Clinical trial NCT02819557
Conditions: Duchenne Muscular Dystrophy
Sponsor: PTC Therapeutics
Start date: 2016-06-09; Completion date: 2018-02-09
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, multiple-dose, open-label study evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ataluren in participants aged ≥2 to \<5 years old with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation in the dystrophin gene.

Detailed description:
In nonsense mutation DMD (nmDMD), early start of treatment is important and necessary and, therefore, it is relevant to understand the correct and tolerable dose in this age group, particularly since ataluren is dosed by weight. This study included a 4-week screening period, a 52-week treatment period (the first 4 weeks of which included PK parameters), and a 4-week follow-up period for participants who completed the treatment period (60 weeks total duration). The objective of the extension period (treatment period after PK parameters have been completed) was to assess the long-term safety of chronic administration of ataluren in this participant population.

Arms: arm 1: Participants will be administered ataluren orally at a dose of 10 milligrams/kilograms (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening (for a total of 40 mg/kg/day) for up to 52 weeks. Dose will be provided based upon the weight of each participant, which will be assessed every 12 weeks.
Interventions: intervention 1: Ataluren
Intervention descriptions: intervention 1: White to off-white powder for oral suspension.

Protocol documents:
Prot_000.pdf: 
CLINICAL PROTOCOL 
A Phase 2 Study of the Safety, Pharmacokinetics, and Pharmacodynamics of 
Ataluren (PTC124®) in Patients Aged ≥2 to <5 Years Old with 
Nonsense Mutation Dystrophinopathy 
Protocol Number PTC124-GD-030-DMD 
28 January 2016 
Version 2.0 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Notice  of  Proprietary  Information:  This  document  contains  confidential  information   belonging   to PTC 
Therapeutics, Inc. Except as may 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. 
NCT02819557


Protocol Number PTC1240-GD-030-DMD 
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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 
68,431 
Included in clinical trials.gov Database 
Pending 
Protocol Number 
PTC124-GD-030-DMD 
Protocol Version 
Version 2.0 
Protocol Phase 
Phase 2 
Protocol Title 
A Phase 2 Study of the Safety, Pharmacokinetics, 
and Pharmacodynamics of Ataluren (PTC124®) 
in Patients Aged ≥2 to <5 Years Old with 
Nonsense Mutation Dystrophinopathy 
 
PTC 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 Clinical Program Scientist 
 
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 
 
 
 
 
  
 
  
 
 
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PTC Therapeutics, Inc. 
 Date 
 
  
 
  
 
  
 
  
 
 
PTC Therapeutics, Inc. 
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PTC Therapeutics, Inc. 
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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: 
E-Mail: 
 
 
 


Protocol Number PTC1240-GD-030-DMD 
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TABLE OF CONTENTS 
1. 
OVERVIEW
 ................................................................................................................................................................................ 
10 
2. 
BACKGROUND
 ................................................................................................................................................................................ 
12 
2.1. 
DISEASE INDICATION
 ..................................................................................................................................................................................................... 
12 
2.2. 
ATALUREN (PTC124®)
 ................................................................................................................................................................ 
13 
2.2.1. 
Therapeutic Concept
 ........................................................................................................................................................... 
13 
2.2.2. 
Chemical Description
 ........................................................................................................................................................... 
14 
2.2.3. 
Clinical Studies
 ........................................................................................................................................................... 
14 
3. 
STUDY OBJECTIVE AND ENDPOINTS
 ................................................................................................................................................................................ 
15 
3.1. 
PRIMARY OBJECTIVE
 ..................................................................................................................................................................................................... 
15 
3.2. 
SECONDARY OBJECTIVES
 ..................................................................................................................................................................................................... 
15 
3.3. 
PRIMARY ENDPOINT
 ..................................................................................................................................................................................................... 
15 
3.4. 
SECONDARY ENDPOINTS
 ..................................................................................................................................................................................................... 
15 
4. 
SUBJECT SELECTION CRITERIA
 ................................................................................................................................................................................ 
16 
4.1. 
OVERVIEW
 ..................................................................................................................................................................................................... 
16 
4.2. 
INCLUSION CRITERIA
 ..................................................................................................................................................................................................... 
16 
4.3. 
EXCLUSION CRITERIA
 ..................................................................................................................................................................................................... 
17 
5. 
ENROLLMENT PROCEDURES
 ................................................................................................................................................................................ 


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18 
5.1. 
SOURCE AND NUMBER OF SUBJECTS
 ..................................................................................................................................................................................................... 
18 
5.2. 
SCREENING AND STUDY DRUG DISPENSATION
 ..................................................................................................................................................................................................... 
18 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT
 ................................................................................................................................................................................ 
19 
6.1. 
STUDY DRUG SUPPLY
 ..................................................................................................................................................................................................... 
19 
6.1.1. 
Study Drug Packaging and Labeling
 ........................................................................................................................................................... 
19 
6.1.2. 
Study Drug Storage
 ........................................................................................................................................................... 
19 
6.1.3. 
Study Drug Dispensing
 ........................................................................................................................................................... 
19 
6.1.4. 
Study Drug Preparation
 19 
6.1.5. 
Study Drug Accountability ................................................................................................................... 20 
6.1.6. 
Overdose Precautions
 ........................................................................................................................................................... 
20 
6.1.7. 
Inadvertent Exposure and Spill Precautions
 ........................................................................................................................................................... 
20 
6.2. 
STUDY DRUG TREATMENT
 ..................................................................................................................................................................................................... 
21 
6.2.1. 
Study Drug Dosing
 ........................................................................................................................................................... 
21 
6.2.2. 
Duration of Treatment
 ........................................................................................................................................................... 
21 
6.2.3. 
Schedule of Administration
 ........................................................................................................................................................... 
21 
6.2.4. 
Instructions for Delays in Dosing
 ........................................................................................................................................................... 
22 
6.3. 
SAFETY MONITORING AND STUDY DRUG DOSE INTERRUPTION/MODIFICATION
 ..................................................................................................................................................................................................... 
22 
6.3.1. 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and 
Potential Drug Interruption/Modification
 
22 
6.3.2. 
Evaluation of Adverse Events or Laboratory Abnormalities
 ........................................................................................................................................................... 
23 


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6.3.3. 
Instructions for Resuming Study Drug Administration after an Interruption for Safety Concerns
 ........................................................................................................................................................... 
23 
6.3.4. 
Instructions for Discontinuation of Study Drug Administration for Safety Concerns
 ........................................................................................................................................................... 
24 
7. 
CONCOMITANT AND SUPPORTIVE THERAPY
 ................................................................................................................................................................................ 
25 
7.1. 
CONCOMITANT MEDICATIONS
 ..................................................................................................................................................................................................... 
25 
7.1.1. 
Corticosteriods
 ........................................................................................................................................................... 
25 
7.1.2. 
Nephrotoxic Medications
 ........................................................................................................................................................... 
25 
7.2. 
NON-DRUG THERAPY
 ..................................................................................................................................................................................................... 
26 
7.2.1. 
Physical Therapy
 ........................................................................................................................................................... 
26 
7.2.2. 
Hydration
 ........................................................................................................................................................... 
26 
7.2.3. 
Dietary Restrictions
 ........................................................................................................................................................... 
26 


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8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS .......................................................................... 27 
8.1. 
SCHEDULE OF EVENTS ..................................................................................................................................................... 27 
8.2. 
EXPLANATION OF STUDY PROCEDURES..................................................................................................................... 28 
8.2.1. 
Study Visits ..................................................................................................................................... 28 
8.2.2. 
Informed Consent ........................................................................................................................... 28 
8.2.3. 
Clinical/Medication History .......................................................................................................... 28 
8.2.4. 
Vital Signs ...................................................................................................................................... 28 
8.2.5. 
Height, Weight, and Physical Examination .................................................................................... 28 
8.2.6. 
Confirmatory Gene Sequencing ..................................................................................................... 29 
8.2.7. 
Central Laboratory Assessments ................................................................................................... 29 
8.2.8. 
12-Lead ECG ................................................................................................................................. 29 
8.2.9. 
Timed Function Tests ..................................................................................................................... 30 
8.2.10. 
North Star Ambulatory Assessment ........................................................................................... 30 
8.2.11. 
Pharmacokinetic Assessment .................................................................................................... 30 
8.2.12. 
Palatability Questionnaire ........................................................................................................ 30 
8.2.13. 
Ataluren Administration ............................................................................................................ 30 
8.2.14. 
Adverse Events .......................................................................................................................... 30 
8.2.15. 
Concomitant Medications ......................................................................................................... 30 
8.3. 
BLOOD COLLECTION SUMMARY .................................................................................................................................. 31 
9. 
ADVERSE EVENT ASSESSMENTS ............................................................................................................. 32 
9.1. 
ADVERSE EVENT DEFINITIONS ..................................................................................................................................... 32 
9.1.1. 
Adverse Events ............................................................................................................................... 32 
9.1.2. 
Serious Adverse Events (SAEs) ...................................................................................................... 33 
9.1.3. 
Unexpected Adverse Events ........................................................................................................... 34 
9.2. 
ELICITING ADVERSE EVENT INFORMATION ............................................................................................................. 34 
9.3. 
ADVERSE EVENT RECORDING ....................................................................................................................................... 34 
9.4. 
DESCRIBING ADVERSE EVENT RELATIONSHIP TO STUDY DRUG ....................................................................... 35 
9.5. 
GRADING OF SEVERITY OF ADVERSE EVENTS ......................................................................................................... 35 
9.6. 
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS .................................................................................................. 36 
9.7. 
ADVERSE EVENT REPORTING PERIOD ........................................................................................................................ 36 
9.8. 
INVESTIGATOR SITE ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 36 
9.9. 
PTC THERAPEUTICS ADVERSE EVENT REPORTING REQUIREMENTS ............................................................... 38 
10. 
WITHDRAWAL OF SUBJECTS ................................................................................................................... 39 
11. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 40 
11.1. 
SAMPLE SIZE ....................................................................................................................................................................... 40 
11.2. 
ANALYSIS POPULATIONS ................................................................................................................................................ 40 
11.3. 
GENERAL STATISTICAL CONSIDERATIONS ............................................................................................................... 40 
11.4. 
SUBJECT DISPOSITION AND BASELINE CHARACTERISTICS .................................................................................. 40 
11.5. 
EFFICACY ENDPOINTS ..................................................................................................................................................... 40 
11.6. 
PHARMACOKINETIC PARAMETERS .............................................................................................................................. 41 
11.7. 
SAFETY ................................................................................................................................................................................. 42 
11.7.1. 
Adverse Events .......................................................................................................................... 42 
11.7.2. 
Laboratory Parameters ............................................................................................................. 42 
11.7.3. 
Vital Signs and ECGs ................................................................................................................ 43 
11.7.4. 
Other Safety Parameters ........................................................................................................... 43 
11.7.5. 
Interim Safety Review ................................................................................................................ 43 
11.8. 
TREATMENT ADMINISTRATION AND DRUG COMPLIANCE ....................................................................................... 43 
11.9. 
USE OF CONCOMITANT MEDICATION AND SUPPORTIVE THERAPY ....................................................................... 43 
11.10. 
PALATABILITY QUESTIONNAIRE ............................................................................................................................ 43 
11.11. 
EXPLORATION OF CORRELATIONS ......................................................................................................................... 43 
12. 
STUDY COMMITTEES .................................................................................................................................. 44 


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13. 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR.......................................................... 45 
13.1. 
COMPLIANCE WITH ETHICAL AND REGULATORY GUIDELINES .......................................................................... 45 
13.2. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ............................................................. 45 
13.3. 
INFORMED CONSENT/ASSENT ....................................................................................................................................... 45 
13.4. 
CASE REPORT FORMS ...................................................................................................................................................... 46 
13.5. 
STUDY RECORDS ............................................................................................................................................................... 46 
13.6. 
CONFIDENTIALITY ............................................................................................................................................................ 47 
13.7. 
RETENTION OF RECORDS ................................................................................................................................................ 47 
13.8. 
MONITORING AND AUDITING ........................................................................................................................................ 47 
13.9. 
TERMINATION OF THE STUDY ....................................................................................................................................... 48 
13.10. 
PUBLIC NOTIFICATION OF STUDY CONDUCT...................................................................................................... 48 
13.11. 
DISSEMINATION OF RESULTS .................................................................................................................................. 48 
13.12. 
COMMUNICATION WITH REGULATORY AUTHORITIES ..................................................................................... 49 
14. 
RATIONALE FOR STUDY DESIGN FEATURES ...................................................................................... 50 
14.1. 
SUBJECT SELECTION ........................................................................................................................................................ 50 
14.1.1. 
General ..................................................................................................................................... 50 
14.1.2. 
Inclusion of Minors ................................................................................................................... 50 
14.1.3. 
Reproductive Considerations .................................................................................................... 51 
14.1.4. 
Prior and Concomitant Therapies ............................................................................................. 51 
14.2. 
TREATMENT RATIONALE ................................................................................................................................................ 52 
14.2.1. 
Ataluren Schedule and Dose Selection ...................................................................................... 52 
14.2.2. 
Duration of Therapy .................................................................................................................. 53 
14.2.3. 
Selection of Endpoint Measures ................................................................................................ 53 
14.2.4. 
Safety Monitoring ...................................................................................................................... 54 
15. 
BENEFITS AND RISKS .................................................................................................................................. 55 
15.1. 
BENEFITS AND RISKS: NON-CLINICAL ...................................................................................................................... 55 
15.2. 
BENEFITS AND RISKS: CLINICAL ................................................................................................................................. 55 
15.3. 
BENEFIT/RISK CONCLUSIONS........................................................................................................................................ 55 
16. 
BIBLIOGRAPHY ............................................................................................................................................. 57 
LIST OF TABLES 
TABLE 1: 
SUGGESTED DAILY DOSING SCHEDULE..................................................................................................................... 22 
TABLE 2: 
SCHEDULE OF EVENTS ..................................................................................................................................................... 27 
TABLE 3: 
RELATIONSHIP OF STUDY DRUG TO ADVERSE EVENT .......................................................................................... 35 
TABLE 4: 
GRADING OF ADVERSE EVENT SEVERITY ................................................................................................................. 36 
TABLE 5: 
INVESTIGATIONAL SITE REQUIREMENTS FOR REPORTING ADVERSE EVENTS .............................................. 37 


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ABBREVIATIONS 
Abbreviation 
Definition 
6MWT 
6-minute walk test 
AE 
Adverse event(s) 
ALT 
Alanine aminotransferase 
AR 
Accumulation Ratio 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC0-t 
Area under the plasma concentration time curve from time zero to the time 
of last quantifiable concentration 
AUC0-10 
Area under the plasma concentration time curve from time zero up to 10 hours 
after the morning dosing 
AUC0-24 
Area under the concentration curve versus time curve from time zero 
to 24 hours 
BMI 
Body mass index 
BCRP 
Breast Cancer Resistant Protein 
BUN 
Blood urea nitrogen 
CD-ROM 
Compact disc read-only memory 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CK 
Creatine kinase 
CI 
Confidence interval 
CL/F 
Apparent clearance 
CLd/F 
Apparent distribution clearance 
Cmax 
Maximum observed plasma concentration 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough@6h 
Concentration at the end of the first (morning) dosage interval 
CV% 
Coefficient of variation 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
DMD 
Duchenne muscular dystrophy 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
HPLC-MS/MS 
High performance liquid chromatography-mass spectrometry 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 


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Abbreviation 
Definition 
ICTRP 
International Clinical Trials Registry Platform 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
Intravenous 
ka 
Rate constant of absorption 
LOQ 
Limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmelonic acidemia 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NCA 
Non-compartmental analysis 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
nmCF 
Nonsense mutation cystic fibrosis 
NSAA 
North Star Ambulatory Assessment 
OAT1 
Organic anion transporter 1 
OAT3 
Organic anion transporter 3 
OATP1B3 
Organic anion transporting polypeptide 1B3 
PD 
Pharmacodynamic(s) 
PIP 
Pediatric Investigation Plan 
PK 
Pharmacokinetic(s) 
popPK 
Population PK 
PTC124 
Ataluren 
SAS 
Statistical Analysis System 
SAE 
Serious adverse event 
t½ 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
TFTs 
Timed function tests 
TID 
3 times per day 
tmax 
Time of maximum observed plasma concentration 
UGT 
Uridine diphosphate glucuronosyltransferase 
UGT1A9 
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A9 
US 
United States 
Vc/F 
Apparent central volume of distribution 
Vp/F 
Apparent peripheral volume of distribution 
WHODRUG 
World Health Organization Drug Dictionary 


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1. 
OVERVIEW 
Duchenne muscular dystrophy (DMD) is a disabling and life-threatening X-linked genetic 
disorder [Worton 2001, Khurana 2003] caused by defects in the gene for dystrophin, a protein 
that stabilizes muscle cell membranes [Lapidos 2004]. Due to muscle fragility, boys with DMD 
develop muscle weakness that leads to deterioration of ambulation, wheelchair dependency, and 
eventual respiratory and cardiac failure with death by 15 to 22 years of age [Brooke 1989, 
McDonald 1995, Worton 2001]. Only chronic administration of corticosteroids has slowed 
progression of DMD.  However, corticosteroids do not address the underlying cause of DMD, 
are typically associated with serious sequelae, and are not always employed. There is no current 
therapy for the underlying cause of DMD. In approximately 13% of boys with DMD, the 
causative defect in the dystrophin gene is a nonsense mutation that truncates dystrophin protein 
production by introducing a premature stop codon into the dystrophin messenger ribonucleic acid 
(mRNA) [Dent 2005]. Nonsense mutation (nm) DMD is estimated to affect approximately 1,700 
boys in the United States (US) and approximately 2,200 boys in Europe [Hirawat 2004a, Hirawat 
2004b]. 
Ataluren is an orally bioavailable, investigational new drug that promotes ribosomal readthrough 
of premature stop codons [Welch 2007, Du 2008, Wang 2010, Goldmann 2011, Tan 2011, 
Kayali 2012]. In reporter assays, as well as in nonclinical models of genetic disease, ataluren 
demonstrates the ability to specifically and selectively enable ribosomal readthrough of mRNA 
containing a premature stop codon, inducing production of protein that localizes to the 
appropriate cellular location and is functionally active [Welch 2007, Du 2008, Wang 2010, 
Goldmann 2011, Tan 2011, Kayali 2012]. In vitro and in vivo studies in nmDMD have shown 
that ataluren can restore production of the missing dystrophin [Welch 2007, Kayali 2012]. 
Ataluren (Translarna) is currently available in Europe and Israel for treatment of nmDMD in 
patients older than 5 years. 
Ataluren has been administered to patients with nonsense mutation cystic fibrosis (nmCF) as 
young as 6 years of age, patients with nmDMD as young as 5 years of age, and patients with 
nonsense mutation methlymelonic acidemia (nmMMA) as young as 3 years of age. No obvious 
differences have been apparent in the activity or safety profiles of ataluren in children relative to 
adults. Although patients <3 years of age have not been included in clinical studies, chronic 
toxicology studies in weanling rats and dogs support dosing of pediatric patients as young as 
2 years of age. Refer to the Ataluren Investigator’s Brochure (IB) for current information on use 
in pediatric patients. 
This protocol describes a Phase 2, multiple-dose, open-label study evaluating the safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ataluren in patients aged ≥2 to <5 years 
old with nmDMD. In nmDMD, early start of treatment is important and necessary and, therefore, 
it is relevant to understand the correct and tolerable dose in this age group, particularly since 
ataluren is dosed by weight. The study will include a 4-week screening period, a 4-week study 
period, and a 48-week extension period for patients who complete the 4-week study period (52 
weeks total treatment). The objective of the extension period is to assess the long-term safety of 
chronic administration of ataluren in this patient population. 


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The primary objective of this study is to evaluate the safety of ataluren as measured by type, 
frequency, severity, timing, and relationship to study drug of treatment-emergent adverse events 
(TEAEs), laboratory abnormalities, and electrocardiograms (ECGs). 
The secondary objectives are to determine the plasma PK of ataluren in patients aged ≥2 to 
<5 years old with nmDMD, to monitor proximal muscle function using timed function tests 
(TFTs), to monitor physical function using the North Star Ambulatory Assessment (NSAA), to 
determine the effect of ataluren on weight, height, and body mass index (BMI), and to assess the 
palatability of ataluren. 
This study provides ongoing safety review during open-label ataluren treatment. Furthermore, a 
planned interim safety analysis will be conducted by an independent data monitoring committee 
(DMC) when all patients have completed 12 weeks of treatment and additionally as needed. 


