow-up will be conducted by phone 4 weeks ± 7 days from last day of study treatment for review of adverse events and concomitant 
medications. Post-treatment follow-up is not required if subjects are transitioning to another ataluren clinical trial.  
e Visits 2, 3, and 5 will be conducted over the course of 24 hours due to the timing of the collection of PK samples and will require an overnight stay. 


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f A signed and dated informed consent must be obtained before conducting any study procedures. Remote informed consent is permitted consistent with local 
policies and procedures. 
g A full physical examination will include evaluation of the cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, 
musculoskeletal system, eyes, ears, nose, mouth, throat, spine, lymph nodes, and extremities. 
h  Blood and urine collection will be obtained locally and submitted to the local or central laboratory for analysis. Use of standard of care labs is permitted when 
samples were obtained within the visit window. Clinical labs will include hematology, biochemistry, and urinalysis parameters as follows: Hematology laboratory 
assessments will include white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry laboratory 
assessments will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total 
protein, albumin, bilirubin (total, direct, and indirect), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatinine kinase, lactate 
dehydrogenase, alkaline phosphatase, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, and cystatin C. Urinalysis assessments will 
include analysis for pH, specific gravity, glucose, ketones, blood, protein, urobilinogen, bilirubin, nitrite, urine protein: urine creatinine ratio (spot), and leukocyte 
esterase.  
i This is to ensure a blood sample has been drawn for sequencing of the dystrophin gene. The sample will be sent to a central laboratory for analysis. 
j Weight-based dose adjustment will be assessed at Week 12. 
k Heart rate and BP determinations will be performed with the subject in a supine position after a 5-minute rest. 
l ECGs will be read locally at investigational sites and interpreted for clinical significance.  
m Concomitant medication information will need to be collected starting 28 days prior to the first dose of study drug (Screening, Visit 1). 
n PK samples (VAMS method) will be drawn at baseline (Visit 2), Week 4 (Visit 3), and Week 24 (EOT/ET) for evaluation. Samples will be drawn immediately pre-
dose, and at 1-, 2-, 3-, and 4-hours post-dose following both the morning and mid-day doses and immediately pre-dose and at 1-, 2-, 3-, 4-, and 12- (before the 
next day morning dose) hours post-dose following the evening dose. 
o Blood sampling via venous draw will be conducted at Visits 2, 3, and 5. These additional samples will be taken at 2.5 -hours and 4.5 -hours post morning dose 
(1.5 ml each timepoint). Out of the 1.5 mL blood sample collected, at the 2.5 hour and 4.5 hour timepoints, 1 mL blood sample will be processed to plasma and the 
remaining 0.5 mL blood will be processed to dried blood sample using a VAMS device.    
p Parent(s)/caregiver(s) will record daily dose administration on a Study Drug Administration Record (dosing sheet) and Subjects are required to return any unused 
study drug. 


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7.1.1. 
Screening (Visit 1) 
The Screening phase of the study will occur from Day -28 to Day -1 prior to the first dose of 
study medication. Screening procedures must take place within 28 days of the baseline visit 
(Visit 2). No study-related procedures should be performed prior to the signing of the informed 
consent document. Thereafter, subjects should undergo the initial set of screening procedures as 
noted in Table 2. 
7.1.2. 
Baseline/ Start of Treatment (Visit 2) 
Information will be gathered, and assessments performed for each subject at baseline (Visit 2) 
according to the schedule in Table 2 Any screening procedure completed within and including 
14 days of Visit 2 can serve as baseline and does not need to be repeated at Visit 2. Ataluren will 
be administered at Visit 2 (See Section 5.1.2.3) and treatment will continue for up to 24 weeks.  
Study participants will report to the clinic on the day of each on-site visit as directed by the 
investigator and will remain in the clinic until released by the investigator after all the 
study -related procedures have been completed and the parent(s)/caregiver(s) have been 
instructed regarding drug storage, reconstitution, and administration. Visit 2 will be conducted 
over the course of 24 hours due to the timing of the collection of PK samples and will require an 
overnight stay. 
7.1.3. 
Treatment Phase (Visits 3-4) 
During the treatment period, each subject will return to the clinical research facility at Week 4 
±7 days (Visit 3) and at Week 12 ±7 days (Visit 4) for procedures and assessments according to 
Table 2. Visit 3 will be conducted over the course of 24 hours due to the timing of the collection 
of PK samples and will require an overnight stay. 
7.1.4. 
End of Treatment/Early Termination (Visit 5) 
Subjects will return to the clinic for the EOT visit (Visit 5) after 24 weeks ±7 days of treatment 
and assessments will be performed according to the schedule in Table 2. Visit 5 will be 
conducted over the course of 24 hours due to the timing of the collection of PK samples and will 
require an overnight stay. 
If the subject discontinues treatment prematurely, the procedures required for the EOT visit 
(Visit 5) should be performed before the subject leaves the study and the subject should be 
contacted by phone for the 4-week post-treatment follow-up (Visit 6). PTC will ensure that 
subjects who complete the 24-week treatment period in this study are offered participation to a 
follow-up extension period for at least 52 weeks from the date of first administration of ataluren 
in this parent study. These subjects will be followed-up for long-term safety and efficacy as an 
exploratory endpoint in the extension study. 
See Section 6.2 for details regarding subject withdrawal procedures. 


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7.1.5. 
Post-treatment Follow-Up/End of Study (Visit 6) 
The subject’s parent/guardian will be contacted by phone 4 weeks ±7 days from the last day of 
study treatment for review of AEs and concomitant medications (see Table 2). Post-treatment 
follow-up is not required if subjects are transitioning to another ataluren clinical trial. 
7.1.6. 
Unscheduled Visits 
An unscheduled visit may take place at any time during the study at the request of the subject’s 
parent/guardian, or as deemed necessary by the investigator due to medical conditions. The date 
and reason for the unscheduled visit will be recorded. Adverse event monitoring and concomitant 
medications will be recorded. Other procedures and assessments will be completed as deemed 
necessary by the investigator and may include (but not be limited to) safety laboratory tests, 
electrocardiogram (ECG), vital signs, and physical examination.  
7.2. 
Eligibility Procedures 
7.2.1. 
Informed Consent  
The investigator/study staff member must inform each study candidate’s parent(s)/caregiver(s) of 
the nature of the study, explain the potential risks, and obtain written informed consent from the 
parent(s)/caregiver(s) prior to performing any study-related screening procedures. Remote 
informed consent is permitted per local policies and procedures.  
No study-related procedures should be performed prior to the signing of the informed consent 
document. Thereafter, subjects should undergo the initial set of screening procedures as noted in 
Table 2. Please refer to Section 4.2 and Section 4.3 respectively for study inclusion and 
exclusion criteria. 
7.2.2. 
Medical History  
The investigator or a qualified designee should review the subject’s clinical history, including 
details relating to nmDMD and any other medical conditions. Information regarding clinical 
history and current medications must be captured on the medical history and prior/concomitant 
medication eCRFs, respectively. Concomitant medications information will need to be collected 
starting 28 days prior to first dose of study drug. 
7.2.3. 
Demographic Information 
Demographic information will be gathered and recorded in source documents and within the 
eCRF. 
7.3. 
Safety Assessments 
7.3.1. 
Physical Examination  
A full physical examination (including evaluation of the cardiovascular system, chest and lungs, 
thyroid, abdomen, nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, 
mouth, throat, spine, lymph nodes, and extremities) will be conducted at all protocol-required 
study visits. 


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Physical examinations may also be performed at any time during the study as clinically 
indicated. 
7.3.2. 
Clinical Laboratory Assessments (hematology, biochemistry, urinalysis) 
Fasting will not be required for laboratory assessments. Laboratory assessments are as follows: 
• Hematology: white blood cell count with differential, hemoglobin, hematocrit, other 
red cell parameters, and platelet count.  
• Biochemistry: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin 
(total, direct, and indirect), aspartate aminotransferase, alanine aminotransferase, 
gamma-glutamyl transferase, CK, lactate dehydrogenase, alkaline phosphatase, total 
cholesterol, HDL, LDL, triglycerides, and cystatin C.  
• Urinalysis: pH, specific gravity, glucose, ketones, blood, protein, urobilinogen, 
bilirubin, nitrite, urine protein: urine creatinine ratio (spot), and leukocyte esterase.  
Please refer to Section 7.5 for further details. 
7.3.3. 
Confirmatory Gene Sequencing 
A blood sample for dystrophin gene sequencing to confirm the presence of a nonsense mutation 
will be drawn at screening (Visit 1). This sample will be sent to a central laboratory for analysis. 
The sample will be destroyed by the central laboratory after test completion and generation of a 
final report. The study manual should be referenced for collection, processing, and shipping 
information. 
Please refer to Section 7.5 for further details. 
7.3.4. 
Pharmacokinetic Assessment 
The PK parameters will be evaluated based on frequent blood sampling. During PK assessments 
at baseline (Visit 2), Week 4 (Visit 3), and EOT at Week 24 (Visit 5), subjects will remain in the 
clinic until all blood draws are complete. At each assessment period, blood sampling will occur 
immediately pre-dose, and at 1-, 2-, 3-, and 4-hours post-dose following the morning and mid-
day doses and immediately pre-dose and at 1-, 2-, 3-, 4-, and 12- (before the next day morning 
dose) hours post-dose following the evening ataluren dose. Blood PK samples will be collected 
by dried blood sampling via volumetric absorptive microsampling (VAMS) technology by 
utilizing the Mitra microsampling device (Neoteryx, CA, USA). An ~80 μL blood sample will be 
collected for each of the 16 time points during each assessment period. These samples will be 
sent to a bioanalytical laboratory for analysis of ataluren levels. The concentration of ataluren in 
the VAMS dried blood sample will be assessed using validated liquid chromatography with 
tandem mass spectrometry (LC-MS/MS) method. Please refer to the laboratory manual for 
instructions regarding the collection, processing, and shipment of all PK samples to the 
bioanalytical laboratory. 
The blood/plasma partition sampling will occur at 2.5 hour and 4.5 hour post morning dose at 
baseline (Visit 2), Week 4 (Visit 3), and EOT at Week 24 (Visit 5). 
Please refer to Section 7.5 for further details. 


