Clinical trial NCT03648827
Conditions: Duchenne Muscular Dystrophy
Sponsor: PTC Therapeutics
Start date: 2018-12-21; Completion date: 2020-10-23
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the ability of ataluren to increase dystrophin protein levels in muscle cells of participants with nmDMD. The study will evaluate the levels of dystrophin before and after 40 weeks of ataluren therapy using muscle biopsies and 2 validated assay methods, electrochemiluminescence (ECL) and immunohistochemistry.

Detailed description:

Arms: arm 1: Participants will receive ataluren oral suspension 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 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: 
V3.0 
PTC Therapeutics, Inc. - Confidential 
Page 1 of 53 
CLINICAL PROTOCOL 
PHASE 2 CLINICAL PHARMACOLOGY STUDY TO ASSESS 
DYSTROPHIN LEVELS IN SUBJECTS WITH nmDMD BEFORE AND 
AFTER TREATMENT WITH ATALUREN 
PTC124-GD-045-DMD 
06 MAY 2019 
VERSION 3.0 
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 #NCT03648827


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
PTC Therapeutics 
Name of Investigational Product: 
Ataluren  
Title of Study:  
Phase 2 clinical pharmacology study to assess dystrophin levels in subjects with nonsense mutation 
Duchenne muscular dystrophy (nmDMD) before and after treatment with ataluren. 
Study center(s): Approximately 10 sites 
Objectives:  
Primary: 
• To assess the change in levels of dystrophin in ambulatory nmDMD subjects after treatment 
with ataluren for 40 weeks using a quantitative dystrophin assay, such as 
electrochemiluminescence (ECL) 
Secondary: 
• To assess dystrophin levels/intensity and protein localization by immunohistochemistry after 
40 weeks of ataluren treatment  
Exploratory: 
• To assess the change from baseline in revised North Star Ambulatory Assessment (rNSAA) 
and timed function tests (TFTs) after 40 weeks of ataluren treatment 
• To assess changes from baseline in creatine kinase (CK) levels after 40 weeks of ataluren 
treatment 
• To evaluate the pharmacokinetics (PK) of ataluren after 40 weeks of treatment  
Primary Endpoint Assessment: 
• The percent change from baseline in dystrophin levels following 40 weeks of ataluren 
therapy, as measured by ECL 
Secondary Endpoint: 
• The percent change in dystrophin levels/intensity from baseline after 40 weeks of ataluren 
therapy as determined by a validated immunohistochemistry assay 
Exploratory Endpoints: 
• Change from baseline in rNSAA after 40 weeks of ataluren treatment 
• Change from baseline in TFTs after 40 weeks of ataluren treatment 
• Change from baseline in CK levels after 40 weeks of ataluren treatment 
• PK assessments at Week 1 and Week 40 
Number of patients (planned):  
Total of approximately 15 to 20 ataluren-naïve subjects age >2 and <8 years 


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Methodology:  
This study is designed to generate additional data on the effect of ataluren on producing dystrophin 
protein in nmDMD subjects. This study will evaluate dystrophin levels from ataluren-naïve 
subjects before and after treatment with ataluren for 40 weeks. 
Due to some of the challenges of dystrophin quantification, the study has been designed to mitigate 
these challenges as best possible. 
• 
Biopsies will be collected from subjects ≥2 and <8 years of age who are symptomatic to 
increase the chance of collecting less heterogenous muscle tissue. 
• 
Up to approximately 450 mg of muscle tissue (up to  cores per muscle) will be collected 
from the 
 and 
 muscles before initiation of ataluren therapy 
and after 40 weeks of treatment. If the 
 muscle is considered by the investigator to be 
too small for a biopsy sample (or the obtained sample is considered not evaluable for 
analysis), the 
 muscle may be used. 
• 
The same muscles will be sampled pre- and post-40 weeks of ataluren therapy. 
• 
Two validated, highly sensitive assays will be used to measure ataluren-associated 
increases in dystrophin levels and to evaluate whether the protein localizes correctly to the 
muscle membrane. 
Dystrophin will be quantified using ECL and immunohistochemistry. 
Main inclusion and exclusion criteria  
Inclusion criteria:  
1. 
Evidence of signed and dated informed consent/assent document(s) indicating that the 
patient (and/or his parent/legal guardian) has been informed of all pertinent aspects of the 
trial.   
2. 
Male sex. 
3. 
Age ≥2 and <8 years. 
4. 
Phenotypic evidence of DMD based on the onset of characteristic clinical symptoms or 
signs (eg, proximal muscle weakness, waddling gait, and Gowers’ maneuver) and an 
elevated serum CK. Medical documentation of phenotypic evidence of DMD needs to be 
provided upon request by the PTC Therapeutics medical monitor. 
5. 
Documentation of the presence of a nonsense point mutation in the dystrophin gene as 
determined by gene sequencing. Note: Review and approval of documentation by sponsor 
or designee is required prior to enrollment. 
6. 
Willing to undergo muscle biopsy  
Exclusion Criteria: 
1. Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy. 
2. Known contra-indication to muscle biopsy (ie, such as bleeding or clotting disorders). 
3. Prior or ongoing therapy with ataluren. 
4. Known hypersensitivity to any of the ingredients or excipients of the study drug (eg, 
refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, 
crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium stearate). 
5. Exposure to another investigational drug within 2 months prior to start of study treatment, 
or ongoing participation in any interventional clinical trial. 
6. Requirement for daytime ventilator assistance or any use of invasive mechanical ventilation 
via tracheostomy. Note: Evening non-invasive mechanical ventilation such as use of bilevel 
positive airway pressure (Bi-PAP) therapy is allowed. 
7. Elevated serum creatinine or cystatin C levels at screening. Note: If the initial test result is 
abnormal, it is permissible to re-test serum creatinine or cystatin C. 


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8. Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, 
behavioral disorder, alcoholism, drug abuse), medical history, physical findings or 
laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety 
of the subject, makes it unlikely that the course of treatment or follow-up would be 
completed, or could impair the assessment of study results. 
Reference therapy, dosage, and mode of administration: 
Ataluren will be dosed at 10, 10, 20 mg/kg per day  
Duration of Treatment 
40 weeks 
 


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Table 1. 
Schedule of Assessments 
Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study4 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Eligibility 
Informed Consent 
X 
 
 
 
 
 
 
A signed and dated informed consent must be 
obtained before conducting any study procedures. 
Inclusion/Exclusion
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Dystrophin 
genotyping 
X 
 
 
 
 
 
 
Documentation of the presence of a nonsense point 
mutation in the dystrophin gene as determined by 
gene sequencing must be reviewed and approved 
by sponsor prior to enrollment. Blood will be drawn 
for sequencing of the dystrophin gene to confirm the 
presence of a nonsense mutation. 
Safety Assessments 
Physical Exam 
X 
X 
 
X 
X 
 
X 
Full physical-exam (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, extremities, and 
genitourinary) will be performed at screening. 
A targeted physical exam will be conducted at Visits 
1 and Visit 3, and follow-up visit. 
A targeted exam will include nervous and 
musculoskeletal systems 
At an unscheduled visit, physical exam will be done 
as necessary. 
Physical exam should be performed prior to rNSAA 
and TFTs assessments and biopsy. 


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Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study4 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Clinical Labs 
X 
X 
 
X 
X 
X 
 
For Visit 1, Visit 3, and unscheduled and early 
termination visits, subjects should fast approximately 
8 hours prior to assessment. Biochemistry and other 
laboratory assessments will be analyzed by the 
central laboratory. Biochemistry, hematology, and 
urinalysis laboratory assessments. Creatine kinase 
will be assessed via the UV method or an equivalent 
method. 
At an unscheduled visit, clinical laboratory 
assessments will be done as necessary. At Visit 1 
and Visit 3, clinical laboratory assessments should 
be performed prior to biopsy. 
Height/Weight/BMI 
 
X 
X 
X 
 
X 
 
Height (in cm) and weight (in kg) will be measured at 
Visit 1, Visit 2, and Visit 3-Early Termination. If the 
subject is unable to stand, sitting arm span and ulna 
length should be assessed as surrogate 
measurements for height. 
Vitals (HR & BP) 
 
X 
 
X 
X 
 
 
Vital signs will include systolic and diastolic blood 
pressure, pulse rate, and body temperature. The 
pulse rate and blood pressure determinations will be 
performed with the subject in a sitting position after a 
5-minute rest. Blood pressure will be measured in 
triplicate and the average will be recorded.  
Vitals should be taken prior to rNSAA and TFTs 
assessments and biopsy.  
AE/SAE 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
AEs must be assessed and documented at each 
clinic visit. Subjects, parents/caregiver or legal 
guardian will be encouraged to report AEs of 
concern at any time in the intervals between visits. 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
Concomitant medications will need to be collected 
starting 30 days prior to first dose of study drug. 
Efficacy Assessments 
Muscle biopsy 
 
X 
 
X 
 
 
 
If a subject received ≥6 months of therapy but early 
terminated, a biopsy may be performed if subject, 
parents or legal guardian agrees. 
rNSAA 
 
X 
 
X 
 
 
 
TFTs 
 
X 
 
X 
 
 
 


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Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study4 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Pharmacokinetic Assessments 
 
 
 
 
 
PK blood sampling 
 
X 
 
X 
 
 
 
PK samples will be drawn on Visit 1, samples will be 
drawn pre-first study dose and 2 hours postdose, 
and on Visit 3 will be drawn pre-morning dose and 
2 hours postdose.   
Study Drug Administration 
Dispense Drug 
 
X 
X 
 
 
 
 
First dose of study drug should be administered 
following completion of all Baseline (Visit 1) 
assessments. 
Because of potential changes in subject body weight 
over time, a dose adjustment may be made based 
on the subject’s bodyweight at Visit 2 (Week 20). 
Central pharmacy to dispense drug direct to subject 
upon completion of Visit 2. 
Unused Drug 
Return/ 
Compliance 
 
 
X 
X 
 
X 
 
All used and unused study drug kits and unused 
sachets will be returned as directed. 
Abbreviations: AE, adverse event; BP, blood pressure; BMI, body mass index; HR, heart rate; PK, pharmacokinetic; rNSAA, Revised North Star Ambulatory 
Assessment; SAE, serious adverse event; TFT, timed-function tests; 
; UV, urine volume 
1 Screening procedures must take place within 45 days of baseline visit (Visit 1). 
2 Any screening procedure completed within and including 7 days of Visit 1 can serve as baseline and does not need to be repeated at Visit 1. 
3 Visit 1 will be performed at 
. Subjects may have to return to the clinic for up to 3 days for completion of assessments and biopsy. 
4 Visit 3 will be performed at 
. 
5 Early termination assessments should be performed for subjects who discontinue prematurely from the study. 
6 The follow-up visit is for subjects who terminated early/discontinued from the study.  Visit to occur ~30 days after termination/discontinuation or until recovery 
from or stabilization of the AE, whichever comes last. The follow-up visit will also occur for subjects who decided to discontinue ataluren therapy even if they 
completed assessments at Visit 3.  
 


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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 
NCT03648827 
Protocol Number  
PTC124-GD-045-DMD 
Protocol Version  
Version 3.0 
Protocol Version Date 
06 May 2019 
Protocol Phase  
Phase 2 
Protocol Title   
Phase 2 Clinical Pharmacology Study to Assess 
Dystrophin Levels in Subjects with nmDMD Before 
and After Treatment with Ataluren 
PTC Clinical Lead/Medical Monitor 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ  07080 USA 
Telephone (office):
Facsimile:
E-mail:
PTC Biostatistician  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ  07080 USA 
Telephone (office):
Facsimile:
E-mail:
PTC Study Manager  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ  07080 USA 
Telephone (office):
Facsimile:
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 
 
 


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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 
 
Date 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province:  
Country: 
 
Phone: 
 
Fax: 
 
Email: 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................2 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ................................................8 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES .................................9 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE .............................10 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF TABLES .................................................................................................................13 
LIST OF FIGURES ...............................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................14 
1 
INTRODUCTION .......................................................................................15 
1.1 
Disease Background ....................................................................................15 
1.2 
Ataluren ........................................................................................................16 
1.2.1 
Ataluren-associated increased ribosomal readthrough of premature 
stop codons ...................................................................................................16 
1.3 
Risk/Benefit Assessment .............................................................................17 
2 
STUDY OBJECTIVE AND ENDPOINTS ...............................................17 
2.1 
Objectives .....................................................................................................17 
2.1.1 
Primary Objective .......................................................................................17 
2.1.2 
Secondary Objectives ..................................................................................17 
2.1.3 
Exploratory Objectives ...............................................................................18 
2.2 
Endpoints ......................................................................................................18 
2.2.1 
Primary Endpoint ........................................................................................18 
2.2.2 
Secondary Endpoints ...................................................................................18 
2.2.3 
Exploratory Endpoints ................................................................................18 
3 
STUDY DESIGN .........................................................................................19 
3.1 
Overall Design ..............................................................................................19 
3.1.1 
Muscle biopsy samples ................................................................................20 
3.1.2 
Evaluation of dystrophin levels ..................................................................20 
3.1.2.1 
Immunohistochemistry .................................................................................20 
3.1.3 
Assessment of rNSAA and TFTs ................................................................20 
3.2 
Scientific Rationale for Study Design ........................................................21 
3.3 
Justification of Dose ....................................................................................22 
3.4 
End of Study Definition ...............................................................................22 
4 
STUDY POPULATION ..............................................................................23 
4.1 
Overview .......................................................................................................23 
4.2 
Inclusion Criteria .........................................................................................23 
4.3 
Exclusion Criteria ........................................................................................23 
5 
ENROLLMENT PROCEDURES ..............................................................24 
5.1 
Source and Number of Subjects .................................................................24 
5.2 
Screening ......................................................................................................24 


