Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Cystic Fibrosis
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: PTC Therapeutics

CLINICAL PROTOCOL 
A PHASE 3 EXTENSION STUDY OF ATALUREN (PTC124) IN 
PATIENTS WITH NONSENSE MUTATION CYSTIC FIBROSIS 
Protocol Number PTC124-GD-021e-CF 
27 March 2015 
Version 1.0  
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information belonging to 
PTC Therapeutics, Inc.  Except as may 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. 
NCT02456103

Protocol Number PTC124-GD-021e-CF 
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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC124-GD 
Therapeutic Area 
Genetic Disorders – Cystic Fibrosis 
PTC Therapeutics Substance Identifier 
Ataluren (PTC124) 
IND Number 
48,648 
EudraCT Number 
2014-005355-83 
Included in clinical trials.gov Database 
Pending 
Protocol Number 
 
PTC124-GD-021e-CF 
Protocol Version 
Version 1.0  
Protocol Version Date 
27 March 2015 
Protocol Phase 
Phase 3 
Protocol Title 
A Phase 3 Extension Study of Ataluren (PTC124) in 
Patients with Nonsense Mutation Cystic Fibrosis 
PTC Medical Monitor 
   
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
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 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 

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

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TABLE OF CONTENTS  
1. 
OVERVIEW ..................................................................................................................................................... 11 
2. 
INTRODUCTION ............................................................................................................................................ 13 
2.1. 
DISEASE INDICATION................................................................................................................................. 13 
2.2. 
ATALUREN (PTC124) ................................................................................................................................ 14 
2.2.1. 
Therapeutic Concept ............................................................................................................................ 14 
2.2.2. 
Chemical Description .......................................................................................................................... 15 
2.2.3. 
Nonclinical Studies .............................................................................................................................. 15 
2.2.4. 
Clinical Studies .................................................................................................................................... 15 
3. 
STUDY OBJECTIVE AND ENDPOINTS .................................................................................................... 16 
3.1. 
PRIMARY OBJECTIVE ................................................................................................................................. 16 
3.2. 
SECONDARY OBJECTIVES .......................................................................................................................... 16 
3.3. 
CLINICAL ENDPOINTS ................................................................................................................................ 16 
4. 
PATIENT SELECTION CRITERIA ............................................................................................................. 17 
4.1. 
OVERVIEW ................................................................................................................................................ 17 
4.2. 
INCLUSION CRITERIA ................................................................................................................................. 17 
4.3. 
EXCLUSION CRITERIA ............................................................................................................................... 17 
5. 
ENROLLMENT PROCEDURES .................................................................................................................. 18 
5.1. 
SOURCE AND NUMBER OF PATIENTS ......................................................................................................... 18 
5.2. 
SCREENING AND STUDY DRUG ALLOCATION ............................................................................................ 18 
6. 
STUDY DRUG ADMINISTRATION ............................................................................................................ 19 
6.1. 
INVESTIGATIONAL PRODUCT ..................................................................................................................... 19 
6.1.1. 
Ataluren (PTC124) .............................................................................................................................. 19 
6.1.2. 
Drug Kits ............................................................................................................................................. 19 
6.1.3. 
Study Drug Packaging and Labeling ................................................................................................... 19 
6.1.4. 
Study Drug Dispensing ........................................................................................................................ 19 
6.1.5. 
Return of Study Drug ........................................................................................................................... 19 
6.1.6. 
Storage and Stability ............................................................................................................................ 20 
6.1.7. 
Study Drug Accountability ................................................................................................................... 20 
6.1.8. 
Overdose Precautions .......................................................................................................................... 20 
6.1.9. 
Inadvertent Exposure and Spill Precautions ....................................................................................... 20 
6.2. 
STUDY DRUG TREATMENT ........................................................................................................................ 20 
6.2.1. 
Duration of Treatment ......................................................................................................................... 20 
6.2.2. 
Schedule of Administration .................................................................................................................. 21 
6.2.3. 
Instructions for Delays in Dosing ........................................................................................................ 21 
6.2.4. 
Study Drug Preparation and Storage .................................................................................................. 21 
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 
6.3.3. 
Instructions for Resuming Study Drug Administration after an Interruption for Safety Concerns ...... 25 
6.3.4. 
Instructions for Discontinuation of Study Drug Administration for Safety Concerns ......................... 25 
7. 
CONCOMITANT AND SUPPORTIVE THERAPY .................................................................................... 26 
7.1. 
CONCOMITANT MEDICATIONS................................................................................................................... 26 
7.1.1. 
Therapy/Prophylaxis for CF-Related Conditions ................................................................................ 26 
7.1.2. 
Therapy for CF Pulmonary Exacerbations or Other CF Complications ............................................. 26 
7.1.3. 
Other Concomitant Medications .......................................................................................................... 27 
7.1.4. 
Drugs Metabolized by Cytochrome P450 Enzymes ............................................................................. 28 
7.1.5. 
Other Potential Drug Interactions ....................................................................................................... 28 

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7.2. 
NON-DRUG THERAPY ................................................................................................................................ 29 
7.2.1. 
Physical and Respiratory Therapy ....................................................................................................... 29 
7.2.2. 
Dietary Restrictions ............................................................................................................................. 29 
7.2.3. 
Hydration ............................................................................................................................................. 29 
8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS ......................................................................... 30 
8.1. 
SCHEDULE OF EVENTS ............................................................................................................................... 30 
8.2. 
EXPLANATION OF STUDY PROCEDURES .................................................................................................... 30 
8.2.1. 
Transition from the Phase 3 Study, Ataluren Treatment, and Follow-up Periods ............................... 30 
8.2.2. 
Screening/Baseline Visit (Visit 1) ........................................................................................................ 30 
8.2.3. 
Treatment Visits during Study (Visits 2 through 9) .............................................................................. 31 
8.2.4. 
End of Treatment ................................................................................................................................. 31 
8.2.5. 
Post-Treatment Visits ........................................................................................................................... 31 
8.2.6. 
Informed Consent ................................................................................................................................. 31 
8.2.7. 
Vital Signs ............................................................................................................................................ 31 
8.2.8. 
Height, Weight, and Physical Examination ......................................................................................... 32 
8.2.9. 
Pregnancy ............................................................................................................................................ 32 
8.2.10. Hematology Laboratory Assessment .................................................................................................... 32 
8.2.11. Serum Biochemistry Laboratory Assessment ....................................................................................... 32 
8.2.12. Urinalysis ............................................................................................................................................. 32 
8.2.13. Renal Ultrasound ................................................................................................................................. 33 
8.2.14. 12-Lead ECG ........................................................................................................................................ 33 
8.2.15. Study Drug Administration ................................................................................................................... 33 
8.2.16. Study Drug Compliance ....................................................................................................................... 33 
8.2.17. Adverse Events ..................................................................................................................................... 34 
8.2.18. Concomitant Medications ..................................................................................................................... 34 
8.2.19. Presence of Pseudomonas aeruginosa in Sputum ................................................................................ 34 
8.2.20. Spirometry ............................................................................................................................................ 34 
8.2.21. Pulmonary Exacerbation Rate ............................................................................................................. 35 
8.2.22. CFQ-R .................................................................................................................................................. 35 
8.2.23. Blood for Analysis of Pharmacokinetics .............................................................................................. 35 
8.3. 
BLOOD COLLECTION SUMMARY ................................................................................................................ 35 
9. 
ADVERSE EVENT ASSESSMENTS ............................................................................................................ 36 
9.1. 
ADVERSE EVENT DEFINITIONS .................................................................................................................. 36 
9.1.1. 
Adverse Events ..................................................................................................................................... 36 
9.1.2. 
Serious Adverse Events (SAEs) ............................................................................................................ 37 
9.1.3. 
Unexpected Adverse Events .................................................................................................................. 38 
9.2. 
ELICITING ADVERSE EVENT INFORMATION ............................................................................................... 39 
9.3. 
ADVERSE EVENT RECORDING ................................................................................................................... 39 
9.4. 
DESCRIBING ADVERSE EVENT RELATIONSHIP TO STUDY DRUG ............................................................... 39 
9.5. 
GRADING OF SEVERITY OF ADVERSE EVENTS ........................................................................................... 40 
9.6. 
PREGNANCY .............................................................................................................................................. 40 
9.7. 
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS ..................................................................................... 41 
9.8. 
ADVERSE EVENT REPORTING PERIOD ....................................................................................................... 41 
9.9. 
INVESTIGATOR SITE ADVERSE EVENT REPORTING REQUIREMENTS .......................................................... 41 
9.10. 
PTC THERAPEUTICS ADVERSE EVENT REPORTING REQUIREMENTS ......................................................... 43 
10. 
WITHDRAWAL OF PATIENTS ................................................................................................................... 44 
11. 
STATISTICS AND DATA MANAGEMENT ............................................................................................... 45 
11.1. 
SAMPLE SIZE CALCULATION ..................................................................................................................... 45 
11.2. 
STUDY POPULATION DEFINITION .............................................................................................................. 45 
11.2.1. As-Treated Population ......................................................................................................................... 45 
11.2.2. Evaluable Populations ......................................................................................................................... 45 
11.3. 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................................ 45 