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2. 
BACKGROUND 
 
2.1. 
Disease Indication 
DMD is an X-linked disorder caused by defects in the gene for dystrophin, a protein that is 
critical to the structural stability of myofibers in skeletal, diaphragmatic, and cardiac muscle 
[Worton 2001, Khurana 2003]. The prevalence is estimated at approximately 13,000 males in the 
US and approximately 17,000 boys in the European Union (EU) [Hirawat 2004a, 
Hirawat 2004b]. 
Dystrophin is a high-molecular-weight cytoskeleton protein localized at the inner surface of the 
muscle membrane [Worton 2001]. It is part of a dystrophin-glycoprotein complex that also 
includes dystroglycan and sarcoglycans. This complex provides a bridge across the muscle 
membrane in which dystrophin couples actin in the cytoplasm with dystroglycan. Dystrophin 
deficiency destabilizes the dystrophin-glycoprotein complex, impairing localization of the 
dystroglycan and sarcoglycans to the muscle membrane, and compromising the structural 
integrity of the membrane. The absence of normally functioning dystrophin results in 
sarcolemmal breakdown, calcium ion influx, phospholipase activation, oxidative muscle injury, 
and, ultimately, myonecrosis. As muscle damage progresses, connective tissue and fat replace 
muscle fibers. 
In patients with DMD, the age at which the earliest sign or symptom of the disease is noted 
ranges from infancy to approximately 6 years old [Ciafaloni 2009]. Initial signs and symptoms of 
DMD include lordosis, a waddling gait, and the Gowers’ sign (a characteristically abnormal 
method of rising from a supine to a standing position) [Brooke 1989, McDonald 1995, Boland 
1996, Worton 2001]. Inexorable progressive weakness is seen, particularly in the proximal 
musculature. Ambulation becomes increasingly abnormal.  By the age of 8 years, most boys 
have difficulty rising from the floor and ascending stairs and they often fall while walking. Boys 
with the disease spend less time walking and walk more slowly than healthy boys 
[McDonald 2005a], and are significantly less active than normal boys of similar age [McDonald 
2002, McDonald 2005b]. By 10 to 14 years of age, most are wheelchair-bound. In ambulatory 
boys with DMD, the most frequent cardiac abnormality is sinus tachycardia and heart rate 
variability, occurring from childhood and persisting throughout life [Finsterer 2003, Gulati 
2005]. Pulmonary function is usually normal before 10 years of age and is well maintained into 
adolescence in boys receiving corticosteroids [Mendell 1989, Griggs 1991, Phillips 2001, 
Tangsrud 2001, Biggar 2001, Biggar 2006]. Later in adolescence, cardiac and diaphragmatic 
muscles become progressively weaker and patients require treatment for cardiac insufficiency 
and ventilatory support. Patients usually die of cardiac or pulmonary failure by 
15 to 22 years of age [Brooke 1989, McDonald 1995, Simonds 1998, Worton 2001, Eagle 2002]. 
Presently, ataluren is the only therapy available to restore dystrophin protein production and 
preserve muscle function. The current standard of care is corticosteroids, which do not address 
the underlying cause of the disease and are not typically initiated prior to the age of 5 years old. 


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2.2. 
Ataluren (PTC124®) 
 
2.2.1. 
Therapeutic Concept 
Among the several types of disease-causing mutations, a nonsense mutation is a single-point 
alteration in one of the nucleotides of deoxyribonucleic acid (DNA) that, when copied to mRNA, 
is interpreted as a stop signal by the ribosomal cellular translational machinery. The presence of 
such a premature stop signal within the protein-coding region of the mRNA for dystrophin 
signals the ribosomes to halt production of the protein before the full-length protein is 
completed. The resulting truncated dystrophin is too short to serve its necessary function and 
causes disease.  It is estimated that approximately 10-15% of all boys with DMD have a 
nonsense mutation as the basis for the disorder [Dent 2005], resulting in a prevalence of 
approximately 1,700 boys in the US and approximately 2,200 boys in Europe. 
It has been known for some time that drugs with translation-modifying mechanisms of action, 
such as the aminoglycoside antibiotics (eg, gentamicin), can ameliorate the effects of nonsense 
mutations in experimental systems. By binding to the ribosomes, such agents permit the 
ribosomes to reinterpret the nonsense mutation stop signal in mRNA such that they can move 
through the obstruction by inserting an amino acid and continuing the translation process to 
produce a full-length functional protein. In experimental animal systems and in pilot studies in 
nmDMD, treatment with high concentrations of gentamicin has restored production of functional 
dystrophin [Barton-Davis 1999, Politano 2003]. Similarly, nonclinical and clinical studies in 
cystic fibrosis (CF) have demonstrated restoration of the CF transmembrane conductance 
regulator, the epithelial chloride channel that is defective in that disease [Clancy 2001, Du 2002, 
Wilschanski 2003]. Data suggest that the geometry of mRNA and associated initiation- 
termination proteins is critically different at a premature stop compared with a normal stop. This 
may explain why a drug can permit the ribosomes to selectively read through the premature stop 
codon, but will not allow the ribosomes to read through the normal stop codon at the end of the 
mRNA protein-coding region [Sachs 2000, Welch 2000, Amrani 2004]. Because serious renal 
and otic toxicities and the need for parenteral administration preclude the long-term clinical use 
of gentamicin, there has been considerable interest in the identification of safer and more 
conveniently administered, low-molecular-weight, synthetic compounds with the ability to 
promote readthrough of disease-causing nonsense mutations. 
PTC Therapeutics is a biopharmaceutical company involved in the discovery and development of 
new therapies for genetic diseases. Based on the clear medical need in dystrophinopathy and 
other genetic disorders, and the unacceptable toxicity that would be associated with chronic 
systemic aminoglycoside use, scientists at the company have conducted a drug discovery 
program with the objective of finding and developing new agents that overcome the effects of 
nonsense mutations. A high-throughput screening program identified sets of novel, non- 
aminoglycoside chemical structures that selectively induce ribosomal readthrough of premature 
stop codons in mRNA. Chemical optimization, pharmacologic characterization, and 
toxicological evaluation have led to identification of ataluren as an orally bioavailable, small 
molecule with potential clinical utility in treating genetic disorders through induction of 
readthrough of nonsense mutations and production of full-length, functional proteins [Welch 
2007, Du 2008]. In the subset of patients whose disease is mediated by a nonsense mutation, 
ataluren may offer a definitive therapy by overcoming the basic cause for dystrophinopathy and 
other disabling and life-threatening genetic disorders.


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2.2.2. 
Chemical Description 
Ataluren is a new chemical entity with a chemical formula of C15H9FN2O3 and a molecular 
weight of 284.2 Daltons. Ataluren is a Biopharmaceutical Classification System Case 2 
compound, possessing low aqueous solubility (<31 µg/mL) but high permeability across 
gastrointestinal epithelium, consistent with its high oral bioavailability. 
 
2.2.3. 
Clinical Studies 
In total, >750 subjects, including healthy subjects as well as adult and pediatric patients with 
several nonsense mutation genetic disorders, have been exposed to ataluren in Phase 1 [Hirawat 
2007], Phase 2 [Kerem 2008, Sermet-Gaudelus 2010, Wilschanski 2011, Finkel 2013] and Phase 
3 [Kerem 2014, Bushby 2014] clinical studies. Refer to the Ataluren IB for a detailed 
presentation of safety, efficacy, and PK data from these clinical studies. 


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3. 
STUDY OBJECTIVE AND ENDPOINTS 
3.1. 
Primary Objective 
The primary objective of this study is to: 
• Evaluate the safety of ataluren as measured by type, frequency, severity, timing, and 
relationship to study drug of TEAEs, laboratory abnormalities and ECGs 
 
3.2. 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate the plasma PK of ataluren in patients aged ≥2 to <5 years old with nmDMD 
• Assess proximal muscle function using TFTs 
• Assess change in physical function using the NSAA 
• Determine the effect of ataluren on weight, height, and BMI 
• Assess the palatability of ataluren 
3.3. 
Primary Endpoint 
The primary endpoints of this study are: 
• Overall safety profile in terms of the type, frequency, severity, timing, and relationship to 
study therapy of any adverse events (AEs) or abnormalities of physical findings, 
laboratory tests, or ECGs 
• Occurrence of any dose-limiting toxicities (DLTs) 
• Drug discontinuations due to AEs 
• Serious adverse events (SAEs) 
3.4. 
Secondary Endpoints 
The secondary endpoints are: 
• Pharmacokinetic parameters (tmax, t1/2, Cmax, Ctrough@6h, AUC0-10), CL/F, and Vc/F based on 
frequent blood sampling for PK on Days 1 and 28 of ataluren treatment. On each of these 
days, blood samples for ataluren concentration assessments will be collected immediately 
pre-dose and at specified time points following the morning, midday, and evening doses. 
Ataluren concentrations in plasma will be analyzed using a validated HPLC-MS/MS 
method. 
• TFTs (time to walk/run 10 meters, time to climb 4 stairs, time to descend 4 stairs, and 
time to stand up from a supine position) 
• NSAA 
• Changes in body weight, height, and BMI 
• Ataluren palatability characteristics as determined by a parent/caregiver questionnaire 


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4. 
SUBJECT SELECTION CRITERIA 
 
4.1. 
Overview 
This clinical study can fulfill its objectives only if appropriate patients are enrolled. The 
following eligibility criteria are designed to select patients for whom study participation is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient. Eligibility 
criteria may not be waived and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) audit or a regulatory authority inspection. Any questions 
regarding a patient’s eligibility should be discussed with the PTC Therapeutics medical monitor 
or designee prior to enrollment. 
 
4.2. 
Inclusion Criteria 
Patients must meet all of the following conditions to be eligible for enrollment into the study:  
 
General inclusion criteria 
1. Evidence of signed and dated informed consent document(s) indicating that the study candidate 
(and/or a parent/legal guardian) has been informed of all pertinent aspects of the study. Note: As 
all study candidates are considered children under local regulation, at least one parent or legal 
guardian must provide written consent prior to initiation of study-related procedures, in 
accordance with local regulation, and the study candidate may be required to provide written 
assent. The rules of the responsible institutional review board/independent ethics committee 
(IRB/IEC) regarding whether one or both parents must provide consent and the appropriate ages 
for obtaining consent and assent from the patient should be followed. 
2. Males ≥2 to <5 years of age 
3. Body weight ≥12 kg 
4. Willingness and ability to comply with scheduled visits, drug administration plan, study 
procedures, and study restrictions. 
5. No clinically significant abnormality based upon laboratory assessments during the 
screening period, in the opinion of the Investigator; good general health, as determined 
during the screening period by medical history and physical examination (including vital 
sign measurements). 
DMD inclusion criteria 
6. Diagnosis of DMD based on an elevated serum CK and genotypic evidence of 
dystrinopathy. Medical documentation of phenotypic evidence of dystrophinopathy needs 
to be provided upon request by the PTC Therapeutics medical monitor. 
7. Documentation of the presence of a nonsense mutation in at least 1 allele of the dystrophin 
gene. 
8. Verification that a blood sample has been drawn for sequencing of the dystrophin gene. 
Note: A patient who has written documentation of a nonsense mutation as the cause of 
dystrophinopathy need not wait for confirmatory results to start study drug. 


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4.3. 
Exclusion Criteria 
The presence of any of the following conditions will exclude a patient from study enrollment: 
General exclusion criteria 
1. Patients participating in any drug or device clinical investigation or having received an 
investigational drug within 3 months prior to Visit 1 (Screening) or who anticipate 
participating in any other drug or device clinical investigation or receiving any other 
investigational drug within the duration of this study. 
2. Expectation of a major surgical procedure during the study period. 
3. Prior or ongoing medical condition, medical history, physical findings, or laboratory 
abnormality that, in the Investigator’s opinion, could adversely affect the safety of the 
patient, or makes it unlikely that the course of study drug administration or follow-up 
would be completed, or could impair the assessment of study results. 
4. Known hypersensitivity to any of the ingredients or excipients of the study drug 
(polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone 
XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate). 
Drug therapies 
5. Ongoing use of the following drugs: 
Drugs metabolized by CYP2C8 (eg, paclitaxel) or CYP2C9 (eg, coumarin anticoagulants 
[warfarin], phenytoin, or tolbutamide) 
Drugs that are inhibitors of breast cancer resistant protein (BCRP) (eg, cyclosporine, 
eltrombopag, geftinib) 
Drugs that are substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, 
OAT3, or OATP1B3 (eg, oseltamivir, acyclovir, captopril, furosemide, bumetanide, 
valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) 
Drugs that are general inhibitors of UGT (eg, probenecid, valproic acid) 
 
6. Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of 
study treatment 
7. Prior therapy with ataluren 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. 
ENROLLMENT PROCEDURES 
 
5.1. 
Source and Number of Subjects 
At least 12 patients will be enrolled. Patients will be recruited from dystrophinopathy 
populations who receive care or are referred for evaluation at the investigational site. The 
principal Investigator or sub-investigator will discuss the possibility of participation directly with 
parent(s)/legal guardian in the clinic. 
 
5.2. 
Screening and Study Drug Dispensation 
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. Once written informed consent/assent has 
been obtained, a site representative should access Medrio (the electronic data capture [EDC] 
system) to indicate that a candidate is being screened. The user will need to supply the EDC 
system with the required information to permit study drug dispensation. Refer to the CRF 
Completion Guidelines for additional details. 
Using forms in the Medrio system, the EDC system will document all screening that has 
occurred. The Medrio Randomization module will be used to assign kit numbers and email 
notifications for shipment of investigational drug kits. Forms in the Medrio system will be used 
to track receipt of the drug shipment at the site. 


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6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
6.1. 
Study Drug Supply 
Ataluren drug product will be provided as a white to off-white powder for oral suspension, also 
referred to as ataluren granules. The drug substance and drug product are manufactured under 
current Good Manufacturing Practices (cGMP) conditions. The formulation includes matrix and 
suspending agents, surfactants, and various excipients that aid in the manufacturing process. 
Ataluren granules are packaged in aluminum foil, child-resistant sachets and supplied in dose 
strengths containing 125 or 250 mg of the active drug substance. 
Ataluren will be supplied free of charge to the investigational site by PTC Therapeutics for 
appropriate distribution to the patients/caregivers. 
 
6.1.1. 
Study Drug Packaging and Labeling 
Sachets and cartons will be color-coded to indicate dosage strength (125 mg – yellow, 
250 mg - pink). Labels will be provided in appropriate languages as required by each country in 
which the study is conducted. The content of the labeling will be in accordance with local 
regulatory specifications and requirements. 
6.1.2. 
Study Drug Storage 
Sachets of ataluren will be shipped to the investigational sites, and stored and monitored at room 
temperature (~15 to 30°C). The available stability data from representative samples support the 
use of the drug product for 48 months when stored at room temperature. 
Study personnel must ensure that all ataluren supplies are kept in a secure locked area with 
access limited to authorized personnel. The study product must not be used outside the context of 
this protocol. Under no circumstances should the Investigator or site personnel supply ataluren to 
other investigators or clinics, or allow the ataluren supplies to be used other than as directed by 
this protocol. 
 
6.1.3. 
Study Drug Dispensing 
Dosing of ataluren will be based on milligrams of drug per kilogram of patient body weight 
assessed every 12 weeks and will be calculated to allow for dosing with the appropriate dose 
strengths (125 mg or 250 mg). 
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
ataluren at the beginning of the study and every 12 weeks during the extension period according 
to the instructions in the study manual. 
 
6.1.4. 
Study Drug Preparation 
Once at the investigational site and/or with the patient/caregiver, ataluren sachets should be 
stored at room temperature, away from the reach of children, until the time of reconstitution. The 
appropriate sachet strength will be used to prepare each dose. The full contents of each sachet 
should be mixed with at least 30 mL (1 ounce) of liquid, or 3 tablespoons of semi-solid 


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food. The prepared dose should be mixed well before administration. The amount of the liquid or 
semi-solid food can be increased based on patient preference. 
Each prepared dose is best administered immediately after preparation. The prepared dose should 
be discarded if not consumed within 3 hours (if kept at room temperature) or within 24 hours of 
preparation (if kept refrigerated). 
Detailed written drug mixing and dosing instructions will be provided to the patient/caregiver 
when ataluren supplies are dispensed. A copy of these instructions will be maintained in the 
Investigator site study file. 
 
6.1.5. 
Study Drug Accountability 
The Investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all ataluren shipped by PTC Therapeutics or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all ataluren. Current 
reconciliation and dispensing records must also be maintained that include the date and amount 
of ataluren dispensed, relevant batch numbers, and patient’s assigned study number. Caregivers 
should return all unused sachets of ataluren to the investigational site at the end of each 12-week 
treatment interval for inventory. The eCRF will serve as the source document for drug supply to 
the patients and will document the return of any unused drug for compliance assessments. 
Depending upon the decision of PTC Therapeutics, unused clinical supplies must be destroyed or 
returned to PTC Therapeutics (or its designee) after the study is completed and drug 
accountability has been verified by the monitor. Records documenting the date of study drug 
destruction or shipping, relevant batch numbers, and amount destroyed or shipped should be kept 
in the investigational site study file. 
The Medrio EDC system will be used to track drug accountability. 
 
6.1.6. 
Overdose Precautions 
For any patient experiencing an overdose (see Section 9.1.1 for the definition of 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 Sections 9.1.1 and 9.1.2). 
 
6.1.7. 
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, 


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inhalation, or ingestion of the material in the packets. Refer to the Ataluren IB for current 
information on inadvertent exposures and spill precautions. 
 
6.2. 
Study Drug Treatment 
 
6.2.1. 
Study Drug Dosing 
Dosing of ataluren will be based on milligrams of drug per kilogram of patient body weight 
assessed every 12 weeks. All patients will receive approximately 10, 10, 20 mg/kg ataluren 3 
times daily (TID) for 4 weeks during the PK portion and for 48 weeks during the extension 
period. 
 
6.2.2. 
Duration of Treatment 
The study duration will be 4 weeks during the PK portion and 48 weeks during the extension 
period (52 weeks total). Initial data assessment and reporting will be after all patients complete 
first 4 weeks (safety and PK) to satisfy Pediatric Investigation Plan (PIP) requirements and an 
additional report will be issued after completion of 48 weeks extension). The study may be 
terminated by the sponsor at any time and for any reason, eg, the clinical development of 
ataluren in dystrophinopathy is discontinued. 
 
6.2.3. 
Schedule of Administration 
As noted in Table 1, 3 doses should be taken per day – the 1st dose in the morning, the 2nd dose 
during the middle of the day (midday), and the 3rd dose in the evening. Intervals for dosing 
should be ~6 hours (±1 hour) between morning and midday doses, ~6 hours (±1 hour) between 
midday and evening doses, and ~12 hours (±1 hour) between evening doses and the morning 
dose on the next day. 


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Table 1: Suggested Daily Dosing Schedule 
 
Dose Designation 
Example Dosing Times 
Morning 
~7:00 AM – 0700 hours (±1 hour) 
↑ 
~6 hours 
↓ 
Mid-day 
~1:00 PM – 1300 hours (±1 hour) 
↑ 
~6 hours 
↓ 
Evening 
~7:00 PM – 1900 hours (±1 hour) 
↑ 
~12 hours 
↓ 
Next Day Morning 
7:00 AM – 0700 hours (±1 hour) 
 
6.2.4. 
Instructions for Delays in Dosing 
Dosing delays should be handled as follows: 
• If there is a delay in the administration of ataluren of <3 hours after the morning or midday 
doses or <6 hours after the evening dose, the planned dose should be taken with no changes 
to the subsequent dose schedules. 
• If there is a delay in the administration of ataluren of >3 hours after the morning or midday 
doses or >6 hours after the evening dose, the planned dose should not be taken and patients 
should resume their usual dosing schedule. 
 
6.3. 
Safety Monitoring and Study Drug Dose Interruption/Modification 
 
6.3.1. 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and 
Potential Drug Interruption/Modification 
Patients must be monitored closely for AEs or laboratory abnormalities during the course of the 
study. 
For AEs or laboratory abnormalities, the Investigator will use judgment in determining whether 
the event or abnormality is clinically significant, whether diagnostic evaluation is warranted, and 
whether potential interruption of study drug treatment is appropriate. In general, life-threatening 
(Grade 4) or severe (Grade 3) AEs 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 4.0 (see 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf ) for 
grading the severity of AEs and laboratory abnormalities. 


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6.3.2. 
Evaluation of Adverse Events or Laboratory Abnormalities 
While specific monitoring, diagnostic testing, and supportive care measures must be instituted 
based on the clinical judgment of the Investigator, Investigators are encouraged to contact either 
the PTC Therapeutics medical monitor (or designee) to obtain guidance and to ascertain whether 
similar events are being seen at other investigational 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 or nephrology consultants or with other experts 
(either at the site or retained by PTC Therapeutics). 
Clinical evaluations for potential hepatic and renal toxicities may include the following: 
• Hepatic: The medical history, hepatitis screening results, all clinical blood values 
(particularly 
serum 
bilirubin, 
gamma-glutamyl 
transferase 
[GGT], 
aspartate 
aminotransferase [AST], and alanine aminotransferase [ALT] values), and all concomitant 
medications should be reviewed. Depending upon changes observed, the recommended 
diagnostic workup may include more frequent monitoring or further evaluations for viral 
hepatitis and immune disorders; tests for cholelithiasis; or abdominal ultrasound, computed 
tomography (CT), magnetic resonance imaging (MRI), or other imaging methods. 
• Renal: The medical history, all clinical blood and urine renal values, serum electrolytes, 
medications, and potential pre- or post renal conditions should be reviewed. Depending 
upon the changes observed, recommended diagnostic workup may include further 
evaluations of blood or urine; tests of glomerular filtration rate (GFR), concentrating 
ability, or other renal functions; CT, MRI, or other imaging methods; and/or renal biopsy. 
Transient reversible mild (Grade 1) hypercreatinemia was seen in ~15% of patients in 
Study 009.  Therefore, renal function should be monitored and only if sustained (ie, >4 
weeks) should dose adjustment or discontinuation be considered after discussion with the 
PTC Therapeutics medical monitor. 
 