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6 
STUDY INTERVENTION .........................................................................25 
6.1 
Study Intervention(s) Administration .......................................................25 
6.1.1 
Study intervention description ...................................................................25 
6.1.2 
Dosing and administration ..........................................................................25 
6.1.3 
Return of study drug ...................................................................................25 
6.1.4 
Inadvertent exposure and spill precautions ..............................................26 
6.2 
Preparation/Handling/Storage/Accountability .........................................26 
6.2.1 
Accountability ..............................................................................................27 
6.2.2 
Formulation, appearance, packaging, and labeling .................................27 
6.3 
Measures to Minimize Bias: Randomization and Blinding .....................27 
6.4 
Concomitant Therapy .................................................................................27 
6.4.1 
Corticosteroids .............................................................................................28 
6.4.2 
Aminoglycosides and Vancomycin .............................................................28 
6.4.3 
Hydration .....................................................................................................29 
6.4.4 
Cardiac Drugs for Cardiomyopathy Prophylaxis/Treatment .................29 
6.4.5 
Drugs Metabolized by Cytochrome P450 Enzymes .................................30 
6.4.6 
Other Potential Drug Interactions .............................................................30 
6.5 
Discontinuation of Study Intervention ......................................................30 
6.6 
Participant Discontinuation/Withdrawal from the Study .......................31 
7 
STUDY ASSESSMENT AND PROCEDURES ........................................32 
7.1 
Schedule of Assessments and Study Parameters ......................................32 
7.2 
Safety Assessments and Other Assessments ..............................................35 
7.3 
Adverse Events and Serious Adverse Events ............................................36 
7.3.1 
Definition of adverse events (AE) ...............................................................36 
7.3.2 
Definition of serious adverse events (SAE) ...............................................37 
7.3.3 
Unexpected Adverse Events ........................................................................38 
7.3.4 
Eliciting adverse event information ...........................................................38 
7.3.5 
Recording Non‑serious AEs and SAEs ......................................................38 
7.3.6 
Describing adverse event relationship to study drug ...............................39 
7.3.7 
Grading of severity of adverse event .........................................................39 
7.3.8 
Adverse Event Reporting ............................................................................40 
7.3.9 
Serious adverse event reporting .................................................................40 
7.3.10 
Reporting Pregnancy ...................................................................................41 
7.3.11 
PTC Therapeutics Adverse Event Reporting Requirement ....................41 
8 
STATISTICAL CONSIDERATIONS .......................................................42 
8.1 
Statistical Hypotheses ..................................................................................42 
8.2 
Sample Size Determination .........................................................................42 
8.3 
Population for Analyses ..............................................................................42 
8.3.1 
Intention-to-treat (ITT) analysis set ..........................................................42 
8.3.2 
Per Protocol Analysis Set ............................................................................43 
8.3.3 
Safety Analysis Set .......................................................................................43 
8.4 
Statistical Analyses ......................................................................................43 
8.4.1 
General approach ........................................................................................43 
8.4.2 
Analysis of primary efficacy endpoint .......................................................43 
8.4.3 
Analysis of secondary efficacy endpoint ....................................................43 
8.4.4 
Pharmacokinetic analyses ...........................................................................43 


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8.4.5 
Safety analyses .............................................................................................44 
8.4.6 
Planned interim analyses ............................................................................44 
8.4.7 
Sub-group analyses ......................................................................................44 
9 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................................44 
9.1 
Regulatory, Ethical, and Study Oversight Considerations ......................44 
9.1.1 
Informed consent process ...........................................................................44 
9.1.2 
Study discontinuation and closure .............................................................45 
9.1.3 
Confidentiality and privacy ........................................................................45 
9.1.4 
Future use of stored specimens and data ..................................................45 
9.1.5 
Clinical monitoring ......................................................................................46 
9.1.6 
Quality assurance and quality control .......................................................46 
9.1.7 
Data handling and record keeping .............................................................47 
9.1.8 
Protocol deviations ......................................................................................47 
9.1.9 
Publication and data sharing policy ..........................................................48 
9.2 
Additional Considerations ..........................................................................49 
9.3 
Protocol Amendment History .....................................................................49 
10 
REFERENCES ............................................................................................51 
11 
APPENDIX ..................................................................................................53 
 
LIST OF TABLES 
Table 1. 
Schedule of Assessments.......................................................................................5 
Table 1. 
Schedule of Assessments.....................................................................................32 
Table 2. 
Renal Monitoring Parameters and Actions To Be Taken ...............................35 
Table 3. 
Relationship of Study Drug to Adverse Event Relationship ...........................39 
Table 4. 
Grading of Adverse Event Severity Grade .......................................................39 
Table 5. 
Investigator Site Requirements for Reporting Adverse Events .....................40 
 
LIST OF FIGURES 
Figure 1. Study Schematic ..................................................................................................19 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
ACE 
Angiotensin-converting enzyme 
AEs 
Adverse events 
ARBs 
Angiotensin receptor blockers 
BMD 
Becker muscular dystrophy 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
cGMP 
Current good manufacturing practice 
CK 
Creatine kinase 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficients of variability 
DMD 
Duchenne muscular dystrophy 
ECL 
Electrochemiluminescence 
EDC 
Electronic Data Capture 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
GCP 
Good clinical practices 
HR 
Heart rate 
IB 
Investigator brochure 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
LOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
nmCF 
Nonsense mutation Cystic Fibrosis 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
RSI 
Reference Safety Information 
rNSAA 
Revised North Star Ambulatory Assessment 
SAEs 
Serious adverse events 
TFTs 
Timed-function tests 
 
 


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1 
INTRODUCTION 
1.1 
Disease Background 
Duchenne muscular dystrophy (DMD) is a rare, debilitating, progressive, and ultimately fatal 
childhood genetic disease (Bushby 2010a, Bushby 2010b). It is an X-linked genetic muscle 
disorder that results from a mutation in the DMD gene, which encodes for the dystrophin 
protein. 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 
(Bushby 2010a, Mah 2016, Rae 2016). It is also expressed in neurons in specific parts of the 
brain, such as the hippocampus (Aartsma-Rus 2016). 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 (Aartsma-Rus 2016). Consequently, dystrophin 
bears the mechanical stresses that occur during muscle contraction, stabilizing muscle cell 
membranes, and protecting muscles from injury (Petrof 1993). 
Dystrophin mutations disrupt the connection with the actin cytoskeleton and connective 
tissue resulting in chronic muscle damage, inflammation, and eventually replacement of 
muscle fibers by fat and fibrotic tissue resulting in progressive and irreversible loss of muscle 
function (Muntoni 2003). The culmination of muscle function loss leads to early death, the 
average life expectancy being 25 years of age. 
Duchenne muscular dystrophy is noticeable in young children, who typically display 
underdeveloped or delayed development of motor skills relative to healthy boys 
(Bushby 2010a). Muscle function continues to deteriorate in pre-adolescence resulting in the 
loss of gross motor functions, including the ability to rise from the floor, the ability to climb 
stairs, and the ability to walk. Complete loss of ambulation typically occurs in the early 
teenage years. Loss of the functional abilities occur sequentially, with the loss of one 
function preceding and predicting the loss of subsequent functions. Importantly, the age at 
loss of ambulation is predictive of the age at onset of severe respiratory insufficiency (forced 
vital capacity [FVC] <1 liter) requiring the need for ventilation assistance 
(Humbertclaude 2012), which in turn is predictive of death within 3 years (Phillips 2001). 
Currently, there are no medications that cure or reverse the effects of DMD. The goals of 
current interventions are to help slow or stabilize disease progression, prolong patients’ 
ability to manage activities of daily living, and 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 (Bushby 2010a, Bushby 2010b). Additional 
treatments are necessary, particularly those that treat 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. 
Approximately 10% to 15% of boys with DMD have the disease due to a nonsense mutation 
in the dystrophin gene (Aartsma-Rus 2006, Bladen 2015), resulting in a premature stop 
codon in the dystrophin mRNA (messenger ribonucleic acid); ribosomal translation of 


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nonsense codon containing mRNA results in premature termination of translation before a 
full-length, functional protein is generated. 
1.2 
Ataluren 
Ataluren is a small molecule being developed for the treatment of nonsense mutation 
Duchenne muscular dystrophy (nmDMD). Ataluren promotes ribosomal readthrough of 
premature stop codons, enabling the formation of full-length, functional dystrophin protein 
(Welch 2007).   
The efficacy and safety of ataluren for the treatment of nmDMD were assessed in 
2 randomized, double-blind, placebo--controlled, 48-week trials (PTC124-GD-007-DMD 
[NCT00592553] [Study 007] and PTC124-GD-020-DMD [NCT01826487] [Study 020]). 
Data from these studies supported conditional marketing authorization of ataluren for the 
treatment of nmDMD in ambulatory patients aged ≥5 years in Europe and subsequently 
extended to ≥2 years of age base on pharmacokinetic extrapolation from study 
PTC124-GD-030-DMD.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of ataluren is 
provided in the Investigator’s Brochure. 
1.2.1 
Ataluren-associated increased ribosomal readthrough of premature stop 
codons 
The ability of ataluren to promote ribosomal readthrough of premature stop codons has been 
evaluated in a wide range of in vivo and in vitro preclinical experiments, including different 
organ and animal model systems, as well as cell-free and cell-based systems. In particular, 
preclinical studies in the mdx mouse and the sapje zebrafish nmDMD models and human 
myotubes consistently demonstrate that ataluren increases dystrophin production across key 
tissues, including skeletal muscle, heart, and diaphragm.  
Production of dystrophin from ataluren treatment was also investigated in nmDMD patients 
in the Phase 2a PTC124-GD-004-DMD study (Study 004) (Finkel 2013). In this trial, 
38 nmDMD patients received treatment with ataluren for 28 days. Results from the proof of 
concept study indicate that ataluren treatment leads to production of full-length dystrophin 
protein; post-treatment increases in dystrophin were quantified in 61% (23/38) of the 
patients. The mean change in muscle biopsy dystrophin expression from baseline to Day 28 
was 11.0% (p=0.008). In addition, immunohistochemistry experiments indicated the protein 
was correctly localized to membranes of muscle cells, suggesting functional activity. 
Myotubes derived from pre-treatment muscle biopsies were cultured in vitro in the presence 
of ataluren and 100% of the samples showed increases in dystrophin expression. Dystrophin 
expression was also evaluated in Study 007 in which nmDMD patients were treated with 
ataluren or placebo. Results from Study 007 were also supportive of an increase in 
dystrophin levels, consistent with Study 004 results. The increase in dystrophin levels in the 
two prior clinical studies are limited by the quality of muscle biopsy samples and the use of a 
non-validated immunofluorescence method of detecting dystrophin. 


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1.3 
Risk/Benefit Assessment 
Under the current standard of care, nmDMD remains a disease with devastating 
consequences and bleak prognosis. 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. 
The mechanism by which ataluren restores dystrophin has been established in comprehensive 
preclinical studies and supported in clinical evaluations. Moreover, the clinical benefit of 
ataluren has been demonstrated in two large randomized controlled trials Study 007 and 
Study 020. 
This study is designed to quantitatively evaluate the increase in dystrophin protein in boys 
with nmDMD. The biopsy technique to be used is less invasive than the standard biopsy and 
is of relative low-risk to the patient. The use of two highly sensitive validated assays to 
evaluate dystrophin protein levels will increase the likelihood that each biopsy sample will 
yield interpretable results. Hence, the study design and the importance of establishing the 
ability of ataluren to increase dystrophin production results in a positive risk/benefit. 
 