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7.3.5. 
Weight, Height, and Body Mass Index 
Height (in cm), weight (in kg) and body mass index (BMI) (kg/m2) will be measured at all study 
visits.  
7.3.6. 
Vital Signs  
Vital signs (heart rate and systolic and diastolic BP) will be monitored at all protocol -required 
study visits. Heart rate and BP determinations will be performed with the subject in a supine 
position after a 5-minute rest. 
7.3.7. 
Electrocardiogram  
A 12-lead ECG will be obtained at screening (Visit 1), baseline (Visit 2), Week 4 (Visit 3), and 
EOT at Week 24 (Visit 5). The ECGs will be read locally at investigational sites and interpreted 
for clinical significance. The findings will be captured in source documents and within the eCRF. 
7.3.8. 
Adverse Events/Serious Adverse Events  
AEs must be assessed and documented at each scheduled clinic visit, beginning at screening 
(Visit 1). Additional tests and other evaluations required to establish the significance or etiology 
of an abnormal result, or to monitor the course of an AE should be obtained when clinically 
indicated. Subjects must be followed for AEs for at least 4 weeks after the last dose of ataluren 
administration, or until any drug-related AEs and/or ongoing SAEs have resolved or become 
stable, whichever is later. Please refer to Section 7.5.1 for further details. 
7.3.9. 
Concomitant Medications  
Concomitant medication information will be collected and documented at each scheduled clinic 
visit, from screening (Visit 1) through EOT at Week 24 (Visit 5). Any concomitant drugs 
(prescribed or over the counter) used during the course of the study and the reason for their use 
will be recorded. Information regarding the timing, type, and amount will be recorded in the 
eCRF. 
7.4. 
Study Drug Administration Procedures 
7.4.1. 
Study Drug Administration  
Ataluren will be supplied at baseline and Week 12 (Visit 4). Because of potential changes in 
subject body weight over time, the subject’s body weight will be assessed and documented at 
Week 12 and dose modifications made as appropriate. 
The PTC medical monitor should be notified of any AE or laboratory abnormality that leads to 
dose interruption and should be apprised of ancillary laboratory or other diagnostic findings and 
the evolving data from any work-up of the initial abnormality. The return of any unused drug 
sachets will be documented for compliance assessments. The subject’s parent(s)/caregiver(s) will 
return all unused sachets of ataluren as instructed for full compliance assessments. 
Please see Section 5 for further information on Study Intervention Procedures, including study 
intervention and compliance.  


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7.5. 
Laboratory Procedures/ Sample Preparation, Handling, Storage and Shipment 
Clinical labs, including hematology, biochemistry, and urinalysis parameters, are to be collected 
following the standard institutional procedures for blood and urine collection and submitted to 
the local or central laboratory by the investigative site for analysis. Please refer to the laboratory 
manual for instructions regarding collection, processing, and shipment of gene sequencing and 
PK blood samples to the central laboratory. 
7.5.1. 
Blood Collection Summary 
Blood collection procedures and total amounts of blood to be drawn over the entire study are 
discussed in the laboratory manual and summarized in Table 3. 
Table 3: 
Summary of Estimated Total Blood Volume by Assessment and Visit 
Study Period 
Screening 
Baseline/ 
Start of 
Treatment 
Week 4 
Week 12 
Week 24 
EOT/ET 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Clinical Labs 
8.5 mL 
8.5 mL 
8.5 mL 
8.5 mL 
8.5 mL 
Blood Sample for Gene 
Sequencing 
6 mL 
 
 
 
 
PK Blood Samplinga 
 
1.28 mL 
1.28 mL 
 
1.28 mL 
Blood/Plasma Partition 
Samplingb 
 
3ml 
3ml 
 
3ml 
Abbreviations: EOT, end of treatment; ET, early termination; PK, pharmacokinetic; VAMS, volumetric absorptive 
microsampling 
a ~80μL blood sample will be collected by dried blood sampling using VAMS technology for each of the 16 time points 
during each assessment period. 
b 1.5 ml blood sample will be collected for each of the 2 timepoints during each assessment period. 
7.6. 
Adverse Events and Serious Adverse events 
Information about AEs, whether reported by the subject’s parent/guardian, discovered by the 
investigator by questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the AE form and followed-up as appropriate. 
Information about SAEs should be reported within 24 hours of obtaining knowledge of the event. 
7.6.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered related to the drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease in a study 
subject who is administered study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
• All AEs during the course of treatment with study drug administration 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose, of study 
drug 
• All AEs resulting from medication errors such as dispensing or administration error 
outside of what is described in the protocol 


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• Apparently unrelated illnesses, including worsening of a preexisting illness 
• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event. Laboratory abnormalities associated with a 
clinical event should be captured in the source documents. Laboratory abnormalities 
not requiring clinical intervention or further investigation will be captured as part of 
overall laboratory monitoring and should not be reported as AEs 
• A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate CRF 
for Visit 1 but should not be reported as an AE unless the condition worsens, or 
episodes increase in frequency during the AE reporting period. Diagnostic and 
therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an 
acute appendicitis that occurs during the treatment with study drug should be reported 
as the AE and the resulting appendectomy should be recorded in the source 
documents and eCRF. If a surgical procedure was planned prior to entry into the 
study, and the surgery is not performed because of a worsening of a baseline 
condition, this should not be reported as an AE. Note that any hospitalization 
occurring as the consequence of an AE during the study period should be reported as 
an SAE. 
Each AE is to be classified as serious or nonserious by the investigator using medical and 
scientific judgment. 
7.6.2. 
Definition of Serious Adverse Events 
An SAE is an untoward medical occurrence or effect associated with the use of a study drug at 
any dose, regardless of whether it is considered related to the study drug, which results in one of 
the following: 
• Results in death. This includes all deaths on treatment or within 4 weeks after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 4 weeks following the last dose need not be reported as an SAE 
unless it is a result of an event that started within the period covered by the on-study 
definition. The reported AE should be the event that caused the death. In addition, 
any AE resulting in death that occurs subsequent to the AE reporting period and that 
the investigator assesses as possibly related to the study drug should also be reported 
as serious. 


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• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or treatment-related diagnostic procedures; other planned hospitalizations; 
or hospitalizations related only to progression of disease). Emergency room visits that 
do not require admission to the hospital do not fall into this category, although the 
event may still be serious due to another seriousness criterion. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions, not related to cancer. 
• Any other medically important event that the investigator or the sponsor judges to be 
serious or which is defined as serious by the regulatory agency in the local country. 
These are AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 
exercised in deciding whether an AE is serious based on above definition. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.6.3. 
Unexpected Adverse Events 
The IB contains the Reference Safety Information (RSI) which will be used for assessing 
expectedness. If an event is not listed in the RSI, it should be considered unexpected or if the AE 
occurs at a greater severity, specificity, or frequency, it should be considered unexpected. 
7.6.4. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject’s parent(s)/caregiver/legally acceptable representative. In addition, each study 
subject’s parent(s)/caregiver/legally acceptable representative will be questioned about AEs at 
each scheduled clinic visit after study drug administration or during any telephone contact with 
the subject’s parent(s)/caregiver/legally acceptable representative. The type of question asked 
should be open-ended, for example, “How have you been feeling?” or a similar type of query. 
7.6.5. 
Recording Nonserious Adverse Events and Serious Adverse Events 
All AEs (both serious and nonserious) that occur in subjects during the AE reporting period must 
be recorded, whether or not the event is considered drug related. In addition, any known 
untoward event that occurs subsequent to the AE reporting period that the investigator assesses 
as possibly related to the investigational drug/product should also be recorded as an AE. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. In addition, the following information should be 
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• Indication of whether the event is serious or nonserious (see Section 7.6.2) 
• Relationship to study drug (see Section 7.6.6) 
• Severity of the event (see Section 7.6.7) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Classification of the event as serious or nonserious determines the reporting procedures to be 
followed. 
7.6.6. 
Describing Adverse Event Relationship to Study Drug 
The investigator should provide an assessment of the relationship of the AE to the study drug, 
ie, whether there is a reasonable possibility that the study drug caused the AE, using the 
considerations outlined in Table 4. 
Table 4: 
Relationship of Study Drug to Adverse Event 
Relationship 
Description 
Probable  
A clinical event in which a relationship to the study drug seems probable because of 
such factors as consistency with known effects of the drug; a clear temporal 
association with the use of the drug; improvement upon withdrawal of the drug; 
recurrence upon rechallenge with the drug; lack of alternative explanations for the 
event.  
Possible  
A clinical event occurring coincident with administration of the study drug and which 
may or may not be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal or rechallenge may be lacking.  
Unlikely  
A clinical event with a temporal relationship to the study drug exposure that does not 
preclude causality but for which there is a clear alternate cause that is more likely to 
have caused the adverse event than study drug. Such alternatives include a 
concomitantly administered drug, the subject’s disease state, other medical 
conditions, or environmental factors.  
Unrelated  
A clinical event, for which a relationship to the study drug seems improbable because 
of factors such as inconsistency with known effects of the study drug, lack of a 
temporal association with study drug administration, lack of association of the event 
with study drug withdrawal or rechallenge, and/or presence of alternative explanations 
for the event. Alternative explanations might include a known relationship of the 
adverse event to a concomitant drug, medical history of a similar event, the subject’s 
disease state, other medical conditions, or environmental factors.  
An AE is considered causally related to the use of the study product when the relationship 
assessment is probable or possible. Events assessed as unlikely related or unrelated to the use of 
study product will be considered as having no relationship to treatment. 


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7.6.7. 
Grading of Severity of Adverse Events 
The severity of AEs will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 (refer to the study manual). For each episode, the highest severity grade 
attained should be reported. 
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 5. 
Table 5: 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects 
clinical status, and may require medical intervention 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up 
Grade 4 
Life-threatening 
Sign or symptom results in a potential threat to life 
Grade 5 
Fatal 
Sign or symptom results in death 
Note the distinction between the seriousness and the severity of an AE. Severity is a measure of 
intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a headache 
may be severe in intensity but would not be classified as serious unless it met one of the criteria 
for serious events listed in Section 7.6.2. 
7.6.8. 
Adverse Event Reporting 
Investigator site reporting requirements for AEs are summarized in Table 6. 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events 
Event 
Recorded on the 
eCRF 
Reported on the SAE Report Form to PTC 
Pharmacovigilance Within 24 Hours of Awareness  
SAE 
All  
All  
Nonserious AE 
All  
None  
Occupational 
Exposure 
None 
Occupational exposure (regardless of whether associated 
with an AE) 
Abbreviations: AEs, adverse events; eCRF, electronic case report form; SAE, serious adverse event 
All AEs should be followed-up by the investigator until they are resolved, or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, the PTC medical monitor or designee should be 
informed via e-mail A subject withdrawn from the study because of an AE must be followed by 
the investigator until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. Follow-up may need to continue after the 
subject has discontinued from the study, and additional investigations may be requested by the 
PTC medical monitoring team. 