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11.4. 
SPECIFIC STATISTICAL ANALYSES ............................................................................................................. 45 
11.4.1. 
Study Conduct and Subject Disposition .............................................................................................. 45 
11.4.2. 
Demographics and Baseline Characteristics...................................................................................... 45 
11.4.3. 
Study Treatment Administration ......................................................................................................... 46 
11.4.4. 
Use of Concomitant Medication and Supportive Therapy .................................................................. 46 
11.4.5. 
Primary Variables .............................................................................................................................. 46 
11.4.5.1 Adverse Event ..................................................................................................................................... 46 
11.4.5.2  Laboratory Data ................................................................................................................................. 46 
11.4.6. 
Secondary Variables ........................................................................................................................... 46 
11.4.6.1 Spirometry .......................................................................................................................................... 46 
11.4.6.2 Pulmonary Exacerbation .................................................................................................................... 47 
11.4.7. 
Tertiary Variables............................................................................................................................... 47 
11.4.7.1  Vital Signs, Renal Ultrasound, 12-Lead ECG, and Other Safety Parameters .................................... 47 
11.4.7.2. Ataluren Plasma Concentrations ........................................................................................................ 47 
11.4.7.3. CFQ-R ................................................................................................................................................ 47 
11.4.7.4 Respiratory Events .............................................................................................................................. 47 
12. 
STUDY COMMITTEES ................................................................................................................................. 48 
13. 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR ......................................................... 49 
13.1. 
COMPLIANCE WITH ETHICAL AND REGULATORY GUIDELINES .................................................................. 49 
13.2. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ....................................................... 49 
13.3. 
INFORMED CONSENT/ASSENT ................................................................................................................... 49 
13.4. 
CASE REPORT FORMS ................................................................................................................................ 50 
13.5. 
STUDY RECORDS ....................................................................................................................................... 50 
13.6. 
CONFIDENTIALITY ..................................................................................................................................... 51 
13.7. 
RETENTION OF RECORDS ........................................................................................................................... 51 
13.8. 
MONITORING AND AUDITING .................................................................................................................... 52 
13.9. 
TERMINATION OF THE STUDY .................................................................................................................... 52 
13.10. 
PUBLIC NOTIFICATION OF STUDY CONDUCT ............................................................................................ 53 
13.11. 
DISSEMINATION OF RESULTS .................................................................................................................... 53 
13.12. 
COMMUNICATION WITH REGULATORY AUTHORITIES ............................................................................... 53 
14. 
RATIONALE FOR STUDY DESIGN FEATURES ..................................................................................... 54 
14.1 
PATIENT SELECTION .................................................................................................................................. 54 
14.1.1 
Overview ............................................................................................................................................. 54 
14.1.2 
Reproductive Considerations .............................................................................................................. 54 
14.1.3 
Concomitant Therapies ....................................................................................................................... 54 
14.1.4 
Safety Profiling ................................................................................................................................... 54 
14.1.5 
Study Drug Compliance ...................................................................................................................... 54 
14.1.6 
Trough Ataluren Plasma Concentrations ........................................................................................... 54 
14.1.7 
Timing of Assessments ........................................................................................................................ 55 
14.2 
TREATMENT AND SAFETY MONITORING PLAN .......................................................................................... 55 
14.2.1  Schedule and Dose Selection .............................................................................................................. 55 
14.2.2  Duration of Therapy ........................................................................................................................... 55 
14.2.3  Safety Monitoring Overview ............................................................................................................... 55 
14.2.4  Renal Monitoring Plan ....................................................................................................................... 56 
14.2.5  Hepatic Monitoring Plan .................................................................................................................... 58 
14.2.6  Blood Pressure Assessment ................................................................................................................ 58 
14.2.7  Other Nonclinical Findings ................................................................................................................ 58 
14.2.8  Other Abnormalities ........................................................................................................................... 59 
14.2.9  Actions to be Taken in Response to Safety Signals ............................................................................. 59 
14.2.10 Concomitant Therapies ....................................................................................................................... 59 
14.3 
STUDY COMMITTEES ................................................................................................................................. 60 
14.4 
EFFICACY MEASUREMENTS ....................................................................................................................... 61 
14.4.1 
Spirometry .......................................................................................................................................... 61 

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14.4.2 
Pulmonary Exacerbations .................................................................................................................. 61 
14.4.3 
HRQL and the CFQ-R ........................................................................................................................ 61 
14.4.4 
Weight/Body Mass Index .................................................................................................................... 62 
14.4.5 
Hepatobiliary Markers ....................................................................................................................... 62 
14.4.6 
New Pseudomonas Aeruginosa Lung Infection .................................................................................. 62 
15 
BENEFITS AND RISKS ................................................................................................................................. 63 
15.1 
BENEFITS AND RISKS: NONCLINICAL ........................................................................................................ 63 
15.2 
BENEFITS AND RISKS: CLINICAL EFFICACY ............................................................................................... 64 
15.3 
BENEFITS AND RISKS: CLINICAL SAFETY .................................................................................................. 65 
15.4 
BENEFIT/RISK CONCLUSIONS .................................................................................................................... 65 
16 
BIBLIOGRAPHY ............................................................................................................................................ 66 
 LIST OF TABLES 
TABLE 1.  SUGGESTED DAILY DOSING SCHEDULE........................................................................................................ 21 
TABLE 2.  SAFETY MONITORING PARAMETERS AND ACTIONS TO BE TAKEN............................................................... 23 
TABLE 3. SCHEDULE OF EVENTS .................................................................................................................................. 30 
TABLE 4.  RELATIONSHIP OF STUDY DRUG TO ADVERSE EVENT .................................................................................. 40 
TABLE 5.  GRADING OF ADVERSE EVENT SEVERITY ..................................................................................................... 40 
TABLE 6.  INVESTIGATOR SITE REPORTING REQUIREMENTS FOR ADVERSE EVENTS .................................................... 42 
  
 

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ABBREVIATIONS 
Abbreviation 
Definition 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
ß-HCG 
Beta human chorionic gonadotropin 
BMI 
Body mass index 
BCRP 
Breast Cancer Resistant Protein 
BUN 
Blood urea nitrogen 
cAMP 
Cyclic adenosine monophosphate 
CD-ROM 
Compact disc read-only memory 
CF 
Cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire-Revised 
CFR 
Code of Federal Regulations 
CFFT-TDN /  
CF-TDN 
Cystic Fibrosis Foundation Therapeutics - Therapeutic Development Network 
CFTR 
Cystic fibrosis transmembrane conductance regulator 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence interval 
CK 
Creatine kinase 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DIOS 
Distal intestinal obstruction syndrome 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act of 1997 
FEF25-75 
Forced expiratory flow between 25% and 75% of expiration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
HDL 
High-density lipoprotein 
HRQL 
Health-related quality of life 
ICH 
International Conference on Harmonization 
IL-8 
Interleukin 8 
IND 
Investigational New Drug (Application) 
ICJME 
International Committee of Medical Journal Editors 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IVR/IWR 
Interactive Voice Response/Interactive Web Response 
LABA 
Long-acting beta agonist 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LS 
Least square 
MCID 
Minimal clinically important difference 