2 
STUDY OBJECTIVE AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
● 
To assess the change in levels of dystrophin in ambulatory nmDMD subjects after 
treatment with ataluren for 40 weeks using quantitative assay, such as 
electrochemiluminescence (ECL) 
2.1.2 
Secondary Objectives 
● 
To assess dystrophin levels/intensity and protein localization by 
immunohistochemistry after 40 weeks of ataluren treatment 


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2.1.3 
Exploratory Objectives 
● 
To assess the change from baseline in revised North Star Ambulatory Assessment 
(rNSAA) and timed-function tests (TFTs) after 40 weeks of ataluren treatment 
● 
To assess changes from baseline in creatine kinase (CK) levels after 40 weeks for 
ataluren treatment 
● 
To evaluate the steady state pharmacokinetics (PK) of ataluren after 40 weeks of 
treatment 
2.2 
Endpoints 
2.2.1 
Primary Endpoint 
The primary endpoint is: 
● 
The percent change from baseline in dystrophin levels after 40 weeks of ataluren 
therapy, as measured by ECL 
2.2.2 
Secondary Endpoints 
The secondary endpoint is: 
● 
The percent change in dystrophin levels/intensity from baseline after 40 weeks of 
ataluren therapy as determined by a validated immunohistochemistry assay 
2.2.3 
Exploratory Endpoints 
Exploratory endpoints include: 
● 
Change from baseline in rNSAA after 40 weeks of treatment 
● 
Change from baseline in TFTs after 40 weeks of treatment 
● 
Change from baseline in CK levels after 40 weeks of treatment 
● 
PK assessments at Week 1 and Week 40 


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3 
STUDY DESIGN 
3.1 
Overall Design 
This is an open-label, single-arm, Phase 2 study designed to evaluate the ability of ataluren 
treatment to increase dystrophin protein levels in muscle cells of patients with nmDMD. The 
study will evaluate the levels of dystrophin before and after 40 weeks of ataluren therapy 
using muscle biopsies and two validated assay methods. 
Approximately, 15 to 20 ataluren-naïve male subjects, aged ≥2 and <8 years of age will be 
administered ataluren. 
Ataluren will be dosed daily 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in 
the evening (10, 10, 20 mg/kg). 
The study will have a screening visit and 3 additional visits (Figure 1). At the screening visit, 
which will be performed at a patient’s local site, inclusion/exclusion criteria, demographics 
and medical history will be assessed. In addition, blood will be drawn for genotyping to 
confirm that a subject carries a nonsense mutation in the dystrophin gene. For all subjects, 
Visit 1 and Visit 3 will occur at the same site, that of 
 
. During Visit 1 and Visit 3 biopsies will be performed and 
used for assessing dystrophin protein levels. At Visit 1, the first dose of ataluren will be 
administered following the biopsy at 
 and subjects, parent/caregivers or legal guardian 
will be dispensed a supply of ataluren which will be administered at home. Visit 2 will be in 
the clinic at the subjects’ local site and weight will be measured to determine if the dose of 
ataluren requires adjustment. Adverse events, (SAEs), and compliance will also be captured, 
and an additional supply of ataluren will be dispensed. 
Figure 1. 
Study Schematic 
 
Screening
•
Inclusion/
exclusion
•
Informed 
consent
Week 1
Visit 1 - Baseline
•
Muscle biopsy
•
Safety assessments
•
Efficacy assessments
•
First dose of ataluren 
administered post-biopsy
Week 20
Week 40
Visit 2 
•
Safety assessments
•
Adjust dosing, if 
necessary
Visit 3
•
Muscle biopsy
•
Safety assessments
•
Efficacy assessments
Week -1 to -4


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3.1.1 
Muscle biopsy samples 
Biopsies will be performed before initiation of ataluren therapy and after 40 weeks of 
treatment by appropriately trained staff at 
. All subjects will have a physical exam and 
a history taken and recorded within 7 days of the procedure, usually on the day before the 
procedure to assess biopsy locations and determine if there is any intercurrent illness that 
places a subject at higher risk. 
Biopsy of the 
 and 
 muscles will be performed using an 
established core biopsy procedure (Gallo 2018). If the 
 muscle is considered by the 
investigator to be too small for a biopsy sample (or the obtained sample is considered not 
evaluable for analysis), the 
 muscle may be used. Up to approximately 
450 mg of muscle tissue (up to  cores per muscle) will be taken from each muscle at both 
Visit 1 and Visit 3. Conscious sedation will be offered with propofol and fentanyl to provide 
sedation and analgesia by physicians credentialed to monitor and provide sedation in an 
outpatient setting. Following sedation, vital signs will be monitored until the subject returns 
to pre-sedation baseline values. These techniques are standard of care at 
 for minor 
procedures on young patients. 
3.1.2 
Evaluation of dystrophin levels 
Two validated assays, ie, ECL and immunohistochemistry, will be used to measure changes 
from baseline in dystrophin levels following ataluren therapy. The assays provide slightly 
different information, and together give a robust analysis. 
 
Electrochemiluminescence technology provides high sensitivity with a low background. The 
assay will be optimized and validated by an external contract research organization (CRO). 
Subject biopsy samples will be shipped to and analyzed for dystrophin levels by a CRO. 
3.1.2.1 
Immunohistochemistry 
Immunohistochemistry will semi-quantitatively assess dystrophin protein levels 
 
 
 Dystrophin measured using this assay will be the 
secondary endpoint. 
 
 Subject biopsy samples will be shipped to and analyzed for dystrophin 
levels by a CRO. 
3.1.3 
Assessment of rNSAA and TFTs 
As exploratory outcomes, the study will also assess the efficacy of ataluren using the rNSAA 
and TFTs using standardized procedures pre- and post-40 weeks of ataluren therapy. The 
rNSAA evaluates physical function and TFTs measure peak physical capacity. 


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3.2 
Scientific Rationale for Study Design  
The study is designed to generate additional data on the effect of ataluren on promoting the 
production of dystrophin protein in nmDMD subjects. It is known that small increases in 
dystrophin levels can result in milder disease phenotype in nmDMD patients. The levels of 
dystrophin in patients with Becker muscular dystrophy (BMD) have been reported to be 
higher than that observed in patients with DMD (Anthony 2014). Consequently, patients with 
BMD generally have less severe disease compared with those with DMD; BMD patients 
often show a later onset of disease and slower disease progression (Muntoni 2003, 
Aartsma-Rus 2006). 
As described in Section 1.2.1, the ability of ataluren to promote ribosomal readthrough of 
premature stop codons has been demonstrated in a range of in vivo and in vitro preclinical 
assays. In addition, ataluren-associated increases in dystrophin protein levels was assessed in 
a prior clinical study. Of patients treated with ataluren 10, 10, 20 mg/kg, 55% (8/20) had an 
increase in dystrophin expression post-ataluren treatment (Finkel 2013). The findings from 
this study were consistent with ataluren treatment increasing dystrophin level and indicated 
that the protein correctly localized to the muscle cell membranes, suggesting functional 
activity (Finkel 2013). 
Assessing dystrophin levels in patients with nmDMD can be challenging due to inherent 
difficulty in obtaining muscle samples that contain sufficient amounts of intact muscle cells 
for analysis, as nmDMD muscle, particularly in older patients, are often heterogenous with 
respect to fibrofatty replacement of muscle. 
From prior clinical trial experience, it is anticipated that although levels or dystrophin may 
increase in nmDMD muscle from baseline following ataluren therapy, the amount of 
dystrophin will still be low; hence, sensitive assays with good specificity are necessary to 
evaluate change in dystrophin levels with treatment. 
Method of biopsy sampling can also impact results. For example, variability can be 
introduced by assessing a bilateral muscle sampled from one side of the body before 
treatment and from the other side after treatment. 
This current study is designed to mitigate some of these difficulties. 
● 
Biopsies will be collected from subjects ≥2 and <8 years of age who are 
symptomatic to increase the chance of collecting less heterogenous muscle tissue. 
● 
Up to approximately 450 mg of muscle tissue (up to  cores per muscle) will be 
collected from the 
 muscles located on the 
 side of 
the body before initiation of ataluren therapy and after 40 weeks of treatment. If 
the 
 muscle is considered by the investigator to be too small for biopsy 
sampling (or the obtained sample is considered not evaluable for analysis), the 
 muscle may be used. 
● 
The same muscles will be sampled pre- and post-40 weeks of ataluren therapy. 


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● 
Two validated, highly sensitive assays will be used to measure ataluren-associated 
increases in dystrophin levels and to evaluate whether the protein localizes 
correctly to the muscle membrane. 
3.3 
Justification of Dose 
The proposed ataluren dosing regimen of 10, 10, 20 mg/kg has been demonstrated to be safe 
and effective in delaying disease progression in nmDMD patients in the Phase 2 clinical 
Study 007 and the Phase 3 Study 020. It is also the dose that received conditional approval by 
the EMA (European Medicines Agency). 
3.4 
End of Study Definition 
The end of the study is defined as completion of assessment on Visit 3, or after follow-up for 
those subjects with early termination or who decided to stop receiving ataluren. PTC will 
ensure that patients who complete the study and want to remain on ataluren will have access 
to the drug. 


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4 
STUDY POPULATION 
4.1 
Overview 
The study population is pre-defined to be homogeneous. The inclusion/exclusion criteria 
select for subjects with severe phenotype only (nmDMD) and against patients with BMD. 
The inclusion criteria require phenotypic evidence of DMD based on signs and symptoms 
onset by 6 years of age. This includes proximal muscle weakness, waddling gait, and 
Gowers’ maneuver and elevated serum CK levels. 
4.2 
Inclusion Criteria 
1. 
Evidence of signed and dated informed consent/assent document(s) indicating that 
the subject (and/or his parent/legal guardian) has been informed of all pertinent 
aspects of the trial. 
2. 
Male sex. 
3. 
Age ≥2 and <8 years. 
4. 
Phenotypic evidence of DMD based on the onset of characteristic clinical 
symptoms or signs (eg, proximal muscle weakness, waddling gait, and Gowers’ 
maneuver) and an elevated serum CK. Medical documentation of phenotypic 
evidence of DMD needs to be provided upon request by the PTC Therapeutics 
medical monitor. 
5. 
Documentation of the presence of a nonsense point mutation in the dystrophin 
gene as determined by gene sequencing. Note: Review and approval of 
documentation by sponsor or designee is required prior to enrollment. 
6. 
Willing to undergo muscle biopsy  
4.3 
Exclusion Criteria 
1. 
Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy. 
2. 
Known contra-indication to muscle biopsy (ie. such as bleeding or clotting 
disorders) 
3. 
Prior or ongoing therapy with ataluren. 
4. 
Known hypersensitivity to any of the ingredients or excipients of the study drug 
(eg, refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 
25C, crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium 
stearate). 


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5. 
Exposure to another investigational drug within 2 months prior to start of study 
treatment, or ongoing participation in any interventional clinical trial.   
6. 
Requirement for daytime ventilator assistance or any use of invasive mechanical 
ventilation via tracheostomy. Note: Evening non-invasive mechanical ventilation 
such as use of bilevel positive airway pressure (Bi-PAP) therapy is allowed. 
7. 
Elevated serum creatinine or cystatin C levels at screening. Note: If the initial test 
result is abnormal, it is permissible to re-test serum creatinine or cystatin C. 
8. 
Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, 
behavioral disorder), medical history, physical findings or laboratory abnormality 
that, in the investigator’s opinion, could adversely affect the safety of the subject, 
makes it unlikely that the course of treatment or follow-up would be completed, or 
could impair the assessment of study results. 
 
5 
ENROLLMENT PROCEDURES 
5.1 
Source and Number of Subjects 
Approximately 15 to 20 subjects will be enrolled. Subjects will be recruited from 
dystrophinopathy populations who receive care or referred for evaluation at the 
investigational site. Investigators will discuss the possibility of participation directly with 
parent(s)/legal guardian in the clinic.  
5.2 
Screening 
The Investigator must inform each parent/legal guardian and study candidate of the nature of 
the study, explain the potential risks, and obtain written informed consent/assent from the 
parent(s)/legal guardian and/or study candidate (as required by local regulations) prior to 
performing any study-related screening procedures. 
 


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6 
STUDY INTERVENTION 
6.1 
Study Intervention(s) Administration 
6.1.1 
Study intervention description 
Open-label ataluren will be provided as white to off-white granules for oral suspension. The 
drug substance and drug product are manufactured under current good manufacturing 
practice (cGMP) conditions. The formulation includes matrix and suspending agents, 
surfactants, and various excipients that aid in the manufacturing process. The granules for 
oral suspension are packaged in aluminum foil, child resistant sachets (packets) and supplied 
in dose strengths containing 125, 250, or 1000 mg of the active drug substance.   
Ataluren will be supplied free of charge by PTC Therapeutics for appropriate distribution to 
the subjects, parent/caregivers or legal guardian. 
6.1.2 
Dosing and administration 
During the 40 week treatment period, dosing of ataluren will be based on milligrams of drug 
per kilogram of subject body weight and will be adjusted to allow for dosing with up to 2 of 
the available sachet dose strengths (125 mg, 250 mg, and/or 1000 mg). The sachet dose 
strengths and number of sachets to be taken per dose will be calculated (see appendix for 
dosing table). 
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to instructions at the Baseline Visit (Visit 1). A central pharmacy will 
ship study drug directly to the subject upon Visit 2 completion. Multiple kits may be 
dispensed at a single visit (maximum of two different strengths) at Visits 1 and 2 (Week 1 
and Week 20). At Visit 1 and Visit 2 drug will be dispensed. 
6.1.3 
Return of study drug 
Subjects and/or parents or legal guardian should return all used and unused kits and unused 
sachets as instructed. Study drug dispensing to the subjects and the return of any unused 
study drug for compliance assessments will be documented.  
For any subject experiencing an overdose, 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 or contraindicated. 
The PTC Therapeutics medical monitor must be contacted if an overdose occurs. Under 
applicable regulations, overdosing may be considered a SAE and should be reported 
accordingly (see Section 7.3). 