6.3.3. 
Instructions for Resuming Study Drug Administration after an Interruption for 
Safety Concerns 
In deciding whether to re-institute study drug after a dose interruption for any clinically 
significant safety concern, the Investigator in consultation with PTC Therapeutics should 
consider factors such as the following: 
• Type and severity of the AE or laboratory abnormality 
• The potential causal relationship of study drug 
• The patient’s status in terms of dystrophinopathy and other health conditions 
• The ability to monitor for recurrence of the event 
For hepatic or renal events, the level of Investigator certainty that an abnormality leading to drug 
interruption is drug-related should be considered strongly in deciding if and when to re-institute 
ataluren treatment. If the Investigator considers the hepatic or renal event that led to ataluren 
interruption as probably related to ataluren, restarting ataluren is not advised. In this case, the 


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patient should be discontinued from the study (see Section 10). If the Investigator considers the 
hepatic or renal event that prompted ataluren interruption to be possibly related or unlikely 
related to ataluren, the Investigator should use best judgment in determining whether to restart 
ataluren. If the hepatic or renal event is considered unrelated to ataluren, re-institution of ataluren 
is recommended. 
If the Investigator believes it is appropriate to do so and the PTC Therapeutics medical monitor 
has been consulted, ataluren may be re-initiated.  If the event was determined to be unrelated to 
ataluren, the treatment may be resumed at full dose.  Otherwise, if the drug is resumed, it should 
be initially re-initiated at half of the original dose.  The appropriate clinic staff should instruct the 
patient/caregiver about the revised number of study drug sachets to be used per dose according to 
the new schedule.  Re-challenge at half dose should be initiated only as a bridge to full dosing. If 
a patient cannot tolerate the full dose, he/she should be discontinued from study participation. 
If further evaluation reveals that the AE that led to dose reduction was not related to the ataluren, 
the dose should be escalated to the original dose level. 
If after dose reduction, the patient experiences a recurrence of a previous abnormality that led to 
ataluren dose interruption or experiences a new occurrence of an unacceptable AE or laboratory 
abnormality, the Investigator should interrupt ataluren and confer with the PTC Therapeutics 
medical monitor regarding the potential need to discontinue ataluren permanently and 
discontinue the patient from the study. 
6.3.4. 
Instructions for Discontinuation of Study Drug Administration for Safety 
Concerns 
Study drug should be permanently discontinued following appropriate consideration of study 
drug interruption/modification and consultation with the PTC Therapeutics medical monitor or 
designee. If permanent discontinuation of study drug is the result of an SAE, then a follow-up 
SAE report form must be completed (see Section 9.7). In the case of treatment discontinuation 
due to an AE that is not an SAE, the PTC Therapeutics medical monitor or designee should be 
notified (see Section 10). In addition, details regarding the reasons for discontinuation and the 
AEs leading to the discontinuation should be recorded in the source documents and in the 
appropriate eCRF. The Early Termination (ET) Visit eCRF should be completed and appropriate 
follow-up (at ~4 weeks post extension period as per protocol or until recovery from or 
stabilization of the AE, whichever comes last) should be instituted. 


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7. 
CONCOMITANT AND SUPPORTIVE THERAPY 
 
7.1. 
Concomitant Medications 
Other than the study drug, any treatments taken by a patient from the screening period through 
the 4-Week Follow-Up are defined as concomitant medications. 
To the extent possible, administration of any treatment other than the study drug should be 
minimized during the study period. Patients should be discouraged from use of herbal remedies, 
growth hormone, self-prescribed drugs, street drugs, tobacco products, or alcohol at any time 
during the study. 
If considered necessary for the patient’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 take into account patient 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. 
Parents/caregivers should be instructed about the importance of informing the clinic staff of the 
patient’s use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before 
and during the course of the study. Information regarding all concomitant medications will be 
collected and documented in the concomitant medication page of the eCRF. 
 
7.1.1. 
Corticosteriods 
To date, corticosteroid use is the only pharmacological intervention that has demonstrated 
benefit in DMD [Mendell 1989, Fenichel 1991a, Fenichel 1991b, Griggs 1991, Biggar 2001, 
Beenakker 2005, Biggar 2006, Pradhan 2006]. Subjects who require corticosteroid interruption, 
dose modification, or reinstitution may remain on study drug therapy. 
Co-administration of systemic corticosteroids with ataluren may cause more frequent instances 
of hypertension than does systemic corticosteroid use alone (without ataluren). However, the 
blood pressure data available to date are not definite about any contributory role of ataluren in 
development of hypertension in patients who are taking corticosteroids. 
 
7.1.2. 
Nephrotoxic Medications 
Renal abnormalities were observed in a Phase 3 trial evaluating ataluren in patients ≥6 years of 
age with nonsense mutation cystic fibrosis (nmCF) who were receiving concomitant IV 
aminoglycosides and IV vancomycin (as described in the Ataluren IB). Caution should therefore 
be exercised during concomitant use of study drug and potentially nephrotoxic agents. 
In patients who require treatment for serious infections, investigators should substitute other 
antibiotics for systemic aminoglycosides or vancomycin when clinically appropriate, if possible. 
If IV aminoglycosides or IV vancomycin are administered, study drug must be interrupted during 
the course of antibiotic therapy. Patients requiring IV aminoglycoside or vancomycin therapy 
should be closely monitored in an appropriate setting, such as a hospital. Investigators should be 
particularly vigilant with patients experiencing nausea, vomiting, diarrhea, fever, or laboratory 


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evidence of dehydration. Treatment with ataluren may be resumed no earlier than 2 days after 
administration of these antibiotics has ceased. 
In patients receiving such agents, antibiotic drug levels and serum creatinine and blood urea 
nitrogen (BUN) should be monitored closely as follows: 
• Creatinine and BUN should be measured: 
o Prior to initiating IV aminoglycoside or vancomycin therapy 
o Within 24 to 48 hours of the first antibiotic administration (and further 
antibiotic dosing should be based on these results) 
o At least twice a week during the course of antibiotic treatment (if possible) 
• Antibiotic trough levels should be measured: 
o Within 24 to 48 hours of the first antibiotic administration (and further 
antibiotic dosing should be based on these results) 
o At intervals during the course of antibiotic treatment based on clinical need 
7.2. 
Non-Drug Therapy 
 
7.2.1. 
Physical Therapy 
There are neither restrictions nor prescriptions for physical therapy during the study. Sites should 
use local best practices in providing physical therapy support for patients participating in the 
study. 
7.2.2. 
Hydration 
Because of the potential risk of renal dysfunction during periods of dehydration in patients 
receiving ataluren, it is important to encourage study patients to maintain adequate hydration 
throughout the study. Patients should be adequately hydrated prior to receiving any potentially 
nephrotoxic agents, and hydration status should be carefully monitored throughout the 
administration of any agent with nephrotoxic characteristics. Investigators should be particularly 
vigilant with patients who are experiencing nausea, vomiting, diarrhea, fever, or laboratory 
evidence of dehydration. 
 
7.2.3. 
Dietary Restrictions 
There are no specific dietary restrictions in the study. 


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8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS 
 
8.1. 
Schedule of Events 
The types and timing of data to be recorded are summarized in Table 2. Please see Section 8.2 
for explanations of the study procedures outlined. 
Table 2: 
Schedule of Events 
 
 
Day (±2) 
Weeks 
Visit 
Informed consent 
Clinical and medication history 
Vital signs 
Height 
Weight 
Physical examination 
Hematology 
Blood sample for gene sequencing c 
Biochemistryd 
Urinalysis 
12-lead ECG 
Timed function tests 
North Star Ambulatory Assessment 
Blood for ataluren PKe 
Palatability questionnaire 
Drug administration 
 
Screening 
-28 
-4 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ataluren Treatment 
1a 
28 
112 
196 
280 
364 
0 
4 
16 
28 
40 
52/ETb 
2 
3 
4 
5 
6 
7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As clinically indicated 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X ------------------------------------------------ X 
4-Week 
Follow-Up 
392 
56 
8 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adverse events 
Concomitant medications 
Non-DMD-related adverse events 
X ---------------------------------------------------------------- X 
X  
X 
X 
a 
All study and laboratory assessments on the first day of treatment must be done prior to ataluren dosing. 
b 
Patients who terminate the study early should complete all assessments required for Week 52/ET (Visit 7) and will be 
required to return 4 weeks from the final dose of study medication for the 4-Week Follow-up Visit. 
c 
Verification that a blood sample has been drawn for sequencing of the dystrophin gene. A patient who has written 
documentation of a nonsense mutation as the cause of DMD need not wait for confirmatory results to start study drug as 
long as the confirmatory blood sample for gene sequencing was drawn. 
d 
Biochemistry laboratory assessments will include hepatic transaminases and additional parameters as specified in 
Section 8.2.7.2. 
e 
On Days 1 and 28, blood samples for PK assessment will be drawn pre-dose and 1 (±15 min), 2 (±15 min), 4 (±30 min), 
6 (±30 min), 8 (±30 min), and 10 (±30 min) hours post-dose. 
Abbreviations: ECG = electrocardiogram, ET = early termination, PK = pharmacokinetics 


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8.2. 
Explanation of Study Procedures 
 
8.2.1. 
Study Visits 
 
8.2.1.1. 
Screening (Visit 1) 
No study-related procedures should be performed prior to the signing of the informed consent/ 
assent document(s). Thereafter, patients should undergo the initial set of screening procedures as 
noted in Table 2. 
Study participants will report to the clinic on the morning of each on-site visit and will remain in 
the clinic until released by the Investigator after all the study-related procedures have been 
completed and the patient and/or parent(s)/caregiver have been instructed regarding drug storage, 
reconstitution, and administration. 
 
8.2.1.2. 
Treatment Visits 
During the treatment period, each patient will return to the clinical research facility during Week 
0 (Visit 2) and Week 4 (Visit 3) for PK testing, and Week 16 (Visit 4), Week 28 (Visit 5), 
Week 40 (Visit 6), and Week 52 (Visit 7/ET). 
 
8.2.1.3. 
End of Treatment 
If the patient discontinues treatment prematurely, the procedures required for Week 52 
(Visit 7/ET) should be performed before the patient leaves the study and the patient should return 
for the 4-Week Post-Treatment Follow-up Visit. 
Please refer to Section 10 for further details regarding patient withdrawal procedures. 
 
8.2.2. 
Informed Consent 
The Investigator/study staff member must inform each study candidate of the nature of the study, 
explain the potential risks, and obtain written informed consent from the parent(s)/legal guardian 
and/or study candidate (as required by local regulations) prior to performing any study-related 
screening procedures. 
 
8.2.3. 
Clinical/Medication History 
The Investigator or a qualified designee should review the patient’s clinical history, including 
details relating to DMD and any other medical conditions. Information regarding clinical history 
and current medications must be captured on the medical history and prior/concomitant 
medication eCRFs, respectively. 
 
8.2.4. 
Vital Signs 
Vital signs (pulse rate and body temperature) will be monitored at all protocol-required study 
visits. Pulse rate determinations will be performed with the patient in a sitting position after a 5-
minute rest. 
8.2.5. 
Height, Weight and Physical Examination 
Height (in cm) and weight (in kg) will be measured at all study visits. A full physical 


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examination (including evaluation of the cardiovascular system, chest and lungs, thyroid, 
abdomen, nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, mouth, 
throat, spine, lymph nodes, and extremities) will be conducted at Screening (Visit 1) and 4-week 
Follow-up (Visit 8), 4 weeks after discontinuation of study drug. 
Physical examinations may also be performed at any time during the study as clinically indicated. 
 
8.2.6. 
Confirmatory Gene Sequencing 
A blood sample for dystrophin gene sequencing will be drawn at Screening (Visit 1). The study 
manual should be referenced for collection, processing, and shipping information. 
 
8.2.7. 
Central Laboratory Assessments 
All laboratory samples will be analyzed by a central laboratory. Please refer to the study manual 
for instructions regarding collection, processing, and shipment of all laboratory samples. 
 
8.2.7.1. 
Hematology Laboratory Assessment 
Hematology laboratory assessments will include white blood cell count with differential, 
hemoglobin, hematocrit, other red cell parameters, and platelet count. These parameters will be 
measured at every protocol-specified study visit. The study manual should be referenced for 
collection, processing, and shipping information. 
 
8.2.7.2. 
Biochemistry Laboratory Assessment 
Biochemistry laboratory assessments will include sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total 
protein, albumin, bilirubin (total, direct, and indirect), AST, ALT, GGT, CK, lactate 
dehydrogenase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, and cystatin C. These parameters will be measured at every protocol- 
specified study visit. The study manual should be referenced for collection, processing, and 
shipping information. 
 
8.2.7.3. 
Urinalysis 
Urinalysis will include analysis for pH, specific gravity, glucose, ketones, blood, protein, 
urobilinogen, bilirubin, nitrite, and leukocyte esterase. These parameters will be measured at 
every protocol-specified study visit. The study manual should be referenced for collection, 
processing, and shipping information. 
 
8.2.8. 
12-Lead ECG 
A 12-lead ECG will be obtained at screening, Week 4 (Visit 3), Week 52 (Visit 7/ET), and 
4-week Follow-up (Visit 8). ECGs will be read locally at investigational sites and interpreted for 
clinical significance. The findings will be captured in source documents and within the eCRF. 


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8.2.9. 
Timed Function Tests 
Timed function tests will include the time taken to run/walk 10 meters, time to climb 4 stairs, 
time to descend 4 stairs, and time to stand up from a supine position [Mendell 1989, Griggs 
1991, Beenakker 2005a, Pradhan 2006] (see Study Manual for detailed instructions). These 
parameters will be assessed prior to ataluren dosing on the first day of treatment (Visit 2), 
Week 28 (Visit 5), and Week 52 (Visit 7/ET). 
 
8.2.10. 
North Star Ambulatory Assessment 
The NSAA will be used to evaluate physical function, using standardized procedures (see Study 
Manual for detailed instructions). The NSAA will be performed prior to ataluren dosing on the 
first day of treatment (Visit 2), Week 28 (Visit 5), and Week 52 (Visit 7/ET). 
 
8.2.11. 
Pharmacokinetic Assessment 
During PK assessment on Days 1 and 28, patients will remain in the clinic until all blood 
draws are complete. On Days 1 and 28, blood samples for PK assessment will be drawn pre-
dose and 1 (±15 min), 2 (±15 min), 4 (±30 min), 6 (±30 min), 8 (±30 min), and 10 (±30 min) 
hours post- dose. These samples will be sent to a central bioanalytical laboratory for analysis 
of ataluren levels. Please refer to the study manual for instructions regarding the collection, 
processing and shipment of all PK samples to the bioanalytical laboratory. 
 
8.2.12. 
Palatability Questionnaire 
The palatability questionnaire assessing characteristics of the study drug such as smell and 
taste will be administered at Week 4 (Visit 3). A parent/caregiver may respond on the 
patient’s behalf after discussing each item with the patient, age permitting. 
 
8.2.13. 
Ataluren Administration 
Refer to Section 6.2. The clinic staff will administer the first dose of the study drug at Day 1 
(Visit 2). 
 
8.2.14. 
Adverse Events 
Systemic AEs must be assessed and documented at each scheduled clinic visit, beginning at 
Day 1. Additional tests and other evaluations required to establish the significance or etiology 
of an abnormal result, or to monitor the course of an AE should be obtained when clinically 
indicated. Patients must be followed for AEs for at least 28 days after the last dose of ataluren 
administration, or until any drug-related AEs and/or ongoing SAEs have resolved or become 
stable, whichever is later. 
 
8.2.15. 
Concomitant Medications 
Concomitant medication information will be collected and documented at each scheduled clinic 
visit, beginning at Screening. Any concomitant drugs (prescribed or over-the-counter) used 
during the course of the study and the reason for their use will be recorded. Information 
regarding the timing, type, and amount will be recorded in the eCRF. 


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8.3. 
Blood Collection Summary 
Assuming a patient completes the study, the maximum amount of blood to be drawn at a visit is 
approximately 12 mL at screening, 24 mL during the 2 PK assessments, and 5 mL during the 
remaining visits. The total amount of blood to be drawn over the entire study (including the 
screening visit, treatment period, and post-treatment follow-up period) is approximately 61 mL. 


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9. 
ADVERSE EVENT ASSESSMENTS 
 
9.1. 
Adverse Event Definitions 
 
9.1.1. 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug (investigational 
medicinal product) 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 patient 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 that are suspected or are not suspected to be due to study drug 
• Overdose (administration of a study drug dose >4 times the intended total daily dose level 
for this protocol [>160 mg/kg/day]) of study drug 
• All reactions from medication misuse, abuse, withdrawal, sensitivity, or toxicity 
• All reactions that result from medication errors or uses of the study drug outside what is 
described in the protocol 
• Apparently unrelated illnesses, including the 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 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 (eg, elevated liver 
enzymes in a patient with jaundice) 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 pre-existing condition (eg, allergic rhinitis) must be noted on the appropriate eCRF for 
Visit 1, but should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period. Diagnostic and therapeutic 
non-invasive 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 begins 
during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded in the source documents. 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 


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described in Section 9.1.2, any inpatient 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. 
 
9.1.2. 
Serious Adverse Events (SAEs) 
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: 
• Death (ie, all deaths on treatment or within 4 weeks after last study drug administration), 
including deaths due to disease progression. Any death occurring later than 4 weeks 
following the last dose need not be reported as an SAE unless it is a result of an event that 
started within the period covered by the on-study definition. The reported AE should be 
the event that caused the death. In addition, any AE resulting in death that occurs 
subsequent to the AE-reporting period and that the Investigator assesses as possibly 
related to the study drug should also be reported as serious. 
• Life-threatening AE. This is an event that, in the view of either the Investigator or the 
sponsor, places the patient at immediate risk of death. It does not include an event that, 
had it occurred in a more severe form, hypothetically might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization (eg, excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or dystrophinopathy-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 
patient to the hospital and observational durations in the emergency room for less than 24 
hours are not considered serious. 
• Persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions, not related to dystrophinopathy. 
• 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. 
Medical judgment should be exercised in deciding whether a reaction is serious in other 
situations. Important medical events that do not result in death, are not immediately life-
threatening, and do not require hospitalization may be considered serious when, based on 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent any of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 
administration in an emergency room or at home, newly diagnosed malignancy, or blood 
dyscrasias, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
• An event need not be reported as a SAE if it exclusively represents a relapse or an expected 
change or progression of the baseline dystrophinopathy. This type of event need only to be 
reported as an AE. 


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Note that any SAEs occurring after the end of the patient’s participation in the study should 
be reported to the sponsor if the Investigator becomes aware of them. 
 
9.1.3. 
Unexpected Adverse Events 
Unexpected AEs are defined as those events that were not previously reported with study drug as 
referenced in the most current Investigator Brochure, or that are symptomatically and 
pathophysiologically related to a known toxicity but differ because of greater severity or 
specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the Ataluren IB only referred to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the IB only listed cerebral vascular accidents. “Unexpected,” as used in this 
definition, also refers to an AE that is mentioned in the most current IB as occurring with the 
class of drugs or as anticipated from the pharmacological properties of the study drug, but is not 
specifically mentioned as occurring with the medicinal product. 
For the purposes of considering expectedness, the Ataluren IB provides a summary of the safety 
profile of ataluren based on available clinical information (also referred to as the reference safety 
information). 
9.2. 
Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study patient or parent/guardian in case of a child. In addition, each study patient will be 
questioned about AEs at each scheduled clinic visit after study drug administration or during any 
telephone contact with the patient or parent/guardian in case of a child. The type of question 
asked should be open-ended, eg, “How has your child been feeling?” or a similar type of query. 
 
9.3. 
Adverse Event Recording 
All AEs (both serious and non-serious) that occur in patients 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 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 9.1.2) 
• Relationship to study drug (see Section 9.4) 
• Severity of the event (see Section 9.5) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 


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Classification of the event as serious or non-serious determines the reporting procedures to be 
followed. 
 
9.4. 
Describing Adverse Event Relationship to Study Drug 
Based on the considerations outlined in Table 3 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. 
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 AE than study drug. 
Such alternatives include a concomitantly administered drug, the patient’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 AE to a concomitant drug, medical history of a similar event, the patient’s disease 
state, other medical conditions, or environmental factors. 
 
9.5. 
Grading of Severity of Adverse Events 
The severity of AEs will be graded using CTCAE v 4.0 (refer to the study manual). For each 
episode, the highest severity grade attained should be reported. 
If a CTCAE criterion does not exist, the Investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 4. 


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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 patient’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects clinical status, 
and may require medical intervention 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and 
likely requires medical intervention and/or close follow up 
Grade 4 
Life-threatening 
Sign or symptom results in a potential threat to life 
Grade 5 
Fatal 
Sign or symptom results in death 
 
Note the distinction between the seriousness and the severity of an AE. Severity is a measure of 
intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a headache 
may be severe in intensity but would not be classified as serious unless it met one of the criteria 
for serious events listed in Section 9.1.2. 
 