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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention-to-treat 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
nmCF 
Nonsense mutation cystic fibrosis 
nmDBMD 
Nonsense mutation Duchenne/Becker muscular dystrophy 
NOAEL 
No-observed-adverse-effect level 
PK 
Pharmacokinetic(s) 
PTCAD 
PTC Therapeutics Awareness Date 
PTC124 
Ataluren 
SABA 
Short-acting beta agonist 
TID 
3 times per day 
TIS 
Tobramycin inhalation solution 
TEPD 
Transepithelial Potential Difference 
ULN 
Upper limit of Normal 
 

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1. 
OVERVIEW 
Cystic fibrosis (CF) is a disabling and life-threatening genetic disorder resulting from mutations 
in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an apical 
cell-surface epithelial chloride channel that promotes chloride efflux.  CFTR dysfunction leads to 
epithelial mucous dehydration and viscous secretions, often causing chronic neutrophilic 
inflammation, occlusion of respiratory airways, and persistent pulmonary infections.  
Obstruction of pancreatic ducts, biliary tree, and vas deferens can occur.  Patients typically 
develop progressive respiratory obstruction, coughing, dyspnea, and episodic infectious 
pulmonary exacerbations.  They may have pancreatic insufficiency, diminished body weight, 
chronic hepatobiliary inflammation, and male infertility.  Respiratory failure is the most common 
cause of death.  Available medical therapies for treatment of the lung manifestations include 
inhaled aztreonam lysine, colistin, tobramycin (TOBI), dornase alfa (Pulmozyme), and 
hypertonic saline; and oral azithromycin and ibuprofen.  Kalydeco, a recently approved 
potentiator for the G551D Class III mutation, does not address the underlying cause for patients 
with CF due to nonsense mutation (nmCF) (US Food and Drug Administration, 2013), one of the 
most severe forms of CF [Shoshani 1992, Cystic Fibrosis Genotype-Phenotype Consortium 
1993, Kerem 1996, de Gracia 2005, McKone 2006]. 
In ~10% of patients with CF, the causative defect in the CFTR gene is a nonsense mutation that 
truncates CFTR protein production by introducing a premature stop codon into the CFTR 
messenger ribonucleic acid (mRNA).  PTC Therapeutics, Inc., a biopharmaceutical company 
located in South Plainfield, NJ, USA has discovered and developed ataluren (PTC124®) as a 
novel, orally bioavailable, small-molecule drug that promotes ribosomal readthrough of mRNA 
containing a premature stop codon.  Through this mechanism of action, ataluren has the potential 
to overcome the genetic defect in patients for whom a nonsense mutation causes CF. 
Pharmacologic proof-of-concept has been demonstrated in animal models and Phase 2 clinical 
trials.  A Phase 3, randomized, double-blind, placebo controlled clinical trial (Study 009) of 
patients ≥6 years of age with nmCF randomized to receive ataluren 10 mg/kg in the morning, 
10 mg/kg mid-day and 20-mg/kg in the evening; or placebo for 48 weeks showed positive trends 
favoring ataluren vs placebo for both the primary endpoint, relative change in %-predicted forced 
expiratory volume in 1 second (FEV1) at Week 48, and the secondary endpoint, pulmonary 
exacerbation rate over 48 weeks [Kerem 2014]. A subgroup effect in FEV1 and pulmonary 
exacerbation rate showing larger differences favoring ataluren was observed in patients who 
were not receiving chronic inhaled antibiotics, which was driven by chronic inhaled tobramycin. 
This same study showed that ataluren was well tolerated; safety profiles were generally similar 
for ataluren and placebo, other than cases of reversible Grade 3-4 creatinine elevations, which 
were associated with the combination of potentially nephrotoxic antibiotics with ataluren. 
These encouraging data led to the conduct of a confirmatory Phase 3, international, multicenter, 
randomized, double-blind, placebo-controlled, efficacy and safety study (Study 
PTC124-GD-021-CF).  This ongoing Phase 3 study includes a treatment period of 48 weeks and 
an estimated recruitment period of 14 months at 93 investigational sites worldwide.  The first 
patient in study PTC124-021-CF initiated study drug treatment on 15 August 2014.   
All patients who successfully complete the Phase 3 double-blind, placebo-controlled study 
(PTC124-GD-021-CF) will be eligible for this Phase 3 open-label, extension study 
(PTC124-GD-021e-CF). 

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The primary objective of this Phase 3 extension study will be to obtain long-term safety data to 
augment the overall safety database.  The secondary objectives will be to augment the efficacy 
data collected in the double-blind study (PTC124-GD-021-CF).   
Screening and baseline procedures are structured to avoid a gap in treatment between the 
double-blind study (PTC124-GD-021-CF) and this extension study.  When possible, 
Screening/Baseline (Visit 1) for this extension study should occur on the same day as the 
End-of-Study visit for the double-blind study (PTC124-GD-021-CF).  During the treatment 
period, study assessments will be performed at clinic visits at Week 12 and thereafter every 12 
weeks until the end of the study. 
Planned interim safety analyses will be conducted by an independent data monitoring committee 
(DMC). The first safety review will occur when ~100 patients have completed >=36 weeks of 
treatment. The second safety review will occur when ~100 patients have completed >=72 weeks 
of treatment. 

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2. 
INTRODUCTION 
2.1. Disease Indication 
CF is one of the most common serious inherited diseases in the United States and Europe, with a 
prevalence estimated at ~30,000 patients in the United States and ~37,000 patients in Europe 
[Farrell 2008].  CF is an autosomal recessive disorder caused by defects in the gene for the 
CFTR, a protein that acts as a chloride channel and is regulated by cyclic adenosine 
monophosphate (cAMP) [Cheng 1991].  Loss of functional CFTR at membranes leads to 
abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces 
[O’Sullivan 2009].  The disruption of chloride transport, together with associated water transport 
abnormalities, results in viscous secretions in the respiratory tract, pancreas, gastrointestinal 
tract, sweat glands, and other exocrine tissues.  Increased viscosity of these secretions makes 
them difficult to clear and patients develop exocrine gland dysfunction of multiple organ systems 
in childhood, resulting in chronic respiratory disease, pancreatic enzyme insufficiency, hepatic 
and biliary abnormalities, intestinal obstruction, and reduced fertility due to agenesis of the vas 
deferens in males and delayed menarche in females. 
In the face of symptoms and/or a family history, the diagnosis of CF is based on evaluation of 
chloride secretion in sweat or on assessment of nasal transepithelial potential difference (TEPD) 
[Stern 1997, LeGrys 2000].  Total sequencing of the CFTR gene to confirm the presence of 
mutations is now available commercially [Ambry Genetics 2001, Danziger 2004]. 
Pulmonary involvement occurs in ~90% of patients, is usually among the most serious 
manifestations of the disease, and most commonly determines outcome [Ramsey 1996].  As 
early as 4 weeks of age, patients with CF begin to develop mucus plugging, bronchiectasis, 
neutrophilic invasion, and inflammation of airways [Khan 1995, Rosenfeld 2001].  High levels 
of the neutrophil chemoattractant interleukin-8 (IL-8) in the airways and sputum contribute to 
persistent neutrophilic inflammation and airway obstruction [Sagel 2007].  Over time, most 
patients develop chronic bacterial colonization/infection of the airways (characteristically with 
Pseudomonas aeruginosa, but also with Burkholderia cepacia, Haemophilus influenzae, 
Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and atypical mycobacterial 
species) resulting in infections and pulmonary dysfunction.  Typically, CF pulmonary 
involvement manifests as an obstructive defect with air trapping and hyperinflation 
[Ramsey 1996, Tiddens 2002].  As the disease progresses, FEV1 is reduced; it is estimated that 
FEV1 declines by 1.9% per year in children and adolescents [FDA 1997].  Ultimately, chronic 
mucopurulent bronchiectasis leads to structural abnormalities and fibrosis, and the total lung 
capacity and forced vital capacity (FVC) decline.  Progressive lung dysfunction leads to 
respiratory failure and death.  The median age of survival is projected to be ~35 years of age if 
all genotypes are considered [Cystic Fibrosis Foundation 2003, Bellis 2006], but survival is 
generally shorter in patients with severe phenotypes [McKone 2006]. 
The primary goals of CF treatment are supportive, and include slowing the decline in lung 
function by clearing airways of mucus and by controlling respiratory infections, and maintaining 
nutritional status by providing pancreatic enzyme replacement therapy [Welsh 2001].  The first 
medical therapy approved by regulatory authorities for treatment/prophylaxis of the lung 
manifestations was dornase alfa (Pulmozyme®), a mucolytic enzyme that hydrolyzes neutrophil 
deoxyribonucleic acid (DNA) [Fuchs 1994].  Since that time, regulatory approval has been 
achieved for inhaled tobramycin (TOBI®) [Ramsey 1993, Ramsey 1999] and inhaled aztreonam 