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6.1.4 
Inadvertent exposure and spill precautions 
Based on available data from nonclinical studies, ataluren does not appear to be acutely toxic 
or genotoxic at levels that are likely to result from inadvertent exposure to the contents of the 
packet, if opened. Based on general experience with the drug during manufacturing, it does 
not appear that exposure to formulated ataluren is likely to be irritating to skin or eyes. 
However, personnel handling the drug should use reasonable precautions to avoid eye 
contact, skin contact, inhalation, or ingestion of the material in the packets. Refer to the 
ataluren Investigator Brochure (IB) for current information on inadvertent exposures and 
spill precautions. 
6.2 
Preparation/Handling/Storage/Accountability 
Study drug sachets should be stored at room temperature, away from the reach of children 
until time of reconstitution and should only be opened at the time of dose preparation. The 
available stability data from representative samples support the use of the drug product for 48 
months when stored at room temperature. The full contents of the sachets should be mixed 
with at least 30 mL (1 ounce) of liquid (water, milk, fruit juice, fruit punch), or 3 tablespoons 
of semi-solid food (yogurt, pudding, or applesauce) and administered with food. The 
prepared dose should be mixed well and stirred for approximately 30 to 60 seconds before 
administration. The amount of the liquid can be increased based on subject preference. 
Each prepared dose is best administered immediately after preparation. The prepared dose 
should be discarded if not consumed within 24 hours of preparation (if kept refrigerated), or 
within 3 hours of preparation (if kept at room temperature). 
The clinic staff will instruct each subject or parent/caregiver or legal guardian on the specific 
number of sachets to be taken from each kit for 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 or parent/caregiver or legal guardian when drug 
supplies are dispensed.   
It is anticipated that palatability of ataluren will not be a concern with this young population 
of nmDMD subjects; and consequently, will not impact ingestion of the drug. Palatability 
was assessed in study PTC124-GD-030-DMD (Study 030), a Phase 2, randomized, open-
label study that evaluated the safety, PK, and pharmacodynamics of ataluren in nmDMD 
patients ≥2 and <5 years of age (N=14). Palatability of ataluren was investigated using a 
palatability questionnaire that assessed characteristics of the drug such as smell and taste. A 
parent/caregiver could respond on behalf of the subject. Of the 14 study subjects, 10 (71.5%) 
agreed or strongly agreed that the medication was pleasant based on the child’s reaction. 
Only 2 (14.3%) respondents reported having problems giving the medication to the child.  


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6.2.1 
Accountability 
Study personnel must ensure that all study drug supplies are kept in a secure locked area with 
access limited to authorized personnel. Study drug must not be used outside the context of 
this protocol. Under no circumstances should the investigator or site personnel supply study 
drug to other investigators, clinics, or allow the study drug supplies to be used other than as 
directed by this protocol. 
The investigator/ site personnel and/or central pharmacy must maintain accurate records of 
the receipt of all study drug shipped by PTC Therapeutics or its designee, including, but not 
limited to, the date received, lot number, amount received, amount returned, and the 
disposition of all study drug product. Drug accountability records must also be maintained by 
the site and central pharmacy that include the subject’s assigned study number, date and 
amount of study drug dispensed, and relevant lot and sachet numbers. 
Study drug must be returned to PTC Therapeutics or its designee, except where sites are 
required to destroy study drug per their local standard operating procedures.  
6.2.2 
Formulation, appearance, packaging, and labeling 
Drug kits will be provided, each of which contains sachets of one of the dose strengths 
(125, 250, or 1000 mg). Sachets and cartons will be color-coded to indicate dosage strength 
(125 mg - yellow, 250 mg -pink, 1000 mg - blue). Each kit will have a unique kit 
identification number. The content of the labeling will be in accordance with local regulatory 
specifications and requirements. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Bias due to sample evaluation will be abrogated by the fact that all biopsy samples will be 
frozen and the pre-therapy and post-treatment biopsy samples will be analyzed at the same 
time for dystrophin levels by ECL and immunohistochemistry assays. In addition, the 
persons performing and evaluating the findings of the two assays will be blinded to the 
timing of sample collection. 
6.4 
Concomitant Therapy 
Other than the study drug, any treatments (including prescription and non-prescription drugs, 
health foods, herbal remedies, self-prescribed drugs, street drug, tobacco products, or alcohol) 
that are taken by a subject during the screening period, during study drug administration, and 
for 4 weeks after discontinuation of study drug are considered concomitant medications. 
Information regarding any concomitant medications will be collected and documented in the 
case report form (CRF) and in the source documents by the clinic staff. Study intervention 
discontinuation and participant discontinuation/withdrawal. 


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To the extent possible, administration of any prescription or over-the-counter drug products 
other than study medication should be minimized during the study period. Subjects should be 
discouraged from use of “health supplements” (eg, creatine, glutamine, coenzyme Q), herbal 
remedies, growth hormone, self-prescribed drugs, at any time during clinical studies of 
ataluren.   
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) should consider the subject’s 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 will 
compromise the outcome or integrity of the study.   
Subjects and parents/caregivers or legal guardian should be instructed about the importance 
of the need to inform the clinic staff of the use of any drugs or remedies (whether prescribed, 
over-the-counter, or illicit) before and during the course of the study.  
The investigator is encouraged to consult the PTC medical monitor or designee with 
questions relating to specific drugs and their potential for interactions with ataluren. 
6.4.1 
Corticosteroids 
Corticosteroid therapy in DMD improves muscle strength and function in the short term 
(Matthews 2016). To minimize potential confounding effects of changes in corticosteroid 
therapy on the interpretation of study results, the use of these medications must be 
standardized as much as possible during the study. 
A stable and standardized corticosteroid regimen should be maintained for 3 months prior to 
Visit 1. Adjustments in corticosteroid dosage for increases in body weight are permitted 
during study treatment but are not mandatory. 
6.4.2 
Aminoglycosides and Vancomycin 
Ataluren should not be co-administered with IV aminoglycosides (eg, tobramycin, 
gentamicin, amikacin, kanamycin and/or IV vancomycin), based on cases of decreased renal 
function observed in a clinical trial of ataluren in patients with nonsense mutation cystic fibrosis 
(nmCF). Elevations of serum creatinine occurred in several nmCF patients treated with 
ataluren and IV aminoglycosides/vancomycin together with other antibiotics for cystic 
fibrosis exacerbations. The serum creatinine elevations resolved in all cases, with 
discontinuation of the IV aminoglycoside/vancomycin, and either continuation or 
interruption of ataluren. These findings suggested that co-administration of ataluren and IV 
aminoglycosides/vancomycin may potentiate the nephrotoxic effect of these antibiotics. For 
additional details, refer to the IB. 


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In subjects, who require treatment for serious infections, investigators should consider 
substituting with alternate antibiotics for systemic aminoglycosides/vancomycin when 
clinically appropriate. For subjects requiring systemic antibiotic therapy, IV 
aminoglycosides/vancomycin may be used when medically necessary. If IV 
aminoglycosides/vancomycin are administered, study drug must be interrupted during the 
course of these antibiotic treatments. Subjects requiring IV aminoglycoside or IV 
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 IV 
vancomycin, antibiotic drug levels (if appropriate) and serum creatinine and blood urea 
nitrogen (BUN) should be followed closely. The antibiotic trough level (if appropriate) 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. Creatinine and 
BUN should be measured prior to initiating IV aminoglycoside or vancomycin therapy and at 
least weekly during the course of antibiotic treatment. 
6.4.3 
Hydration 
Because of the potential risk of renal dysfunction during periods of dehydration in subjects 
receiving study drug, it is important to encourage study subjects to maintain adequate 
hydration throughout the study. Subjects should be adequately hydrated prior to receiving 
potentially nephrotoxic agents such as IV aminoglycosides or IV 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. 
6.4.4 
Cardiac Drugs for Cardiomyopathy Prophylaxis/Treatment 
The use of angiotensin-converting enzyme (ACE) inhibitors for the management of 
DMD-associated cardiomyopathy has become widespread in the DMD population 
(El-Aloul 2017). In subjects who are unable to tolerate ACE inhibitors, angiotensin receptor 
blockers (ARBs) are sometimes used. Beta-blocker therapy is sometimes initiated after ACE 
inhibitor/ARB therapy for progressive cardiac decline. Finally, the use of an aldosterone 
antagonist has recently demonstrated favorable effects on cardiac function in DMD 
(Raman 2015). Because changes in the use of cardiac drugs could introduce confounding 
influences on the interpretation of results, such changes should be minimized during study 
drug therapy. 
For subjects who are not on cardiac drugs for the prophylaxis/treatment of cardiomyopathy, 
initiation of such drugs during the 40 weeks of study drug treatment is discouraged unless 
there is a strong medical need. 
For subjects who are on cardiac drugs, they should be on a stable dose for at least 1 month 
prior to Visit 1 and a stable regimen should be maintained during the 40 weeks of study drug 
treatment. Adjustments in dosage or type of drug are permitted to avoid symptoms (eg, cough 
associated with ACE inhibitors) but attempts should be made to avoid entirely removing 
subjects from cardiomyopathy prophylaxis/treatment. Subjects who require initiation, 


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interruption, dose modification, or reinstitution of cardiomyopathy prophylaxis/ treatment 
may remain on study drug therapy. 
6.4.5 
Drugs Metabolized by Cytochrome P450 Enzymes 
As the primary route of ataluren metabolism is via glucuronidation by UDPglucuronosyl 
transferase 1-9 (UGT1A9), clinically significant interactions between ataluren and 
coadministered drugs metabolized by cytochrome P450 enzymes (CYPs) are unlikely. In 
particular, ataluren is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, CYP2D6, and 
CYP3A4/5, and does not have induction potential on the major CYP enzymes. 
In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug 
interactions mediated by these enzymes are not expected according to the criteria described 
in the EMA guideline on the investigation of drug interactions (EMA 2012). As an added 
measure of safety, however, investigators should pay specific attention to use of drugs that 
are known substrates of these enzymes, particularly when such drugs may have a low 
therapeutic index. 
6.4.6 
Other Potential Drug Interactions  
Based on in vitro studies, ataluren is a substrate of UGT1A9. Coadministration with 
rifampin, a strong inducer of metabolic enzymes, including UGT1A9, decreased ataluren 
exposure by 30%. The significance of these findings is unknown. Caution should be 
exercised when ataluren is coadministered with medicinal products that are inducers of 
UGT1A9 (eg, rifampicin). 
In vitro data indicate that ataluren is an inhibitor of 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 e.g. OAT1, 
OAT3, or OATP1B3 (eg, oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, 
bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) because of the risk 
of increased plasma concentration of these drugs. 
6.5 
Discontinuation of Study Intervention 
If after appropriate consideration of study drug interruption/modification and consultation 
with the PTC Therapeutics 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 Therapeutics medical monitor 
should be notified (see Section 7.3). In addition, details regarding the reasons for 
discontinuation and the adverse events (AEs) leading to the discontinuation should be 
recorded in the source documents and in the appropriate CRF. The Early Termination 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. 


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6.6 
Participant Discontinuation/Withdrawal from the Study 
All subjects who receive ataluren should remain in the study whenever possible. However: 
● 
The parent/caregiver or legal guardian has the right to withdraw consent and 
discontinue ataluren at any time. 
● 
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. 
● 
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. 
● 
Compliance will be evaluated at Visit 2, Visit 3, and at an early termination visit. 
Compliance is defined as a subject taking 80% to 120% of doses. In the event a 
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. 
● 
If genotyping of the dystrophin gene indicates that patient does not carry a 
nonsense mutation in the gene. 
● 
This study may be discontinued by the relevant regulatory authority, IRB/EC 
(Institutional Review Board/Ethics Committee), and/or PTC Therapeutics at any 
time. 
The date ataluren is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the electronic case report form (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 the evaluations required at the end of study 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. 
 


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7 
STUDY ASSESSMENT AND PROCEDURES 
7.1 
Schedule of Assessments and Study Parameters 
Table 1. 
Schedule of Assessments 
Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study3 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Eligibility 
Informed Consent 
X 
 
 
 
 
 
 
A signed and dated informed consent must be 
obtained before conducting any study procedures. 
Inclusion/Exclusion
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Dystrophin 
genotyping 
X 
 
 
 
 
 
 
Documentation of the presence of a nonsense 
point mutation in the dystrophin gene as 
determined by gene sequencing must be reviewed 
and approved by sponsor prior to enrollment. Blood 
will be drawn for sequencing of the dystrophin gene 
to confirm the presence of a nonsense mutation. 
Safety Assessments 
Physical Exam 
X 
X 
 
X 
X 
 
X 
Full physical-exam (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, extremities, and 
genitourinary) will be performed at screening.  
A Full physical-exam will be performed at screening 
and targeted physical exams at Visits 1 and Visit 3, 
and follow-up visit. 
A targeted exam will include nervous and 
musculoskeletal systems. 
At an unscheduled visit, physical exam will be done 
as necessaryPhysical exam should be performed 
prior to rNSAA and TFTs assessments and biopsy. 