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The first day of AE reporting will coincide with the date of signing of informed consent and 
including a minimum of 4 weeks after the last administration of study drug. 
7.6.9. 
Serious Adverse Event Reporting 
All SAEs should be reported via the SAE report form to PTC Therapeutics Pharmacovigilance 
Department within 24 hours of becoming aware of the event(s). In addition, the AE portion of 
the eCRF must also be completed. 
The SAE report form should be signed by the investigator; however, if the investigator is unable 
to sign at the time of the event or within 24 hours, the form should be signed by the clinical staff 
member reporting the SAE (eg, the study coordinator). The SAE report form must be faxed or 
e-mailed to the PTC Therapeutics Pharmacovigilance Department or designee and to the site 
IRB/Ethics Committee (EC) (if required by local regulations) within 24 hours. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
report form and must also be faxed or e-mailed to the same party. All follow-up SAE report 
forms for the event must be signed by the investigator. Any source documents (eg, progress 
notes, nurses’ notes, laboratory and diagnostic test results, discharge summaries) provided to the 
sponsor should be redacted so that the subject’s name, address, and other personal identity 
information are obscured. Only the subject’s study number and initials are to be provided 
(in regions where the provision of such information is permitted). The information in the AE 
portion of the eCRF and the SAE report form(s) must match or be reconciled. Where the same 
data are collected, the forms must be completed in a consistent manner. For example, the same 
AE term should be used on both forms. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is to 
report the event within 24 hours after learning of it and to document his/her first awareness of the 
SAE. 
The PTC Therapeutics Pharmacovigilance Department contact information for reporting SAEs is 
provided below. This information is also provided in the Study Manual and in the SAE report 
form. 
PTC Therapeutics Pharmacovigilance Department 
E-mail: 
  
Fax: 
 
7.6.10. 
Reporting Pregnancy 
Subjects enrolled in this trial will have not reached sexual maturity; therefore, there are no 
requirements for pregnancy avoidance for study participants. 


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7.6.11. 
PTC Therapeutics Adverse Event Reporting Requirement 
As the sponsor of the study, PTC is responsible for reporting certain safety information, such as 
suspected unexpected serious adverse reactions (SUSARs) and other significant safety findings, 
per local reporting requirements, to each investigator in an expedited manner. If notification of a 
SUSAR requiring expedited reporting to investigators is received, PTC or its designated 
representative will contact each investigational site participating in this study by e-mail, fax, 
and/or overnight mail such that the investigator can promptly notify the site IRB/EC per their 
local requirements. The initial expedited safety report will be provided as required according to 
local regulations, eg, within 15 days after the earliest date PTC or an agent of PTC (eg, a site 
monitor) becomes aware of the event. This awareness date is the date the regulatory reporting 
clock begins, and the date is considered Day 0. 
7.6.12. 
Describing Outcome of Adverse Event  
The outcome of an AE is assessed by the investigator using the following definitions: 
• Recovered: Fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first study-related activity after the 
parent/guardian signed the informed consent. 
• Recovering: The condition is improving, and the subject is expected to recover from 
the event.  
• Recovered with sequelae: As a result of the AE the subject suffered persistent and 
significant disability/incapacity (eg, became blind, deaf, paralyzed). Any AE 
recovered with sequelae should be classified as SAE. 
• Not recovered: The subject’s condition has not improved, and the symptoms are 
unchanged. 
• Fatal. 
• Unknown: The subject’s condition is unknown. This term should only be used when 
no other definition is possible, eg, the subject is lost to follow-up. 
7.6.13. 
Follow-up of Unresolved Adverse Events 
All AEs should be followed-up by the investigator until they are resolved, or the investigator 
assesses them as chronic or stable.  
Follow-up of any SAE that is fatal or life-threatening should be provided within one additional 
calendar week. The investigator should consider protocol guidelines and use his/her discretion in 
ordering additional tests as necessary to monitor the resolution of such events. In the event of 
additional investigations, the PTC medical monitor should be informed via e-mail A subject 
withdrawn from the study because of an AE must be followed by the investigator until clinical 
recovery is complete and laboratory results have returned to normal, or until progression has 
been stabilized. Follow-up may need to continue after the subject has discontinued from the 
study, and additional investigations may be requested by the medical monitoring team. 


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8. 
STATISTICAL METHODS AND DATA ANALYSIS 
8.1. 
Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan.  
By-subject listings will be created for each eCRF module. Statistical methods will be descriptive 
in nature. Summary tables for continuous variables will contain the following statistics: N, mean, 
standard deviation, minimum, and maximum as appropriate. Summary tables for categorical 
variables will include N, n, and percentage. Graphic displays will be used when such methods 
are appropriate and informative.  
No interim analyses are planned. 
8.2. 
Sample Size Determination  
Sample size is not based on any formal statistical hypothesis for this study. It is anticipated that 
up to 10 subjects (minimum of 6 subjects) will be enrolled.  
8.3. 
Statistical Significance 
Statistical analyses will be descriptive in nature. 
8.4. 
Population for Analyses 
Two analysis populations are planned for this study, the Safety population and the PK population 
defined as follows: 
• The Safety Population will include all subjects who receive at least one dose of 
ataluren and will be used for all safety analyses. 
• The PK Population will include all subjects who receive at least 1 dose of ataluren 
and have at least 1 PK concentration datum. The PK Population will be used for all 
PK analyses. 
8.5. 
Specific Planned Statistical Analyses 
8.5.1. 
Subject Disposition and Baseline Characteristics 
The number of subjects in each analysis population will be summarized using frequency count.  
The number of subjects who completed or discontinued from the study and the reasons of 
discontinuation will be summarized based on both the Safety and the PK populations.  
Reasons for screening failures and early discontinuations, and time of withdrawal from study 
will be described.  
8.5.2. 
Use of Concomitant Medication and Supportive Therapy 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary into Anatomical Therapeutic Chemical classification codes. The type and timing of 
use of specific concomitant medications will be listed and summarized. 


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8.5.3. 
Primary Variables – Safety 
The primary safety analysis will use the Safety population and assess the type, frequency, 
severity (Section 7.6.7), seriousness (Section 7.6.2), timing, and relationship (Section 7.6.6) of 
TEAEs to study therapy.  
All TEAEs will be tabulated using the MedDRA classification system (Version 22.1 or higher). 
The severity of TEAEs will be graded using the CTCAE (Version 5.0 or higher) whenever 
possible. For TEAEs that are not included in the CTCAE, the grading categories (mild, 
moderate, severe, life-threatening, and fatal) described in Table 5 will be used. The frequency of 
subjects experiencing a specific TEAE will be tabulated by system organ class; preferred term; 
seriousness (serious vs nonserious); timing of occurrence, outcome, relationship to study drug; 
and worst severity. In the by-subject analysis, a subject having the same event more than once 
will be counted only once and will be classified at the highest severity and/or relatedness for 
those events. 
Adverse Events classified as CTCAE Grade ≥3; study-drug-related events; hepatic, and renal 
events leading to special diagnostic evaluations; events leading to discontinuation of ataluren, 
events leading to death, and SAEs will be considered with special attention. 
8.5.4. 
Secondary Variables - PK Parameters 
The PK analyses will be performed using the PK population defined above (Section 8.4). The PK 
parameters will be summarized and described using descriptive statistics and results placed into 
context with PK data from previous studies.  
The following PK parameters will be derived, when appropriate and data permitting, using 
noncompartmental analysis methods following the morning dose at baseline (Visit 2), Week 4 
(Visit 3), and EOT at Week 24 (Visit 5): 
• AUC will be derived using the linear trapezoidal rule during the ascending portion of 
the curve and the log-trapezoidal rule during the descending portion of the curve. 
AUC0-24 after the morning dose and AUC0-τ following every dose will be derived. 
• Cmax 
• Tmax 
• Ctrough (concentration prior to the morning dose) 
Apparent clearance (CL/F) and T1/2 may also be assessed, if feasible.  
The PK parameters will be investigated based on frequent blood sampling. At each assessment 
period, blood sampling will occur at pre-dose, and 1-, 2-, 3-, and 4-hours post-dose following the 
morning and mid-day ataluren doses, and at pre-dose, 1-, 2-, 3-, 4-, and 12- (before the next day 
dose) hours after the evening ataluren dose.  
Blood/plasma partitioning will be determined at 2.5 hour and 4.5 hour post morning ataluren 
dose at each visit. 


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8.5.4.1. 
PK Analysis Methods 
Observed values of plasma concentrations for ataluren will be summarized at baseline (Visit 2), 
Week 4 (Visit 3), and EOT at Week 24 (Visit 5). 
Individual PK parameters will be derived using actual sampling and dosing times. The PK 
parameters will be summarized with descriptive statistics at baseline (Visit 2), Week 4 (Visit 3), 
and EOT at Week 24 (Visit 5).(eg, n, arithmetic mean, standard deviation, standard error, 
median, min, and max, CV% mean, geometric mean, and CV% geometric mean). The analysis 
will be performed with a fully validated version of Phoenix WinNonlin V6.3 or higher.  
Additional information will be provided in the PK analysis plan.  
8.5.5. 
Other Variables  
8.5.5.1. 
Vital Signs and Physical Examination 
Vital signs (height, weight, BMI, systolic and diastolic BP, and heart rate) and physical 
examination data will be listed and summarized by visit and overall. Where appropriate, changes 
from baseline will be summarized by visit. 
8.5.5.2. 
Laboratory Values 
Laboratory data (hematology, biochemistry, and urinalysis) will be summarized by treatment 
visit and overall. Where appropriate, changes from baseline will be presented by visit. 
8.5.5.3. 
Electrocardiogram  
All ECG data will be listed and summarized by treatment visit and overall. Where appropriate, 
changes from baseline will be presented by visit. 
8.5.6. 
Treatment Administration and Drug Compliance 
For each subject, ataluren administration will be described in terms of the total duration of 
therapy, dose modifications, dose delays, and dose omissions, and reasons for deviations from 
planned therapy. 
Study drug administration data and compliance will be presented in a by-subject listing from data 
reported in the electronic data capture (EDC). 
 


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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations 
9.1.1. 
Informed Consent Process 
By signing the protocol, the investigator assures that written informed consent will be obtained 
from each subject’s parent(s)/caregiver(s) prior to study entry and that the informed consent will 
be obtained in accordance with current regulations. 
The investigator or sub-investigator must inform each subject’s parent(s)/caregiver(s) of the 
nature of the study, explain the potential risks, and obtain written informed consent from the 
subject’s parent(s)/caregiver(s) (as required by local regulations) prior to performing any 
study -related screening procedures. 
Each subject’s parent(s)/caregiver(s) must be given full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent document will be provided to each parent(s)/caregiver(s) in a language in 
which the parent(s)/caregiver is fluent. This information must be provided to the 
parent(s)/caregiver(s) prior to undertaking any study-related procedure. Adequate time should be 
provided for the parent(s)/caregiver(s) to read the informed consent, to understand the risks and 
benefits of participating in the study, and to ask any questions that the parent(s)/caregiver(s) may 
have about the study. The parent(s)/caregiver(s) should be able to ask additional questions as and 
when needed during the conduct of the study.  
Each subject’s parent(s)/caregiver(s) will be given a copy of the signed informed consent form. 
The original signed informed consent forms will be retained by the investigator with the study 
records. 
The written subject information must not be changed without prior approval by PTC and the 
IRB/IEC. 
9.1.2. 
Study Discontinuation and Closure 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the PTC medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time-period set by PTC. As directed by 
PTC, all study materials must be collected, and all electronic data entry forms completed to the 
greatest extent possible. 