9.6. 
Follow-Up of Unresolved Adverse Events 
All AEs should be followed up by the Investigator until they are resolved, or the Investigator 
assesses them as chronic or stable. Follow-up of any SAE that is fatal or life-threatening should 
be provided within one additional calendar week. The Investigator should consider protocol 
guidelines and use his/her discretion in ordering additional tests as necessary to monitor the 
resolution of such events. In the event of additional investigations, the PTC Therapeutics Safety 
Department or designee should be informed via e-mail or fax. A patient 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 patient has discontinued from the study, and additional 
investigations may be requested by the medical monitoring team. 
 
9.7. 
Adverse Event Reporting Period 
The first day of AE reporting will coincide with the day the first dose of study drug is 
administered. The AE reporting period for this study ends with the 4-week post-treatment 
follow-up visit, except as described in Section 9.3. In addition, SAEs occurring in a patient after 
the study period should be reported to the sponsor if the Investigator becomes aware of them. 
 
9.8. 
Investigator Site Adverse Event Reporting Requirements 
Classification of an event as serious or non-serious (see Section 9.1.2) determines the reporting 
procedures to be followed. Investigator site reporting requirements for AEs are summarized in 
Table 5. 


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Table 5: 
Investigational Site Requirements for Reporting Adverse Events 
 
Classification 
Reporting Time 
Reporting 
Action 
Serious 
Within 24 hours 
E-mail, fax or telephone call to the PTC Therapeutics 
Safety Department/designee within 24 hours. 
Within 5 calendar days 
Provide photocopies or document scan of relevant source 
documentsa (eg, progress notes, nurses’ notes, laboratory and 
diagnostic test results, discharge summaries) as requested by 
the PTC Therapeutics Safety Department/designee. 
Per CRF submission procedure Record and submit information on appropriate CRFs 
(eg, Medical History and Concomitant Medications CRFs) 
AESI 
Within 24 hours 
E-mail, fax or telephone call to the PTC Therapeutics Safety 
Department/designee within 24 hours. 
Within 5 calendar days 
Provide photocopies of relevant source documentsa (eg, 
progress notes, nurses’ notes, laboratory and diagnostic test 
results, 
discharge summaries) as requested by the PTC 
Therapeutics Safety Department/designee. 
Per CRF submission procedure Record and submit information on appropriate CRFs 
(eg, Medical History and Concomitant Medications CRFs) 
Nonserious 
Per CRF submission procedure 
Record and submit information on appropriate CRFs 
(eg, Adverse Events, Medical History and 
Concomitant Medications CRFs) 
a 
Patient name, address, and other personal identifiers should be obscured. 
Abbreviations: AESI = AEs of special interest, eCRF = electronic case report form, IRB/IEC = Institutional Review 
Board/Independent Ethics Committee, SAE = Serious Adverse Event 
 
For SAEs, in addition to completing the AE eCRF, the SAE report form 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 
emailed to the PTC Therapeutics Safety Department or designee and to the site IRB/IEC (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 emailed to 
the same parties. 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 must be redacted so that the patient’s 
name, address, and other personal identifiers are obscured. Only the patient’s study number and 
initials are to be provided (in regions where the provision of such information is permitted). The 
information in the AE 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 patient initially seeks treatment elsewhere), the Investigator is to 
document his/her first awareness of the AE and report the event within 24 hours after learning of 
it. 
The PTC Therapeutics Safety Department/designee contact information for reporting SAEs is 
provided below. This information is also provided in the Investigator File and the back-up paper 
SAE report form. 


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PTC Therapeutics Safety Department  
Attention: 
  
Telephone 
 
Facsimile: 
 
E-mail: 
 
 
9.9. 
PTC Therapeutics Adverse Event Reporting Requirements 
As the sponsor of the study, PTC Therapeutics is responsible for reporting certain safety 
information, particularly SAEs and patient 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/IEC 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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10. 
WITHDRAWAL OF SUBJECTS 
All patients who receive ataluren should remain in the study whenever possible. However: 
• The parent/caregiver has the right to withdraw consent and discontinue ataluren at any 
time. 
• If the patient’s condition substantially worsens after initiating ataluren, 
the patient will be carefully evaluated by the Investigator. The patient 
will be withdrawn from treatment if continuing would place them at 
risk. 
• The Investigator may withdraw the patient from ataluren, if, in the 
Investigator’s clinical judgment, it is not in the patient’s best interest 
to continue. 
• In the event that the patient becomes significantly noncompliant with 
ataluren administration, study procedures, or study requirements, the 
patient should be withdrawn from ataluren when the circumstances 
surrounding noncompliance increase risk to the patient or are anticipated to 
substantially compromise the interpretation of study results. 
• This study may be discontinued by the relevant regulatory 
authority, IRB/EC, 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 eCRF. The PTC medical monitor (or designee) should be informed 
via e-mail of when a patient discontinues study drug. 
When ataluren is discontinued (regardless of the reason), the Investigator is expected to capture 
all of the evaluations required at the end of treatment or Follow-up and any additional 
evaluations should be completed that may be necessary to ensure that the patient is free of 
untoward effects. The patient should be encouraged to seek appropriate follow-up for any 
continuing health problems. 


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11. 
STATISTICAL CONSIDERATIONS 
 
11.1. 
Sample Size 
The sample size of 12 patients for this study is not based on formal statistical considerations. 
However, preliminary results from population PK (popPK) simulation indicate that the current 
study design (sample size and sparse sampling strategy) will provide adequate precision for the 
prediction of PK parameters (apparent clearance and volume of distribution) even considering 
the usual potential for subject dropouts and/or missing samples [Wang 2012, FDA General 
Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products 
2014]. 
 
11.2. 
Analysis Populations 
All patients who receive at least 1 dose of ataluren will be included in the analyses of safety. For 
each outcome measure, evaluable populations of patients will be considered to comprise all 
patients who have sufficient baseline and on-study measurements to provide interpretable results 
for the test of interest. 
 
11.3. 
General Statistical Considerations 
By-subject listings will be created for each eCRF module. Summary tables for continuous 
variables will contain the following statistics: N, mean, median, standard deviation, standard 
error, minimum, maximum, and 95% confidence intervals (CIs) as appropriate. Summary tables 
for categorical variables will include N and percentage. Graphical techniques will be used when 
such methods are appropriate and informative. 
Transformations of the data may be explored if warranted by the distribution of the data. 
All analyses will be performed using Statistical Analysis System (SAS® Version 9.0 or higher). 
The primary analysis will be conducted on data obtained during the 4-week PK period of the 
study and may be reported separately from the extension study data. 
 
11.4. 
Subject Disposition and Baseline Characteristics 
The numbers of patients screened and enrolled will be summarized. Reasons for screen failures 
will be presented. The number of patients receiving ataluren will be described. Patients who do 
not complete the planned observations will be described and evaluated separately. Patients 
receiving ataluren who are found not to have fully met the eligibility criteria will be described. 
On-study protocol violations will also be presented. Reasons for study discontinuation and dates 
of withdrawal from study will be described. 
Patient characteristics at baseline will be summarized using appropriate descriptive statistics. 
 
11.5. 
Efficacy Endpoints 
Observed values and changes from baseline in timed function tests, NSAA total score and 
composite score will be summarized descriptively. 


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11.6. 
Pharmacokinetic Parameters 
PK parameters of ataluren on Day 1 and 28 will be derived using non-compartmental analysis 
(NCA) methods. The PK parameters of ataluren listed below will be derived following the 
morning dose on Day 1 and 28 using NCA methods. 
 
Parameters 
Definition 
AUC0-t 
Area under the plasma concentration time curve from time zero to the time of last quantifiable 
concentration (Ctrough) using the linear trapezoidal rule during the ascending portion of the curve 
and the log-trapezoidal rule during the descending portion of the curve 
AUC0-10 
Area under the plasma concentration time curve from time zero up to 10 hours after the morning 
dosing using the linear trapezoidal rule during the ascending portion of the curve and the log- 
trapezoidal rule during the descending portion of the curve 
Cmax 
Maximum observed plasma concentration 
Ctrough@6h 
Concentration at the end of the first (morning) dosage interval 
tmax 
Time of maximum observed plasma concentration 
λz 
Terminal rate constant 
t1/2 
Terminal half-life, calculated as ln(2) / λZ 
 
 
The accumulation ratio on Day 28 will be calculated as follows: 
 
Parameter 
Description 
AR(AUC) 
AR(AUC) = (AUC0-t)Day28 / (AUC0-t) Day 1 
AR(Cmax) 
AR(Cmax) = (Cmax) Day28 / (Cmax)Day 1 
 
Individual PK parameters will be derived using actual sampling and dosing times. 
Concentrations below the limit of quantitation (LOQ) will be set to zero for the calculation of 
NCA parameters. PK parameters will be summarized with descriptive statistics on Day 1 and 28 
(eg, n, arithmetic mean, standard deviation, standard error, median, minimum, and maximum, 
CV% mean, geometric mean, and CV% geometric mean). The analysis will be performed with a 
fully validated version of Phoenix WinNonlin V6.3. 
In addition, a popPK analysis will be performed by simultaneously assessing concentrations on 
Days 1 and 28 in order to explore the potential time-dependency of ataluren and derive the 
following additional PK parameters. 


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Parameter 
Description 
ka 
Rate constant of absorption 
CL/F 
Apparent clearance 
CLd/F 
Apparent distribution clearance 
Vc/F 
Apparent volume of distribution 
Vp/F 
Apparent peripheral volume of distribution 
 
The above PopPK model will be used to simulate rich concentration-time profiles and derive the 
area under the curve over 24 hours (AUC0-24). 
A two-compartment model with time-dependent clearance (between the morning and midday 
dose), was previously used to assess the concentration-time profiles of ataluren in adult patients 
with nonsense-mutation Duchenne-Becker muscular dystrophy. If required, data collected in the 
current study (≥2 to <5 year old nmDMD patients) may be merged with data collected in adult 
patients with nmDMD to assess potential effect of age and/or body weight on PK parameters of 
ataluren. 
Additional information will be provided in the PK analysis plan. 
 
11.7. 
Safety 
 
11.7.1. 
Adverse Events 
Adverse events will be tabulated by using the MedDRA classification system. The severity of the 
AE will be graded using the CTCAE whenever possible. For AEs that are not included in the 
CTCAE, the grading categories (mild, moderate, severe, life-threatening, and fatal) described in 
Table 4 will be used. The frequency of patients experiencing a specific AE will be tabulated by 
system organ class; preferred term; seriousness (serious vs nonserious; see Section 9.1.2); timing 
of occurrence, outcome, and relationship to study drug (see Section 9.4); and worst severity (see 
Section 9.5) In the by-subject analysis, a patient having the same event more than once will be 
counted only once and will be classified at the highest severity and/or relatedness for those 
events. 
Adverse events classified as CTCAE Grade ≥3; study-drug-related events; hepatic, and renal 
events leading to special diagnostic evaluations; events leading to discontinuation of ataluren, 
events leading to death, and SAEs will be considered with special attention. 
 
11.7.2. 
Laboratory Parameters 
Hematological and biochemistry data will be summarized by visit and will be graded according 
to CTCAE severity grade, when applicable. The frequencies of the worst severity grade observed 
will be displayed. For variables graded according to CTCAE severity grade, the frequencies of 


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the worst severity grade observed will be displayed. For parameters for which a CTCAE scale 
does not exist, the frequency of patients with values below, within, and above the normal ranges 
will be summarized. In the by-subject analysis, a patient having the same abnormality more than 
once will be counted only once based on the worst severity grade observed. 
 
11.7.3. 
Vital Signs and ECGs 
Vital signs (height, weight, BMI, pulse rate, and body temperature) and ECGs will be listed and 
summarized by visit. Where appropriate, changes from baseline will be presented by visit. 
 
11.7.4. 
Other Safety Parameters 
Physical examination data will be described. Where appropriate, changes from baseline will be 
presented by visit. 
 
11.7.5. 
Interim Safety Review 
An interim safety analysis is planned with the assistance of the DMC; the analysis will be a 
safety review when all patients have completed ≥12 weeks of treatment. If this review indicates 
potential safety concerns, the DMC may elect to have additional safety reviews for specific 
patients or all patients. 
 
11.8. 
Treatment Administration and Drug Compliance 
Study drug compliance will be assessed by unused study drug reporting. Compliance will be 
analyzed as a percentage of drug actually taken relative to the amount that was specified to be 
taken during the study. 
 
11.9. 
Use of Concomitant Medication and Supportive Therapy 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) into Anatomical-Therapeutic-Chemical (ATC) classification codes. 
The type and timing of use of specific concomitant medications will be listed and summarized. 
The frequency, timing, type, and amount of any other therapies for dystrophinopathy will be 
considered with special interest. 
 
11.10. 
Palatability Questionnaire 
Palatability data will be summarized descriptively. 
 
11.11. 
Exploration of Correlations 
Correlations between patient characteristics and outcome measures, and correlations among 
outcomes measures may be explored using regression models or other appropriate techniques. 


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12. 
STUDY COMMITTEES 
A DMC, operating autonomously from the sponsor and the clinical investigators, will be 
responsible for providing independent recommendations to PTC Therapeutics about evolving 
risk-benefit observed in the course of the study and any modifications required during the course 
of the study. The DMC will comprise appropriately qualified personnel as detailed in the DMC 
charter. The DMC will be chaired by one of those individuals. DMC members must not be 
actively involved in study design, conduct, or daily management of this study and must not have 
financial, proprietary, professional, or other interests that may affect impartial, independent 
decision-making. Specialists may be invited to participate as non-voting members at any time if 
additional expertise is desired. 


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13. 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR 
 
13.1. 
Compliance with Ethical and Regulatory Guidelines 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the International Council on Harmonisation (ICH) GCP guidance documents and the 
Declaration of Helsinki. 
13.2. 
Institutional Review Board/Independent Ethics Committee 
Prior to enrollment of patients into the study, as required by regulatory authorities, the protocol 
and informed consent document will be reviewed and approved by an appropriate IRB/IEC. By 
signing the protocol, the Investigator assures that approval of the protocol will be obtained from 
the IRB/IEC and that all aspects of the IRB/IEC review will be conducted in accordance with 
current regulations. Amendments to the protocol will be subject to the same IRB/IEC review 
requirements as the original protocol. Only changes necessary to eliminate apparent immediate 
hazards to the patients may be initiated prior to IRB/IEC approval. In that event, the Investigator 
must notify the IRB/IEC and PTC Therapeutics in writing within 5 working days after 
implementation. The Investigator will also promptly notify the IRB/IEC of any serious, 
unexpected AEs or any other information that may affect the safe use of the drug during the 
course of the study. 
A letter documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members must be received by PTC Therapeutics prior to the initiation of the study. All 
correspondence with the IRB/IEC should be retained in the Investigator’s study file. 
The Investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to PTC Therapeutics. As soon as possible after completion or termination of the 
study, the Investigator will submit a final report to the IRB/IEC and to PTC Therapeutics. This 
report should include the dates of initiation and completion of the study, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of patients evaluated, the number of patients who discontinued (and the 
reasons for discontinuation), the number of patients who completed the study, and the results of 
the study, including a description of any AEs. PTC Therapeutics will assist the Investigator in 
the preparation of this report, as needed. 
 
13.3. 
Informed Consent/Assent 
By signing the protocol, the Investigator assures that informed consent/assent will be obtained 
from each patient and/or 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 patient and/or parent/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 
patient and/or parent/guardian in a language in which the patient or parent/guardian is fluent. 
This information must be provided to the patient or parent/guardian prior to undertaking any 
study-related procedure. Adequate time should be provided for the patient and/or 


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parent/guardian to read the informed consent, to understand the risks and benefits of participating 
in the study, and to ask any questions that the patient and/or parent/guardian may have about the 
study. The patient and/or parent/guardian should be able to ask additional questions as and when 
needed during the conduct of the study. The patient’s and/or parent(s)/guardian signature (as 
required by local regulations) on the informed consent form should be obtained at the 
investigational site in the presence of the Investigator or a qualified representative 
(eg, sub-investigator). Where applicable, the patient will sign an age-appropriate assent form. 
Each patient or parent/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. 
The written patient information must not be changed without prior approval by PTC 
Therapeutics and the IRB/IEC. 
 
13.4. 
Case Report Forms 
An eCRF is required and must be completed for each patient, with all required study data 
accurately recorded such that the information matches the data contained in medical records (eg, 
physicians’ notes, nurses’ notes, clinic charts, and other study-specific source documents). 
The eCRFs exist within a Web-based EDC system managed by the data management CRO for 
this study. After the Investigator or the Investigator’s designees (eg, research coordinators) have 
been appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail. 
With an electronic signature, the Investigator certifies that the data are complete and accurate 
prior to database lock. This electronic signature serves to attest that the information contained in 
the eCRFs is true. After database lock, the investigational site will receive a CD-ROM and/or 
paper copies of the patient data for archiving at the investigational site. At all times, the principal 
Investigator has final responsibility for the accuracy and authenticity of all clinical data entered 
onto the eCRFs and/or reported to PTC Therapeutics from the investigational site. 
 
13.5. 
Study Records 
During the study, the Investigator will maintain adequate records for the study, including 
medical records, source document records detailing the progress of the study for each patient, 
laboratory reports, a CD-ROM or paper copy of the data that have been captured in the EDC for 
each patient (electronic equivalents of CRFs), paper CRFs, signed informed consent forms, 
ataluren reconciliation and dispensing records, correspondence with the IRB/IEC, AE reports, 
and information regarding patient discontinuation and completion of the study. Current 
regulations require PTC Therapeutics (or an authorized designee) to inspect all documents and 
records required to be maintained by the Investigator, including but not limited to medical 
records (office, clinic, or hospital) for the patients enrolled in this study. These regulations also 
allow the same records to be inspected by authorized representatives of the FDA, Health Canada, 
or other regulatory authorities. 


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13.6. 
Confidentiality 
Research records will be collected and stored in a manner that protects the confidentiality of 
patient information. The names and identities of all research patients 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 patients need 
not be divulged; however, the records must nevertheless be inspected. This will be accomplished 
by redacting the patient’s name and replacing the name with the patient’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. 
 
13.7. 
Retention of Records 
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 patients (sufficient information to link eCRFs and clinic records), all original signed 
informed consent forms, CD-ROM or paper copies of the data that have been captured in the 
EDC for each patient (electronic equivalents of CRFs), and detailed records of ataluren 
disposition. All records and documents pertaining to the study (including but not limited to those 
outlined in Section 13.5 above) 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. In order to avoid any possible errors, the Investigator will contact PTC Therapeutics 
prior to the destruction of any study 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. 
 
13.8. 
Monitoring and Auditing 
In accordance with 21 CFR Part 312.56 and/or relevant ICH guidelines, PTC Therapeutics or a 
designee will periodically inspect all eCRFs (see Section 13.4), 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, other 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 
patients in this study. The names and identities of all research subjects will be kept in strict 


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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. 
The investigational site may also be subject to review by the IRB/IEC, to quality assurance 
audits performed by PTC Therapeutics or a designee, and/or to inspection by regulatory 
authorities. The GCP regulations also require the Investigator to allow authorized representatives 
of the regulatory authorities to inspect and make copies of the same records. 
It is important that the Investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections, and that sufficient time is devoted to the 
process. 
13.9. 
Termination of the Study 
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 investigational 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. 
 
13.10. 
Public Notification of Study Conduct 
Consistent with requirements of the International Committee of Medical Journal Editors 
(ICJME) as a condition of consideration for publication of study results, PTC Therapeutics will 
be responsible for ensuring that this protocol is listed at the ClinicalTrials.gov website. 
PTC Therapeutics will also be responsible for ensuring that information at this website relating 
to study design and conduct is appropriately updated during the course of the study. In order to 
facilitate this process, investigators will need to supply PTC Therapeutics with appropriate 
contact information for investigational site personnel. 
 
13.11. 
Dissemination of Results 
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. 
To allow for the use of the information derived from this clinical study and to ensure compliance 
with current regulations, the Investigator is obliged to provide PTC Therapeutics with complete 
test results and all data developed in this study. The information obtained during this study may 
be made available by PTC Therapeutics to other physicians who are conducting similar studies 
and to the FDA, Health Canada, or other regulatory authorities. Such information may be 
disclosed as deemed necessary by PTC Therapeutics. 
PTC Therapeutics intends for the data from this study to be presented and published. The PTC 
Therapeutics staff under the direction of the PTC Therapeutics chief medical officer in 
collaboration with the Investigator will be responsible for writing presentations and manuscripts 


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for publication. Investigators will not be allowed to publish or present the data from this study 
without prior agreement with PTC Therapeutics. 
 
13.12. 
Communication with Regulatory Authorities 
PTC Therapeutics will assume responsibility for regulatory interactions with the FDA, Health 
Canada, and/or other regulatory authorities. In fulfilling this responsibility, PTC Therapeutics (or 
a designee) will collect, assemble, and communicate all required regulatory documents (eg, 
Investigator financial disclosure forms, protocol and protocol amendments, investigator 
brochures, informed consent documents, annual reports) as required by regulation. 
PTC Therapeutics (or a designee) will also assume responsibility for AE reporting to regulatory 
authorities as described in Section 9.9. 