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Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study3 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Clinical Labs 
X 
X 
 
X 
X 
X 
 
For Visit 1, Visit 3, and unscheduled and early 
termination visits, subjects should fast 
approximately 8 hours prior to assessment. 
Biochemistry and other laboratory assessments will 
be analyzed by the central laboratory. 
Biochemistry, hematology, and urinalysis laboratory 
assessments. Creatine kinase will be assessed via 
the UV method or an equivalent method. 
At an unscheduled visit, clinical laboratory 
assessments will be done as necessary. At Visit 1 
and Visit 3, clinical laboratory assessments should 
be performed prior to biopsy. 
Height/Weight/BMI 
 
X 
X 
X 
 
X 
 
Height (in cm) and weight (in kg) will be measured 
at Visit 1, Visit 2, and Visit 3-Early Termination. If 
the subject is unable to stand, sitting arm span and 
ulna length should be assessed as surrogate 
measurements for height. 
Vitals (HR & BP) 
 
X 
 
X 
X 
 
 
Vital signs will include systolic and diastolic blood 
pressure, pulse rate, and body temperature. The 
pulse rate and blood pressure determinations will 
be performed with the subject in a sitting position 
after a 5-minute rest. Blood pressure will be 
measured in triplicate and the average will be 
recorded.  
Vitals should be taken prior to rNSAA and TFTs 
assessments and biopsy.  
AE/SAE 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
AEs must be assessed and documented at each 
clinic visit. Subjects, parents/caregiver or legal 
guardian will be encouraged to report AEs of 
concern at any time in the intervals between visits. 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
Concomitant medications will need to be collected 
starting 30 days prior to first dose of study drug. 
Efficacy Assessments 
Muscle biopsy 
 
X 
 
X 
 
 
 
If a subject received ≥6 months of therapy but early 
terminated, a biopsy may be performed if subject, 
parents or legal guardian agrees. 
rNSAA 
 
X 
 
X 
 
 
 
TFTs 
 
X 
 
X 
 
 
 


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Study Procedure Screening1 Visit 1
2,3 
Visit 2 
Visit 3 End 
of Study3 
Unscheduled
Visit 
Early 
Termination4 Follow-up5 
Notes 
Week 
(visit window) 
-45 to -1 
days 
Baseline 
Week 1 
Week 20 
(± 14 days) 
Week 40 
(± 14 days) 
 
 
 
 
Pharmacokinetic Assessments 
 
 
 
 
 
PK blood sampling 
 
X 
 
X 
 
 
 
PK samples will be drawn on Visit 1, samples will 
be drawn pre-first study dose and 2 hours 
postdose, and on Visit 3 will be drawn pre-morning 
dose and 2 hours postdose.  
Study Drug Administration 
Dispense Drug 
 
X 
X 
 
 
 
 
First dose of study drug should be administered 
following completion of all Baseline (Visit 1) 
assessments. 
Because of potential changes in subject body 
weight over time, a dose adjustment may be made 
based on the subject’s bodyweight at Visit 2 (Week 
20). Central pharmacy to dispense drug direct to 
subject upon completion of Visit 2. 
Unused Drug 
Return/ 
Compliance 
 
 
X 
X 
 
X 
 
All used and unused study drug kits and unused 
sachets will be returned as directed. 
Abbreviations: AE, adverse event; BP, blood pressure; BMI, body mass index; HR, heart rate; PK, pharmacokinetic; rNSAA, Revised North Star Ambulatory 
Assessment; SAE, serious adverse event; TFT, timed-function tests; 
, 
 UV, urine volume 
1 Screening procedures must take place within 45 days of baseline visit (Visit 1). 
2 Any screening procedure completed within and including 7 days of Visit 1 can serve as baseline and does not need to be repeated at Visit 1. 
3 Visit 1 and Visit 3 will be performed at 
. Subjects may have to return to the clinic for up to 3 days for completion of assessments and biopsy. 
4 Early termination assessments should be performed for subjects who discontinue prematurely from the study. 
5 The follow-up visit is for subjects who terminated early/discontinued from the study.  Visit to occur~30 days after termination/discontinuation or until recovery 
from or stabilization of the AE, whichever comes last. The follow-up visit will also occur for subjects who decided to discontinue ataluren therapy even if they 
completed assessments at Visit 3.  
 


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7.2 
Safety Assessments and Other Assessments 
Subjects will be monitored closely for AEs and laboratory abnormalities during the study. 
For AEs and laboratory abnormalities, the investigator should use his/her judgment in 
determining whether the event or abnormality is clinically significant, whether diagnostic 
evaluation is warranted, and whether potential interruption of study drug therapy is 
appropriate. In general, life-threatening (Grade 4) or severe (Grade 3) AE or laboratory 
abnormalities should be considered clinically significant, although recurrent or persistent 
moderate events (Grade 2) may also be considered clinically significant in certain 
circumstances. Reference should be made to the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 for grading the severity of adverse events and laboratory 
abnormalities.CTCAE 
While specific monitoring, diagnostic testing, and supportive care measures must be 
instituted based on the clinical judgment of the investigator, investigators should contact the 
PTC Therapeutics medical monitor to obtain guidance and to ascertain whether similar 
events are being seen at other sites. The PTC Therapeutics 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 PTC Therapeutics medical monitor may suggest 
review of the case with gastroenterology, endocrinology, nephrology consultants or with 
other experts (either at the site or retained by PTC Therapeutics). 
Cases of decreased renal function have been observed in patients with nmCF receiving 
ataluren and IV aminoglycosides together with other antibiotics for cystic fibrosis 
exacerbations (Section 6.4.2). As a precaution, Table 2provides information on actions to be 
taken in the event that abnormalities are noted in specified renal laboratory parameters.  
Thresholds are provided for interrupting study drug immediately or for interrupting study 
drug after confirmation of a value beyond the threshold. For AEs or laboratory abnormalities 
not listed in Table 2, the investigator should use his/her judgment in determining whether the 
event or abnormality is clinically significant, whether diagnostic evaluation is warranted, and 
whether potential interruption of study drug is appropriate. 
Table 2. 
Renal Monitoring Parameters and Actions To Be Taken 
 
Laboratory Parameter 
Stop Study Drug Immediately, 
Confirm Abnormal Value, 
and Then Start Work-Up 
Stop Study Drug After  
Confirminga Abnormal Value,  
and Then Start Work-Up 
Serum cystatin C 
>2.00 mg/L 
>1.33 - 2.00 mg/L 
Serum creatinine 
≥ Grade 2 (≥1.5 x ULN for age) 
Grade 1 (>ULN - 1.5 x ULN for age) 
Serum BUN 
≥3.0 x ULN 
≥1.5 - 3.0 x ULN 
Abbreviations: BUN = blood urea nitrogen; ULN = upper limit of normal  
a  Laboratory abnormalities may be confirmed immediately or at the next scheduled clinic visit based on 
investigator judgment. 
 
 


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7.3 
Adverse Events and Serious Adverse Events 
7.3.1 
Definition of adverse events (AE) 
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. 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 
● 
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 electrocardiogram 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; however, it 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 


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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, 
as described in Section 7.3.2 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 non-serious by the investigator using medical and 
scientific judgment. 
7.3.2 
Definition of serious adverse events (SAE) 
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 to be related to the study drug, which 
results in one of the following: 
● 
Results in death. This includes all deaths on treatment or within 30 days after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 30 days 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. 
● 
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). 
Treatments in the emergency room for procedures such as hydration that do not 
require admitting the subject to the hospital and observational durations in the 
emergency room for less than 24 hours do not fall into this category. 
● 
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. 


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7.3.3 
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. 
7.3.4 
Eliciting adverse event information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent(s)/legal guardian/legally acceptable representative. In addition, each 
study subject/parent(s)/legal guardian/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/parent(s)/legal guardian/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. 
7.3.5 
Recording Non‑serious AEs and SAEs 
All AEs (both serious and non-serious) 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 
recorded: 
● 
Indication of whether the event is serious or non-serious (see Section 7.3.2) 
● 
Relationship to study drug (see Section 7.3.6) 
● 
Severity of the event (see Section 7.3.7) 
● 
Onset date 
● 
Resolution date, or date of death 
● 
Action taken 
● 
Outcome of the event 
Classification of the event as serious or non-serious determines the reporting procedures to 
be followed. 


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7.3.6 
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 3. 
Table 3. 
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.  
7.3.7 
Grading of severity of adverse event 
The severity of AE will be graded using the CTCAE Version 5.0. 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 4. 
Table 4. 
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  


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7.3.8 
Adverse Event Reporting 
Investigator site reporting requirements for AEs are summarized in Table 5. 
Table 5. 
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   
Serious AE 
All  
All  
Non-Serious AE 
All  
None  
Occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure 
Occupational exposure (regardless of 
whether associated with an AE) 
Abbreviations: 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 Therapeutics 
Pharmacovigilance Department or designee should be informed via e-mail or fax. 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 
Therapeutics medical monitoring team. 
The first day of AE reporting will coincide with the date of signing of Informed Consent and 
including a minimum of 30 calendar days after the last administration of study drug. 
7.3.9 
Serious adverse event reporting 
All SAEs should be reported via the SAE report form to PTC Therapeutics 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/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 


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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 AE. 
The PTC Therapeutics Pharmacovigilance Department contact information for reporting 
SAEs is provided below.  
PTC Therapeutics Safety Department 
Attention: Pharmacovigilance 
E-mail:
Facsimile:
7.3.10 
Reporting Pregnancy 
Subjects enrolled in this trial will have not reached sexual maturity; therefore, there are 
no requirements for pregnancy avoidance for study participants. 
7.3.11 
PTC Therapeutics Adverse Event Reporting Requirement 
As the sponsor of the study, PTC Therapeutics is responsible for reporting certain safety 
information, particularly SAEs and subject deaths related to participation in the study, to 
each investigator in an expedited manner. If notification of an AE requiring expedited 
reporting to investigators is received, PTC Therapeutics 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 Therapeutics or an agent of 
PTC Therapeutics (eg, a site monitor) becomes aware of an AE. This awareness date is the 
date the regulatory reporting clock begins and the date is considered Day 0. 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
Statistical Hypotheses 
The null hypothesis of this study is that the change in dystrophin levels following 40 weeks 
of ataluren therapy, as measured by an immunoassay such as ECL is zero with the alternative 
hypothesis being that the change is greater than zero. To evaluate this hypothesis a one-sided 
test at the 5% alpha level will be employed. 
8.2 
Sample Size Determination 
Approximately, 15 to 20 ataluren-naïve male subjects, aged ≥2 and <8 years of age is 
planned to be enrolled in this study. Limited information is available about the magnitude 
and intra-subject variability of the change in dystrophin levels, as measured by an 
immunoassay such as ECL following 40 weeks ataluren therapy in this patient population. 
Assuming a baseline dystrophin level of 0.2% (as per previous dystrophin replacement 
therapy [Center for Drug Evaluation and research Application number: 206488Orig1s000 
Eteplirsen Summary Review]), Table 6 shows the number of subjects needed to achieve a 
85% power to detect an increase from baseline in dystrophin of 0.04%, 0.06% and 0.08%, for 
intra-subject coefficients of variability (CV) ranging from 20% to 35%, using a one-sided test 
at alpha 5%. As an example, if the increase from baseline is 0.08% and the intra-subject 
coefficient is 30%, 13 evaluable subjects would be required to have a power of 85% to detect 
this increase.  
Table 6. 
Summary of number of subjects required to achieve 85% power to detect 
increase in dystrophin levels from baseline 
Increase of dystrophin 
from baseline 
Intra Subject CV 
 
20% 
25% 
30% 
35% 
0.04% 
19 
29 
41 
55 
0.06% 
10 
15 
21 
28 
0.08% 
7 
10 
13 
18 
Abbreviations: CV, coefficients of variability 
The sample size will be re-assessed after the 10th subject has completed the Week 40 
assessments. 
8.3 
Population for Analyses 
8.3.1 
Intention-to-treat (ITT) analysis set 
This analysis set will include all enrolled subjects with treatment assignments. In addition, 
subjects in this analysis set must have a valid assessment of dystrophin levels at baseline, as 
measured by ECL. This analysis set will be used for the primary endpoint analyses and 
summaries of other efficacy endpoints. 


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8.3.2 
Per Protocol Analysis Set 
This analysis set will include all subjects in the ITT set who meet the following additional 
criteria: received study treatment, completed the 40-week treatment period without major 
protocol violations and dose interruptions and have a valid assessment of dystrophin levels at 
Week 40.  This analysis set will be used for supportive efficacy analyses 
8.3.3 
Safety Analysis Set 
This analysis set will include all subjects who received at least one dose of ataluren and will 
be used for all summaries of safety. 
8.4 
Statistical Analyses 
8.4.1 
General approach 
8.4.2 
Analysis of primary efficacy endpoint 
The primary endpoint will be log transformed and analyzed in a mixed model of repeated 
measures with week/treatment as a fixed effect and subject as a random effect. Two-sided 
90% CI for the ratio (%) of dystrophin level at Week 40 versus baseline will be constructed. 
The dystrophin level will be summarized by muscle biopsy locations using descriptive 
statistics. 
Baseline dystrophin levels in this patient population is expected to be close to zero, in case 
any measured dystrophin levels are below the lower limit of quantification (LOQ), the levels 
will be set at 0.5*LOQ for the statistical analysis. Subjects with baseline dystrophin levels 
 of the predicted levels will be excluded from the primary analysis to minimize the 
potential bias in the assessment of change in dystrophin levels. 
8.4.3 
Analysis of secondary efficacy endpoint 
The secondary endpoint will be analyzed in the same way as the primary endpoint. 
8.4.4 
Pharmacokinetic analyses 
Plasma concentration will be summarized with descriptive statistics. 
A separate analysis to evaluate the PK data observed in the study will be conducted in 
parallel if the plasma concentrations are within in the established therapeutic range. 