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9.1.3. 
Confidentiality and Privacy 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs, paper CRFs, or other records provided to or retained 
by PTC (or its authorized designee). The names and identities of the subjects need not be 
divulged; however, the records must nevertheless be inspected. This will be accomplished by 
blanking out the subject’s name and replacing the name with the subject’s study identification 
number on any record provided to or retained by PTC. The informed consent form must include 
appropriate statements explaining these requirements. 
By signing this protocol, the investigator affirms to PTC that the investigator will maintain, in 
confidence, information furnished by PTC and will divulge such information to the IRB/IEC 
under an appropriate understanding of confidentiality with such board. 
9.1.4. 
Clinical Monitoring 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant International 
Council on Harmonization (ICH) guidelines, PTC or a designee will periodically inspect all 
eCRFs (see Section 9.1.10), study documents, research facilities, and clinical laboratory facilities 
associated with this study at mutually convenient times, before, during, and after completion of 
the study. As required by applicable regulations (Responsibilities of sponsors and investigators), 
the monitoring visits provide PTC with the opportunity to evaluate the progress of the study; 
verify the accuracy and completeness of data in the eCRFs; ensure that all protocol requirements, 
relevant regulations, and investigator’s obligations are being fulfilled; and resolve any 
inconsistencies in the study records. This includes inspection of all documents and records 
required to be maintained by the investigator, including but not limited to medical records 
(office, clinic, or hospital) for the subjects in this study. The names and identities of all research 
subjects will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by PTC. The investigator/institution guarantees direct access to source documents 
by PTC and appropriate regulatory authorities. 
The investigator site may also be subject to review by the IRB/IEC, to quality assurance audits 
performed by PTC or a designee, and/or to inspection by the Food and Drug Administration 
(FDA) and/or other regulatory authorities. The Investigational New Drug (IND) regulations also 
require the investigator to allow authorized representatives of the FDA to inspect and make 
copies of the same records. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
9.1.5. 
Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, the protocol, 
and the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for good clinical practice (GCP) (ICH 1996 and revisions), and the 
Declaration of Helsinki (World Medical Association).  


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The investigator is responsible for ensuring that the clinical study is performed in accordance 
with applicable legal and regulatory requirements, the Declaration of Helsinki, the ICH GCP 
guidance documents, and the protocol. 
9.1.6. 
Study Discontinuation and Closure 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the PTC medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time-period set by PTC. As directed by 
PTC, all study materials must be collected, and all electronic data entry forms completed to the 
greatest extent possible. 
9.1.7. 
Quality Assurance and Quality Control 
To ensure compliance with GCP and all applicable regulatory requirements, PTC, PTC’s 
representatives, a regulatory authority or and Institutional Review board may conduct a quality 
assurance audit. Reasons for quality assurance audit may include but are not limited to random 
selection, geographic proximity, suspected GCP violation, high enrolling site, recurring protocol 
deviations, etc. The purpose of a sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. 
The investigator should contact the sponsor immediately if contacted by a regulatory agency 
about an inspection. 
9.1.8. 
Institutional Review Board/Independent Ethics Committee 
Prior to enrollment of subject into the study, as required by the FDA and other regulatory 
authorities, the protocol and informed consent document will be reviewed and approved by an 
appropriate IRB/IEC. By signing the Statement of Investigator Form (FDA Form 1572), the 
investigator assures that approval of the study protocol will be obtained from the IRB/IEC and 
that all aspects of the IRB/IEC review will be conducted in accordance with current regulations. 
Amendments to the protocol will be subject to the same IRB/IEC review requirements as the 
original protocol. Only changes necessary to eliminate apparent immediate hazards to the 
subjects may be initiated prior to IRB/IEC approval. In that event, the investigator must notify 
the IRB/IEC and PTC in writing within 5 working days after implementation. The investigator 
will also promptly notify the IRB/IEC of any serious, unexpected AEs, or any other information 
that may affect the safe use of the drug during the study. 
A letter documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members must be received by PTC prior to the initiation of the study. All correspondence with 
the IRB/IEC should be retained in the investigator’s study file. 


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to PTC. As soon as possible after completion or termination of the study, the 
investigator will submit a final report to the IRB/IEC and to PTC. This report should include the 
dates of initiation and completion of the study, a description of any changes in study procedures 
or amendments to the protocol, any deviations from the protocol, the number and type of 
subjects evaluated, the number of subjects who discontinued (and the) reasons for 
discontinuation), the number of subjects who completed the study, and the results of the study, 
including a description of any AEs. PTC will assist the investigator in the preparation of this 
report, as needed. 
9.1.9. 
Data Handling and Record Keeping 
During the study, the investigator will maintain adequate records for the study, including medical 
records, source document records detailing the progress of the study for each subject, laboratory 
reports, a CD-ROM or paper copy of the data that have been captured in the EDC for each 
subject (electronic equivalents of CRFs), paper CRFs, signed informed consent forms, study 
drug disposition records, correspondence with the IRB/IEC, AE reports, and information 
regarding subject discontinuation and completion of the study. Current regulations require PTC 
(or an authorized designee) to inspect all documents and records required to be maintained by the 
investigator, including but not limited to medical records (office, clinic, or hospital) for the 
subjects enrolled in this study. These regulations also allow the same records to be inspected by 
authorized representatives of the FDA or other regulatory authorities. 
9.1.10. 
Case Report Forms  
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, reasons for screen failure, physicians’ notes, nurses’ notes, clinic charts, and other 
study-specific source documents). The eCRFs exist within a Web-based EDC system managed 
by the data management contract research organization (CRO) for this study. After the 
investigator or the investigator’s designees (eg, research coordinators) have been appropriately 
trained, they will be given access to the EDC system and will enter the data required by the 
protocol into the EDC system. Any change of data will be made via the EDC system, with all 
changes tracked by the system to provide an audit trail. 
With an electronic signature, the investigator certifies that the data are complete and accurate 
prior to database lock. This electronic signature serves to attest that the information contained in 
the eCRFs is true. After database lock, the investigator will receive a CD-ROM and/ or paper 
copies of the subject data for archiving at the investigator site. At all times, the principal 
investigator has final responsibility for the accuracy and authenticity of all clinical data entered 
onto the eCRFs and/or reported to PTC from the investigator site. 
9.1.11. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements.  
Deviations may result from the action or inaction of the subject, investigator, or site staff. 
Examples of deviations include, but are not limited to: 


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• Failure to adhere to study exclusion and inclusion criteria 
• Use of medications that are specifically prohibited in the protocol  
• Missed or out-of-window visits 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. - either tests not done, incorrect 
tests done, or not done within the time frame specified in the protocol  
• Procedural deviations such as failure to update the Informed Consent Form (ICF) 
when new risks become known, or failure to obtain IRB approvals for the protocol 
and ICF revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety or a subject’s ability to continue in the clinical 
study. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the CRO. This will include determining which deviations will be designated 
major; thus, requiring immediate notification to the PTC medical monitor and the sponsor. 
Prospective deviations (eg, protocol waivers) are prohibited per PTC policy. 
The investigator is responsible for seeing that any known protocol deviations are recorded 
handled as agreed. 
9.1.12. 
Publication and Data Sharing Policy 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Medical Officer or designee in collaboration with the investigator 
will be responsible for writing presentations and manuscripts for publication. Investigators will 
not be allowed to publish or present the data from this study without prior agreement with PTC. 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any 
public disclosure (including publicly accessible websites) related to the protocol or study results, 
other than study recruitment materials and/or advertisements, is the sole responsibility of the 
sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 


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Data from all sites participating in the study will be pooled and analyzed by the sponsor or the 
sponsor’s designee. The first publication of the study results shall be made in conjunction with 
the results from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 
The investigator will provide the sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication. The sponsor shall inform the investigator in writing of any changes or deletions 
in such presentation or publication required to protect the sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results. At the expiration of such 60-day period, the 
investigator may proceed with the presentation or submission for publication unless the sponsor 
has notified the institution or the investigator in writing that such proposed publication or 
presentation discloses the sponsor’s confidential and proprietary technical information. Further, 
upon the request of the sponsor, the investigator will delay the publication or presentation for an 
additional 90 days to permit the sponsor to take necessary actions to protect its intellectual 
property interests. 
9.2. 
Additional Considerations 
Not applicable 
9.3. 
Protocol Amendment History 
Version 1.0: 14 April 2020 
Amendment 1: 29 April 2021 (Version 2.0) 
Amendment 2: 01 July 2021 (Version 3.0) 
Amendment 3: 06 May 2022 (Version 4.0) 
9.3.1. 
Amendment 1: 29 April 2021 (Version 2.0) 
No. 
Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
1 
Protocol 
identifiers and 
study 
personnel, 
Protocol 
approval 
signatures 
Study personnel and protocol approvers were updated 
Update 
2 
Synopsis 
Synopsis was updated to reflect the changes in the 
protocol 
 
3 
List of 
Abbreviations 
List of abbreviations was updated to reflect the changes in 
the protocol 
Update 
4 
Protocol 
Document date/version were updated 
Update 
5 
Protocol 
Minor clarifications and editorial/formatting updates 
Update 
6 
Protocol 
Updated the end of treatment timepoint to occur at Week 
24 instead of Week 52 
Update 


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No. 
Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
7 
Protocol 
Removed efficacy endpoint from this study (ie, change in 
motor development).  
 
Removed the exploratory endpoint “abnormalities of 
physical findings, clinical laboratory tests, or 
electrocardiograms (ECGs)” since this information will be 
captured as part of the primary endpoint 
Update 
8 
Protocol 
Clarified that AUC would also be derived from time zero up 
to hour 6. 
 
The definition of Ctrough was clarified to trough 
concentration (plasma concentration pre morning dose). 
 
It was clarified that apparent volume of distribution (Vc/F) 
would not be assessed. 
Clarification 
9 
Protocol 
The following sections were removed: 
“End of Study Definition” 
“Motor Development” 
 
Section added on home care services at week 4. 
Update 
10 
Section 2.1  
The exploratory objective of “to assess changes from 
baseline in CK levels after 24 weeks of ataluren treatment” 
was added 
Update 
11 
Section 2.2  
The exploratory endpoint of “change from baseline in CK 
levels” was added 
Update 
12 
Section 3.2  
The following text was added: “A new request for 
modification is currently being reviewed by the agency.” 
Update 
13 
Section 3.1 
and 
Section 8.2  
Clarified the planned sample size for this study 
Clarification 


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No. 
Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
14 
Section 3.2  
Removed the following language from criterion 2 as this 
information is included in Exclusion Criterion 1: 
“Participant’s sibling, if enrolled in another ataluren study, 
must be on open-label study drug at the time of subject’s 
enrollment in this study”. 
 