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14. 
RATIONALE FOR STUDY DESIGN FEATURES 
 
14.1. 
Subject Selection 
 
14.1.1. 
General 
This study is an open-label PK, efficacy, and safety study of ataluren in subjects with nmDMD. 
Consistent with GCP guidelines, parents/guardians and subjects must provide informed 
consent/assent before initiation of any study procedures. To minimize missing data and 
premature discontinuations, subjects must have the personal and family resources to comply with 
study procedures and restrictions. In addition, subjects must not have serious concomitant 
conditions that would compromise safety, compliance, or evaluation. 
 
14.1.2. 
Inclusion of Minors 
Inclusion of children ≥2 to <5 years old in this protocol is appropriate and necessary. The 
benefit-risk ratio is enhanced by the known severity of the disease phenotype in patients with 
dystrophinopathy caused by nonsense mutations, the generally favorable safety profile of 
ataluren, and the limited population of patients with nonsense-mutation-mediated disease (~13% 
of the total dystrophinopathy population). Inclusion of young children will allow an 
understanding of how age-dependent disease characteristics may affect PK parameters and, 
therefore, dosing. 
In standard toxicology studies, dosing is initiated in young adult rats (6 to 8 weeks old) and in 4- 
to 6-month old dogs. However, the chronic toxicology studies conducted with ataluren initiated 
dosing in weanling animals (approximately 4- to 5-week-old rats, and dogs <3 months 
of age) to support dosing of pediatric subjects as young as 2 years of age. A detailed summary of 
methods and results of these chronic toxicity studies is provided in Section 7 of the Ataluren IB. 
In the clinic, ataluren has previously been administered to patients as young as 3 years old. A 
Phase 2 study of ataluren in patients with methylmelonic acidemia (MMA) enrolled 11 patients, 
including 2 patients who were 3 years old and 1 patient who was 4 years old. All 3 of these 
patients completed the study as planned, receiving ataluren 5, 5, 10 mg/kg for 28 days in Cycle 1 
and ataluren 10, 10, 20 mg/kg for 28 days in Cycle 2; there was a washout period of 21 days 
between the cycles. 
Ataluren was well tolerated by the 3 patients <6 years old in the MMA study. Treatment- 
emergent AEs in these patients were vomiting, pyrexia, nasopharyngitis, cough, flatulence, and 
rash. All treatment-emergent AEs were mild or moderate in severity, and none were serious or 
led to discontinuation of treatment. Overall, the ataluren safety profile was similar in patients <6 
years old and ≥6 years old. 
Twenty-four hour blood sampling for ataluren PK assessments was performed on Day 28 of each 
cycle; the data from Cycle 2, in which a dose of 10, 10, 20 mg/kg was administered, are of 
particular relevance to the proposed study. Ataluren plasma concentrations in the 3 patients 
<6 years old were comparable to ataluren plasma concentrations in the 8 patients ≥6 years old 
who participated in the MMA study. Mean AUC0-24h was 279.3 h•µg/mL and 358.4 h•µg/mL for 
patients <6 and ≥6 years old, respectively, on Day 28 of Cycle 2. Mean Cmax was 28.2 µg/mL 


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and 29.9 µg/mL for patients <6 and ≥6 years old, respectively, on Day 28 of Cycle 2 (10, 10, 20 
mg/kg). These data suggest similar ataluren PK profiles in patients <6 and ≥6 years old. 
In Phase 2 clinical studies, ataluren has demonstrated comparable PD activity and safety, as well 
as PK profiles similar to adult patients, in children >6 years old with CF [Clancy 2006, Kerem 
2008, Sermet-Gaudelus 2010, Wilschanski 2011]. The drug has also shown PD activity and was 
generally well-tolerated at the dose used in that study and a higher dose level in children with 
DMD [Finkel 2013]. 
During study conduct, patients will be monitored closely for adverse clinical and laboratory 
events. This protocol clearly defines the actions to be taken if AEs occur. Procedures have been 
established for defining AEs, eliciting AE information, recording AEs, evaluating the 
relationship of AEs to the study drug, grading the severity of AEs, following up on unresolved 
AEs, and reporting AEs. These procedures are fully detailed in Section 9.  Additional risk/benefit 
information that becomes available during the conduct of the study will be provided to each 
investigational site as a “letter to the Investigator” or safety alert. In addition, pain and 
discomfort will be prevented as much as possible, and investigations will be limited to a 
minimum necessary to provide meaningful data and performed using size/age appropriate 
material and devices. 
 
14.1.3. 
Reproductive Considerations 
Ataluren is not genotoxic, did not affect fertility in male and female rats, and was not teratogenic 
in rats and rabbits. In addition, lack of sexual maturity in the subjects enrolled in this study limits 
reproductive risks. 
 
14.1.4. 
Prior and Concomitant Therapies 
Conventional supportive therapies will be permitted; however, efforts will be made to avoid use 
of concomitant medications that might confound interpretation of study results or pose a safety 
risk. Ataluren has not proved allergenic in studies performed to date, but review of known 
allergies to excipients containing in the formulation is prudent. As substantial modification of 
corticosteroid dosing due to manifestation of undesirable side effects such as osteoporosis during 
the study may confound study results, investigators and subjects are encouraged to maintain 
corticosteroid dosing as uniformly as possible. 
In vitro studies have suggested that ataluren is potentially an inhibitor of CYP450, 2C8 and 2C9 
at concentrations that may be achieved in the clinic. Because ataluren may slow the clearance of 
medications that are primarily metabolized by CYP2C8 or CYP2C9, investigators should pay 
specific attention to use of drugs that are known substrates of this enzyme, particularly when 
such drugs may have a low therapeutic index. 
While no clinical evidence of drug-drug interactions has been demonstrated, the potential for 
ataluren interactions with other drugs has been assessed. Based on in vitro studies, ataluren is a 
substrate of UGT1A9 and BCRP. The clinical drug-drug interaction study for ataluren with a 
strong UGT1A9 inducer (eg, rifampin) has been conducted. Although the average ataluren Cmax 
and AUC were reduced posttreatment of rifampin (~11% and ~29%, respectively), these changes 
are considered not to be clinically important. Caution should be exercised when ataluren is co- 
administered with drugs that are inhibitors of BCRP. 


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In vitro data indicate that ataluren is an inhibitor of UGT1A9, OAT1, OAT3 and OATP1B3. 
Caution should be exercised when ataluren is co-administered with drugs that are substrates of 
UGT1A9, OAT1, OAT3, or OATP1B3 because of the risk of increased concentration of these 
drugs. 
Physicians and subjects are encouraged to avoid the use of extraneous drugs or alternative 
therapies in order to minimize the possibility that drug-drug interactions might occur. In 
particular, physicians are advised to closely monitor subjects when drugs of low therapeutic 
index that are cleared by CYP2C9 are administered concomitantly with ataluren. 
Specific drugs that are prohibited during the study are listed in the Exclusion Criteria (see 
Section 4.3). 
 
14.2. 
Treatment Rationale 
 
14.2.1. 
Ataluren Schedule and Dose Selection 
Dosing based on body weight will be employed. Such dosing is common in pediatrics and 
reduces variability in exposure by accommodating differences in patient size across the span of 
ages of the patients who will participate in the clinical study. The preliminary results from a 
popPK simulation indicated that the current study design of 10, 10, 20 mg/kg dose in 12 patients 
with 7-point sampling after the morning dose would provide good precision of the estimates of 
CL/F and Vd/F, according to FDA recommendation. 
The schedule of drug administration was derived directly from Phase 1 PK modeling and from 
Phase 2 exposure information. The intent of administering 2 smaller doses at 6-hour intervals 
during the day and a larger dose at a 12-hour interval overnight (eg, at 7:00 AM, 1:00 PM, and 
7:00 PM) is to optimally sustain target plasma concentrations while minimizing total exposures. 
This schedule is likely to fit well with daily patterns of living for patients, thus enhancing 
compliance. As confirmation of that premise, compliance with ataluren dosing in Phase 2 and 
Phase 3 testing has been excellent. 
In clinical studies of ataluren in nmDMD, ataluren has been studied most extensively at the 10, 
10, 20 mg/kg dose level. In the Phase 2b, randomized, double-blinded, placebo-controlled study 
of ataluren in nmDMD (Study 007), 57 patients received ataluren 10, 10, 20 mg/kg for 48 weeks. 
In addition, all patients in the ongoing open-label safety studies of ataluren in nmDMD 
(Studies 016 and 019) are receiving the 10, 10, 20 mg/kg dose level. As of 31 January 2015, the 
estimated median duration of exposure was 196.6 weeks for Study 016 (N=108) and 102.4 weeks 
for Study 019 (N=93).  Across the Phase 3, randomized, double-blinded, placebo-controlled 
study of ataluren in nmCF (Study 009) and its open-label extension (009e), a total of 164 nmCF 
patients have received ataluren 10, 10, 20 mg/kg for ≥48 weeks, including 45 patients who have 
received ataluren 10, 10, 20 mg/kg for ≥96 weeks. The controlled studies in nmDMD (Study 
007) and nmCF (Study 009) have documented a favorable risk-benefit at the 10, 10, 20 mg/kg 
dose level in these indications [Bushby 2014, Kerem 2014]. In nmDMD, ataluren has been 
conditionally approved at a dose of 10, 10, 20 mg/kg for the treatment of nmDMD. Based on the 
collective clinical experience with ataluren 10, 10, 20 mg/kg, this dose level will be evaluated in 
patients with dystrophinopathy aged 2 to <5 years. 


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14.2.2. 
Duration of Therapy 
The primary objective of this Phase 2 study is to determine whether ataluren can be safely 
administered as a chronic treatment for patients 2 to <5 years of age. In patients ≥6 years old, 
ataluren has been generally well tolerated when administered chronically for >4 years. 
Therefore, exposure to ataluren for 52 weeks in this study is not expected to pose undue safety 
risk. 
 
14.2.3. 
Selection of Endpoint Measures 
The proposed safety PK and PD evaluations were chosen based on relevance to the 
pathophysiology and clinical manifestations of the disease, and past experience that these tests 
can be performed with acceptable accuracy in this young patient population. 
 
14.2.3.1. Timed Function Tests 
Commonly employed over many years [Brooke 1989, McDonald 1995] TFTs are relevant to the 
disease in that they assess functional aspects of proximal muscle strength required for everyday 
activities. TFTs are substantially abnormal in boys with DMD compared to healthy boys 
[Beenakker 2005b]. Worsening values have been correlated with time to wheelchair dependency 
and these tests can be sensitive to medical intervention [Mendell 1989, Griggs 1991, Beenakker 
2005b]. Given their long-standing use, there is substantial experience with the conduct of the 
tests, the analyses of the data, and very high reproducibility has been demonstrated [Mayhew 
2007]. 
 
14.2.3.2. North Star Ambulatory Assessment 
The NSAA is a functional scale specifically designed for ambulant DMD patients.  The scale 
was developed and piloted in the United Kingdom by the North Star Clinical Network for 
Paediatric Neuromuscular Disease Management with good intra- and inter-observer reliability 
and has recently been used in a large multicenter study [Mazzone 2011]. The scale includes 
items assessing abilities that are necessary to remain functionally ambulant, ie, ability to rise 
from the floor, ability to get from lying to sitting and sitting to standing, and that are known to 
progressively deteriorate in untreated patients. The scale also includes items assessing head raise 
and standing on heels that can be partly present in the early stages of the disease and a number of 
activities such as hopping, jumping, and running [Mazzone 2011]. 
 
14.2.3.3. Ataluren Plasma Concentrations 
Collection of blood for ataluren plasma concentration analysis is critical for evaluating exposure- 
safety relationships in this population. Based on the preliminary popPK simulation results, 
sampling pre-dose and then at 1, 2, 4, 6, 8, and 10 hours post-dose on Days 1 and 28 will provide 
information about single-dose and steady-state after 28-day ataluren PK parameters in this 
population. Additionally, the ataluren PK profile has been well characterized in existing 
Phase 2a and Phase 3 studies in patients with CF. 
The high performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) 
method that will be used to quantify ataluren plasma concentrations has been fully validated in 
the context of the prior Phase 1 and Phase 2 studies. 


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14.2.4. 
Safety Monitoring 
In defining therapeutic activity in a particular clinical setting, it is imperative that the drug’s 
safety profile be fully characterized. As is conventional in all clinical studies, proper description 
of each AE or laboratory abnormality requires an understanding of the type, incidence, timing, 
severity, and relatedness to study drug. In this study, particular focus will be placed on 
monitoring for renal adverse findings. For consistency of interpretation, AEs will be coded using 
the standard MedDRA, and the severity of these events will be graded using the well-defined 
CTCAE Version 4.0. Standard definitions for seriousness will be applied. Particular attention 
will be paid to any AEs causing discontinuation of ataluren and to SAEs requiring rapid 
regulatory reporting. 


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15. 
BENEFITS AND RISKS 
 
15.1. 
Benefits and Risks: Non-Clinical 
Nonclinical safety pharmacology and toxicology studies indicate that ataluren has an acceptable 
safety profile. The findings seen pose a low human safety risk and the program supports chronic 
administration of ataluren for the treatment of nmCF in patients as young as 2 years of age. 
15.2. 
Benefits and Risks: Clinical 
Multiple Phase 2 and Phase 3 trials have now shown the potential benefit and safety of ataluren 
in the treatment nmDMD in adults and children (details are provided in the Ataluren IB). 
Decline in ambulation is the hallmark of dystrophinopathy, and the major goal of intervention 
during the ambulatory phase of dystrophinopathy is to maintain ambulation for as long as 
possible. Ataluren at a dose of 10, 10, 20 mg/kg slowed the decline in ambulation in nmDMD 
patients. In the placebo-controlled study, Study 007, the targeted difference of 30 meters between 
ataluren 10, 10, 20 mg/kg and placebo in the 6-minute walk test (6MWT) was achieved (Δ=31.3 
meters). The 30-meter distance meets the threshold for minimal clinically important difference in 
dystrophinopathy and other diseases, and is in the range of the 6MWT results for approved 
therapies in a variety of conditions. The 30-meter distance is meaningful to dystrophinopathy 
patients, providing greater ability to walk in their daily lives, for example, walking to and from 
the school bus and taking part in social activities. 
The time-to-event analysis of 6MWT progression further showed that ataluren 10, 10, 20 mg/kg 
slowed disease progression in patients with nmDMD. Only 26% of patients who received 
ataluren 10, 10, 20 mg/kg, compared with 44% of the patients who received placebo, had 
persistent 10% worsening in the 6MWT at Week 48. Delaying ambulatory decline provides 
direct clinical benefit by affording boys with nmDMD a longer period of self-sufficiency before 
transitioning to full-time wheelchair use. Maintenance of ambulatory capacity can prevent, delay 
the onset of, or reduce the severity of scoliosis, a debilitating complication of dystrophinopathy, 
and is beneficial to the patient’s pulmonary status. 
Positive trends in secondary endpoints in Study 007 support the 6MWT results. Patients who 
were treated with ataluren 10, 10, 20 mg/kg trended toward less decline in muscle function than 
patients who were treated with placebo and met the threshold (~1.5 seconds) for clinically 
meaningful differences. Among the TFTs, the largest effect for ataluren 10, 10, 20 mg/kg was 
seen in stair climbing, which is one of the most difficult activities of daily living for patients with 
dystrophinopathy. Positive trends, favoring ataluren 10, 10, 20 mg/kg over placebo were also 
observed for TFT method grading, accidental fall frequency, activity and wheelchair use in the 
community setting, myometry, and patient-reported physical functioning domain of the Pediatric 
Quality of Life Inventory.  The consistency of these findings across outcome measures supports 
a treatment effect of ataluren 10, 10, 20 mg/kg in patients with nmDMD. 
 
15.3. 
Benefit/Risk Conclusions 
Dystrophinopathy is a disabling and life-threatening genetic disorder resulting from mutations in 
the gene encoding the dystrophin gene. Dystrophin dysfunction leads to multiple organ 


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dysfunction starting in early childhood. An urgent unmet medical need exists for a therapy that 
addresses the underlying cause of nmDMD, a condition with high unmet medical need. Ataluren 
10, 10, 20 mg/kg represents the first potentially disease-modifying therapy for a subset of 
patients with this severely disabling, progressive, and ultimately fatal disease. 
The collective nonclinical and clinical data provide the basis for the continued development of 
ataluren treatment for nmDMD. The clinical efficacy data, in addition to an overall generally 
favorable safety profile collected from Phase 2 and 3 clinical trials supports a positive benefit- 
risk profile for ataluren. Appropriate safety monitoring and laboratory evaluation, as detailed in 
Section 14, is incorporated in this protocol in order to minimize risk to study participants. The 
current trial (Study 030) is feasible and will provide additional safety, PK, efficacy, and exposure 
data of ataluren in young children with nmDMD. 
Participants in this trial have the potential for direct benefit from treatment with ataluren, which 
justifies the known and potential risks. Substantial nonclinical and clinical safety experience 
provides appropriate risk-benefit information that supports the conduct of this study. This 
information is detailed in the Ataluren IB and is summarized in Section 9.8 of the IB. The 
potential risks (real and theoretical) have been weighed against the expected benefits for the 
children enrolled in the clinical trial. It is believed that the balance of risks versus expected 
benefits will be positive for the clinical trial. 


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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
PRODUCT UNDER INVESTIGATION: 
PTC124 
NCT #: NCT02819557
TITLE: 
A PHASE 2 STUDY OF THE SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF ATALUREN (PTC124®) IN SUBJECTS AGED ≥2 TO 
<5 YEARS OLD WITH NONSENSE MUTATION 
DYSTROPHINOPATHY 
PROTOCOL NUMBER 
PTC124-GD-030-DMD 
STUDY SPONSOR 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
PREPARED BY 
WCCT Global 
5630 Cerritos Ave. 
Cypress CA 90630 
DATE AND VERSION 
March 19, 2018 
(Based on Protocol Version 2 dated January 28, 2016) 
CONFIDENTIALITY: 
The information in this document is confidential and is the property of PTC Therapeutics, Inc. The information may be provided only to Investigators, sub-Investigators, and appropriate 
trial personnel, members of the Institutional Review Board/Institutional Ethics Committee (IRB) and personnel of the authorities to whom it is submitted. This Statistical Analysis Plan 
may not be photocopied or discussed with third parties not involved in the trial without the prior written authorization from PTC Therapeutics, Inc. 


PTC Therapeutics, Inc. 
Protocol PTC124-GD-030-DMD 
Statistical Analysis Plan 
March 19, 2018 
Final Version 
Confidential 
Page 2 of 45 
 
STATISTICAL ANALYSIS PLAN  
DOCUMENT NUMBER: PTC124-GD-030-DMD–SAP-001 
TITLE 
A PHASE 2 STUDY OF THE SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF ATALUREN (PTC124®) IN SUBJECTS AGED ≥2 TO 
<5 YEARS OLD WITH NONSENSE MUTATION  
DYSTROPHINOPATHY 
 
SPONSOR 
PTC Therapeutics, Inc.  
100 Corporate Court 
South Plainfield, NJ 07080 USA 
 
PRODUCT 
PTC124 
 
STUDY PHASE 
Phase II 
 
 
PREPARED BY 
WCCT Global 
5630 Cerritos Ave. 
Cypress CA 90630 
 
DATE AND VERSION 
March 19, 2018 
(Based on Protocol Version 2 dated January 28, 2016) 
 


PTC Therapeutics, Inc. 
Protocol PTC124-GD-030-DMD 
Statistical Analysis Plan 
March 19, 2018 
Final Version 
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SIGNATURE PAGE – PTC THERAPEUTICS, INC. 
 