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8.4.5 
Safety analyses 
Evaluations of safety will be performed using the safety analysis set. The incidence of AEs 
and SAEs will be tabulated using frequency count. Change from baseline results will be 
presented for clinical laboratory values and vital signs. 
8.4.6 
Planned interim analyses 
There are no planned interim analyses for this study. 
8.4.7 
Sub-group analyses 
Not Applicable 
 
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 informed consent/assent will be 
obtained from each parent/legal guardian prior to study entry and that the informed 
consent/assent will be obtained in accordance with current regulations. 
The investigator or sub-investigator will give each parent/legal guardian full and adequate 
verbal and written information regarding the objectives and procedures of the study and the 
possible risks involved. An informed consent/assent document will be provided to each 
parent/legal guardian in a language in which the parent/legal guardian is fluent. This 
information must be provided to the parent/legal guardian prior to undertaking any study 
related procedure. Adequate time should be provided for the parent/legal guardian to read the 
informed consent, to understand the risks and benefits of participating in the study, and to ask 
any questions that the parent/legal guardian may have about the study. The parent/legal 
guardian should be able to ask additional questions as and when needed during the conduct 
of the study. The parent/legal guardian's signature on the informed consent form should be 
obtained at the investigator site in the presence of the investigator or a qualified 
representative (eg, sub investigator). Where applicable, the subject will sign an age-
appropriate assent form. 
Each parent/legal guardian will be given a copy of the signed consent/assent form. The 
original signed informed consent forms will be retained by the investigator with the study 
records. 


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The written subject information must not be changed without prior approval by PTC 
Therapeutics and the IRB/IEC. 
9.1.2 
Study discontinuation and closure 
PTC Therapeutics reserves the right to discontinue the study prior to inclusion of the 
intended number of subjects. The investigator, after consultation with the PTC Therapeutics 
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 
Therapeutics. As directed by PTC Therapeutics, all study materials must be collected and all 
electronic data entry forms completed to the greatest extent possible. 
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 Therapeutics (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 
Therapeutics. The informed consent form must include appropriate statements explaining 
these requirements. 
By signing this protocol, the investigator affirms to PTC Therapeutics that the investigator 
will maintain, in confidence, information furnished by PTC Therapeutics and will divulge 
such information to the IRB/IEC under an appropriate understanding of confidentiality with 
such board. 
9.1.4 
Future use of stored specimens and data 
As part of the current study, muscle tissue via biopsies will be collected to evaluate the effect 
of ataluren treatment on the expression of dystrophin protein as measured by ECL and 
immunohistochemistry. All biopsy samples/extracts will be deidentified. The samples will be 
stored for 10-years. Only PTC Therapeutics and 
 will have access to biopsy/extracts 
and they will not be shared with secondary researchers 
These same samples will potentially be used to look at biochemical biomarkers that may be 
altered due to increased dystrophin levels. No additional genetic testing will be done or cell 
lines created. The results will be communicated to PTC Therapeutics. 


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The subject/parent/caregiver will provide confirmation to allow any remaining specimens to 
be used for exploratory research work by PTC Therapeutics within the Informed Consent 
Form. Participants who decline to participate in this optional research may do so. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research. Participants will be told 
that it is optional to participate in exploratory research and may withdraw their consent at any 
time and for any reason during the storage period.  
9.1.5 
Clinical monitoring 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH 
guidelines, PTC Therapeutics or a designee will periodically inspect all eCRFs, 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 Therapeutics 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 Therapeutics.  The investigator/institution guarantees 
direct access to source documents by PTC Therapeutics and appropriate regulatory 
authorities. 
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. 
9.1.6 
Quality assurance and quality control 
To ensure compliance with good clinical practices (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, Good Clinical Practice 
guidelines of the International Council on Harmonisation, and any applicable regulatory 
requirements.  The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection. 


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9.1.7 
Data handling and record keeping 
To enable evaluations and/or audits from regulatory authorities or PTC Therapeutics, the 
investigator agrees to keep accurate and complete records, including the identity of all 
participating subjects (sufficient information to link eCRFs and clinic records/source 
documents), all original signed informed consent forms, electronic copies (ie, CD-ROM, 
USB, etc.) or paper copies of the data that have been captured in the Electronic Data Capture 
(EDC) for each subject (eCRFs), and detailed records of study drug disposition. All records 
and documents pertaining to the study will be maintained by the investigator until 
notification is received from PTC Therapeutics that the records no longer need to be retained. 
The investigator must obtain written permission from PTC Therapeutics before disposing of 
any records. The investigator will promptly notify PTC Therapeutics in the event of 
accidental loss or destruction of any study records. If the investigator relocates, retires, or for 
any reason withdraws from the study, the study records may be transferred to an acceptable 
designee, such as another investigator, another institution, or to PTC Therapeutics as 
applicable. 
9.1.8 
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: 
● 
Failure to adhere to study exclusion and inclusion criteria 
● 
Failure to comply with dispensing or dosing requirements 
● 
Use of medications that are specifically prohibited in the protocol 
● 
Missed or out-of-window visits 
● 
Drug dosing not administered within the time frame specified in the protocol 
● 
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 incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB approvals for the 
protocol and ICF revisions 
Significant 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 
trial. 


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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 
significant; thus, requiring immediate notification to the PTC Therapeutics 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. 
9.1.9 
Publication and data sharing policy 
The information developed during the conduct of this clinical study is considered 
confidential by PTC Therapeutics.  This information may be disclosed as deemed necessary 
by PTC Therapeutics. 
PTC Therapeutics intends that the data from this study will be presented and published.  The 
PTC Therapeutics staff under the direction of the PTC Therapeutics 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 Therapeutics. 
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. 
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 


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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 
Amendment 1:  22 Oct 2018 (Version 2.0) 
Amendment 2:  06 May 2019 (Version 3.0) 
The overall reason for the amendment: The overall reason for the amendment was to 
ensure that sufficient muscle tissue for analysis was obtained from the biopsy procedure, to 
extend the screening window, to add information on concomitant use of corticosteroids and 
cardiac drugs for cardiomyopathy prophylaxis/treatment, to update the exploratory PK 
assessments and analyses, and to update the ataluren dosing table. 
Item 
No. 
Protocol Section 
Amendment/Update 
Reason/Rationale 
1 
Synopsis and 
Sec 2.2.3 
Exploratory endpoints: deleted specific PK 
parameters 
Allow for analysis of 
other parameters 
2 
Synopsis, 
Sec 3.1.1, and 
Sec 3.2 Bullet #2  
Revised from  muscle biopsy samples to up 
to approximately 450 mg of muscle tissue 
(up to  cores per muscle); allowed sample 
from the 
 muscle if 
obtained sample is not evaluable for analysis 
To ensure sufficient 
muscle tissue for analysis 
3 
Synopsis Table 1 
and Sec 7 Table 1 
Extended screening window from 30 to 
45 days; added details for assessing 
height/weight and physical exams, deleted 
details of PK analyses 
Increase visit window; 
clarification 
4 
Section 3.1.4 
Information on PK analyses moved to 
Section 8.4.4 
Clarification 
5 
Section 4.1 
Added text on homogeneity of study 
population 
Clarification 
6 
Section 6.2 
Added that drug will be administered with 
food.  
Clarification 
7 
Section 6.4.1 
Added information on Corticosteroids 
Clarification 
8 
Section 6.4.4 
Added information on Cardiac Drugs for 
Cardiomyopathy Prophylaxis/Treatment 
Concomitant use of 
cardiac drugs for 
cardiomyopathy 
prophylaxis/treatment 
9 
Section 7.2 
Added text and table on renal functioning 
and monitoring parameters 
Safety precautions 


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Item 
No. 
Protocol Section 
Amendment/Update 
Reason/Rationale 
10 
Sec 7.3.8, Table 5 Deleted:  Exposure during pregnancy or 
breastfeeding” 
Clarification 
11 
Section 7.3.9 
Deleted:  “This information is also provided 
in the Study Manual and in the SAE report 
form.” 
Deleted telephone number for SAE reporting.
Clarification 
12 
Section 8.4.2 
Added:  “The dystrophin level will be 
summarized by muscle biopsy locations 
using descriptive statistics.” 
Clarification 
13 
Section 8.4.4 
Added information on PK analyses 
Clarification 
14 
Section 8.4.5 
Added information on safety evaluations 
Clarification 
15 
Section 9.3 
Added Protocol Amendment History 
Update 
16 
Appendix 
Added dosing table 
Update 
17 
Synopsis and 
Protocol 
Document date/version, abbreviations and 
references were updated; small grammatical 
changes were made throughout. 
Update 


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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. 
Anthony, K, Arechavala-Gomeza, V, Ricotti, V, Torelli, S, Feng, L, Janghra, N, et al. 
Biochemical characterization of patients with in-frame or out-of-frame DMD deletions 
pertinent to exon 44 or 45 skipping. JAMA Neurol 2014;71(1):32-40. 
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, 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, Birnkrant, DJ, Case, LE, Clemens, PR, Cripe, L, et al. Diagnosis and 
management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary 
care. Lancet Neurol 2010b;9(2):177-189. 
El-Aloul, B, Altamirano-Diaz, L, Zapata-Aldana, E, Rodrigues, R, Malvankar-Mehta, MS, 
Nguyen, CT, et al. Pharmacological therapy for the prevention and management of 
cardiomyopathy in Duchenne muscular dystrophy: A systematic review. Neuromuscul 
Disord 2017;27(1):4-14. 
EMA. Guideline on the investigation of drug interactions.  2012;(CPMP/EWP/560/95/Rev. 1 
Corr.*). 
Finkel, RS, Flanigan, KM, Wong, B, Bonnemann, C, Sampson, J, Sweeney, HL, et al. Phase 
2a study of ataluren-mediated dystrophin production in patients with nonsense mutation 
Duchenne muscular dystrophy. PLoS One 2013;8(12):e81302. 
Gallo, A, Abraham, A, Katzberg, HD, Ilaalagan, S, Bril, V and Breiner, A. Muscle biopsy 
technical safety and quality using a self-contained, vacuum-assisted biopsy technique. 
Neuromuscul Disord 2018;28(5):450-453. 
Humbertclaude, V, Hamroun, D, Bezzou, K, Berard, C, Boespflug-Tanguy, O, Bommelaer, 
C, et al. Motor and respiratory heterogeneity in Duchenne patients: implication for clinical 
trials. Eur J Paediatr Neurol 2012;16(2):149-160. 
Mah, JK. Current and emerging treatment strategies for Duchenne muscular dystrophy. 
Neuropsychiatr Dis Treat 2016;12:1795-1807. 


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Matthews, E, Brassington, R, Kuntzer, T, Jichi, F and Manzur, AY. Corticosteroids for the 
treatment of Duchenne muscular dystrophy. Cochrane Database Syst Rev 
2016;(5):Cd003725. 
Muntoni, F, Torelli, S and Ferlini, A. Dystrophin and mutations: one gene, several proteins, 
multiple phenotypes. Lancet Neurol 2003;2(12):731-740. 
Petrof, BJ, Shrager, JB, Stedman, HH, Kelly, AM and Sweeney, HL. Dystrophin protects the 
sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 
1993;90(8):3710-3714. 
Phillips, MF, Quinlivan, RC, Edwards, RH and Calverley, PM. Changes in spirometry over 
time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit 
Care Med 2001;164(12):2191-2194. 
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. 
Raman, SV, Hor, KN, Mazur, W, Halnon, NJ, Kissel, JT, He, X, et al. Eplerenone for early 
cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol 2015;14(2):153-161. 
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. 
 


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11 
APPENDIX 
PTC124-GD-045-DMD Dosing Table 

SAP_001.pdf: 
V1.0 
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STATISTICAL ANALYSIS PLAN 
PHASE 2 CLINICAL PHARMACOLOGY STUDY TO ASSESS DYSTROPHIN LEVELS IN 
SUBJECTS WITH NMDMD BEFORE AND AFTER TREATMENT WITH ATALUREN 
PTC124-GD-045-DMD 
11 JANUARY 2021 
VERSION 1.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
NCT #NCT03648827


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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.