Removed “Good general health, as determined by the 
investigator during the screening period based on medical 
history and physical examination (including vital sign 
measurements), as no clinically significant abnormal 
laboratory assessments” as this information is included in 
Exclusion Criterion 3. 
 
Removed the following language in relation to the 
diagnosis of Duchenne muscular dystrophy: “Medical 
documentation of phenotypic evidence of dystrophinopathy 
needs to be provided upon request by the PTC 
Therapeutics medical monitor” 
 
Clarified that the presence of a nonsense mutation of the 
dystrophin gene needs to be confirmed by a PTC designee 
prior to enrollment. 
 
Removed “verification that a blood sample was drawn for 
sequencing of the dystrophin gene” as an inclusion 
criterion 
Update 
15 
Section 3.3  
Removed “prior and concomitant use of corticosteroids” as 
an exclusion criterion. 
 
Clarified that subjects whose sibling is currently 
participating in a blinded portion of another ataluren study 
are excluded from this study 
Update 
16 
Section 5.1.2.1  Duration of treatment was changed from “52 weeks” to 
“24 weeks” 
Update 
17 
Section 5.1.2.2  Updated text to “weight will be reassessed at Week 12 and 
ataluren dosing adjusted accordingly” in line with the 
change to duration of treatment 
Update 
18 
Section 5.1.2.3  Duration of treatment was changed from “52 weeks” to 
“24 weeks” 
Update 
19 
Section 5.1.2.6  The following text was added: “During the course of the 
study, breastfeeding and milk formula are allowed as part 
of a normal alimentation regime.” 
Update 
20 
Section 5.1.5  
Removed exclusion of orange juice for the constitution of 
ataluren 
 
Language regarding study drug preparation was modified 
for clarity.  
Update 
21 
Section 5.3  
Updated text to ““Parents/caregivers should return all 
remaining study drug (all unused sachets and drug kits) to 
the study site at Week 12 (Visit 4), if the visit is conducted 
on-site, and EOT at Week 24 (Visit 5).” 
Update 
22 
Section 5.4.1  
Provided additional information regarding corticosteroid 
use in the study 
Update 


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No. 
Protocol 
Section 
Version 2.0/Update 
Reason/ 
Rationale 
23 
Section 7.1.2  
Duration of treatment was changed from “52 weeks” to 
“24 weeks” 
 
The following text was added for clarification: “Visit 2 will 
be conducted over the course of 24 hours due to the timing 
of the collection of PK samples and will require an 
overnight stay.” 
Update 
24 
Section 7.1.3  
and Table 2  
Updated the treatment phase to include Visit 3 (Week 4) 
and Visit 4 (Week 12) 
Update 
25 
Section 7.1.4  
Added that subjects who completed the 24-week treatment 
period in this study were offered participation to a follow-up 
extension period for at least 52 weeks from the date of first 
administration of ataluren in this parent study. 
Update 
26 
Section 7.3.3  
Added additional information related to confirmatory gene 
sequencing 
Update 
27 
Section 7.3.4  
Revised the process by which blood PK samples will be 
collected 
Update 
28 
Section 7.3.6 
and Table 2  
Clarified that heart rate and blood pressure determinations 
will be performed with the subject in a supine position 
Clarification 
29 
Section 7.4.1  
Clarified that “ataluren will be supplied at baseline and 
Week 12 (Visit 4)” 
Clarification 
30 
Section 7.5  
Clarified that clinical labs will be analyzed locally at the 
investigational sites 
Clarification 
31 
Section 7.5.1   
Updated to reflect the revisions to the study timepoints and 
updated the volume and process by which blood PK 
samples will be collected 
Update 
32 
Section 7.6.2  
It was clarified that emergency room visits that do not 
require admission to the hospital would not be reported as 
SAEs on that basis alone. 
Clarification 
33 
Section 7.6.11 
Details regarding PTC adverse event reporting were 
clarified. 
Clarification 
34 
Section 8.5.6  
Clarified that study drug administration will be presented in 
a by-subject listing 
Clarification 
35 
Section 9.3  
Updated protocol version history to reflect Version 2.0 
Update 


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9.3.2. 
Amendment 2: 01 July 2021 (Version 3.0) 
Protocol 
Section 
Version 3/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. Editorial and 
administrative revisions (eg, typographical error, punctuation, tenses, 
abbreviations) were incorporated to provide clarity. The synopsis and 
Schedule of Assessments were updated to be consistent with 
changes in the protocol.  
Update 
Section 5.1.2 
Section 5.3   
Details on the Study Drug Administration Record were clarified. 
Clarification 
Section 7.1.7 
Section on Home Care Services at Visit 4 was removed 
Update 
Section 7.3.4  
Blood/plasma partition sampling was added. 
Update 
9.3.3. 
Amendment 3: 06 May 2022 (Version 4.0) 
Protocol 
Section 
Version 3/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. Editorial and 
administrative revisions (including, personnel changes, and the 
addressing of minor editorial issues) were incorporated to provide 
clarity. The synopsis and Schedule of Assessments were updated to 
be consistent with changes in the protocol.  
Update 
Section 3.2  
Text, previously included in error, referring to agency review of a 
modification was deleted. 
Correction 
Section 7.1 , 
Table 2 
The window during which screening procedures can serve as baseline 
assessments was revised from 7 days to 14 days prior to baseline.  
Language was added to explicitly permit obtaining informed consent 
remotely in keeping with local policy and procedures. 
Urine protein: urine creatinine ratio (spot) was added to the list of 
clinical laboratory assessments.  
Language was added to allow for clinical laboratory assessments in 
keeping with standard of care to serve as the clinical laboratory 
assessments if conducted within the visit window. 
Update 
Section 7.1.2  
The window during which screening procedures can serve as baseline 
assessments was revised from 7 days to 14 days prior to baseline. 
Update 
Section 7.2.1  
Language was added to explicitly permit obtaining informed consent 
remotely in keeping with local policy and procedures. 
Update 
Section 7.3.2  
Urine protein: urine creatinine ratio (spot) was added to the list of 
clinical laboratory assessments. 
Update 
Section 7.5  
The phrase “or central” was added to clarify that either central or local 
laboratory analysis of clinical laboratory specimens is permitted.  
Clarification 
Section 8.5.4  
Clarification was provided regarding the pharmacokinetic analysis. 
Clarification 
 


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10. 
REFERENCES 
Aartsma-Rus, A, Ginjaar, IB and Bushby, K. The importance of genetic diagnosis for Duchenne 
muscular dystrophy. J Med Genet 2016;53(3):145-151. 
Aartsma-Rus, A, Van Deutekom, JC, Fokkema, IF, Van Ommen, GJ and Den Dunnen, JT. 
Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation 
types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 2006;34(2):135-
144. 
Beenakker, EA, Fock, JM, Van Tol, MJ, Maurits, NM, Koopman, HM, Brouwer, OF, et al. 
Intermittent prednisone therapy in Duchenne muscular dystrophy: a randomized controlled trial. 
Arch Neurol 2005a;62(1):128-132. 
Biggar, WD, Gingras, M, Fehlings, DL, Harris, VA and Steele, CA. Deflazacort treatment of 
Duchenne muscular dystrophy. J. Pediatr. 2001;138(1):45-50. 
Biggar, WD, Harris, VA, Eliasoph, L and Alman, B. Long-term benefits of deflazacort treatment 
for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 
2006;16(4):249-255. 
Bladen, CL, Salgado, D, Monges, S, Foncuberta, ME, Kekou, K, Kosma, K, et al. The TREAT-
NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy 
mutations. Hum Mutat 2015;36(4):395-402. 
Bushby, K, Finkel, R, Birnkrant, D, Case, LE, Clemens, PR, Cripe, L, et al. Diagnosis and 
management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. 
The Lancet 2010b;09:177-189. 
Bushby, K, Finkel, R, Birnkrant, DJ, Case, LE, Clemens, PR, Cripe, L, et al. Diagnosis and 
management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and 
psychosocial management. Lancet Neurol. 2010a;9(1):77-93. 
Bushby, K, Finkel, R, Wong, B, Barohn, R, Campbell, C, Comi, GP, et al. Ataluren treatment of 
patients with nonsense mutation dystrophinopathy. Muscle Nerve 2014;50(4):477-487. 
Du, M, Liu, X, Welch, EM, Hirawat, S, Peltz, SW and Bedwell, DM. PTC124 is an orally 
bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in 
a CF mouse model. Proc Natl Acad Sci U S A 2008;105(6):2064-2069. 
Fenichel, GM, Florence, JM, Pestronk, A, Mendell, JR, Moxley, RT, 3rd, Griggs, RC, et al. 
Long-term benefit from prednisone therapy in Duchenne muscular dystrophy. Neurology 
1991a;41(12):1874-1877. 
Fenichel, GM, Mendell, JR, Moxley, RT, 3rd, Griggs, RC, Brooke, MH, Miller, JP, et al. A 
comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular 
dystrophy. Arch Neurol 1991b;48(6):575-579. 
Goldmann, T, Overlack, N, Wolfrum, U and Nagel-Wolfrum, K. PTC124-mediated translational 
readthrough of a nonsense mutation causing Usher syndrome type 1C. Hum Gene Ther 
2011;22(5):537-547. 


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Griggs, RC, Moxley, RT, 3rd, Mendell, JR, Fenichel, GM, Brooke, MH, Pestronk, A, et al. 
Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and 
dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol 
1991;48(4):383-388. 
Kayali, R, Ku, JM, Khitrov, G, Jung, ME, Prikhodko, O and Bertoni, C. Read-through 
compound 13 restores dystrophin expression and improves muscle function in the mdx mouse 
model for Duchenne muscular dystrophy. Hum Mol Genet 2012;21(18):4007-4020. 
Kerem, E, Konstan, MW, De Boeck, K, Accurso, FJ, Sermet-Gaudelus, I, Wilschanski, M, et al. 
Ataluren for the treatment of nonsense-mutation cystic fibrosis: a , double-blind, placebo-
controlled phase 3 trial. The Lancet Respiratory Medicine 2014;2(7):539-547. 
Mah, JK. Current and emerging treatment strategies for Duchenne muscular dystrophy. 
Neuropsychiatric disease and treatment 2016;12:1795-1807. 
Mendell, JR, Moxley, RT, Griggs, RC, Brooke, MH, Fenichel, GM, Miller, JP, et al. 
Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N 
Engl J Med 1989;320(24):1592-1597. 
Muntoni, F, Torelli, S and Ferlini, A. Dystrophin and mutations: one gene, several proteins, 
multiple phenotypes. Lancet Neurol 2003;2(12):731-740. 
Pradhan, S, Ghosh, D, Srivastava, NK, Kumar, A, Mittal, B, Pandey, CM, et al. Prednisolone in 
Duchenne muscular dystrophy with imminent loss of ambulation. J Neurol 2006;253(10):1309-
1316. 
Rae, MG and O'Malley, D. Cognitive dysfunction in Duchenne muscular dystrophy: a possible 
role for neuromodulatory immune molecules. J Neurophysiol 2016;116(3):1304-1315. 
Tan, L, Narayan, SB, Chen, J, Meyers, GD and Bennett, MJ. PTC124 improves readthrough and 
increases enzymatic activity of the CPT1A R160X nonsense mutation. Journal of inherited 
metabolic disease 2011;34(2):443-447. 
Wang, B, Yang, Z, Brisson, BK, Feng, H, Zhang, Z, Welch, EM, et al. Membrane blebbing as an 
assessment of functional rescue of dysferlin-deficient human myotubes via nonsense 
suppression. J Appl Physiol (1985) 2010;109(3):901-905. 
Welch, EM, Barton, ER, Zhuo, J, Tomizawa, Y, Friesen, WJ, Trifillis, P, et al. PTC124 targets 
genetic disorders caused by nonsense mutations. Nature 2007;447(7140):87-91. 
 