Declaration 
 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
 
  
 
  
 
  
 
  
 
PTC Therapeutics, Inc. 
 Date (dd mmm yyyy) 
 
  
 
  
 
  
 
  
 
 
PTC Therapeutics, Inc. 
 Date (dd mmm yyyy) 
 
  
 
  
 
  
 
  
 
 
PTC Therapeutics, Inc. 
 Date (dd mmm yyyy) 
 


PTC Therapeutics, Inc. 
Protocol PTC124-GD-030-DMD 
Statistical Analysis Plan 
March 19, 2018 
Final Version 
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SIGNATURE PAGE - WCCT 
Declaration 
 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
WCCT Global 
 
Date (dd mmm yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WCCT Global 
 
Date (dd mmm yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PTC Therapeutics, Inc. 
Protocol PTC124-GD-030-DMD 
Statistical Analysis Plan 
March 19, 2018 
Final Version 
Confidential 
Page 5 of 45 
Table of Contents 
SIGNATURE PAGE – PTC THERAPEUTICS, INC. ................................................................3 
SIGNATURE PAGE - WCCT .....................................................................................................4 
1. 
LIST OF ABBREVIATIONS ...................................................................................7 
2. 
INTRODUCTION ....................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................10 
3.1. 
Study Objectives .....................................................................................................10 
3.2. 
Study Design ...........................................................................................................10 
3.3. 
Schedule of Assessments ........................................................................................10 
3.4. 
Endpoints ................................................................................................................10 
3.4.1. 
Primary Endpoints ...................................................................................................10 
3.4.2. 
Secondary Endpoints ...............................................................................................12 
3.5. 
Sample Size Justification ........................................................................................14 
3.6. 
Study Treatments and Dose Administration ...........................................................14 
3.7. 
Estimated Duration of Subject Participation and Follow-up ..................................14 
3.8. 
Interim Analyses .....................................................................................................14 
3.9. 
CINRG Natural History Population ........................................................................14 
4. 
ANALYSIS POPULATIONS .................................................................................16 
5. 
ANALYSIS CONVENTIONS ...............................................................................17 
6. 
STUDY DISPOSITION ..........................................................................................19 
7. 
PROTOCOL DEVIATIONS ..................................................................................20 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...............21 
8.1. 
Baseline Demographic Factors and Medical History .............................................21 
8.2. 
Medical History.......................................................................................................21 
8.3. 
Prior and Concomitant Medications .......................................................................21 
9. 
STUDY DRUG ACCOUNTABILITY ...................................................................23 
10. 
EFFICACY .............................................................................................................24 
10.1. 
Timed Function Test ...............................................................................................24 
10.2. 
North Star Ambulatory Assessment (NSAA) .........................................................24 
10.3. 
Palatability Characteristics ......................................................................................27 
11. 
PHARMACOKINETICS ........................................................................................28 
11.1. 
Plasma Concentration .............................................................................................28 


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Protocol PTC124-GD-030-DMD 
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11.2. 
Pharmacokinetic Analysis .......................................................................................28 
12. 
SAFETY ..................................................................................................................31 
12.1. 
Adverse Events ........................................................................................................31 
12.1.1. 
Definition of an Adverse Event (AE) ......................................................................31 
12.1.2. 
Definition of Serious Adverse Event ......................................................................31 
12.1.3. 
Summaries of Adverse Events ................................................................................31 
12.2. 
Clinical Laboratory Assessments ............................................................................34 
12.3. 
Vital Signs ...............................................................................................................36 
12.4. 
Electrocardiogram Results ......................................................................................37 
12.5. 
Physical Examination Results .................................................................................37 
13. 
REFERENCES ........................................................................................................39 
14. 
TABLES, LISTINGS, AND FIGURES ..................................................................40 
15. 
MISSING AND PARTIAL ADVERSE EVENT DATES .....................................43 
16. 
SCHEDULE OF EVENTS .....................................................................................45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
LIST OF ABBREVIATIONS 
 
Abbreviation or 
Specialist Term 
Explanation 
6MWT 
6-minute walk test 
AE 
Adverse event(s) 
ALT 
Alanine aminotransferase 
AR 
Accumulation Ratio 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC0-t 
Area under the plasma concentration time curve from time zero to the time of 
last quantifiable concentration 
AUC0-10 
Area under the plasma concentration time curve from time zero up to 10 hours 
after the morning dosing 
AUC0-24 
Area under the concentration curve versus time curve from time zero to 24 
hours 
BMI 
Body mass index 
BCRP 
Breast Cancer Resistant Protein 
BUN 
Blood urea nitrogen 
Bayley-III 
Bayley-III Scales of Infant and Toddler Development 
CD-ROM 
Compact disc read-only memory 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CK 
Creatine kinase 
CI 
Confidence interval 
CINRG 
Cooperative International Neuromuscular Research Group 
CL/F 
Apparent clearance 
CLd/F 
Apparent distribution clearance 
Cmax 
Maximum observed plasma concentration 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough@6h 
Concentration at the end of the first (morning) dosage interval 
CV% 
Coefficient of variation 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
DMD 
Duchenne muscular dystrophy 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 


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Protocol PTC124-GD-030-DMD 
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HPLC-MS/MS 
High performance liquid chromatography-mass spectrometry 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
ICTRP 
International Clinical Trials Registry Platform 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
Intravenous 
ka 
Rate constant of absorption 
LOQ 
Limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmelonic acidemia 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NCA 
Non-compartmental analysis 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
nmCF 
Nonsense mutation cystic fibrosis 
NSAA 
North Star Ambulatory Assessment 
OAT1 
Organic anion transporter 1 
OAT3 
Organic anion transporter 3 
OATP1B3 
Organic anion transporting polypeptide 1B3 
PD 
Pharmacodynamic(s) 
PIP 
Pediatric Investigation 
PK 
Pharmacokinetic(s) 
popPK 
Population PK 
PTC124 
Ataluren 
SAS 
Statistical Analysis System 
SAE 
Serious adverse event 
t½ 
Terminal half-life 
TEAE 
Treatment-emergent adverse event 
TFT 
Timed function tests 
TID 
3 times per day 
tmax 
Time of maximum observed plasma concentration 
UGT 
Uridine diphosphate glucuronosyltransferase 
UGT1A9 
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A9 
US 
United States 
Vc/F 
Apparent central volume of distribution 
Vp/F 
Apparent peripheral volume of distribution 
WHODRUG 
World Health Organization Drug Dictionary 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to prospectively (a priori) outline the types of 
analyses and presentations of the safety, efficacy, and PK data. 
 
This document contains information to support the generation of a Clinical Study Report (CSR) 
for Clinical Protocol PTC124-GD-030-DMD, including detailed descriptions of the statistical 
methodologies to be applied, as well as the post-text tables, figures, analysis summary tables, and 
subject data listings intended to present the analysis results. 
 
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the FDA and International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical Principles in 
Clinical Trials. 
 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
The primary objective of this study is to evaluate the safety of ataluren as measured by type, 
frequency, severity, timing, and relationship to study drug of treatment emergent adverse events 
(TEAEs), laboratory abnormalities and electrocardiograms (ECGs). 
There are 5 secondary objectives of the study, presented in the order from section 3.2 of the 
protocol: 
• Evaluate the plasma pharmacokinetics (PK) of ataluren in subjects aged ≥2 to <5 years 
old with nmDMD 
• Assess proximal muscle function using timed function tests (TFTs) 
• Assess change in physical function using the North Star Ambulatory Assessment 
(NSAA) 
• Determine the effect of ataluren on weight, height, and body mass index (BMI) 
• Assess the palatability of ataluren 
3.2. 
Study Design 
Protocol PTC124-GD-030-DMD is a Phase 2, multiple-dose, open-label study evaluating the 
safety, and pharmacokinetics (PK) of ataluren in subjects aged ≥2 to <5 years old with Nonsense 
Mutation Dystrophinopathy (nmDMD). In nmDMD, early start of treatment is important and, 
therefore, it is relevant to understand the correct and tolerable dose in this age group, particularly 
since ataluren is dosed by weight. This study is composed of 4 periods: a 4-week screening period, 
a 4-week study period, and a 48-week extension period for subjects who complete the 4- week 
study period (52 weeks total treatment), and a 4-week post-treatment follow-up period. The 
objective of the 48-week extension period is to assess the long-term safety of chronic 
administration of ataluren in this subject population. 
3.3. 
Schedule of Assessments 
The Schedule of Assessments is presented in Table 2 of the protocol. The planned assessment 
times are Day -28 (Screening); Day 1 for Baseline assessment for the Ataluren Treatment Period; 
Day 28, 112, 196, 280, 364 (Ataluren Treatment Period), and Day 392 (Follow-up Period). 
 
3.4. 
Endpoints 
3.4.1. 
Primary Endpoints 
There are 4 primary endpoints defined in the protocol for the study. 
• Overall safety profile in terms of the type, frequency, severity, timing, and relationship 
to study therapy of any adverse events or abnormalities of physical findings, laboratory 
tests, or ECGs 


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• Occurrence of any dose-limiting toxicities (DLTs) 
• Drug discontinuations due to adverse events 
• Serious adverse events (SAEs) 
Adverse events will be monitored throughout the course of the study and TEAEs will be reported 
from the time of study drug administration during the 4-week PK study period through the 
extension period (study day 392 / week 56). Subjects must be followed for adverse events and 
serious adverse events for at least 28 days after the last dose of ataluren. A subject withdrawn from 
the study because of an AE or SAE must be followed by the Investigator until clinical recovery is 
complete and laboratory results have returned to normal, or until progression has been stabilized. 
The physical examinations will include the following body system or organ assessments. The 
results will be classified as normal or abnormal. 
 
• 
Cardiovascular system 
• 
Chest and lungs 
• 
Thyroid 
• 
Abdomen 
• 
Nervous System 
• 
Skin and mucosae 
• 
Musculoskeletal 
• 
Eyes, Ears, Nose, Mouth, Throat 
• 
Spine 
• 
Lymph Nodes 
• 
Extremities 
• 
Other 
 
Abnormal laboratory tests will be reported as adverse events under the system organ class of 
Investigations. Hematology laboratory assessments will include white blood cell count with 
differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. These 
parameters will be measured at every protocol-specified study visit. Biochemistry laboratory 
assessments will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (total, direct, 
and indirect), AST, ALT, GGT, CK, lactate dehydrogenase, alkaline phosphatase, total cholesterol, 
high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. These parameters 
will be measured at every protocol-specified study visit. Urinalysis will include analysis for pH, 
specific gravity, glucose, ketones, blood, protein, urobilinogen,  bilirubin, nitrite, and leukocyte 
esterase. These parameters will be measured at every protocol- specified study visit. 
A 12-lead ECG will be obtained at screening, Week 4 (Visit 3), Week 52 (Visit 7/End of 
Treatment), and 4-week Follow-up (Visit 8). ECGs will be interpreted for clinical significance and 
classified as Normal, Abnormal, Not Clinically Significant, or Abnormal, Clinically Significant. 


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3.4.2. 
Secondary Endpoints 
There are 5 secondary endpoints that cover PK, performance measurements, physical examination 
and palatability (ref. Section 3.4 from the protocol): 
 
Ataluren concentrations in plasma will be analyzed to derive the pharmacokinetics using standard, 
non-compartmental methods. On each of the sampling days (Study Days 1 and 28), blood samples 
for ataluren concentration assessments will be collected immediately pre-dose and at specified 
time points following the morning, midday, and evening doses. The parameters to  be derived are 
as follow: 
 
• Area under the plasma concentration time curve from time zero to the time of last 
quantifiable concentration (AUC0-t) 
• Area under the plasma concentration time curve from time zero up to 10 hours after the 
morning dosing (AUC0-10) 
• Maximum observed plasma concentration (Cmax) 
• Concentration at the end of the first (morning) dosage interval (Ctrough@6h) 
• Time of maximum observed plasma concentration (tmax) 
• The accumulation ratio for the AUC from day 1 and 28: 
AR(AUC) = (AUC0-t) on Day 28 / (AUC0-t) on Day 1 
• The accumulation ratio for the Cmax from day 1 and 28: AR(Cmax) = (Cmax) on Day28 / (Cmax) 
on Day 1 
 
TFTs assessed prior to ataluren dosing on the first day of treatment (Visit 2), Week 28 (Visit 5), 
and Week 52 (Visit 7/ET). TFTs include: 
 
• Time taken to run/walk 10 meters, 
• Time to climb 4 stairs, 
• Time to descend 4 stairs, and 
• Time to stand up from a supine position. 
 
NSAA will be performed prior to ataluren dosing on the first day of treatment (Visit 2), Week 28 
(Visit 5), and Week 52 (Visit 7/ET). For each of the evaluations, the subject will be scored with  a 
0 (Unable to achieve independently), 1 (Modified method but achieves goal independent of 
physical assistance from another) or a 2 (Normal – no obvious modification of activity). The full 
scale is presented below. 
 
• Stand (0, 1 or 2) 
• Walk (0, 1 or 2) 
• Stand up from chair (0, 1 or 2) 
• Stand on one leg – right (0, 1 or 2) 
• Stand on one leg – left (0, 1 or 2) 
• Climb box step – right (0, 1 or 2) 
• Climb box step – left (0, 1 or 2) 
• Descend box step – right (0, 1 or 2) 
• Descend box step – left (0, 1 or 2) 


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• Gets to sitting (0, 1 or 2) 
• Rise from floor (0, 1 or 2) 
• Lifts head (0, 1 or 2) 
• Stands on heel (0, 1 or 2) 
• Jump (0, 1 or 2) 
• Hop right leg (0, 1 or 2) 
• Hop left leg (0, 1 or 2) 
• Run (10m) (0, 1 or 2) 
 
The total of the previous 17 items will be summed on an intra-subject basis to obtain the total 
score. The best total score is 34 and the worst is 0. 
 
Recent updates to the NSAA have removed ‘Lifts Head’ from the total score. Although the results 
from all 17 items have been collected, a summary will be presented based on the 16 items without 
the result from ‘Lifts Head’. The results of these 16 items will be summed on an intra- subject 
basis to obtain the total score. The best total score is 32 and the worst is 0. 
 
Two additional subset summaries will be generated from the 17 items in the NSAA. The first is an 
8-item NSAA subscale. This 8-item subscale will include the following 8 items from the full 
NSAA. 
 
• Stand (0, 1 or 2) 
• Walk (0, 1 or 2) 
• Stand up from chair (0, 1 or 2) 
• Climb box step – right (0, 1 or 2) 
• Climb box step – left (0, 1 or 2) 
• Gets to sitting (0, 1 or 2) 
• Jump (0, 1 or 2) 
• Run (10m) (0, 1 or 2) 
 
The total of these 8 items will be summed on an intra-subject basis to obtain the total score for 
the 8-item subscale. The best total score is 16 and the worst is 0. 
 
The second is a 3-item NSAA subscale. This 3-item subscale will include the following 3 items 
from the full NSAA. 
 
• Stand (0, 1 or 2) 
• Walk (0, 1 or 2) 
• Stand up from chair (0, 1 or 2) 
 
The total of these 3 items will be summed on an intra-subject basis to obtain the total score for 
the 3-item subscale. The best total score is 6 and the worst is 0. 
 
Two additional measures will also be recorded and summarized. 


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• Rise from Floor Time (seconds) 
• Run (10m) Time (seconds) 
 
Ataluren palatability characteristics will be based on the parent/caregiver questionnaire.  The  first 
question below will be asked of the subject and the response from the subjects will be recorded as 
bad, not sure, or good. The second and third questions will be asked of the caregiver and the 
response from the caregiver will be recorded as strongly disagree, disagree, neither agree nor 
disagree, agree, or strongly agree. The specific questions are presented below. 
• How did the medicine taste? 
• On the basis of reaction ⁄ facial expression of your child, do you think that the medication 
is pleasant? 
• You sometimes have problems in giving the medication to your child because he/she 
refuses to take it or throws it up. 
 
3.5. 
Sample Size Justification 
The planned sample size of 12 subjects for this study should provide adequate precision for the 
prediction of PK parameters (apparent clearance and volume of distribution). 
 
3.6. 
Study Treatments and Dose Administration 
Dosing of ataluren is based on milligrams of drug per kilogram of subject body weight; body 
weight is re-assessed every 12 weeks. All subjects will receive approximately 10, 10, 20 mg/kg 
ataluren 3 times daily (TID) for 4 weeks during the PK portion and for 48 weeks during the 
extension period. Three doses will be administered each day; the first dose will be in the 
morning, the second dose will be administered in the middle of the day (midday), and the third 
dose will be administered in the evening. 
3.7. 
Estimated Duration of Subject Participation and Follow-up 
Subjects who do not terminate early from the study will be followed for 56 weeks; a total of 52 
weeks after the initial administration of the study drug. If a subject completes the study with an 
ongoing AE, the site will continue to follow up with the subject until resolution if ≤28 days from 
the last dose of study drug. If, after 28 days the AE is still continuing but not assessed as serious, 
the outcome will be recorded as ongoing and no further follow up will be necessary. If a subject 
completes the study with an ongoing SAE, the subject will be followed until resolution or 
stabilization or until no further information can be obtained. 
 
3.8. 
Interim Analyses 
An interim safety analysis is planned and will be conducted by an independent Data Monitoring 
Committee (DMC). The analysis will be based on a safety review when all subjects have completed 
at least 12 weeks of treatment. The safety analysis plan will be prepared separately. 
 
3.9. 
CINRG Natural History Population 
The largest prospective multicenter study of the natural history of DMD, performed by the 
Cooperative International Neuromuscular Research Group (CINRG), enrolled more than 400 


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ambulant and non-ambulant male patients with DMD and collected a comprehensive set of clinical 
measures over a 10-year period. In order to illustrate the clinical benefit of ataluren in subjects ≥2 
and ≤5 years of age in Protocol PTC124-GD-030-DMD, subjects from the CINRG database will 
be selected based on ≥2 and ≤5 of age-match at study entry. Additional selection criteria (i.e. 
baseline TFTs, NSAA scores, etc.) maybe selected if significant differences in baseline 
demographics are observed between the CINRG cohort and the Study 030 population. The data 
extracted from the CINRG database will include demographics at study entry, and available Timed 
Function Test and North Star Ambulatory Assessment by the same time points: study entry, Weeks 
28 and 52. The selected CINRG data will be summarized similarly to Study 030. 
The data extracted from the CINRG database will not be included in study databases with the data 
collected in PTC124-GD-030-DMD. That is, the CINRG data will not be included in the SDTM 
and ADaM databases which support the tables, listings, and figures for the study CSR and will not 
be included in the study submission package. 
Instead, the data from the CINRG database will exist as standalone SAS datasets. Separate ADaM 
datasets, tables, and listings will be generated to present results from the natural history CINRG 
database alongside results from PTC124-GD-030-DMD. These summaries will be kept separate 
from the study CSR. 
 


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4. 
ANALYSIS POPULATIONS 
All subjects who receive at least 1 dose of ataluren will be included in the analyses of safety.  The 
results from this study will be presented using 4 populations: 
Enrolled Subjects: All subjects who were successfully screened and enrolled into the study. 
Safety Population: All subjects who receive at least 1 dose of ataluren. The safety population will 
be used for the safety summary. 
PK Population: All subjects who receive at least 1 dose of ataluren and have at least 1 PK 
concentration data. The PK population will be used for PK analyses. 
Evaluable Population: All subjects who receive at least 1 dose of ataluren and have baseline and 
at least 1 post-baseline measurement for TFTs, NSAA, or response to the palatability of ataluren 
questions. The evaluable population will be used for the efficacy analyses. 
 


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5. 
ANALYSIS CONVENTIONS 
Post-text tables and listings will be prepared in accordance with the current ICH Guidelines. The 
information and explanatory notes to be provided in the footer of each table and listing will include 
the following information: 
 
1. Date and time of output generation; 
2. SAS® program name, including the path that generates the output; 
3. Any other output specific details that require further elaboration. 
 
In general, tables will be formatted with a column displaying findings for all subjects combined. 
Row entries in tables are made only if data exist for at least 1 subject (i.e., a row with all zeros will 
not appear). The only exception to this rule applies to tables that list the termination status  of 
subjects (e.g., reasons for not completing the study). In this case, zeros will appear for study 
termination reasons that no subject satisfied. The summary tables will clearly indicate the number 
of subjects to which the data apply and data points that are “unknown” or “not performed” will be 
distinguished from missing data. 
 
Individual Subject Data Listings will be sorted and presented by subject number and visit date, if 
applicable. Listings will also include the number of days relative to the exposure to the study drug 
(active or placebo), if applicable. 
 
Specific algorithms are discussed for imputing missing or partially missing dates, if deemed 
appropriate, under specific data topics. Imputed or derived data are flagged in the individual 
subject data listings. Imputed data  will not be incorporated into any raw or primary datasets.  The 
imputed data will be retained in the derived / analysis datasets. 
The total duration for a subject on study will be calculated as the difference between the date of 
initial exposure to the study drug and the last day of observation plus one day. All calculations for 
defining the duration on study will follow the algorithm DURATION = [STUDY COMPLETION 
OR WITHDRAW DATE –DRUG DOSE DATE + 1]. 
 
This section details general conventions to be used for the statistical analyses. The following 
conventions will be applied to all data presentations and analyses. 
 
• Summary statistics will comprise the number and percentage of responses in each level 
for categorical variables, and the sample size (n), mean, median, standard deviation (SD), 
minimum, and maximum values for continuous variables. 
 
• All mean and median values will be formatted to one more decimal place than the 
measured value. SD values will be formatted to 2 more decimal places than the measured 
value. Minimum and maximum values will be presented with the same number of 
decimal places as the measured value. 


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• The number and percentage of responses will be presented in the form XX (XX.X%). 
 
• Although the primary interest will be descriptive for summarizing the results from this 
study, there may be interest in calculating probability values for certain parameters for 
informational purposes. If presented, probability values will be rounded to 4 decimal 
places. All probability values that round to 0.0000 will be presented as ‘<0.0001’ and p- 
values that round to 1.0000 will be presented as ‘>0.9999’. Probability values <0.05 will 
be considered statistically significant. 
 
• All summary tables will include the analysis population sample size (i.e., number of 
subjects). 
 
• Study Day 1 is defined as the day the subject is exposed to the study drug. All study 
days 
are determined relative to the day of exposure to the study drug (active or placebo). 
 
• Baseline values will be defined as those values recorded closest to, but prior to, the first 
study treatment on Day 1. 
 
• Change from baseline will be calculated as follows: 
 
Change = Post-baseline value − baseline value 
 
• Missing data may have an impact upon the interpretation of the trial data. However, as 
this study is of short duration, it is anticipated that missing data will be minimal. Missing 
data will not be imputed; however, a methodology is defined for missing and partial 
dates (see Section 9.1.3). In the event of a missing laboratory test result, the result will 
be treated as missing for the laboratory abnormality summary. 
 
• Date variables will be formatted as DDMMMYYYY for presentation. 
 