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[Retsch-Bogart 2007, McCoy 2008, Oermann 2008, Retsch-Bogart 2008], antibiotics that 
suppress Pseudomonas colonization.  Inhaled colistin and oral cephalosporins or 
fluoroquinolones are sometimes employed to reduce respiratory complications related to 
bacterial infection [Bell 2007].  Intravenous antibiotics are often administered in response to CF 
pulmonary exacerbations [Smyth 2008].  Clinical trial data from randomized studies also 
indicate that oral ibuprofen, oral azithromycin, and inhaled hypertonic saline have salutary 
effects on lung dysfunction and pulmonary complications [Konstan 1995, Saiman 2003, Elkins 
2006].  
Despite the advances in care offered by these types of drugs, and the recent approval of ivacaftor 
(Kalydeco®), a drug that targets the G551D gating mutation, there are no approved systemic 
therapies that address the underlying cause of CF caused by other mutations, such as premature 
stop codons. New agents are therefore needed that can overcome the fundamental genetic defect 
by restoring CFTR production and function.   
2.2. Ataluren (PTC124) 
2.2.1. Therapeutic Concept 
Among the several types of disease-causing mutations, a nonsense mutation is an alteration in 
one of the nucleotides of 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 CFTR tells the ribosomes to halt production of the 
protein before the full-length protein is completed.  The resulting truncated CFTR is too short to 
serve its necessary function and causes disease.  It is estimated that nonsense mutations account 
for ~10% of the individual cases of CF [Bobadilla 2002, Du 2002, Cystic Fibrosis Genetic 
Analysis Consortium 2004, Bellis 2006], resulting in a prevalence of nonsense mutation-
mediated disease of ~2800 patients in the United States and ~3600 patients in Europe (total 
~6400 patients).  However, in certain populations, the incidence of this type of mutation is much 
higher.  For example, in Ashkenazi Jews, nonsense mutations (eg, R553X, G542X, or W1282X) 
account for ~65% of all abnormal CFTR alleles [Kerem 1995, Kerem 1997].  In CF, the presence 
of a nonsense mutation in the CFTR gene leads to little or no production of the CFTR chloride 
channel and has been associated with a particularly severe phenotype [Shoshani 1992, Cystic 
Fibrosis Genotype-Phenotype Consortium 1993, Kerem 1996, de Gracia 2005, McKone 2006].   
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 clinical 
studies in nmCF, treatment with high concentrations of gentamicin has restored production of 
functional CFTR [Clancy 2001, Du 2002, Wilschanski 2003].  Similarly, preclinical and clinical 
studies in nonsense mutation Duchenne muscular dystrophy (nmDMD) have demonstrated 
gentamicin-induced restoration of dystrophin, the structural protein that is defective in that 
disease [Barton-Davis 1999, Politano 2003].  Current data suggest that the geometry of mRNA 
and associated initiation-termination proteins is critically different at a premature stop codon 
than at a normal stop codon.  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 

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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 CF 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 read-through 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 read-through 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, clinical development of ataluren may offer a 
definitive therapy by overcoming the basic cause for CF and other disabling and life-threatening 
genetic disorders. 
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.  The drug has been 
manufactured and formulated under current Good Manufacturing Practices (cGMP) and is 
provided as a vanilla-flavored, white to off-white powder for oral suspension.   
2.2.3. Nonclinical Studies 
Refer to the Ataluren Investigator Brochure for a detailed presentation of efficacy pharmacology, 
safety pharmacology, toxicology, and PK data from ataluren nonclinical studies.   
2.2.4. Clinical Studies 
In total, ~700 patients, including healthy volunteers as well as 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 Investigator Brochure 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 
To evaluate the long-term safety of 10-, 10-, 20-mg/kg ataluren in patients with nonsense 
mutation cystic fibrosis (nmCF), who previously participated in pivotal study PTC124-GD-021-
CF, as determined by adverse events and laboratory abnormalities.  
3.2. Secondary Objectives 
The secondary objectives are: 
• To evaluate the long-term effect of ataluren on pulmonary function 
• To evaluate the long-term effect of ataluren on pulmonary exacerbation 
• To determine the long-term effect of ataluren on medical interventions 
• To evaluate the long-term effect of ataluren on HRQL 
• To evaluate the long-term effect of ataluren on general well-being 
• To assess long-term ataluren plasma exposure 
3.3. Clinical Endpoints 
Primary 
• Safety profile characterized by type, frequency, severity, timing, and relationship to ataluren 
of any adverse events or laboratory abnormalities 
Secondary 
• Changes in FEV1, FVC, and FEF25-75 as assessed by spirometry 
• Rate, incidence, and duration of pulmonary exacerbations (modified Fuchs criteria) 
• Incidences, rates, and durations of interventions (eg, antibiotic use and hospitalization) and 
disruptions to daily living (eg, missed school or work) resulting from pulmonary symptoms 
• Changes in CFQ-R domains 
• Changes in body weight and BMI 
• New Pseudomonas aeruginosa lung infection 
• Pre-dose ataluren plasma concentrations prior to morning ataluren administration at each 
clinic visit as assessed by a validated bioanalytical method  
• Change from baseline in other safety parameters (eg, vital signs) 

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4. 
PATIENT 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) or a regulatory authority audit.  Any questions regarding 
a patient’s eligibility should be discussed with the PTC Therapeutics medical monitor prior to 
enrollment. 
4.2. Inclusion Criteria 
Patients must meet all of the following conditions to be eligible for enrollment into the study: 
1. Completion of study treatment (placebo or active) in the previous Phase 3, double-blind 
study protocol (Protocol PTC124-GD-021-CF). 
2. Evidence of signed and dated informed consent/assent document(s) indicating that the patient 
(and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial.  
Note: If the study candidate is considered a child under local regulation, a parent or legal 
guardian must provide written consent prior to initiation of study screening procedures 
and the study candidate may be required to provide written assent.  The rules of the 
responsible Institutional Review Board/Independent Ethic 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.   
3. In patients who are sexually active, willingness to abstain from sexual intercourse or employ 
a barrier or medical method of contraception during the study drug administration and 
4-week follow-up period. 
4. Willingness and ability to comply with scheduled visits, ataluren administration plan, study 
procedures, laboratory tests, and study restrictions.   
4.3. Exclusion Criteria 
Prior to treatment with study drug, it will be confirmed that the patient meets none of the 
following conditions: 
1. Known hypersensitivity to any of the ingredients or excipients of the study drug (Litesse® 
UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127 [poloxamer 
407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab-O-Sil® M5P 
[colloidal silica], magnesium stearate). 
2. Ongoing participation in any other therapeutic clinical trial.  
3. Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition, behavioral 
disorder, alcoholism, drug abuse), medical history, physical findings, ECG findings, or 
laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of 
the patient, makes it unlikely that the course of treatment or follow-up would be completed, 
or could impair the assessment of study results. 