SAP_001.pdf: 
V1.0 
PTC Therapeutics - Confidential 
Page 1 of 26 
STATISTICAL ANALYSIS PLAN 
AN OPEN-LABEL STUDY EVALUTATING THE SAFETY AND 
PHARMACOKINETICS OF ATALUREN IN CHILDREN FROM 
≥6 MONTHS TO <2 YEARS WITH NONSENSE MUTATION DUCHENNE 
MUSCULAR DYSTROPHY 
PTC124-GD-048-DMD 
01 JUNE 2023 
VERSION 1.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information belonging to PTC Therapeutics, 
Inc. Except as may be otherwise permitted in writing, by accepting or reviewing these materials, it is agreed that this 
information should not be disclosed to others (except where required by applicable law) and should not be used for 
unauthorized purposes. In the event of an actual or suspected breach of this obligation, PTC Therapeutics, Inc. should 
be notified promptly. 
NCT #: NCT04336826


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APPROVAL SIGNATURES 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 


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TABLE OF CONTENTS 
APPROVAL SIGNATURES...........................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................7 
2. 
STUDY OVERVIEW ...................................................................................................8 
2.1. 
Study Design .................................................................................................................8 
2.2. 
Study Objectives ...........................................................................................................8 
2.2.1. 
Primary Objective .........................................................................................................8 
2.2.2. 
Secondary Objectives ...................................................................................................8 
2.2.3. 
Exploratory Objectives .................................................................................................9 
2.3. 
Study Endpoints ............................................................................................................9 
2.3.1. 
Primary Endpoint ..........................................................................................................9 
2.3.2. 
Secondary Endpoints ....................................................................................................9 
2.3.3. 
Exploratory Endpoints ..................................................................................................9 
2.4. 
Sample Size ..................................................................................................................9 
2.5. 
Randomization ..............................................................................................................9 
2.6. 
Blinding ........................................................................................................................9 
2.7. 
Study Assessments ........................................................................................................9 
2.7.1. 
Physical Examination ...................................................................................................9 
2.7.2. 
Laboratory Assessment ...............................................................................................10 
2.7.3. 
Confirmation Gene Sequencing ..................................................................................10 
2.7.4. 
Pharmacokinetic Assessment ......................................................................................10 
2.7.5. 
Height, Weight, and Body Mass Index .......................................................................10 
2.7.6. 
Vital Signs ..................................................................................................................10 
2.7.7. 
Electrocardiogram .......................................................................................................10 
2.7.8. 
Adverse Events ...........................................................................................................10 
2.7.9. 
Concomitant Medications ...........................................................................................11 
3. 
STUDY POPULATIONS ...........................................................................................12 
3.1. 
Safety Population ........................................................................................................12 
3.2. 
PK Population .............................................................................................................12 
4. 
GENERAL CONSIDERATIONS ..............................................................................13 


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4.1. 
Tables, Figures, and Listings ......................................................................................13 
4.2. 
Baseline and Endpoint Definitions .............................................................................13 
4.3. 
Interim Analyses .........................................................................................................13 
4.4. 
Missing Data Handling ...............................................................................................13 
4.5. 
Analysis Visits ............................................................................................................13 
5. 
SUBJECT DATA .......................................................................................................14 
5.1. 
Subject Disposition and Study Populations ................................................................14 
5.2. 
Duration of Treatment with Study Drug .....................................................................14 
5.3. 
Treatment Administration and Drug Compliance ......................................................14 
5.4. 
Demographic and Baseline Characteristics ................................................................14 
5.5. 
Disease Characteristics ...............................................................................................14 
5.6. 
Medical History ..........................................................................................................14 
5.7. 
Concomitant Medications and Non-Drug Treatments ................................................14 
6. 
EFFICACY EVALUATION ......................................................................................16 
6.1. 
Primary Analysis ........................................................................................................16 
6.2. 
Exploratory Endpoints ................................................................................................16 
7. 
ATALUREN CONCENTRATIONS AND PHARMACOKINETIC 
PARAMETERS ..........................................................................................................17 
7.1. 
Descriptive Analysis ...................................................................................................17 
7.2. 
Blood and Plasma Concentrations ..............................................................................17 
7.3. 
Blood Pharmacokinetic Parameters ............................................................................17 
8. 
SAFETY EVALUATION ..........................................................................................20 
8.1. 
Adverse Events ...........................................................................................................20 
8.2. 
Clinical Laboratory .....................................................................................................20 
8.3. 
Electrocardiogram .......................................................................................................20 
8.4. 
Physical Examination .................................................................................................20 
8.5. 
Vital Signs ..................................................................................................................21 
9. 
CHANGES FROM THE PROTOCOL ......................................................................22 
10. 
BIBLIOGRAPHY .......................................................................................................23 
11. 
TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS...................24 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................25 
 


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LIST OF TABLES 
Table 1:Clinical Laboratory Parameters ........................................................................................20 
 


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 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE 
Adverse event 
BMI 
Body mass index 
BP 
Blood pressure 
CK 
Creatine kinase 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DMD 
Duchenne muscular dystrophy 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day 
WHODRUG 
World Health Organization Drug Dictionary 


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1. 
OVERVIEW 
This statistical analysis plan (SAP) details the statistical methods to be used in the analyses and 
presentation of the data collected in Study PTC124-GD-048-DMD, also referred to as Study 048. 
This document is prepared on the basis of the final study protocol version 4.0 (dated 
06May2022). The reader is referred to the study protocol, the electronic case report form 
(eCRF), general eCRF completion guidelines, and various data collection instruments employed 
in the study for details of study design, conduct and data collection. 
This SAP is to be reviewed and approved prior to the study database lock. 


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2. 
STUDY OVERVIEW 
2.1. 
Study Design 
Study 048 is a Phase 2, open-label study to evaluate safety, tolerability, and PK of ataluren in 
male children with nmDMD aged ≥6 months to <2 years of age treated three times a day (TID) 
for 24 weeks with orally administered ataluren 10, 10, 20 mg/kg (morning, mid-day, and evening 
dose, respectively). 
This study will include five on-site visits, each at screening (Visit 1), Week 0 (Visit 2), Week 4 
(Visit 3), Week 12 (Visit 4), and Week 24 (Visit 5) and one follow-up phone call at Week 28 
(Visit 6). A minimum of 6 subjects (up to 10 subjects) will be selected according to the study 
inclusion and exclusion criteria. Visits 2, 3, and 5 will be conducted over the course of 24 hours 
due to the timing of the collection of PK samples and will require an overnight stay. 
Ataluren administration will begin at baseline (Visit 2) and continue for up to 24 weeks. Three 
ataluren doses should be taken per day; the first dose in the morning, the second dose during the 
middle of the day (mid-day), and the third dose in the evening. Ideally each dose should be taken 
within ~30 minutes after a meal (eg, ~7:00 AM after breakfast, ~1:00 PM after lunch, and ~7:00 
PM after dinner). Intervals for dosing should be ~6 hours (±1 hour) between morning and mid-
day doses, ~6 hours (±1 hour) between mid-day and evening doses, and ~12 hours (±1 hour) 
between evening doses and the morning dose on the next day. 
The study will include 3 PK profile assessments (baseline, Week 4, and end of treatment (EOT) 
at Week 24). At these visits, PK parameters will be investigated based on blood sampling at pre-
dose, and 1-, 2-, 3-, and 4-hours post-dose following both the morning and mid-day ataluren 
doses, and immediately pre-dose, and 1, 2, 3, 4 and 12 (before the next day morning dose) hours 
post-dose following the evening dose. The PK parameters, including AUC0-24 (following the 
morning dose), AUC0-tau (AUC0-6 following the morning and mid-day dose and AUC0-12 
following the evening dose), and Tmax, Cmax, Ctrough after each dose. If feasible, apparent 
clearance (CL/F), and T1/2 will also be assessed after each dose. Additional samples will be taken 
at 2.5 hours and 4.5 hours post morning dose to be processed to plasma. 
Data from clinical labs, vital signs, ECGs, and physical examinations will be collected at each 
on-site visit (note: ECG data are not collected at Week 12/Visit 12). The detailed schedule of 
assessments is attached in Appendix 1. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of ataluren in male 
children with nmDMD aged ≥6 months to <2 years old. 
2.2.2. 
Secondary Objectives 
The secondary objective of this study is to assess the PK of ataluren in male children with 
nmDMD aged ≥6 months to <2 years old. 


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2.2.3. 
Exploratory Objectives 
The exploratory objective of this study is to assess changes from baseline in creatine kinase (CK) 
levels. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoint 
The primary endpoint of this study is the overall safety profile of ataluren in terms of type, 
frequency, severity, seriousness, timing, and relationship to study therapy of any TEAE during 
the 24 weeks of treatment. 
2.3.2. 
Secondary Endpoints 
The secondary endpoint of this study is the evaluation of PK parameters after 24 weeks of 
treatment as follows: 
• AUC0-24 and AUC0-6 
• Tmax 
• Cmax 
• Ctrough 
2.3.3. 
Exploratory Endpoints 
Changes from baseline in CK levels after 24 weeks of treatment 
2.4. 
Sample Size 
Sample size is not based on any formal statistical hypothesis for this study. It is anticipated that 
up to 10 subjects (minimum of 6 subjects) will be enrolled. 
2.5. 
Randomization 
Not applicable for this study. 
2.6. 
Blinding 
Not applicable for this study. 
2.7. 
Study Assessments 
2.7.1. 
Physical Examination 
A full physical examination (including evaluation of cardiovascular system, chest and lungs, 
thyroid, abdomen, nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, 
mouth, throat, spine, lymph nodes, and extremities) will be conducted at Screening (Visit 1), 
Week 0 (Baseline/Visit 2), Week 4 (Visit 3), Week 12 (Visit 4), and Week 24 (Visit 5- 
EOT/Early Termination). 