• Tables, figures, and listings will be presented in landscape orientation. 
 
• SAS Version 9.3 or higher will be the statistical software package used for all data 
analyses. 
 
• The subject number will be included in all data listings. All listings will be sorted by 
subject number and visit date, as applicable. 
 
 


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6. 
STUDY DISPOSITION 
A complete accounting of subject participation in the study will be presented in Table 14.1.1 
entitled Subject Disposition (All Screened Subjects). The purpose of this table is to provide an 
accounting of subjects from their entrance into the study through the final visit and to account for 
subject evaluation in major analyses of safety and tolerability, including reasons for early study 
termination. The table will display the number and percentage of subjects that: 
• were enrolled, 
• are included in the Safety population, 
• are included in the PK population, 
• are included in the evaluable population 
• completed or discontinued the study. 
In addition, the reason for early study termination will be summarized separately using the 
number and percentage of subjects for each reason. 
 
Listing 16.2.1 entitled Subject Disposition supports Table 14.1.1. This listing will be sorted by 
subject number. 
 
Listing 16.2.3.1 entitled Inclusion and Exclusion Criteria displays the data from the Inclusion 
Criteria and Exclusion Criteria case report forms (CRF). The data will be displayed for each subject 
and for each inclusion criterion not met or each exclusion criterion met. The listing will be sorted 
by subject number and inclusion/exclusion criterion number. 
 
Listing 16.2.3.2 entitled Eligibility Criteria displays the data from the Study Eligibility CRF. This 
form confirms that the appropriate informed consent has been obtained for study participation. The 
listing will be sorted by subject number. 
 
 


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7. 
PROTOCOL DEVIATIONS 
In accordance with ICH E3, Sponsor-defined eligibility and important post-dosing protocol 
deviations will be identified and listed separately by subject. Deviation type/code provided by 
the Sponsor will be used to classify the events as: 
 
• Subjects who developed withdrawal criteria during the study but were not withdrawn 
• Subjects who entered the study even though they did not satisfy the entry criteria 
• Subjects who received an excluded concomitant treatment 
• Subjects who received the wrong treatment or incorrect dose 
• Other 
 
Deviations are then categorized into: 
 
• Major 
• Minor 
 
Table 14.1.2 entitled Summary of Protocol Deviations (All Screened Subjects) will provide a 
tabular summary of the protocol deviations by category and type of deviation. Listing 16.2.2 
entitled Protocol Deviations supports Table 14.1.2. The listing will be sorted by subject number 
and date of the protocol violation. 
 
 


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8. 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
8.1. 
Baseline Demographic Factors and Medical History 
All subjects in the Safety Population will be included in summary of demographic information in 
Table 14.1.3 entitled Demographics and Baseline Characteristics (Safety Population).  This table 
summarizes the subject population with respect to gender, age (years) at screening, race and 
ethnicity. Age will be reported in months and years and summarized with descriptive statistics:  n, 
arithmetic mean, SD, median, range (i.e., minimum and maximum values). The number and 
percent of each gender, race, and ethnicity category will be presented using counts and 
percentages. Race will be presented using the following categories: 
 
• Caucasian or White 
• Black or African American 
• Asian 
• American Indian or Alaska Native 
• Native Hawaiian or other Pacific Islander 
• Other 
 
The supportive data for Table 14.1.3 are presented in Listing 16.2.4.1 entitled Demographics and 
Subject Characteristics (Safety Population). This listing will be sorted by subject number. 
 
8.2. 
Medical History 
Medical history data will be mapped with the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 and categorized by system organ class (SOC) and preferred term (PT). 
The medical history will be summarized using counts and percentages by SOC and PT for the 
Safety Population in Table 14.1.4 entitled Summary of Medical History. 
 
Medical history will be presented in Listing 16.2.4.2 entitled Medical History (Safety Population). 
This listing will be sorted by subject number and start date of the medical history. 
8.3. 
Prior and Concomitant Medications 
A prior medication is a medication that was started and ended prior to the first dose of study 
medication. Concomitant medications are medications that the subject starts after the first dose  of 
study medication or medications that began prior to the first dose of study medication and continue 
afterwards. 
 
All prior and concomitant medications will be coded using the Anatomical-Therapeutic- Chemical 
(ATC) classification text from the WHO Drug Dictionary. Medications will be presented by ATC 
Class 1, ATC Class 3, and Preferred Term. The data will be presented for subjects in the Safety 
Population. Subjects will only be counted one time in each unique ATC Class 1, ATC Class 3, and 
Preferred Term. For the summary tables, the count and percentage of subjects under each 
anatomical therapeutic chemical (ATC) class and PT will be summarized. 


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Prior medications will be summarized in Table 14.1.5.1 entitled Summary of Prior Medications 
(Safety Population). Concomitant medications, prescribed and over the counter, that the subject 
takes or continues to take after the first dose of study medication will be summarized in Table 
14.1.5.2 entitled Summary of Concomitant Medications (Safety Population). Concomitant non- 
drug treatments will be summarized in Table 14.1.5.3 entitled Summary of Concomitant Non- drug 
Treatments (Safety Population). 
 
Corticosteroids that the subject takes or continues to take after the first dose of study medication 
will be summarized in Table 14.1.5.4 entitled Summary of Corticosteroids (Safety Population). 
 
Nephrotoxic medications that the subject takes or continues to take after the first dose of study 
medication will be summarized in Table 14.1.5.5 entitled Summary of Nephrotoxic Medications 
(Safety Population). 
 
A listing of prior and concomitant medications will be provided for all enrolled subjects. A flag 
will be included in the listing to distinguish concomitant versus prior medications. Listing 
16.2.8.7 entitled Prior and Concomitant Medications and Non-drug Treatments supports the 
analysis presented in Tables 14.1.5.1 through 14.1.5.5. This listing will be sorted by subject 
number and medication start date. A flag will be added to the listings to identify corticosteroids 
and nephrotoxic medications summarized in the tables. 
 
 


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9. 
STUDY DRUG ACCOUNTABILITY 
A summary of study drug administration will be presented in Table 14.1.6 entitled Summary of 
Administration of Study Drug (Safety Population). The total duration of treatment in days will  be 
summarized with descriptive statistics: n, arithmetic mean, SD, median, range (i.e., minimum and 
maximum values). Total Duration will be calculated as the last date of treatment minus the first 
date of treatment + 1 day. Treatment duration will also be presented using a series of non- 
overlapping categories. The number and percent of each treatment duration category will be 
presented using counts and percentages. The treatment duration categories will be presented using 
the following categories: 
 
• 1 to 28 Days 
• 29 to 112 Days 
• 113 to 196 Days 
• 197 to 280 Days 
• 281 to 364 Days 
• > 364 Days 
 
Listing 16.2.5.1 entitled Administration of Study Drug will support the analysis presented in Table 
14.1.6. This listing will be sorted by subject number and relative day. 
 
Listing 16.2.5.2 entitled Study Drug Accountability presents the accountability of the study drug 
including the number of sachets dispensed, the number of used sachets returned, and the number 
of unused sachets returned. This listing will be sorted by subject number and date dispensed. 


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10. 
EFFICACY 
Observed values and changes from baseline in timed function tests and NSAA total score will be 
summarized using descriptive statistics for the evaluable population. 
 
10.1. 
Timed Function Test 
The timed function tests will be performed on the first day of treatment (Visit 2 - Study Day 1), 
Week 28 (Visit 5 - Study Day 196), and Week 52 (Visit 7/ET - Study Day 365). Results 
summarizing the baseline values (Study Day 1), post-baseline values, and the change from baseline 
values will be presented separately for each of the 4 tests: 
• Time taken to run/walk 10 meters, 
• Time taken to climb four standard sized stairs, 
• Time taken to descend four standard sized stairs, and 
• Time to stand up from a supine position 
If the time taken to perform a test exceeds 30 seconds or if a subject cannot perform the test due 
to disease progression, a value of 30 seconds will be set for the summary analysis. A sensitivity 
analysis will also be performed using a maximum time threshold of 45 seconds instead of 30 
seconds. 
The time values in seconds will be summarized using descriptive statistics: n, mean, SD, median, 
range, and 95% confidence intervals. Only paired quantitative data will be summarized in the 
tables; all data will be presented in the listings. Results will be summarized and presented in Table 
14.2.1 entitled Summary of Timed Function Tests by Visit (Evaluable Population). The supportive 
listing will be Listing 16.2.6.1 entitled Timed Function Tests. This listing will be sorted by subject 
number and relative day. 
 
10.2. 
North Star Ambulatory Assessment (NSAA) 
NSAA will be performed prior to ataluren dosing on the first day of treatment (Visit 2), Week 28 
(Visit 5), and Week 52 (Visit 7/ET). The NSAA consists of 17 activities. For each of the 
evaluations, the subject will be scored with a 0 (Unable to achieve independently), 1 (Modified 
method but achieves goal independent of physical assistance from another) or a 2 (Normal – no 
obvious modification of activity). The maximum score is 34; the sum of the responses to the 17 
individual questions will be the total score. If fewer than 13 of the 17 activities are performed, the 
total score will be considered missing. If from 13 to 16 activities are performed, the total score 
will be calculated by multiplying the sum of the scores in the x activities that were performed by 
17/x. If an activity cannot be performed due to disease progression/loss of ambulation, a score of 
zero will be assigned. 
 
Recent updates to the NSAA have removed ‘Lifts Head’ from the total score. Although the results 
from all 17 items have been collected, a summary will be presented based on the 16 items without 
the result from ‘Lifts Head’. The results of these 16 items will be summed on an intra- subject 
basis to obtain the total score. The best total score is 32 and the worst is 0. 


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In addition, the logit score will be performed per a linear transformation of the NSAA score to a 
scale of 0 to 100 [Mayhew 2013] based on the following table. This table illustrates the 
transformation of the raw score to the linearized measurement on a scale of 0 to 100 via a logit 
transformation. For example, a male who scored 12 out of 32 on the NSAA (excluding his score 
on item12 – lifts head) can be calculated to have a linearized measurement of 42 out of 100. 
 
Results from the 16-item NSAA subscale will be presented in Table 14.2.2.1 entitled Summary  of 
16-item North Star Ambulatory Assessment Total Score by Visit (Evaluable Population) and Table 
14.2.2.2 entitled Summary of 16-item North Star Ambulatory Assessment Logit Score by Visit 
(Evaluable Population). 
 
The results of the entire 17-item NSAA scale will be presented in Table 14.2.2.1.1 entitled 
Summary of the North Star Ambulatory Assessment Total Score by Visit (Evaluable Population). 
 
The results of the 8-item NSAA subscale will be presented in Table 14.2.2.1.2 entitled Summary 
of the 8-item North Star Ambulatory Assessment Subscale by Visit (Evaluable Population). The 
maximum score on the 8-item subscale is 16. If any of the 8 items are not performed, the total 
score will be considered missing. 
 
The results of the 3-item NSAA subscale will be presented in Table 14.2.2.1.3 entitled Summary 
of the 3-item North Star Ambulatory Assessment Subscale by Visit (Evaluable Population). The 
maximum score on the 3-item subscale is 6. If any of the 3 items are not performed, the total score 
will be considered missing. 
 
The supportive listing will be Listing 16.2.6.2 entitled North Star Ambulatory Assessment. This 
listing will be sorted by subject number and relative day. 
 


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10.3. 
Palatability Characteristics 
The responses to the Ataluren Palatability Questionnaire will be summarized in Table 14.2.3 
entitled Summary of the Palatability Characteristics at Visit 3 for all subjects in the Evaluable 
Population. The Ataluren Palatability Questionnaire has three questions, one for the child and two 
for the parent/caregiver. The questions, along with the response choices are: 
 
1. Child: How did the medicine taste?  
Responses: Bad, Not Sure, Good 
 
2. Parent / Caregiver: On the basis of reaction ⁄ facial expression of your child, do you 
think that the medication is pleasant? 
Responses: Strongly Disagree, Disagree, Neither Agree nor Disagree, Agree, 
Strongly Agree 
 
3. Parent / Caregiver: You sometimes have problems in giving the medication to your 
child because he/she refuses to take it or throws it up. 
Responses: Strongly Disagree, Disagree, Neither Agree nor Disagree, Agree, 
Strongly Agree 
 
The counts and percentages for each question and response will be summarized at Visit 3. The 
supportive listing will be Listing 16.2.6.3 entitled Palatability Characteristics. This listing will be 
sorted by subject number and question. 
 


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11. 
PHARMACOKINETICS 
11.1. 
Plasma Concentration 
Collection of blood for ataluren plasma concentration analysis is critical for evaluating the 
exposure / safety relationships and profile in this study. Sampling pre-dose and then at 1, 2, 4, 6, 
8, and 10 hours post-dose on Days 1 (Visit 2) and 28 (Visit 3) will provide information about 
single-dose and steady-state after 28-days of administration of ataluren. Plasma concentrations that 
are below the lower limit of detection will be set to zero for the tabular summary of the plasma 
concentrations by time point. Missing plasma concentrations will be excluded from the summary 
of the plasma concentrations by time point. The plasma concentration results will be summarized 
using descriptive statistics and presented in Table 14.2.4 entitled Summary of the Plasma 
Concentrations of Ataluren by Visit (PK Population). Listing 16.2.6.4 entitled Plasma 
Concentrations of Ataluren will contain the individual subject-level data sorted by subject number 
and date of the venipuncture sample used in the determination. Plasma concentrations will be 
summarized by scheduled time point in the tabular summary and all figures. However, the actual 
sampling times and the planned time points will be displayed in the plasma concentration listing. 
Observed values of plasma concentrations for ataluren will be summarized at each visit and time 
point by dose level in the PK population. The descriptive statistics (n, mean, SD, CV%, median, 
minimum, and maximum) will be provided. In addition, geometric mean, its 95% CI, and CV% 
will be presented. 
 
Figure 14.2.1 entitled Mean (±SD) Ataluren Plasma Concentration by Visit over Time – Linear 
Scale (PK Population) will plot the mean ataluren plasma concentrations over time for each visit 
in a linear scale. Figure 14.2.1.1 entitled Mean (±SD) Ataluren Plasma Concentration by Visit over 
Time – Semi-Logarithmic Scale (PK Population) will plot the mean ataluren plasma concentrations 
over time for each visit using a semi-logarithmic scale. 
 
Plots of the plasma concentrations by subject will be presented in both linear and semi- logarithmic 
scale in Figure 14.2.2 entitled Ataluren Plasma Concentration by Subject and Visit over Time – 
Linear Scale (PK Population) and Figure 14.2.2.1 entitled Ataluren Plasma Concentration by 
Subject and Visit over Time – Semi-Logarithmic Scale (PK Population). 
 
11.2. 
Pharmacokinetic Analysis 
PK parameters (AUC0-t, AUC0-10, Cmax, Ctrough@6h, tmax, AR(AUC), AR(Cmax)) will be derived using 
actual sampling and dosing times. Concentrations below the limit of quantitation (LOQ) will be 
set to zero for the calculation of NCA parameters. 
 
Parameters Definition 
AUC0-10 
Area under the plasma concentration time curve from time zero to the time of 
last quantifiable concentration (Ctrough) prior to the midday dose 6 hours after the 
morning dose using the linear trapezoidal rule during the ascending portion of the 


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Parameters Definition 
curve. For the purpose of calculating AUC, when two consecutive BLQ plasma 
concentrations are encountered after tmax, these and all subsequent values will be 
excluded from the analysis. If missing values occur between two quantifiable 
concentrations, they will be excluded from the analysis. 
AUC0-10 
Area under the plasma concentration time curve from time zero up to 10 hours 
after the morning dosing using the linear trapezoidal rule during the ascending 
portion of the curve and the log-trapezoidal rule during the descending portion of 
the curve. For the purpose of calculating AUC, when two consecutive BLQ 
plasma concentrations are encountered after tmax, these and all subsequent values 
will be excluded from the analysis. If missing values occur between two 
quantifiable concentrations, they will be excluded from the analysis. 
Cmax 
Maximum observed plasma concentration prior to the midday dose 6 hours after 
the morning dose. If multiple maxima occurred at equal concentrations, the first 
temporal value will be taken. 
Ctrough@6h 
Concentration at the end of the first (morning) dosage interval (prior to the 
midday dose 6 hours after the morning dose) 
tmax 
Time of maximum observed plasma concentration prior to the midday dose 6 
hours after the morning dose. If multiple maxima occurred at equal 
concentrations, the first temporal value will be taken. 
 
The accumulation ratio on Day 28 will be calculated as follows: 
 
Parameter 
Description 
AR(AUC) 
AR(AUC) = (AUC0-t) on Day28 / (AUC0-t) on Day 1 
AR(Cmax) 
AR(Cmax) = (Cmax) on Day28 / (Cmax) on Day 1 
 
Note that Section 11.6 of the protocol also calls for the following PK 
parameters to be calculated: 
λz 
The terminal rate constant 
t1/2 
The terminal half-life, calculated as ln(2) / λz 
However, the dosing intervals, as planned by the protocol, will not allow for the calculation of 
these parameters. 


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PK parameters will be summarized with descriptive statistics on Day 1 and 28 (e.g., n, arithmetic 
mean, standard deviation, arithmetic CV %, median, minimum, and maximum, geometric mean, 
and geometric CV%). The analysis will be performed with a fully validated version of Phoenix 
WinNonlin V6.3. The individual pharmacokinetic parameters will be summarized using 
descriptive statistics and presented in the PK population in Table 14.2.5 entitled Summary of the 
Ataluren Pharmacokinetics by Visit (PK Population). Listing 16.2.6.5 entitled Ataluren 
Pharmacokinetic Results will contain the individual subject-level data sorted by subject number 
and date of the venipuncture sample used in the determination. 
 
 


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12. 
SAFETY 
The following sections describe how the safety endpoints will be summarized. 
 
12.1. 
Adverse Events 
12.1.1. 
Definition of an Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not the event is considered causally related to the use of the 
product. Such an event can result from use of the product as stipulated in the protocol or  labeling, 
as well as from accidental use or intentional misuse. Any worsening of a pre-existing condition or 
illness is considered an AE. Changes in vital signs are considered to be AEs only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, and/or if the 
investigator considers them to be an AE. An elective surgery/procedure scheduled to occur during 
a study will not be considered an AE if the surgery/procedure is being performed for a preexisting 
condition and the surgery/procedure has been pre-planned prior to study entry. However, if the 
preexisting condition deteriorates unexpectedly during the study (e.g. surgery performed earlier 
than planned), the deterioration of the condition for which the elective surgery/procedure is being 
done will be considered an AE. A treatment-emergent adverse event (TEAE) will be defined as 
any AE that first occurs after the first dose of study medication or any AE recorded prior to the 
first dose of study medication that worsens (increase in event severity) after the first dose of study 
medication. 
 
12.1.2. 
Definition of Serious Adverse Event 
An SAE is any AE occurring at any dose that meets one or more of the following definitions or 
outcomes: 
• death 
• life-threatening AE; the subject is at risk of death at the time of the 
event. It does not  refer to an event that hypothetically might cause 
death if it were more severe 
• in subject hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a medically important event that the Investigator or the sponsor judges to be serious 
12.1.3. 
Summaries of Adverse Events 
All summaries of adverse events will be based on treatment-emergent adverse events. Adverse 
events will be mapped to preferred terms and body systems using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary version 19.0. The number and percentage of 
subjects experiencing adverse events will be summarized by system organ class (SOC) and 
preferred term (PT). Summaries by maximum severity and relationship to study treatment will also 
be provided. Serious adverse events and adverse events leading to discontinuation from the study 
will be presented by SOC and PT. 


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12.1.3.1 
Overall Summary of Treatment-Emergent Adverse Events 
Table 14.3.1.1 entitled Overall Summary of Treatment-Emergent Adverse Events (Safety 
Population) provides an overview of the treatment-emergent adverse event (TEAE) data. This table 
will include the total number of TEAE, and the number and percentage of: 
• Subjects with any TEAE 
• Subjects with TEAE related to study drug 
• Subjects with any TEAE leading to discontinuation of the study drug 
• Subjects with any serious TEAE 
• Subjects with any TEAE by maximum CTCAE grade 
 
12.1.3.2 
Summary of adverse events by System Organ Class and Preferred Term 
Table 14.3.1.2.1 entitled Summary of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) contains the primary presentation of the AE data. This 
table is prepared without regard to causality or relationship to the study drug. Subjects will be 
counted only once at the SOC level and will be counted once for each applicable PT; multiple 
occurrences of the same PT for a subject will be counted only once. The number and percentage 
of subjects experiencing each SOC and PT will be displayed. SOCs, and PTs within SOC, will  be 
displayed alphabetically. The overall incidence of AEs will be summarized using counts and 
percentages by phase of study. 
 
Table 14.3.1.2.2 entitled Summary of Adverse Events that Occurred in the 4-Week Follow-up 
Phase by System Organ Class and Preferred Term (Safety Population) contains a summary of only 
those adverse events which occurred within 4 weeks after the last dose of study medication. The 
number and percentage of subjects experiencing adverse events for each body system and preferred 
term will be displayed by phase of study. 
 