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5. 
ENROLLMENT PROCEDURES 
5.1. Source and Number of Patients 
Approximately 200 patients for this Phase 3 extension study are derived only from those who 
completed blinded study drug in the Phase 3 study (PTC124-GD-021-CF). 
5.2. Screening and Study Drug Allocation 
The investigator must inform each prospective patient of the nature of the study, explain the 
potential risks, and obtain written informed consent/assent from the patient and/or the 
parent/legal guardian prior to performing any study related screening procedures.   
The patient number used in the prior Phase 3 study (Protocol Number PTC124-GD-021-CF) 
shall be retained for use in this study.  This patient number must be used for patient identification 
on all study-related documents (case report forms [CRFs], clinic notes, laboratory samples, etc).  
The user will need to supply the Interactive Voice Response/Interactive Web Response 
(IVR/IWR) system with the information required by the system (eg, site number, patient 
number). 

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6. 
STUDY DRUG ADMINISTRATION 
6.1. Investigational Product 
6.1.1. Ataluren (PTC124) 
Ataluren will be provided as a white to off-white powder for oral suspension.  The drug has been 
manufactured under cGMP conditions.  The formulation includes matrix and suspending agents, 
surfactants, and various excipients that aid in the manufacturing process.  The powder for oral 
suspension are packaged in aluminum-foil, child-resistant sachets (packets) and supplied in dose 
strengths containing 125, 250, or 1000 mg of the active drug substance.  For administration, the 
powder in the sachet may be mixed with water, milk (skim, 1% fat, 2% fat, whole milk, 
chocolate milk, or lactose-free milk), or in semi-solid food (yogurt, pudding, or applesauce). 
6.1.2. Drug Kits 
Drug kits will be provided, each of which contains 120 sachets of one of the dose strengths 
(125, 250, or 1000 mg.). 
6.1.3. Study Drug Packaging and Labeling 
Sachets and cartons will be color coded to indicate dosage strength (125 mg – yellow, 250 mg – 
pink, 1000 mg – blue).   
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.  
6.1.4. Study Drug Dispensing 
Dosing of ataluren will be based on milligrams of drug per kilogram of patient body weight at 
Screening/Baseline (Visit 1) and will be adjusted to allow for dosing with the available sachet 
dose strengths. All subjects will receive approximately 10-, 10-, 20-mg/kg ataluren TID for 
~96 weeks. The sachet dosage strengths and number of sachets to be taken per dose will be 
provided by the IVR/IWR system.   
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IVR/IWR system directions.  Sufficient study drug will be provided 
for each study period at the beginning of the period.  
Because of potential changes in subject body weight over time, at Week 24 (Visit 3) and Week 
60 (Visit 6), the possibility of a dose adjustment will be evaluated based on the subject’s body 
weight at that visit. Depending upon the magnitude of change in subject body weight since 
baseline, the number and strengths of sachets to be used by the subject may remain the same or 
may be adjusted. 
6.1.5. Return of Study Drug 
Patients should return all remaining study drug (all unused sachets) to the study site at the end of 
each 12-week treatment period for inventory.  The Subject Study Drug Accountability Log will 
serve as the source document for drug supply to the patients and will document the return of any 
unused drug for compliance assessments.   

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6.1.6. Storage and Stability 
Kits containing sachets of study drug will be stored 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.  The stability of the clinical study samples or 
representative samples will be monitored to support the clinical study, as necessary.   
6.1.7. Study Drug Accountability 
Study personnel must ensure that all study drug supplies are temperature monitored and kept in a 
secure locked area with access limited to authorized personnel.  This study product must not be 
used outside the context of this protocol.  Under no circumstances should the investigator or site 
personnel supply study product to other investigators or clinics, or allow the supplies to be used 
other than as directed by this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by PTC Therapeutics or its designee, including, but not limited 
to, the date received, lot number, amount received, and the disposition of all study drug.  Current 
reconciliation and dispensing records must also be maintained that include the date and amount 
of drug dispensed, and patient’s assigned study number.   
Depending upon the decision of PTC Therapeutics, unused clinical supplies must be destroyed or 
must be returned to PTC Therapeutics or its designee after the study is completed.  
Accountability must be verified by the site monitor prior to return or destruction.  Records 
documenting the date of study drug destruction or shipping, relevant sachet numbers, and 
amount destroyed or shipped should be kept in the investigator site study file. 
6.1.8. Overdose Precautions 
For any patient experiencing an overdose (administration of a study drug dose >4 times the 
highest intended total daily dose level for this protocol [>160 mg/kg/day]), observation for any 
symptomatic side effects should be instituted, and vital signs and biochemical and hematological 
parameters should be followed closely (consistent with the protocol or more frequently, as 
needed).  Appropriate supportive management to mitigate adverse effects should be initiated.  
Pending the acquisition of sufficient human experience with the drug, use of gastric lavage or 
induction of emesis is not specifically recommended nor contraindicated.   
The PTC Therapeutics medical monitor must be contacted if an overdose occurs.  Under 
applicable regulations, overdosing may be considered an SAE and should be reported 
accordingly (see Sections 9.1.1 and 9.1.2).   
6.1.9. Inadvertent Exposure and Spill Precautions 
Reference can be made to the Ataluren Investigator Brochure for current information on 
inadvertent exposures and spill precautions.   
6.2. Study Drug Treatment 
6.2.1. Duration of Treatment 
In this study, treatment will comprise continuous daily treatment with ataluren for up to 
96 weeks (~2 years).  This study may be further extended by amendment until either ataluren 

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becomes commercially available or the clinical development of ataluren in nmCF is 
discontinued.   
6.2.2. 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 (mid-day), and the 3rd dose in the evening.  Ideally each dose should 
be taken within ~30 minutes before or after a meal (eg, ~7:00 AM after breakfast, ~1:00 PM 
after lunch, and ~7:00 PM after dinner).  Intervals for dosing should be ~6 hours (±1 hour) 
between morning and mid-day doses, ~6 hours (±1 hour) between mid-day and evening doses, 
and ~12 hours (±1 hour) between evening doses and the morning dose on the next day.  While it 
is realized that variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen (including dosing intervals and the relationship of dosing to meals) should be followed 
closely on the day preceding PK sample collection in the clinic.   
Table 1.  Suggested Daily Dosing Schedule 
Dose Designation 
Preceding Meal 
Example Dosing Timesa 
Morning 
Breakfast 
~7:00 AM –  0700 hours (±1 hour) 
 
 
↑ 
 
 
~6 hours 
 
 
↓ 
Mid-day 
Lunch 
~1:00 PM – 1300 hours (±1 hour) 
 
 
↑ 
 
 
~6 hours 
 
 
↓ 
Evening 
Dinner 
~7:00 PM – 1900 hours (±1 hour) 
 
 
↑ 
 
 
~12 hours 
 
 
↓ 
Next Day Morning 
Breakfast 
7:00 AM –  0700 hours (±1 hour) 
a 
Dosing times are examples and may be varied to suit each patient’s schedule.  
However, the time between morning and midday doses and between midday 
and evening doses should be maintained at ~6 hour intervals, while the time 
between the evening and next morning dose should be maintained at an ~12 
hour interval.   
 