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2.7.2. 
Laboratory Assessment 
Hematology, biochemistry, and urinalysis laboratory assessment will be analyzed by the local 
laboratory at the investigative site. These parameters will be collected at Screening (Visit 1), 
Week 0 (Visit 2/Baseline), Week 4 (Visit 3), Week 12 (Visit 4), and Week 24 (Visit 5 - 
EOT/Early Termination). 
2.7.3. 
Confirmation Gene Sequencing 
A blood sample for dystrophin gene sequencing to confirm the presence of a nonsense mutation 
will be drawn at screening (Visit 1). 
2.7.4. 
Pharmacokinetic Assessment 
The PK parameters will be evaluated based on frequent blood sampling During PK assessments 
at baseline (Visit 2) Week 4 (Visit 3), and EOT at Week 24 (Visit 5), subjects will remain in the 
clinic until all blood draws are complete. At each assessment period, blood sampling will occur 
immediately pre-dose, and at 1-, 2-, 3-, and 4-hours post-dose following the morning and midday 
doses and immediately pre-dose and at 1, 2, 3, 4 and 12 (before the next day morning dose) 
hours post-dose following the evening ataluren dose. The PK parameters, including AUC0-24 
(following the morning ataluren dose), AUC0-tau (AUC0-6 following the morning and mid-day 
ataluren doses and AUC0-12 following the evening ataluren doses), Tmax, Cmax, and Ctrough 
after each dose will be assessed. 
The blood/plasma partition sampling will occur at 2.5 hour and 4.5 hour post morning dose at 
baseline (Visit 2), Week 4 (Visit 3), and EOT at Week 24 (Visit 5). 
2.7.5. 
Height, Weight, and Body Mass Index 
Height (in cm), weight (in kg) and body mass index (BMI) (kg/m2) will be measured at all study 
visits. 
2.7.6. 
Vital Signs 
Vital signs (heart rate and systolic and diastolic blood pressure [BP]) will be monitored at all 
protocol -required study visits. Heart rate and BP determinations will be performed with the 
subject in a supine position after a 5-minute rest. 
2.7.7. 
Electrocardiogram 
A 12-lead ECG will be obtained at screening (Visit 1), baseline (Visit 2), Week 4 (Visit 3), and 
EOT at Week 24(Visit 5). The ECGs will be read locally at investigational sites and interpreted 
for clinical significance. The findings will be captured in source documents and within the eCRF. 
2.7.8. 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered related to the drug. 
All AEs (both serious and nonserious) that occur in subjects during the AE reporting period must 
be recorded. All AEs are to be recorded in the source documents and on the eCRF using concise 


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medical terminology; whenever possible terms contained in Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. 
2.7.9. 
Concomitant Medications 
Concomitant medication information will be collected and documented at each scheduled clinic 
visit, from screening (Visit 1) through EOT at Week 24 (Visit 5) and at the post-treatment 
follow-up visit (if applicable). 


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3. 
STUDY POPULATIONS 
3.1. 
Safety Population 
The safety population will include all subjects who receive at least one dose of ataluren and will 
be used for all safety analyses. 
3.2. 
PK Population 
The PK population will include all subjects who receive at least one dose of ataluren and have 
one PK concentration datum. The PK population will be used for all PK analyses. 


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4. 
GENERAL CONSIDERATIONS 
4.1. 
Tables, Figures, and Listings 
Summary statistics for continuous variables will include n (number of subjects), mean, median, 
minimum, and maximum. For PK analysis, n, mean, SD, coefficient of variation (CV), geometric 
mean, and geometric mean CV will also be provided for PK population only. Summary statistics 
for categorical variables will include N (number of subjects in population), n (number of subjects 
in category), % (percent of subjects in category). Where applicable, the summary data will also 
be provided in graphical presentation. 
By-subject data listings will be created for each eCRF domain sorted by treatment, subject, and 
associated dates, where applicable. 
4.2. 
Baseline and Endpoint Definitions 
The study baseline, defined as the last assessment prior to the first dose of ataluren, will be used 
for analyzing and summarizing safety endpoints. 
4.3. 
Interim Analyses 
There is no interim analysis planned for this study. 
4.4. 
Missing Data Handling 
No missing value imputation will be applied to this study. 
4.5. 
Analysis Visits 
All data analyses for this study will be performed based on nominal visits collected on the eCRF. 


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5. 
SUBJECT DATA 
All subject data described in this section will be summarized based on safety population. 
Additional summaries will be provided based on PK population if PK population is different 
from the safety population in demographic tables. 
5.1. 
Subject Disposition and Study Populations 
The number of subjects in each analysis population will be summarized using frequency count. 
The number of subjects who completed or discontinued from the study and the reasons of 
discontinuation will be summarized based the safety population. Reasons for screening failures 
and early discontinuations, and time of withdrawal from study will also be summarized. 
5.2. 
Duration of Treatment with Study Drug 
Duration of treatment with study drug during study will be calculated as: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 − 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔+ 1 
Duration of treatment with study drug in days will be presented in by-subject listing only on 
safety population. 
5.3. 
Treatment Administration and Drug Compliance 
Study drug administration information including study drug start and end dates, dose 
interruptions start and stop dates, and reasons for dose interruption or dose deviations will be 
presented in a by-subject listing based on safety population. 
5.4. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics including age (in month), gender, race, ethnicity, 
height, weight, and BMI will be summarized for safety population. 
5.5. 
Disease Characteristics 
Disease characteristics including prior dystrophin gene sequencing, location of nonsense point 
mutation, and stop codon type will be provided in the by-subject listings only. Age at diagnosis 
of dystrophinopathy, signs/symptoms/laboratory results used to support diagnosis will be listed 
as well. 
5.6. 
Medical History 
Medical history will be presented in the by-subject listing for safety population. 
5.7. 
Concomitant Medications and Non-Drug Treatments 
Concomitant medications and non-drug treatments will be coded using the World Health 
Organization Drug Dictionary (WHODD), version March 2023 or higher. 
Prior medications and non-drug treatments are defined as those taken any time prior to the first 
dose of ataluren (Week 0). Concomitant medications and non-drug treatments are defined as 
those taken any time during the study treatment period (the first dose date of Ataluren through 
the last follow-up date within study). 


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The use of concomitant medications and non-drug treatments will be listed. 


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6. 
EFFICACY EVALUATION 
No functional assessments will be captured for this study. The change from baseline in the CK 
levels will be considered as an exploratory efficacy endpoint for this study. 
6.1. 
Primary Analysis 
Not applicable to this study. 
6.2. 
Exploratory Endpoints 
Summary tables on change from baseline in CK levels by visits will be provided. 


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7. 
ATALUREN CONCENTRATIONS AND PHARMACOKINETIC 
PARAMETERS 
7.1. 
Descriptive Analysis 
Descriptive statistics (n, mean, SD, CV%, Geo mean, Geo CV%, median, min, and max) will be 
used to summarize the blood and plasma ataluren concentrations at each timepoint and PK 
parameters by cycle, day, and dose interval at 2.5 hour and 4.5 hour post morning ataluren dose 
at each visit. 
7.2. 
Blood and Plasma Concentrations 
Blood and plasma concentration values below the quantitation limit (BQL) of the bioanalytical 
assays were treated as zero for the descriptive statistics. Individual values that were BQL were 
presented as BQL in the concentration data listing. For the presentation of summary and order 
statistics, if at least 1 subject had a concentration value BQL for the given timepoint, then the 
minimum value was displayed as BQL. If over 50% of the subjects at a given timepoint have 
values BQL then the descriptive statistics will not be presented and will instead display as 
‘<LLOQ’ for the mean and missing for all other statistics. Concentration values that were BQL 
were considered missing for any ratio or natural log transformed statistical analyses. 
7.3. 
Blood Pharmacokinetic Parameters 
Blood PK parameters for ataluren will be estimated using non-compartmental methods with 
WinNonlin®. Any data points designated as anomalous values that would impact PK should be 
predefined before database lock if possible and identified in the report with a rationale for 
exclusion. The PK parameters will be estimated from the concentration-time profiles, and AUCs 
will be calculated using the Linear-Log Trapezoidal method (equivalent to the linear up / log 
down option in WinNonlin). For the estimation of PK parameters, BQL concentration following 
first dose at pre-dose and up to the first measurable concentration will be set to zero, BQL 
concentration will be set to missing otherwise. Actual sampling times, rather than scheduled 
sampling times, will be used in all computations involving sampling times. Actual dose will be 
used to calculate dose-dependent parameters. Parameters will be summarized by dose (morning, 
mid-day, evening) and entire day, and visits (baseline, Week 4, and EOT at Week 24). AUC0-tau 
and AUC0-inf for a subject at any specific dose interval will be reported as NR (not reportable) 
if there is one sample missing during the dose interval, and consequently the AUC0-24 for the 
subject at the specified day will be reported as NR. 
The following blood PK parameters will be determined using non-compartmental methods as 
appropriate, for each visit: 
Parameter 
Description 
Dose 
Cmax 
Maximum blood concentration; determined directly from the 
concentration time profile; if the maximum blood concentration 
occurs at more than one time point, Cmax is defined as the first 
maximum value. 
Morning, Mid-
day, Evening 
Tmax 
Time to Cmax; if the maximum value occurs at more than one time 
point, Tmax is defined as the first time point with this value. 
Morning, Mid-
day, Evening 
Ctrough 
Trough blood concentration; measured blood concentration at the 
end of the dosing interval, directly before next administration. 
Morning,  