12.1.3.3 
Assessment of Severity 
All adverse events, both serious and non-serious, will be assessed for severity or intensity. The 
investigator or designee will use the following classification to rate the severity of each AE. 
Section 9.5 of the protocol contains the description of each of these severity grades. 
• 
CTCAE Grade 1 Mild 
• 
CTCAE Grade 2 Moderate 
• 
CTCAE Grade 3 Severe 
• 
CTCAE Grade 4 Life-threatening 
• 
CTCAE Grade 5 Fatal 
 
Table 14.3.1.3 entitled Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Severity (Safety Population) provides the presentation of adverse events with 
respect to the severity or intensity of the event using the scale presented above. Subjects with 
multiple occurrences of the same system organ class or preferred term will be summarized at the 
maximum severity reported for that AE. The number and percentage of subjects experiencing 
adverse events for each body system and preferred term will be displayed by phase of study. 


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12.1.3.4 
Summary of Adverse Events by Descending Incidence of Preferred Term 
Table 14.3.1.4 entitled Summary of Treatment-Emergent Adverse Events by Descending Incidence 
of Preferred Term (Safety Population) displays the AE data by descending incidence of preferred 
term in the PK phase. Subjects will be counted only once for each applicable PT. The number and 
percentage of subjects experiencing each PT will be displayed by phase of study. 
 
12.1.3.5 
Assessment of Relationship to Study Medication 
The principal investigator must review each AE and make the determination of relationship to 
study drug using the following classification: 
• Probable 
• Possible 
• Unlikely 
• Unrelated 
 
Table 14.3.1.5 entitled Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship to the Study Medication (Safety Population) provides the 
presentation of adverse events by the relationship to the study drug. Subjects with multiple 
occurrences of the same system organ class or preferred term will be summarized using the event 
with the strongest relationship to study medication. The number and percentage of subjects 
experiencing each system organ class and preferred term will be displayed by phase of study. 
Probable and Possible will be group together into the Related category. Unlikely and Unrelated 
will be grouped together into the Not Related category. 
 
Listing 16.2.7.1 entitled Adverse Events provides supportive data for Tables 14.3.1.1 through 
14.3.1.5 and will be sorted by subject number and relative day of the onset of the event. 
 
12.1.3.6 
Summary of Adverse Events Leading to Discontinuation of the Study Drug 
Table 14.3.1.6 entitled Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of the Study Drug by System Organ Class and Preferred Term (Safety Population) 
displays all treatment-emergent adverse events resulting in an action taken of ‘Discontinued’. This 
table will have the same structure as that of Table 14.3.1.1, however, only those treatment-
emergent adverse events that led to discontinuation of study medication will be displayed. Subjects 
will be counted only once at the system organ class level and will be  counted once for each 
applicable preferred term; multiple occurrences of the same preferred term for a subject will be 
counted only once. The number and percentage of subjects experiencing each body system and 
preferred term leading to discontinuation of study drug will be displayed by phase of study. These 
summarized results will be supported by Listing 14.3.2.2 entitled Treatment-Emergent Adverse 
Events Leading to Discontinuation of the Study Drug; this listing will be sorted by subject number 
and relative day of the onset of the event. 
 
12.1.3.7 
Summary of Adverse Events Associated with Specific Toxicities 
This table constitutes a subset of the events reported in Table 14.3.1.1 specific to potential hepatic 
and renal toxicities. Subjects with hepatic or renal events will be counted only once at the system 
organ class level and will be counted once for each applicable preferred term; multiple occurrences 
of the same preferred term for a subject will be counted only once. The number and percentage of 


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subjects experiencing each system organ class and preferred term will be presented. All adverse 
events that meet this definition will be summarized in Table 14.3.1.7 entitled Summary of Treatment-
Emergent Adverse Events Associated with Specific Toxicities by System Organ Class and 
Preferred Term (Safety Population) by phase of study. These summarized results will be supported 
by Listing 14.3.2.3 entitled Treatment-Emergent Adverse Events Associated with Specific 
Toxicities; this listing will be sorted by subject number and relative day of the onset of the event. 
 
12.1.3.8 
Summary of Serious Adverse Events 
All serious adverse events will be summarized in Table 14.3.1.8 entitled Summary of Serious 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. This table 
constitutes a subset of the events reported in Table 14.3.1.1. Subjects with multiple serious adverse 
events will be counted only once at the system organ class level and will be counted once for each 
applicable preferred term; multiple occurrences of the same preferred term for a subject will be 
counted only once. The number and percentage of subjects experiencing each system organ class 
and preferred term will be displayed by phase of study. These summarized results will be supported 
by Listing 14.3.2.1 entitled Serious Treatment-Emergent Adverse Events; this listing will be sorted 
by subject number and relative day of the onset of the event. This listing constitutes a subset of the 
data provided in Listing 16.2.7.1 and will contain all serious adverse events. 
 
12.2. 
Clinical Laboratory Assessments 
Laboratory assessments performed during each study visit and will include hematology, 
biochemistry and urinalysis. The presentation of laboratory results focuses on the descriptive 
summaries at Baseline, each scheduled follow-up evaluation, and the change from baseline. All 
subjects in the Safety Population who have a baseline and at least one follow-up laboratory 
assessment will be included in the presentation of the laboratory data. In order for a subject to be 
included in the analysis for a particular laboratory test, the subject must have a baseline value and 
a follow-up laboratory assessment for the laboratory test. Unscheduled laboratory evaluations will 
be presented in the listings. The summarized results will be presented for the 4 week primary PK 
period of the study and for the extension study data. 
For each quantitative laboratory parameter, the baseline results will be summarized using 
descriptive statistics: n, mean, SD, median, and range. Only paired quantitative data will be 
summarized in the tables; all data will be presented in the listings. Results will be summarized and 
presented in Tables 14.3.6.1 entitled Summary of Hematology Results by Visit (Safety Population), 
14.3.6.2 entitled Summary of Biochemistry Results by Visit (Safety Population), and 
14.3.6.3 entitled Summary of Urinalysis Results by Visit (Safety Population). 
 
Laboratory shift tables will be prepared and presented based on the normal reference ranges and 
presented by parameter and the scheduled observation time. Shift tables will be prepared and 
presented for each quantitative hematology parameter in Table 14.3.6.4 entitled Hematology Shift 
Table Results by Visit (Safety Population). Shift tables will be prepared and presented for each 
quantitative biochemistry parameter in Table 14.3.6.5 entitled Biochemistry Shift Table Results by 
Visit (Safety Population). Shift tables will be prepared and presented for each 


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quantitative urinalysis parameter in Table 14.3.6.6 entitled Urinalysis Shift Table Results by Visit 
(Safety Population). 
 
The supportive data for Tables 14.3.6.1 through 14.3.6.6 are presented in Listing 16.2.8.4 entitled 
Hematology Results, Listing 16.2.8.5 entitled Biochemistry Results, and Listing 16.2.8.6 entitled 
Urinalysis Results. These listings will be sorted by subject number, parameter, and relative day. 
 
A summary of abnormalities in laboratory variables pre-defined for safety monitoring will be 
summarized in Table 14.3.6.7 entitled Summary of Abnormal Laboratory Results by Visit (Safety 
Population). The supportive data for this table can be found in Listing 14.3.7.1 entitled Abnormal 
Hematology Values, Listing 14.3.7.2 entitled Abnormal Biochemistry Values, and Listing 
14.3.7.3 entitled Abnormal Urinalysis Values. These listings will be sorted by 
subject number, parameter, and relative day. 
 


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12.3. 
Vital Signs 
All vital signs will be taken each visit and include the following parameters: 
• Pulse Rate (beats per minute) 
• Temperature (0C) 
• Respiratory Rate (breaths/min) 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
Vital signs will be summarized for each clinical assessment using the summary statistics of n, 
mean, SD, median, and range. These summaries will be presented for the subjects who have data 
at baseline and the specific follow-up visit. The summarized results will be presented for the 4 
week primary PK period of the study and for the extension study data. The organization of the 


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Final Version 
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results is commensurate with the organization of the laboratory data. All subjects in the Safety 
Population who have a baseline and at least one follow-up vital sign assessment will be included 
in the presentation of the data. In order for a subject to be included in the analysis for a  particular 
evaluation, the subject must have a baseline value and a follow-up assessment. Unscheduled 
laboratory evaluations will be presented in the listings. The summarized results  will be presented 
for the 4 week primary PK period of the study and for the extension study data. The results will be 
presented in Table 14.3.3 entitled Summary of Vital Sign Results by Visit (Safety Population). The 
supportive data listing is Listing 16.2.8.1 entitled Vital Signs. This listing will be sorted by subject 
number, parameter, and relative day. 
 
12.4. 
Electrocardiogram Results 
ECGs will be taken at Screening, Day 28, Day 364, and at the 4 week follow-up visit (Visit 7 - 
Study Day 392) and include the classification of the findings Normal, Abnormal, Clinically 
Significant, and Abnormal, Not Clinically Significant. The results at each time point will be 
summarized using counts and percentages. 
Shift tables for each digital ECG parameter will be prepared and presented by time point using the 
matched pairs for the qualitative interpretation of the ECG measurements. Results will be 
presented in Table 14.3.4entitled Electrocardiogram Shift Table Results by Visit (Safety 
Population). The number and percentage of subjects will be presented. 
The supportive data for the ECG tables are presented in Listing 16.2.8.2 entitled 
Electrocardiogram Results. This listing will be sorted by subject. 
 
12.5. 
Physical Examination Results 
A physical examination will be performed for all subjects at Screening, at the 4 week follow-up 
visit (Visit 7 / Study Day 365), and whenever it is clinically indicated. Any findings or absence of 
findings relative to each subject’s physical examination will be documented in the subject’s eCRF. 
All subjects in the Safety population will be included in Table 14.3.5 entitled Summary of Physical 
Examination Results (Safety Population). This table will summarize the subject population with 
respect to 12 specific physical characteristics: 
 
• Cardiovascular system 
• Chest and lungs 
• Thyroid 
• Abdomen 
• Nervous System 
• Skin and mucosae 
• Musculoskeletal 
• Eyes, Ears, Nose, Mouth, Throat 
• Spine 
• Lymph Nodes 
• Extremities 
• Genitourinary 


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For each characteristic, the number and percentage of subjects found to be abnormal will be 
presented. The supportive data for Table 14.3.5 will be presented in Listing 16.2.8.3 entitled 
Physical Examination Results. This listing will be sorted by subject number and relative day; 
unscheduled physical examinations will be presented in the listings. 
 
 


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13. 
REFERENCES 
1. SAS Institute Inc., SAS Version 9.3 software, Cary, NC. 
 


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Statistical Analysis Plan 
March 19, 2018 
Final Version 
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14. 
TABLES, LISTINGS, AND FIGURES 
1. 
Demographic Data Summary Tables 
 
● Table 14.1.1 
Subject Disposition (All Screened Subjects) 
● Table 14.1.2 
Summary of Protocol Deviations (All Screened Subjects) 
● Table 14.1.3 
Demographics and Baseline Characteristics (Safety Population) 
● Table 14.1.4 
Summary of Medical History (Safety Population) 
● Table 14.1.5.1 
Summary of Prior Medications (Safety Population) 
● Table 14.1.5.2 
Summary of Concomitant Medications (Safety Population) 
● Table 14.1.5.3 
Summary of Concomitant Non-drug Treatments (Safety Population) 
● Table 14.1.5.4 
Summary of Corticosteroids (Safety Population) 
● Table 14.1.5.5 
Summary of Nephrotoxic Medications (Safety Population) 
● Table 14.1.6 
Summary of Administration of Study Drug (Safety Population) 
 
 
2. 
Efficacy and Pharmacokinetic Data Summary Tables and Figures 
● Table 14.2.1 
Summary of Timed Function Tests by Visit (Evaluable Population) 
● Table 14.2.2.1 
Summary of the 16-item North Star Ambulatory Assessment Total Score by 
Visit (Evaluable Population) 
● Table 14.2.2.1.1  Summary of the North Star Ambulatory Assessment Total Score by Visit 
(Evaluable Population) 
● Table 14.2.2.1.2 Summary of the 8-item North Star Ambulatory Assessment Subscale by 
Visit (Evaluable Population) 
● Table 14.2.2.1.3 Summary of the 3-item North Star Ambulatory Assessment Subscale by 
Visit (Evaluable Population) 
● Table 14.2.2.2 
Summary of 16-item North Star Ambulatory Assessment Logit Score by 
Visit (Evaluable Population) 
● Table 14.2.3 
Summary of the Palatability Characteristics at Visit 3 (Evaluable 
Population) 
● Table 14.2.4 
Summary of the Plasma Concentrations of Ataluren by Visit (PK 
Population) 
● Table 14.2.5 
Summary of the Ataluren Pharmacokinetics by Visit (PK Population) 
● Figure 14.2.1 
Mean (±SD) Ataluren Plasma Concentration by Visit over Time – Linear 
Scale (PK Population) 
● Figure 14.2.1.1  
Mean (±SD) Ataluren Plasma Concentration by Visit over Time – Semi- 
Logarithmic Scale (PK Population) 
● Figure 14.2.2 
Ataluren Plasma Concentration by Subject and Visit over Time – Linear 
Scale (PK Population) 
● Figure 14.2.2.1  
Ataluren Plasma Concentration by Subject and Visit over Time – Semi- 
Logarithmic Scale (PK Population) 
 
 


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3. 
Safety Data Summary Tables 
● Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety 
Population) 
● Table 14.3.1.2.1  Summary of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
● Table 14.3.1.2.2  Summary of Adverse Events that Occurred in the 4-Week Follow-up Phase 
by System Organ Class and Preferred Term (Safety Population) 
● Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Severity (Safety Population) 
● Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Descending Incidence 
of Preferred Term (Safety Population) 
● Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to the Study Medication (Safety 
Population) 
● Table 14.3.1.6 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of the Study Drug by System Organ Class and Preferred 
Term (Safety Population) 
● Table 14.3.1.7 
Summary of Treatment-Emergent Adverse Events Associated with Specific 
Toxicities by System Organ Class and Preferred Term (Safety Population) 
● Table 14.3.1.8 
Summary of Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term (Safety Population) 
● Listing 14.3.2.1  Serious Treatment-Emergent Adverse Events 
● Listing 14.3.2.2  Treatment-Emergent Adverse Events Leading to Discontinuation of Study 
Drug 
● Listing 14.3.2.3  Treatment-Emergent Adverse Events Associated with Specific Toxicities 
 
● Table 14.3.3 
Summary of Vital Sign Results by Visit (Safety Population) 
● Table 14.3.4 
Electrocardiogram Shift Table Results by Visit (Safety Population) 
● Table 14.3.5 
Summary of Physical Examination Results by Visit (Safety Population) 
● Table 14.3.6.1 
Summary of Hematology Results by Visit (Safety Population) 
● Table 14.3.6.2 
Summary of Biochemistry Results by Visit (Safety Population) 
● Table 14.3.6.3 
Summary of Urinalysis Results by Visit (Safety Population) 
● Table 14.3.6.4 
Hematology Shift Table Results by Visit (Safety Population) 
● Table 14.3.6.5 
Biochemistry Shift Table Results by Visit (Safety Population) 
● Table 14.3.6.6 
Urinalysis Shift Table Results by Visit (Safety Population) 
● Table 14.3.6.7 
Summary of Abnormal Laboratory Results by Visit (Safety Population) 
● Listing 14.3.7.1  
Abnormal Hematology Values 
● Listing 14.3.7.2  
Abnormal Biochemistry Values 
● Listing 14.3.7.3  
Abnormal Urinalysis Values 
4. 
Patient Data Listings 
● Listing 16.2.1 
Subject Disposition 
● Listing 16.2.2 
Protocol Deviations 
● Listing 16.2.3.1 
Inclusion and Exclusion Criteria 
● Listing 16.2.3.2 
Eligibility Criteria 
● Listing 16.2.4.1 
Demographics and Subject Characteristics 


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● Listing 16.2.4.2 
Medical History 
● Listing 16.2.5.1 
Administration of Study Drug 
● Listing 16.2.5.2 
Study Drug Accountability 
● Listing 16.2.6.1 
Timed Function Tests 
● Listing 16.2.6.2 
North Star Ambulatory Assessment 
● Listing 16.2.6.3 
Palatability Characteristics 
● Listing 16.2.6.4 
Plasma Concentrations of Ataluren 
● Listing 16.2.6.5 
Ataluren Pharmacokinetic Results 
● Listing 16.2.7.1 
Adverse Events 
● Listing 16.2.8.1 
Vital Signs 
● Listing 16.2.8.2 
Electrocardiogram Results 
● Listing 16.2.8.3 
Physical Examination Results 
● Listing 16.2.8.4 
Hematology Results 
● Listing 16.2.8.5 
Biochemistry Results 
● Listing 16.2.8.6  
Urinalysis Results 
● Listing 16.2.8.7 
Prior and Concomitant Medications and Non-drug Treatments 
 


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15. 
MISSING AND PARTIAL ADVERSE EVENT DATES 
If the concomitant medication start date is completely missing then the medication will be 
considered concomitant unless it can be determined that the medication end date occurred prior 
to the start of the study. If the medication start date is partially missing and the partial date is not 
sufficient to determine if the medication was taken after the start of the study, then the 
medication will be considered concomitant for the study unless it can be ruled out by the partial 
date and/or medication end date. 
 
The start dates for adverse events are important for defining the treatment emergent algorithm, 
and the designation of unique AE occurrences. Completely missing or partially missing AE  
onset dates will be imputed as follows after due diligence to obtain accurate AE information has 
failed. 
 
If the AE start date is completely missing then the AE will be considered treatment emergent 
unless it can be determined that the AE end date occurred prior to the start of the study. If this 
is the case, the AE will not be considered treatment emergent. 
 
If the AE start date is partially missing and the partial date is not sufficient to determine if the 
event occurred after the start of the study, then the AE will be considered treatment emergent 
unless it can be determined that the AE end date occurred prior to the start of the study. 
 
Handling of Missing AE Start-dates (missing AE stop-dates are not filled) 
Rules for assuming a full date for adverse events with incomplete or missing start-dates are 
addressed below. In the unusual case that the month portion of an AE start-date is missing but 
the day portion is not missing, the day portion of the AE will be assumed to be missing. Likewise 
in the case where the year portion of an AE start-date is missing but the month and/or day portion 
is not missing, the month and/or day portion of the AE will be assumed to be missing. All 
missing portion(s) of the AE start-dates will be handled using the same rules. 
• In the event that the day portion (and only the day portion) of the AE onset date is 
missing: 
o If the AE started in the same month and year as the study procedure, the AE onset 
date will be assumed to be the date of the study procedure (i.e., Study Day 1); 
o Otherwise, the AE onset date will be assumed to be the 15th day of the given 
month and year, e.g., XX–DEC-2013  15-DEC-2013 where XX represents an 
unknown value. 
• In the event that the day and month portion (and only the day and month portion) of the 
AE onset date are missing: 
o If the AE started in the same year as the study procedure, the AE onset date will 
be assumed the study procedure (i.e., Study Day 1); 


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o Otherwise, the AE onset date will be treated as June 15th of the given year, e.g., 
XX-XXX-2013  15-JUN-2013. 
• In the event that the day, month, and year portion of the AE onset date are missing, the 
start-date of the AE will be assumed to be the study procedure (i.e., Study Day 1). 
Special Cases on Missing AE Start-dates 
• If the assumed AE onset date using the above rules for handling of missing AE dates 
o is earlier than the screening date, the assumed AE onset date will be reset and 
assumed to be the screening date. 
o is later than the reported AE stop-date, the assumed AE onset date will be reset 
and assumed to be the AE stop-date. 
o is later than the date of study completion and the AE stop-date missing, the AE 
will be assumed to be treatment-emergent. 
 


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16. 
SCHEDULE OF EVENTS 
 
Screening 
Ataluren Treatment 
4-Week 
Follow-Up 
Day (±2) 
-28 
1a 
28 
112 
196 
280 
364 
392 
Weeks 
-4 
0 
4 
16 
28 
40 
52/ETb 
56 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
Clinical and medication history 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
As clinically indicated 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for gene sequencing c 
X 
Biochemistryd 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
Palatability questionnaire 
X 
Blood for ataluren PKe 
X 
X 
Drug administration 
X -------------------------------------------------- X 
Adverse events 
X ---------------------------------------------------------------- X 
Concomitant medications 
X  
X 
Non-DMD-related adverse events 
X 
A 
All study and laboratory assessments on the first day of treatment must be done prior to ataluren 
dosing. 
b 
Patients who terminate the study early should complete all assessments required for Week 52/ET 
(Visit 7) and will be required to return 4 weeks from the final dose of study medication for the 4-Week 
Follow-up Visit. 
c 
Verification that a blood sample has been drawn for sequencing of the dystrophin gene. A patient 
who has written documentation of a nonsense mutation as the cause of DMD need not wait for 
confirmatory results to start study drug as long as the confirmatory blood sample for gene sequencing has 
been drawn. 
d 
Biochemistry laboratory assessments will include hepatic transaminases and additional parameters as 
specified in Section 8.2.7.2. 
e 
On Days 1 and 28, blood samples for PK assessment will be drawn pre-dose and 1 (±15 min), 2 
(±15 min), 4 (±30 min), 
6 (±30 min), 8 (±30 min), and 10 (±30 min) hours post-dose. 
Abbreviations: ECG = electrocardiogram, ET = early termination, PK = pharmacokinetics