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


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TABLE OF CONTENTS 
PTC THERAPEUTICS APPROVAL SIGNATURES ....................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................8 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
3.1. 
Study Objectives ...........................................................................................................9 
3.1.1. 
Primary Objective .........................................................................................................9 
3.1.2. 
Secondary Objective .....................................................................................................9 
3.1.3. 
Exploratory Objectives .................................................................................................9 
3.2. 
Study Endpoints ............................................................................................................9 
3.2.1. 
Primary Endpoint ..........................................................................................................9 
3.2.2. 
Secondary Endpoint ......................................................................................................9 
3.2.3. 
Exploratory Endpoints ..................................................................................................9 
3.3. 
Sample Size Determination ........................................................................................10 
4. 
STUDY POPULATIONS ...........................................................................................10 
4.1. 
Screened Population ...................................................................................................10 
4.2. 
Enrolled Population ....................................................................................................10 
4.3. 
Intent-to-Treat Population ..........................................................................................10 
4.4. 
Per Protocol Population ..............................................................................................11 
4.5. 
Safety Population ........................................................................................................11 
5. 
GENERAL CONSIDERATIONS ..............................................................................11 
5.1. 
Tables, Figures, and Listings ......................................................................................11 
5.2. 
Visit Window ..............................................................................................................11 
5.3. 
Missing Data Handling ...............................................................................................11 
5.4. 
Interim Analysis ..........................................................................................................12 
5.5. 
Multicenter, Multiplicity control ................................................................................12 
5.6. 
COVID-19 Related Considerations ............................................................................12 
6. 
SUBJECT DATA .......................................................................................................12 
6.1. 
Subject Disposition and Study Populations ................................................................12 


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6.2. 
Treatment Exposure ....................................................................................................12 
6.3. 
Study Drug Compliance .............................................................................................13 
6.4. 
Demographic and Baseline Characteristics ................................................................13 
6.5. 
Concomitant Medications and Non-Drug Treatments ................................................13 
6.6. 
Medical History ..........................................................................................................13 
7. 
EFFICACY EVALUATION ......................................................................................14 
7.1. 
Primary Efficacy Analyses .........................................................................................14 
7.1.1. 
Primary Analysis ........................................................................................................14 
7.1.2. 
Subgroup Analyses .....................................................................................................15 
7.1.3. 
Sensitivity Analyses ....................................................................................................15 
7.2. 
Secondary Efficacy Analyses .....................................................................................16 
7.2.1. 
Secondary Efficacy Analysis ......................................................................................16 
7.2.2. 
Sensitivity Analyses ....................................................................................................16 
7.3. 
Exploratory Analyses ..................................................................................................17 
7.3.1. 
Revised North Star Ambulatory Assessment .............................................................17 
7.3.2. 
Timed Function Test ...................................................................................................17 
7.3.3. 
Creatine kinase levels .................................................................................................17 
8. 
SAFETY EVALUATION ..........................................................................................17 
8.1. 
Adverse Events ...........................................................................................................17 
8.2. 
Clinical Laboratory .....................................................................................................18 
8.3. 
Vital Signs ..................................................................................................................18 
8.4. 
Other Safety Assessments ...........................................................................................18 
9. 
PHARMACOKINETIC BLOOD SAMPLE ..............................................................18 
10. 
CHANGES FROM THE PLANNED ANALYSES ...................................................18 
11. 
REFERENCES ...........................................................................................................19 
 


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LIST OF TABLES 
Table 1: 
Summary of number of subjects required to achieve 85% power to detect 
increase in dystrophin levels from baseline ................................................................10 
Table 2: 
Visit Window for Safety Analyses .............................................................................11 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ...........................................................................................................8 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
AE 
Adverse event 
CK 
Creatine kinase 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case report form 
CV 
Coefficients of variability 
ECL 
Electrochemiluminescence 
eCRF 
Electronic case report form 
IHC 
Immunohistochemistry 
ITT 
Intent-to-treat 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effect model repeated measurement 
N 
Number of subjects 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy  
PK 
Pharmacokinetics 
PP 
Per protocol 
% normal 
Percentage of the predicted levels 
PT 
Preferred term 
rNSAA 
Revised North Star Ambulatory Assessment 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
TFT 
Timed function test 
TEAE 
Treatment-emergent adverse event 
 
 


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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the procedures and the 
statistical methods that will be used in analyzing and reporting results for study 
PTC124-GD-045-DMD (hereafter referred to as Study 045). This SAP is prepared based on the 
study protocol V3.0 (dated 06May2019). 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. 
2. 
STUDY DESIGN 
This is an open-label, single-arm, Phase 2 study designed to evaluate the ability of ataluren 
treatment to increase dystrophin protein levels in muscle cells of patients with nonsense mutation 
Duchenne muscular dystrophy (nmDMD). The study will evaluate the levels of dystrophin 
before and after 40 weeks of ataluren therapy using muscle biopsies and two validated assay 
methods. 
Approximately, 15 to 20 ataluren-naïve male subjects, aged >=2 and <8 years of age will be 
administered ataluren. 
Ataluren will be dosed daily 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the 
evening (10, 10, 20 mg/kg). 
The study will have a screening visit and 3 additional visits (Figure 1). At the screening visit, 
which will be performed at a patient’s local site, inclusion/exclusion criteria, demographics and 
medical history will be assessed. In addition, blood will be drawn for genotyping to confirm that 
a subject carries a nonsense mutation in the dystrophin gene. For all subjects, Visit 1 and Visit 3 
will occur at the same site, that of 
 
. During Visit 1 and Visit 3 biopsies will be performed and used for assessing 
dystrophin protein levels. At Visit 1, the first dose of ataluren will be administered following the 
biopsy at 
 and subjects, parent/caregivers or legal guardian will be dispensed a supply of 
ataluren which will be administered at home. Visit 2 will be in the clinic at the subjects’ local 
site and weight will be measured to determine if the dose of ataluren requires adjustment. 
Adverse events (AE), serious adverse events (SAE), concomitant medications, and compliance 
will also be captured, and an additional supply of ataluren will be dispensed. 
Figure 1: 
Study Schematic 
 
No interim analysis will be conducted for this study. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
To assess the change in levels of dystrophin in ambulatory nmDMD subjects after treatment with 
ataluren for 40 weeks using quantitative assay, such as electrochemiluminescence (ECL). 
3.1.2. 
Secondary Objective 
To assess dystrophin levels/intensity and protein localization by immunohistochemistry (IHC). 
3.1.3. 
Exploratory Objectives 
The exploratory objectives are as follows: 
• To assess the change from baseline in revised North Star Ambulatory Assessment 
(rNSAA) and timed function tests (TFTs) after 40 weeks of ataluren treatment 
• To assess changes from baseline in creatine kinase (CK) levels after 40 weeks for 
ataluren treatment 
• To evaluate the steady state pharmacokinetics (PK) of ataluren after 40 weeks of 
treatment 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
The percent change from baseline in dystrophin levels (final concentration) following 40 weeks 
of ataluren therapy, as measured by an ECL-based immunoassay that has been validated and will 
be run under Good Laboratory Practice conditions. 
3.2.2. 
Secondary Endpoint 
The percent change in dystrophin levels (mean membrane stain density) from baseline after 
40 weeks of ataluren therapy as determined by a validated IHC assay. 
3.2.3. 
Exploratory Endpoints 
The exploratory endpoints are as follows:  
• Change from baseline in rNSAA after 40 weeks of treatment 
• Change from baseline in TFTs after 40 weeks of treatment 
• Change from baseline in CK levels after 40 weeks of treatment 
• PK assessments at Week 1 and Week 40 


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3.3. 
Sample Size Determination 
Approximately, 15 to 20 ataluren-naïve male subjects, aged >=2 and <8 years of age is planned 
to be enrolled in this study. Limited information is available about the magnitude and 
intra-subject variability of the change in dystrophin levels, as measured by an immunoassay such 
as ECL following 40 weeks ataluren therapy in this patient population. Assuming a baseline 
dystrophin level of 0.2% of control levels (as per previous dystrophin replacement therapy 
[Center for Drug Evaluation and research Application number: 206488Orig1s000 Eteplirsen 
Summary Review]), Table 1 shows the number of subjects needed to achieve an 85% power to 
detect an increase from baseline in dystrophin of 0.04%, 0.06% and 0.08%, for intra-subject 
coefficients of variability ranging from 20% to 35%, using a one-sided test at alpha 5%. As an 
example, if the increase from baseline is 0.08% and the intra-subject coefficient is 30%, 
13 evaluable subjects would be required to have a power of 85% to detect this increase. 
Table 1: 
Summary of number of subjects required to achieve 85% power to detect increase 
in dystrophin levels from baseline 
 
Abbreviations: CV, coefficients of variability 
4. 
STUDY POPULATIONS 
4.1. 
Screened Population 
Screened population is defined as all patients who have signed informed consent. 
4.2. 
Enrolled Population 
Enrolled population is defined as the subset of screen population who are not screen failures. 
4.3. 
Intent-to-Treat Population 
This analysis set will include all enrolled subjects with treatment assignments. In addition, 
subjects in this analysis set must have a valid assessment of dystrophin levels at baseline, 
as measured by ECL. This analysis set will be used for the primary endpoint analyses and 
summaries of other efficacy endpoints.  


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4.4. 
Per Protocol Population 
The per protocol (PP) analysis set consists of all ITT subjects without major protocol deviation 
that will impact the efficacy analyses. Any ITT subjects who meet the following criteria will be 
excluded from the PP population:  
• study treatment not received 
• Week 40 visit not within 38 to 42 weeks from the Baseline visit 
• not compliant to study drug dose regiment; treatment compliance <80% or >120% 
• baseline dystrophin levels 
 predicted 
• do not have a valid assessment of dystrophin levels at either Baseline or Week 40 
visits 
This analysis set will be used for supportive efficacy analyses. 
4.5. 
Safety Population 
This analysis set will include all subjects who received at least one dose of ataluren and will be 
used for all safety summaries. 
5. 
GENERAL CONSIDERATIONS 
5.1. 
Tables, Figures, and Listings 
In general, continuous variables will be summarized using descriptive statistics including n 
(number of subjects), mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using frequency count as number and percentage of subjects. 
Unless specified, all hypothesis testings are 1-sided at a 5% alpha level. 
By subject data listings will be created for selected electronic case report form (CRF) domains 
sorted by subject and associated dates. 
5.2. 
Visit Window 
Study day 1 (baseline) is defined as the date of the first dose of study drug during the treatment 
period. The nominal visit (ie, study visit captured on the CRF) will be used as the analysis visits 
in all efficacy analyses. For safety analyses, the unscheduled and Early Termination visits will be 
reclassified into analysis visits according to Table 2. If multiple visits occurred within the same 
visit window, the one closest to the target visit date will be used in the analysis. If two visits are 
equidistant to the target visit date, the latest will be used.  
Table 2: 
Visit Window for Safety Analyses 
Timepoint 
Target Visit Date 
Visit window (in study days) 
Visit 1 (baseline) 
1 
-45 to 1 
Visit 2 (week 20) 
140 
71 to 210 
Visit 3 (week 40) 
280 
>=211 
5.3. 
Missing Data Handling  
Unless specified, observed data will be used for all analyses. Missing data will not be imputed. 


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5.4. 
Interim Analysis 
No interim analysis will be conducted for this study. 
5.5. 
Multicenter, Multiplicity control 
This is a multicenter study with all muscle biopsies performed at one center. No multicenter 
analysis will be conducted for this study. 
There is only one primary efficacy endpoint, and one secondary efficacy endpoint for this study. 
The secondary efficacy endpoint will be analyzed if the primary efficacy endpoint is statistically 
significant at 0.05 significance level. All other endpoints and analyses are supportive. Therefore, 
no multiplicity adjustment will be conducted for this study. 
5.6. 
COVID-19 Related Considerations 
Due to the Coronavirus Disease of 2019 (COVID-19) pandemic, 8 subjects will have Visit 3 
(Week 40 visit) later than planned due to closure of the study site to study procedures. These 
subjects will receive continued therapy with ataluren until final study biopsies can be obtained. 
Since many subjects will have their Week 40 biopsy performed much later than after 40 weeks of 
ataluren treatment therapy, a sensitivity analysis will be conducted to include the Week 40 
biopsy study day as a covariate in the analysis model. This sensitivity analysis will be performed 
for both the primary and secondary efficacy endpoints as detailed in Section 7.1.3 (Sensitivity 
Analyses) for the primary efficacy endpoint and in Section 7.2.2 (Sensitivity Analyses) for the 
secondary efficacy endpoint. 
6. 
SUBJECT DATA 
6.1. 
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 on both the ITT and the safety populations if they are 
different. 
6.2. 
Treatment Exposure 
The extent of exposure (duration of exposure) to study drug will be summarized using 
descriptive statistics and tabulated with frequency count by categories. Duration of exposure of 
study drug will be defined as the number of days between the date the subject received the first 
dose of study drug during treatment period and the date the subject received the last dose of 
study drug during treatment period, inclusive. Duration of exposure will be categories as 
<266 days, 266 to 295 days and >295 days. Treatment exposure will be summarized based on 
both the ITT and safety populations if they are different. 