 
6.2.3. Instructions for Delays in Dosing 
If a patient experiences a delay in the administration of study drug of ≤1 hour, the planned dose 
should be taken with no changes to the subsequent dose schedules.  For a patient who has a delay 
of >1 hour but ≤4 hours, the planned dose should be taken; however, all future doses for that day 
should be shifted later by an approximately corresponding amount.  For a patient who has a 
delay in administration of study drug of >4 hours, the dose should not be taken.  Study drug 
administration may continue but the missed dose should not be made up and the planned timing 
of subsequent study drug dosing should not be altered.   
6.2.4. Study Drug Preparation and Storage 
Study drug sachets should be stored at room temperature, away from the reach of children until 
time of reconstitution and should only be opened at the time of dose preparation. The powder in 
the sachet may be mixed with water, milk (skim, 1% fat, 2% fat, whole milk, chocolate milk, 

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soy, or lactose free milk), or in semi-solid food (yogurt, pudding, or applesauce). The full 
contents of the sachets should be mixed with at least 30 mL (1 ounce) of liquid (water, milk 
[skim, 1% fat, 2% fat, whole milk, chocolate milk, or lactose-free milk], or 3 tablespoons of 
semi-solid food (yogurt, pudding, or applesauce). 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 24 hours of preparation if kept refrigerated, or within 
3 hours of preparation if kept at room temperature. 
The clinic staff will instruct each subject or parent/caregiver on the specific number of sachets to 
be taken from each kit for each dose and will provide detailed oral directions regarding drug 
preparation. In addition, detailed written drug mixing and dosing instructions will be provided to 
the subject or parent/caregiver when drug supplies are dispensed. 
 
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 adverse events or laboratory abnormalities during the 
course of the study.   
For adverse events 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) adverse events 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 3.0 (see 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdffor grading 
the severity of adverse events and laboratory abnormalities.   
Table 2 provides information on actions to be taken in the event that abnormalities are noted in 
specified laboratory parameters.  Thresholds are provided for interrupting study drug 
immediately, for interrupting study drug after confirmation of a value beyond the threshold, or 
for continuing study drug while evaluating for potential drug-related toxicity.  For adverse events 
or laboratory abnormalities not listed in Table 2, the investigator should use his/her judgment in 
determining whether the event or abnormality is clinically significant, whether diagnostic 
evaluation is warranted, and whether potential interruption of study drug is appropriate.  

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Table 2.  Safety Monitoring Parameters and Actions To Be Taken  
Organ System and 
Laboratory Parameter 
Stop Study Drug 
Immediately, Confirm 
Abnormal Value, 
and Then Start Work-Upa 
Stop Study Drug After  
Confirming Abnormal Value,  
and Then Start Work-Upa 
Continue Study Drug,  
Confirm Abnormal Value,  
and then Start Work-Upa 
Hepatic 
 
 
 
Serum total bilirubinb 
≥Grade 3 (≥3.0 x ULN) 
Grade 2 (1.5 – 3.0 x ULN) 
--- 
Serum ALT 
≥Grade 3 (≥5.0 x ULN) 
Grade 2 (>2.5 – 5.0 x ULN) 
--- 
Serum AST 
≥Grade 3 (≥5.0 x ULN) 
Grade 2 (>2.5 – 5.0 x ULN) 
--- 
Serum GGT 
≥Grade 3 (≥5.0 x ULN) 
Grade 2 (>2.5 – 5.0 x ULN) 
--- 
Renal 
 
 
 
Serum cystatin C 
>2.00 mg/L 
>1.33 – 2.00 mg/L 
--- 
Serum creatinine 
≥ Grade 2 (≥1.5 x ULN for 
age) 
Grade 1 (>ULN – 1.5 x ULN for 
age) 
--- 
Serum BUN 
≥3.0 x ULN 
≥1.5 – 3.0 x ULN 
--- 
a Laboratory abnormalities may be confirmed immediately or at the next scheduled clinic visit based on investigator 
judgment. 
b Patients with a diagnosis of Gilbert’s syndrome need not confirm the laboratory parameter and/or stop study drug 
unless the total bilirubin value exceeds 3.0 x ULN. 
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, 
GGT = gamma glutamyl transferase, ULN = upper limit of normal 
It should be noted that blood samples for cortisol, renin and aldosterone determinations will be 
obtained at screening, and, as necessary during the study, for patients with treatment-emergent 
evidence of adrenal dysfunction. 
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 investigator sites.  The PTC Therapeutics medical monitor 
should be notified of any adverse event 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, GGT, AST, and 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, baseline ultrasound data, 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. 

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Laboratory evaluation for adrenal function (cortisol, renin and aldosterone) will be performed at 
screening to determine normal clinical function. The results of placebo-controlled clinical trials 
with ataluren in nmCF and nmDBMD showed no meaningful imbalances in adrenal laboratory 
assessments between the ataluren and placebo arms; therefore, regular monitoring of function is 
not warranted and will not be performed routinely during study participation.  However, adrenal 
function (via these or other parameters) may be tested in patients with evidence of adrenal 
dysfunction as clinically indicated. 
The incidence of new onset nephrolithiasis was similar in both the ataluren and placebo arm in 
the previous double-blind study (4.2% on ataluren vs 3.4% on placebo).  All cases involving the 
diagnosis of urinary tract calculi should be reported as adverse events of special interest to the 
CRO Pharmacovigilance Unit (see Section 9.1.2).  Once it has been documented that a patient 
has symptomatic nephrolithiasis, determining the type of stone and the possible presence of 
either biochemical abnormalities or underlying conditions that predispose to stone formation are 
essential for guiding therapy to prevent recurrent disease.  Patients should be encouraged to 
retrieve stones they pass or have removed for analysis.  Analysis of the stone is an essential part 
of the evaluation.  All patients presenting with their first stone should undergo a focused history, 
radiologic imaging, and at least a limited laboratory evaluation.  A complete metabolic 
evaluation, in addition to the basic laboratory testing, is indicated in all patients with multiple 
stones at first presentation, in patients with a strong family history of stones, and in individuals 
with active stone disease, which is defined as recurrent stone formation, enlargement of existing 
stones, or the recurrent passage of gravel.  The purpose of the focused history is to identify stone 
risk factors, such as a family history of stone disease and certain dietary habits.  Adverse dietary 
habits include:  
• Low fluid intake or a high fluid loss (eg, from sweating or gastrointestinal losses), which 
leads to a lower urine output and, therefore, a higher concentration of lithogenic factors. 
• Higher animal protein diet, which can lead to hypercalciuria, hyperuricosuria, hypocitraturia, 
and elevated urinary acid excretion. 
• Higher salt diet, which increases urinary calcium excretion. 
• Increased intake of higher oxalate-containing foods, particularly spinach (the exact 
contribution of dietary oxalate to urinary oxalate is controversial and likely varies 
considerably from person to person).  
• Lower calcium intake, which acts by increasing the absorption and subsequent excretion of 
oxalate due to decreased calcium oxalate complex formation within the intestinal lumen 
[Curhan 1997, von Unruh 2004].  The effect on oxalate more than counterbalances the 
decrease in calcium absorption and excretion.  
• Excessive vitamin C and D supplementation.  
• Excessive sugar (fructose) intake, which may increase calcium and/or oxalate excretion.  
Because the risk of nephrolithiasis is influenced by urine composition, which can be affected by 
certain diseases and patient habits, a thorough clinical history and analysis of urine composition 
should be completed.  For calcium oxalate stones, urinary risk factors include hypercalciuria, 
hyperoxaluria, hypocitraturia, and dietary risk factors such as a low calcium intake, high oxalate 
intake, high animal protein intake, high sodium intake, or low fluid intake.  The patient should be 