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Parameter 
Description 
Dose 
AUC0-24 
Area under the blood concentration vs time curve (AUC) from time 
0 to 24 hours post first morning dose. 
Morning 
AUC0-τ 
AUC from time 0 to 6 hours post-dose following the morning and 
mid-day ataluren doses and AUC from time 0 to 12 hours post-
dose following the evening ataluren doses. AUC from time 0 to 6 
hours post-dose following the evening ataluren dose will also be 
calculated. 
Morning, Mid-
day, Evening 
AUC0-t 
AUC from time 0 to the last quantifiable blood concentration (Clast) 
Morning, Mid-
day, Evening 
AUC0-inf 
AUC from time 0 to infinity; calculated as (AUC0-τ + Clast/λz) 
Morning, Mid-
day, Evening 
AUC%extrap 
Percent of AUC0-inf extrapolated, represented as (1 – AUC0-t/AUC0-
inf)*100. 
Morning, Mid-
day, Evening 
λz 
Apparent first-order terminal elimination rate constant calculated 
from a semi-log plot of the blood concentration versus time curve.  
The parameter will be calculated by linear least-squares 
regression analysis using points in the terminal log-linear phase. 
Morning, Mid-
day, Evening 
T1/2 
Apparent first-order terminal half-life; calculated as ln(2)/λz 
Morning, Mid-
day, Evening 
CL/F 
Apparent total blood clearance after oral administration; calculated 
as Dose/AUC0-inf 
Morning, Mid-
day, Evening 
Vz/F 
Apparent volume of distribution during terminal elimination phase 
after oral administration; calculated as Dose/[λz* AUC0-inf] 
Morning, Mid-
day, Evening 
ARCmax 
Accumulation ratio calculated as Cmax Visit 3 Dose / Cmax Visit 2 
Dose 
Morning, Mid-
day, Evening  
ARCmax 
Accumulation ratio calculated as Cmax Visit 5 Dose / Cmax Visit 2 
Dose 
Morning, Mid-
day, Evening  
 ARAUC 
Accumulation ratio calculated as AUC0-τ Visit 3 Dose / AUC0-τ Visit 
2 Dose 
Morning, Mid-
day, Evening  
 ARAUC 
Accumulation ratio calculated as AUC0-τ Visit 5 Dose / AUC0-τ Visit 
2 Dose 
Morning, Mid-
day, Evening  
Planned dose will be used for the derivation of dose-dependent PK Parameters, planned dose will 
be determined with use of the PTC124-GD-048-DMD Ataluren Dosing Table (10-, 10-, 20-
mg/kg). 
In order to estimate the apparent first-order terminal elimination constant, λz, linear regression of 
concentration in logarithmic scale versus time will be performed using at least three data points 
spanning 1.5 T1/2. Uniform weighting will be selected to perform the regression analysis to 
estimate λz. The constant λz will not be assigned if one of the following occurs: 
1. The terminal elimination phase is not linear (as it appears on a semi-logarithmic scale) as 
determined by R2adj <0.8. 
2. The terminal elimination rate constant indicates a positive slope (λz > 0). 
3. Tmax is one of the three last data points. 
Subject experiences vomiting within 3 hours of dose administration will be flagged for the dose 
period and the day. The PK parameters of the flagged period and day will be excluded from 
descriptive analysis. Subjects experienced other deviations which may significantly impact PK 
analysis may be flagged and excluded from descriptive analysis for the specified dose 
period/day. 


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No PK parameters will be calculated for subjects with two or fewer detectable concentrations in 
their PK profile. 
No value for λz, AUC0-inf, AUC%extrap, CL/F, Vz/F, or T½ will be reported for cases that do not 
exhibit an acceptable terminal log-linear phase in the concentration-time profile. 


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8. 
SAFETY EVALUATION 
8.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 26.0 or higher) lower level 
term closest to the verbatim term. The linked MedDRA Preferred Terms (PT) and primary 
system organ class (SOC) are also captured in the database. The severity of AEs will be graded 
using the latest version of the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0. 
A treatment-emergent adverse event (TEAE) during study is defined as an AE that occurs or 
worsens while on ataluren (on or after first dose of ataluren) up to 4 weeks after last dose of 
ataluren. 
Only those AEs that are treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. An overview table of 
TEAEs, including number of subjects with TEAEs, treatment-emergent serious adverse events 
(SAEs), deaths, TEAEs classified as CTCAE Grade 3 or higher, study drug related TEAEs, 
TEAEs leading to study drug withdrawal will be provided. A summary table on the incidence of 
TEAEs by SOC and PT will be produced. 
In the summary tables subjects may be counted under multiple SOCs and PTs, but for each SOC 
and PT, subjects are only counted once. If a subject has the same AE on multiple occasions, the 
highest severity (5=fatal, 4=life-threatening, 3=severe, 2=moderate, 1=mild) recorded for the 
event will be presented and the highest drug relationship (1 = ‘Unrelated’, 2 = ‘Unlikely to be 
Related’, 3 = ‘Possibly Related’, 4 = ‘Probably Related’), reclassified into Related (‘Possibly 
Related’, ‘Probably Related’) or Not Related (‘Unrelated’), will be presented on the respective 
tables. Percentages are based on the number of subjects in the safety population. 
8.2. 
Clinical Laboratory 
Mean and mean change from baseline in clinical laboratory parameters listed in Table 1 will be 
summarized at each scheduled visit. Shift tables for laboratory parameters listed in Table 1 from 
baseline to each of the post-baseline visit will also be provided. Other laboratory parameters will 
be presented in the by-subject listings only. 
Table 1:Clinical Laboratory Parameters 
Type 
Parameters 
Biochemistry 
creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-
glutamyl transferase, creatinine kinase, and cystatin C 
8.3. 
Electrocardiogram 
Overall interpretation of ECG data, including normal, abnormal and clinically significant, 
abnormal and not clinically significant will be presented in the by-subject listings only. 
8.4. 
Physical Examination 
Physical examination results will be presented in the by-subject listings only. 


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8.5. 
Vital Signs 
Mean and mean change from baseline in height, weight, and vital signs data will be summarized 
by visit. The hypertension status will be classified as below based on age, gender, and height-
adjusted systolic or diastolic BP percentile results [Flynn 2017]. The hypertension status will be 
summarized by visit. 
• Normal BP: BP <90th percentile for age, sex, and height; or <120/<80 mm Hg for 
adolescents ≥13 years old; 
• Elevated BP: BP reading ≥90th percentile and <95th percentile for age, sex, and 
height; or 120 to 129/<80 mm Hg for adolescents ≥13 years old; 
• Hypertension: BP ≥95th percentile for age, sex, and height; or ≥130/80 mm Hg for 
adolescents ≥13 years old. 


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9. 
CHANGES FROM THE PROTOCOL 
No changes are made to the planned analyses from the study protocol. 


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10. 
BIBLIOGRAPHY 
Flynn, JT and Falkner, BE. New Clinical Practice Guideline for the Management of High Blood 
Pressure in Children and Adolescents. Hypertension 2017;70(4):683-686. 


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11. 
TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS 
The tables, listings, and graphs shells for the study will be provided in a separate document. 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Period 
Screeninga Baseline/ 
Start of 
Treatmentb 
Treatment Phase 
EOT/ETc 
Post- 
Treatment 
Follow-
Up/ EOSd 
Visit 
Visit 1 
Visit 2e 
Visit 3e 
Visit 4 
Visit 5e 
Visit 6 
Week 
- 
Week 0 
Week 4 
Week 12 
Week 24 
Week 28 
Visit Window (days) 
(-28 to -1) 
0 
±7 
±7 
±7 
±7 
Eligibility 
 
 
 
 
 
 
Informed Consentf 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Medical/Surgical 
History 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
Physical Examinationg 
X 
X 
X 
X 
X 
 
Clinical Labsh 
X 
X 
X 
X 
X 
 
Blood Sample for 
Gene Sequencingi 
X 
 
 
 
 
 
Height/Weightj/BMI 
X 
X 
X 
X 
X 
 
Vitals (HR and BP)k 
X 
X 
X 
X 
X 
 
ECGl 
X 
X 
X 
 
X 
 
AE/SAE Monitoring 
X 
X 
X 
X 
X 
X 
Concomitant 
Medicationsm 
X 
X 
X 
X 
X 
X 
PK Blood Sampling 
(VAMS)n 
 
X 
X 
 
X 
 
Blood/Plasma Partition 
Samplingo 
 
X 
X 
 
X 
 
Study Drug 
Administration 
 
 
 
 
 
 
Dispense Drug 
 
X 
 
X 
 
 
Unused Drug 
Return/Compliance 
 
 
X 
Xp 
X 
 
Abbreviations: AE, adverse event; BMI, body mass index; BP, blood pressure; CL/F, apparent clearance; Ctrough, 
trough concentration (plasma concentration pre morning dose); ECG, electrocardiogram; EOS, end of study; EOT, 
end of treatment; ET, early termination; HR, heart rate; PK, pharmacokinetic; SAE, serious adverse event; VAMS, 
volumetric absorptive microsampling 
a Screening procedures must take place within 28 days of baseline (Visit 2). 
b Any screening procedure completed within and including 14 days of baseline (Visit 2) can serve as baseline 
assessment and does not need to be repeated at Visit 2. 
c Subjects who terminate the study early are to complete all assessments required for EOT/ET (Visit 5) prior to 
leaving the study and will be contacted by phone 4 weeks from the final dose of study medication for the post-
treatment follow-up/EOS (Visit 6). 
d Post-treatment follow-up will be conducted by phone 4 weeks ± 7 days from last day of study treatment for review of 
adverse events and concomitant medications. Post-treatment follow-up is not required if subjects are transitioning to 
another ataluren clinical trial. 
e Visits 2, 3, and 5 will be conducted over the course of 24 hours due to the timing of the collection of PK samples 
and will require an overnight stay. 
f A signed and dated informed consent must be obtained before conducting any study procedures. Remote informed 
consent is permitted consistent with local policies and procedures. 
g A full physical examination will include evaluation of the cardiovascular system, chest and lungs, thyroid, abdomen, 
nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, mouth, throat, spine, lymph nodes, 
and extremities. 


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h  Blood and urine collection will be obtained locally and submitted to the local or central laboratory for analysis. Use 
of standard of care labs is permitted when samples were obtained within the visit window. Clinical labs will include 
hematology, biochemistry, and urinalysis parameters as follows: Hematology laboratory assessments will include 
white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. 
Biochemistry laboratory assessments will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (total, direct, and 
indirect), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatinine kinase, 
lactate dehydrogenase, alkaline phosphatase, total cholesterol, high density lipoprotein, low density lipoprotein, 
triglycerides, and cystatin C. Urinalysis assessments will include analysis for pH, specific gravity, glucose, ketones, 
blood, protein, urobilinogen, bilirubin, nitrite, urine protein: urine creatinine ratio (spot), and leukocyte esterase.  
i This is to ensure a blood sample has been drawn for sequencing of the dystrophin gene. The sample will be sent to 
a central laboratory for analysis. 
j Weight-based dose adjustment will be assessed at Week 12. 
k Heart rate and BP determinations will be performed with the subject in a supine position after a 5-minute rest. 
l ECGs will be read locally at investigational sites and interpreted for clinical significance.  
m Concomitant medication information will need to be collected starting 28 days prior to the first dose of study drug 
(Screening, Visit 1). 
n PK samples (VAMS method) will be drawn at baseline (Visit 2), Week 4 (Visit 3), and Week 24 (EOT/ET) for 
evaluation. Samples will be drawn immediately pre-dose, and at 1-, 2-, 3-, and 4-hours post-dose following both the 
morning and mid-day doses and immediately pre-dose and at 1-, 2-, 3-, 4-, and 12- (before the next day morning 
dose) hours post-dose following the evening dose. 
o Blood sampling via venous draw will be conducted at Visits 2, 3, and 5. These additional samples will be taken at 
2.5 -hours and 4.5 -hours post morning dose (1.5 ml each timepoint). Out of the 1.5 mL blood sample collected, at the 
2.5 hour and 4.5 hour timepoints, 1 mL blood sample will be processed to plasma and the remaining 0.5 mL blood will 
be processed to dried blood sample using a VAMS device. 
p Parent(s)/caregiver(s) will record daily dose administration on a Study Drug Administration Record (dosing sheet) 
and Subjects are required to return any unused study drug.