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6.3. 
Study Drug Compliance 
Treatment compliance (in %) is defined as follows: 
100 x (total number of sachets dispensed - total number of sachets returned or lost) 
number of sachets expected to be taken  
Treatment compliance will be summarized using descriptive statistics based on the safety 
population. Treatment compliance will also be summarized using the categories <80%, ≥80% to 
≤100%, >100% to ≤120%, and >120%. 
6.4. 
Demographic and Baseline Characteristics 
Unless otherwise specified, baseline measurement is the last observed measurement prior to the 
first dose of study drug for a given assessment. 
Continuous demographic and baseline variables including age, age at onset of phenotypic 
evidence, age at first observation of difficulty with ambulation, height, weight, and body mass 
index will be summarized using descriptive statistics. Categorical variables including ethnicity 
group, race, and type of corticosteroid use will be tabulated using frequency count. Demographic 
and baseline characteristics will be summarized based on both the ITT and safety populations if 
they are different.  
Genotype information including the location of nonsense point mutation (exon number) and the 
stop codon type will be tabulated using frequency count and displayed in subject listings. 
6.5. 
Concomitant Medications and Non-Drug Treatments 
Medications and non-drug treatments will be coded using the World Health Organization Drug 
Dictionary, version September 1, 2020. Prior medications and prior non-drug treatments are 
defined as those taken any time prior to first dose of study drug. Concomitant medications and 
non-drug treatments are defined as those taken any time on or after first dose of study drug. 
The number and percentage of subjects who take prior and concomitant medications will be 
summarized using the safety population by Anatomical Therapeutic Chemical class, and 
WHO DD preferred term (PT) for safety populations. If a subject takes the same medications for 
the same class level or drug name, the subject will be counted only once for that class level or 
drug name. 
6.6. 
Medical History 
Medical history other than the history of dystrophinopathy will be coded using the Medical 
Dictionary for Regulatory Affairs (MedDRA), version 23.1. The number and percent of subjects 
with medical history will be summarized by System Organ Class (SOC) and PT based on safety 
population. 


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7. 
EFFICACY EVALUATION 
The primary efficacy assessment for this study is the dystrophin levels obtained from muscle 
biopsies. Muscle biopsies of 
 muscles will be performed 
using an established core biopsy procedure at baseline and after 40 weeks of ataluren therapy. 
If the 
 muscle is considered by the investigator to be too small for a biopsy sample (or the 
obtained sample is considered not evaluable for analysis), the 
 muscle may 
be used. 
 cores of muscles will be taken from each location and multiple samples will be 
prepared from each muscle cores. Dystrophin levels will be measured from each sample by both 
ECL and IHC. The dystrophin levels measured by ECL will be considered as the primary 
efficacy endpoint. The dystrophin levels measured by IHC will be considered as the secondary 
efficacy endpoint. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Primary Analysis 
The primary efficacy endpoint is the percent change from baseline in dystrophin levels (final 
concentration) following 40 weeks of ataluren therapy, as measured by ECL. The final 
concentration is calculated by dividing a sample’s dystrophin concentration by its total protein 
concentration. In addition, the percentage of the predicted levels (% normal) will also be 
calculated as dystrophin levels normalized to dystrophin concentration of the control population 
(Syneos Health Report No. 14597.051619.A):  
% normal (in %) = 100* final concentration/33.8 
Within each muscle location, the best, median, and the average of the dystrophin levels and the 
corresponding % normal values of the muscle cores will be summarized using descriptive 
statistics for each subject. In case any measured dystrophin concentrations are below the lower 
limit of quantification (LLOQ), the dystrophin concentrations will be set at 0.5*LLOQ in the 
final concentration calculation for the statistical analysis.  
The null hypothesis of the primary analysis is that the percent change from baseline in 
dystrophin levels following 40 weeks of ataluren therapy as measured by ECL is zero with the 
alternative hypothesis being that the change is greater than zero. To evaluate this hypothesis, 
a one-sided test at the 5% significance level will be employed. 
The percent change from baseline at Week 40 in dystrophin levels measured by ECL will be 
analyzed using the mixed effect model repeated measurement (MMRM) analysis with factors of 
muscle locations, visits (baseline and Week 40) as fixed effects, and subjects as a random effect, 
based on ITT population. An unstructured covariance matrix will be used, and if the model fails 
to converge, then a compound symmetry matrix will be used. Since dystrophin level is known to 
be non-normally distributed, a log-transformation will be used in the analysis. The best 
dystrophin levels across all muscles are considered the primary analysis. A sample SAS code of 
the MMRM model is provided as follows: 


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proc mixed data = dataset; 
   class subjid visit mlocation;       /*mlocation is muscle location*/ 
   model lnaval = visit mlocation; /*lnaval is log-transformed dystrophin level*/ 
   random subjid; 
   repeated visit / type = un; 
   estimate "Week 40 change from baseline" visit -1 1; 
run; 
As supportive analyses, the average and median dystrophin levels across all muscles, and the 
subgroup analyses of the best, median, and mean dystrophin levels within each muscle location 
will be considered. In addition, the two-sided 90% confidence interval of percent change from 
baseline in dystrophin levels at Week 40 and the ratio (%) of dystrophin level at Week 40 versus 
baseline will also be provided.  
7.1.2. 
Subgroup Analyses 
The primary endpoint described in Section 7.1.1 will be summarized using descriptive statistics 
by each subgroup listed below. No hypothesis testing will be performed in the subgroup 
analyses. 
• Muscle location  
• Steroid use  
• Exon mutation location  
• Visit 3 biopsy date (impacted by COVID-19 and not impacted by COVID-19) 
7.1.3. 
Sensitivity Analyses 
The following analyses will be considered as sensitivity analyses: 
• PP analysis: The same primary efficacy analysis described in Section 7.1.1 (Primary 
Analysis) will be repeated based on the PP population for the primary efficacy 
endpoint. 
• The average and median dystrophin levels across all muscle locations based on the 
same method as described in Section 7.1.1 (Primary Analysis). 
• Excluding subjects with baseline dystrophin levels 
 of the predicted levels: 
The same primary analysis described in Section 7.1.1 (Primary Analysis) will be 
repeated excluding subjects with baseline dystrophin levels 
 of the predicted 
levels. The same analysis on the average and median dystrophin levels across all 
muscle locations will also be repeated excluding such subjects. 
• COVID-19 consideration: The Week 40 biopsy study day (defined as Week 40 biopsy 
date – first study drug date +1) will be added to the primary efficacy analysis model 
described in Section 7.1.1 (Primary Analysis) as a covariate. This analysis model will 


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be applied to the best, average, and median dystrophin levels analyses based on the 
ITT population. 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Secondary Efficacy Analysis 
The secondary efficacy endpoint is the percent change from baseline in dystrophin levels (mean 
membrane stain density) after 40 weeks of ataluren therapy as determined by a validated IHC 
assay. Within each muscle location, the best, median, and the average dystrophin levels of the 
muscle cores will be summarized using descriptive statistics for each subject. The secondary 
efficacy endpoint will be analyzed using the same method as described in Section 7.1.1 (Primary 
Analysis). The best dystrophin levels across all muscles are considered the primary interest. 
As supportive analyses, the average and median dystrophin levels across all muscles, and 
subgroup analyses of the best, median, and mean dystrophin levels within each muscle location 
will be considered. In addition to dystrophin levels (the mean staining intensity), the percentage 
of positive fibers will also be summarized using descriptive statistics. 
7.2.2. 
Sensitivity Analyses 
The following analyses will be considered as sensitivity analyses for the secondary efficacy 
endpoint: 
• PP analysis: The same secondary efficacy analysis described in Section 7.2.1 
(Secondary Analysis) will be repeated based on PP population for the secondary 
efficacy endpoint. 
• The average and median dystrophin levels (mean membrane stain density) across all 
muscle locations will be analyzed using the same analysis method as described in 
Section 7.2.1 (Secondary Analysis). 
• Excluding subjects with baseline dystrophin levels 
 of the predicted levels: 
The same analysis described in Section 7.2.1 (Secondary Analysis) will be repeated 
excluding subjects with baseline dystrophin levels 
 of the predicted 
levels. The same analysis on the average and median dystrophin levels across all 
muscle locations will also be repeated excluding such subjects. 
• Subgroup analysis: The subgroup analysis by muscle location will be performed on 
secondary efficacy endpoint as described in Section 7.1.2 (Subgroup Analyses). 
• COVID-19 considerations: The Week 40 study day (defined as Week 40 biopsy date 
– first study drug date +1) will be added to the efficacy analysis model described in 
Section 7.2.1 (Secondary Analysis) as a covariate. This analysis model will be 
applied to the best, average, and median dystrophin levels analyses based on the ITT 
population. 


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7.3. 
Exploratory Analyses 
No hypothesis testing will be performed on all exploratory endpoints. All exploratory endpoints 
will be summarized using descriptive statistics based on ITT population. 
7.3.1. 
Revised North Star Ambulatory Assessment 
The rNSAA consists of 17 activities, each scored as 0, 1, or 2. The sum of the 16 activities 
(exclude head lift) will form a total score. If fewer than 13 of the 16 activities are performed, the 
total score will be considered missing. If from 13 to 16 activities are performed, the total score 
will be standardized as follows: 
Standardized total score    =                observed total score                  x   16 
number of non-missing activities 
Transformation of the total score into a linear scale (Mayhew 2013a) will also be performed. 
The mean and mean change from baseline in the total score and its linear transformation will be 
summarized at the Baseline and Week 40 visits based on ITT population. In addition, 
the proportion of subjects who has lost function after 40 weeks of ataluren treatment, defined as 
a drop of score from 1 or 2 at baseline to a score of 0 at the Week 40 visit, will be tabulated for 
each activity. 
7.3.2. 
Timed Function Test 
The TFTs, the time taken to run/walk 10 meters, climb 4 stairs, descend 4 stairs, and stand from 
supine, will be assessed at the Baseline and Week 40 visits. Subjects who cannot perform a timed 
function test within 30 seconds, including those who loss of ambulation or the timed function test 
is above 30 seconds, will be assigned a value of 30 seconds for the respective test. The mean and 
mean change from baseline for each timed function test will be summarized at each visit based 
on the ITT population. 
7.3.3. 
Creatine kinase levels 
The CK levels will be assessed at the Screening and Week 40 visits. The mean and mean change 
from baseline of CK levels will be summarized at each visit based on the ITT population. 
8. 
SAFETY EVALUATION 
All safety summaries will be generated based on the safety population. 
8.1. 
Adverse Events 
Adverse events will be coded using the MedDRA version 23.0. A treatment-emergent adverse 
event (TEAE) is defined as an adverse event that occurs or worsens on or after the first dose of 
study drug up to 6 weeks after the last dose of st\udy drug. Any AE with an end date prior to the 
first dose of the study drug will not be considered as an TEAE. 
The following summaries will be provided for TEAEs: 
• TEAE overview 
• TEAEs by SOC and PT 


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If a subject has multiple events under any given SOC and PT, the subject will be counted only 
once under that SOC and PT. If a subject has the same AE on multiple occasions, the highest 
severity reported on the CRFs (“life-threatening”, “severe”, “moderate”, “mild”, “unknown”, and 
“not reported”) will be presented in the summaries.  
In addition, subjects with treatment-emergent SAE and TEAE leading to discontinuation will 
also be summarized.  
8.2. 
Clinical Laboratory 
Clinical laboratory assessments for hematology, biochemistry, and urine evaluations are 
collected at Screening, Baseline and Week 40 visits. Mean and mean change from baseline for 
all hematology and biochemistry laboratory assessments, and continuous variables for urinalysis 
will be summarized using descriptive statistics at Baseline and Week 40 visits. Categorial 
variables for urinalysis will be tabulated using frequency count at Baseline and Week 40 visits. 
In addition, shift tables for each laboratory parameters from baseline to post-baseline visits will 
also be provided.  
Creatine kinase, summarized as an efficacy endpoint, will be excluded from all laboratory 
summaries and listings.  
8.3. 
Vital Signs 
Vital signs including systolic blood pressure, diastolic blood pressure, pulse rate, and oral 
temperature are collected at Baseline and Week 40 visits. Mean and mean change from baseline 
for each vital sign parameters will be summarized using descriptive statistics at each visit.  
8.4. 
Other Safety Assessments 
Other safety assessments including physician assessments will be presented in the subject listings 
only. 
9. 
PHARMACOKINETIC BLOOD SAMPLE 
The PK assessments using sparse sampling and population PK modeling will be presented in a 
separate report. The mean, median, minimum, maximum, %CV and geometric mean of plasma 
concentration at pre-dose and post-dose at each visit will be summarized based on the ITT 
population. In case any measured plasma concentrations are below LLOQ, the plasma 
concentrations will be set as 0 in calculations for the statistical analysis.  
10. 
CHANGES FROM THE PLANNED ANALYSES 
The following changes to study protocol V3.0 (dated 06May2019) are implemented in this SAP: 
• As requested by US FDA, inference for the primary and secondary efficacy endpoints 
will be evaluated using a one-sided test at the 0.025% significance level. 
• The primary and secondary efficacy analyses will be performed including all subjects. 
Subjects with baseline dystrophin levels 
 predicted will not be removed 
from the primary and secondary efficacy analyses.  
• Sensitivity analyses excluding subjects with baseline dystrophin levels 
 
predicted will be added to both primary and secondary efficacy endpoints. 


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11. 
REFERENCES 
Mayhew, AG, Cano, SJ, Scott, E, Eagle, M, Bushby, K, Manzur, A, et al. Detecting meaningful 
change using the north star ambulatory assessment in duchenne muscular dystrophy. Dev Med 
Child Neurol 2013a;55(11):1046-1052. 
Syneos Health Report No. 14597.051619.A, Analysis of dystrophin in human muscle tissue 
homogenate samples from control subjects for baseline determination and preparation of assay 
quality controls (non-regulated).