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evaluated for possible underlying causes of stone disease, including hypercalcemia, 
hypercalciuria, hyperuricosuria, hypocitraturia, hyperoxaluria, and urine volume. 
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 should consider factors such as the following:  
• Type and severity of the adverse event or laboratory abnormality 
• The potential causal relationship of study drug 
• The patient’s status in terms of CF and other health conditions 
• The ability to monitor for recurrence of the event 
For hepatic or renal events (refer to Table 2), the level of investigator certainty that an 
abnormality leading to drug interruption is drug-related should be considered strongly in 
deciding whether or not to re-institute study drug treatment.  If the investigator considers the 
hepatic or renal event that led to study drug interruption to be probably related to study drug, 
restarting study drug is not advised.  In this case, the patient should be discontinued from the 
study (see Sections 6.3.4 and 10).  If the investigator considers the hepatic or renal event that 
prompted study drug interruption to be possibly related or unlikely related to study drug, the 
investigator should use best judgment in determining whether to restart study drug.  If the hepatic 
or renal event is considered unrelated to study drug, re-institution of study drug is recommended.   
If the investigator believes it is appropriate, after consultation with the PTC Therapeutics 
medical monitor , study drug may be re-initiated.  If the event was determined to be unrelated to 
study drug, the treatment may be resumed at full dose.  Otherwise, if the drug is resumed, it may 
be initially re-initiated at half of the original dose.    If a patient cannot tolerate the full dose 
within 30 days of dosing re-initiation, then the patient is to be discontinued from study 
participation.  
If after dose reduction, the patient experiences a recurrence of a previous abnormality that led to 
study drug dose interruption or experiences the new occurrence of an unacceptable adverse event 
or laboratory abnormality, the investigator should interrupt study drug and confer with the 
PTC Therapeutics medical monitor regarding the potential need to discontinue study drug 
permanently. 
6.3.4. Instructions for Discontinuation of Study Drug Administration for 
Safety Concerns 
If after appropriate consideration of study drug interruption/modification and consultation with 
the PTC Therapeutics medical monitor, it is not appropriate for a patient to continue with study 
treatment, then study drug should be permanently discontinued.  After permanent discontinuation 
of study drug for a safety concern, and if the initial event was reported as a SAE, then the SAE 
portion of the CRF should be updated.  In the case of a treatment discontinuation due to an event 
that is not an SAE, the PTC Therapeutics medical monitor should be notified (see Section 9).  In 
addition, details regarding the reasons for discontinuation and the adverse events leading to the 
discontinuation should be recorded in the source documents and in the appropriate CRF.  The 
End of Treatment Visit CRF should be completed and appropriate follow-up (at ~4 weeks as per 
protocol or until recovery from or stabilization of the adverse event, 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 (including prescription and non-prescription drugs, 
health foods, herbal remedies, self-prescribed drugs, street drug, tobacco products, or alcohol) 
taken by a patient during the screening period, during study drug administration, and for 4 weeks 
after discontinuation of study drug are considered concomitant medications.  Information 
regarding all concomitant medications will be collected and documented in the concomitant 
medication page of the CRF. 
7.1.1. 
Therapy/Prophylaxis for CF-Related Conditions 
Study patients may receive existing therapy/prophylaxis for treatment of CF or CF-related 
conditions.  To the extent possible, changes in drug regimens should be avoided because this 
may confound interpretation of study results.  The decision to authorize the use of any drug other 
than ataluren 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.   
For patients who are not on a particular type of CF-specific therapy/prophylaxis (eg, dornase 
alfa, hypertonic saline oral azithromycin or ibuprofen), initiation of such therapy/prophylaxis 
during ataluren treatment is discouraged unless there is a strong medical need.  For patients who 
are on CF-specific therapy/prophylaxis at baseline, a stable regimen should be maintained during 
the 96 weeks of ataluren treatment.  Adjustments in dosage or type of drug are permitted to avoid 
symptoms, but attempts should be made to avoid entirely removing or substituting CF 
treatments.  However, patients who do require initiation, interruption, dose modification, or 
substitution of CF treatment may remain on ataluren therapy. 
7.1.2. 
Therapy for CF Pulmonary Exacerbations or Other CF Complications 
Patients should receive appropriate antibiotic or other therapy for CF pulmonary exacerbations or 
other CF-related complications (eg, DIOS) consistent with local best practices and guidelines. 
For patients requiring systemic antibiotic therapy, IV aminoglycosides may be used when 
medically necessary.  However, given ataluren’s ribosomal mechanism of action, and the 
possibility of aminoglycosides exhibiting a confounding effect upon study results, investigators 
should substitute other antibiotics for systemic aminoglycosides in patients who require 
treatment for serious infections whenever possible.  For such severe infections, consideration 
should be given to use of appropriate alternative anti-pseudomonal agents including macrolide 
and glycopeptide antibiotics.  Patients requiring IV therapy with an aminoglycoside or 
glycopeptide antibiotic (eg, vancomycin), should be closely monitored in an appropriate setting.  
Particular caution should be used for patients with a previous history of clinically significant 
creatinine elevations.  Based on the increased incidence of creatinine elevation in patients treated 
with IV aminoglycosides and/or vancomycin, concomitant use of these medications with ataluren 
is contraindicated.  If nephrotoxic antibiotics (eg, tobramycin or vancomycin) are administered, 
ataluren treatment must be interrupted for the duration of  IV antibiotic treatment.  In patients 
receiving any type of potentially nephrotoxic antibiotics, antibiotic drug levels, and renal 
function should be closely monitored.  Creatinine and BUN should be measured prior to 
initiating IV aminoglycosides or other potentially nephrotoxic therapy, and at least twice a week 
during the course of such antibiotic treatment.  The antibiotic trough level, creatinine and BUN 

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should be measured within 24 to 48 hours of administration of the first antibiotic dose, and 
further antibiotic dosing should be based on these results.  Trough levels should also be 
measured at intervals during the course of antibiotic treatment.   
Additionally, patients should be adequately hydrated prior to receiving potentially nephrotoxic 
IV antibiotics, and hydration status should be carefully monitored throughout the administration 
of these agents.  Investigators should be particularly vigilant with patients who are experiencing 
nausea, vomiting, diarrhea, fever, or who have laboratory evidence of dehydration.  Treatment 
with ataluren may be resumed no earlier than 2 days after administration of nephrotoxic 
antibiotics has ceased.  
In patients receiving non-nephrotoxic systemic antibiotics, creatinine and BUN should be 
measured at least once per week during the course of treatment for a pulmonary exacerbation. 
It should be emphasized to patients/caregivers that they must always carry with them the existing 
24-hour emergency card for the study to enable non-study physicians providing care at local 
hospitals or emergency facilities to communicate with the investigational site to ensure that 
appropriate supportive care and monitoring recommendations are followed. 
Information regarding the types and durations of intervention for CF pulmonary exacerbations 
should be recorded on source documents and will be specifically collected in the CRFs in 
support of both the safety and efficacy analyses of the study. 
Chronic use of inhaled aminoglycosides (eg, tobramycin and gentamicin) is prohibited during 
study participation based on the results of Study 009, although short regimens (up to 3 months 
total) are permitted for eradication of newly acquired Pseudomonas aeruginosa infection but 
must be completed during the first 12 weeks of treatment.  However, eradication protocols with 
alternative antibiotics should be considered.  Patients requiring Pseudomonas aeruginosa 
eradication protocols including inhaled tobramycin in the last 12 weeks of the study must be 
withdrawn from study participation.  Start and stop dates for all inhaled antibiotics used during 
the study must be captured in the eCRF. If there is a time gap between the end of the pivotal 021 
study and this 021 extension of longer than one month, the participating subjects must have been 
off inhaled tobramycin at least 4 weeks prior to screening into 021e. 
7.1.3. 
Other Concomitant Medications 
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period.  Patients should be 
discouraged from use of “health supplements” (eg, creatine, glutamine, coenzyme Q), herbal 
remedies, growth hormone, self-prescribed drugs, street drugs, tobacco products, or alcohol at any 
time during the study.  Caution should be exercised during concomitant use of study drug and 
potentially nephrotoxic agents.   
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.   

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Patients/caregivers should be instructed about the importance of  informing the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study.  Information regarding any concomitant drugs taken by a patient during 
the course of the study and the reason for use will be recorded in the source documents and in the 
concomitant medication CRF. 
Pharmacokinetic data indicate that no ataluren dose adjustment is required when ataluren is 
co-administered with systemic corticosteroids (deflazacort, prednisone, or prednisolone), and no 
corticosteroid dose adjustments are required when they are co-administered with ataluren.  
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 unequivocal about any contributory role of ataluren 
in development of hypertension in patients who are taking corticosteriods.   
7.1.4. Drugs Metabolized by Cytochrome P450 Enzymes 
As the primary route of ataluren metabolism is via glucuronidation by UGT1A9, clinically 
significant interactions between ataluren and co-administered drugs metabolized by cytochrome 
P450 enzymes (CYPs) are unlikely.  In particular, ataluren is not an inhibitor of CYP1A2, 
CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5, and does not have induction potential on the 
major CYP enzymes.  
In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug interactions 
mediated by these enzymes are not expected according to the criteria described in the EMA 
guideline on the investigation of drug interactions [EMA 2012].  As an added measure of safety, 
investigators should pay specific attention to use of drugs that are known substrates of these 
enzymes, particularly when such drugs may have a low therapeutic index. 
Drugs that are metabolized by CYP2C8 or CYP2C9 that have low therapeutics indices (in 
particular, paclitaxel for CYP2C8 and coumarin anticoagulants [eg, warfarin], phenytoin, or 
tolbutamide for CYP2C9) may be of particular concern and patients who require the use of these 
drugs will not be enrolled to the study.  Coumarin anticoagulants are cleared by CYP2C9 and 
increases in plasma concentrations of coumarin anticoagulants may result in serious clinical 
consequences.  For patients who require anticoagulation during the study, use of an alternative 
form of anticoagulation (eg, fractionated heparin) should be considered.  Phenytoin is 
metabolized by CYP2C9 and concomitant use with ataluren may be of potential concern.  For 
patients who require anticonvulsant therapy during the study, use of alternative anticonvulsant 
drugs should be considered. The metabolism of losartan to its active metabolite may, in part, be 
mediated by CYP2C9.  However, concomitant use of losartan and inhibitors of CYP2C9 have 
not been examined.  Because this drug does not have a narrow therapeutic window, the potential 
for mild to moderate changes in activity does not require a dose modification. 
7.1.5.  Other Potential Drug Interactions 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and breast cancer resistant protein 
(BCRP).  Caution should be exercised when ataluren is co-administered with drugs that are 
inducers of UGT1A9 (eg, phenobarbital, rifampin), or inhibitors of BCRP (eg, cyclosporine, 
eltrombopag, geftinib). 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
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(OATP1B3).  Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 (eg, 
oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration of these 
drugs. 
The investigator is encouraged to consult the PTC medical monitor (or qualified designee) with 
questions relating to specific drugs and their potential for interactions with ataluren. 
7.2. Non-Drug Therapy 
7.2.1. Physical and Respiratory Therapy 
There are neither restrictions nor prescriptions for physical or respiratory therapy during the 
study.  Sites should use local best practices in providing physical therapy support for patients 
participating in the study.  Respiratory care guidelines as suggested by the American Thoracic 
Society/European Thoracic Society should be followed [Miller 2005a, Miller 2005b].  If changes 
in the physical or respiratory therapy regimen are planned, sites are encouraged to initiate these 
changes prior to enrollment and to maintain the same general level of support throughout the 
duration of the study. 
7.2.2. Dietary Restrictions 
There are no specific dietary restrictions in the study.   
7.2.3. 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.   

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8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS 
8.1. Schedule of Events 
The proposed types and timing of data to be recorded are described in Table 3.  Please see 
Section 8.2 for cross-referenced explanations of the study procedures described in the tables. 
Table 3. Schedule of Events 
Study Period 
Screening/
Baseline 
Treatment Period 
Post-Treatment     
Study Week 
(±7 days) 
Day 
1 
12 
24 
36 
48 
60 
72 
84 
End of Tx/ 
Premature 
D/C 
96 
4 Weeks 
Post-Tx 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
CFQ-R administration 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
Xa 
 
 
 
X 
 
 
 
X 
X 
Hematology  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal ultrasound 
Xa 
 
 
 
X 
 
 
 
X 
 
12-lead ECG  
Xa 
 
 
 
X 
 
 
  
X 
X 
Study drug assignment 
X 
 
 
 
 
 
 
 
 
 
Drug dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug compliance  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Respiratory event evaluationb 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
P. aeruginosa in sputum 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics 
 
 
X 
 
X 
 
X 
 
X 
 
a Study procedure need not be performed if Day 1 is within 14 days of the end of study evaluations at Week 48 
(Visit 8) of the preceding Phase 3 double-blind study (PTC124-GD-021-CF).  If Day 1 is >14 days from the end of 
study visit, study procedure must be performed; however, it is not required to assess serum electrolytes, urine 
protein; urine creatinine ratio (spot sample), or urine blood (by dipstick). 
b Includes completion of the Respiratory Event Form. 
c Abbreviations: D/C = discontinuation; ECG = electrocardiogram; F/U = follow up; Tx = treatment 
8.2. Explanation of Study Procedures 
8.2.1. Transition from the Phase 3 Study, Ataluren Treatment, and 
Follow-up Periods 
Every effort should be made to conduct the Screening/Baseline visit (Visit 1) on the day of the 
End-of-Treatment visit (Visit 8/Week 48) of the Phase 3 double-blind study 
(PTC124-GD-021-CF) to avoid interruption in treatment with study drug.  Signature of the 
informed consent/assent document(s) for this study should be obtained after completion of the 
study procedures at the End-of-Treatment visit (Visit 8/Week 48) of the Phase 3 double-blind 
study (PTC124-GD-021-CF).   
8.2.2. Screening/Baseline Visit (Visit 1) 
Following signature of the informed consent/assent document(s), the patient will complete the 
necessary screening evaluations.  It should be noted that results from safety laboratory tests from 
End-of-Treatment visit (Visit 8/Week 48) of the Phase 3 study (PTC124-GD-021-CF) are not 

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required to determine eligibility.  Patients who have been confirmed to be eligible by the 
investigator for this extension study should complete all Screening/Baseline (Visit 1) study 
procedures.  Most of the data collected during the End-of-Treatment visit (Visit 8/Week 48) of 
the Phase 3 study (PTC124-GD-021-CF) can be utilized for the baseline assessments (see 
footnote “a” of Table 3.  If the Baseline visit (Visit 1) is not completed within 14 days of the 
End-of-Treatment visit (Visit 8/Week 48) of the Phase 3 study (PTC124-GD-021-CF), all study 
procedures should be performed; however, it is not required to assess serum electrolytes, urine 
protein; urine creatinine ratio (spot sample), or urine blood (by dipstick).   
After the completion of the baseline study procedures, a site representative should access the 
IVR/IWR system and supply the necessary information to obtain ataluren dosing instructions.  
The patient will remain at the clinic until ataluren supply for the next 12 weeks has been 
dispensed and the patient/caregiver has been instructed regarding ataluren storage, preparation, 
and administration. 
8.2.3. Treatment Visits during Study (Visits 2 through 9) 
Each patient will subsequently return to the clinical research facility during Week 12 (Visit 2), 
Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), 
Week 84 (Visit 8), and Week 96 (Visit 9).   
8.2.4. End of Treatment  
The patient will return to the clinical research facility at Week 96 (Visit 9) for the 
End-of-Treatment visit.  If the patient discontinues prematurely (ie, before Week 96), the 
procedures that would normally be performed at Week 96 should be performed as a 
Premature-Discontinuation Visit before the patient leaves the study.   
8.2.5. Post-Treatment Visits 
All patients who discontinue study drug must return for a Post-Treatment Visit at the investigator 
site 4 weeks (±7 days) after the last dose of study drug and the End of Treatment Visit, for final 
study-related evaluations.  If the End-of-Treatment Visit occurs >4 weeks after the last dose of 
study drug, the Post-Treatment Visit does not need to be performed. 
8.2.6. Informed Consent 
The investigator or sub-investigator must inform each prospective patient of the nature of the 
study, explain the potential risks, and obtain written informed consent/assent from the patient 
and/or the parent/legal guardian prior to performing any study-related screening procedures.  
Patients will be re-consented with the appropriate age-related documents as needed, if required 
by local regulations. 
8.2.7. Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, pulse oximetry, and body 
temperature) will be monitored at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 
(Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 
(Visit 8), Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation), and at the 
Post-Treatment visit (4 weeks post discontinuation of study drug).  The pulse rate and blood 
pressure determinations will be performed with the patient in a sitting position after a 5-minute 
rest.   

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8.2.8. Height, Weight, and Physical Examination  
Height (in cm) and weight (in kg) will be measured at Screening/Baseline on Visit 1, Week 12 
(Visit 2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 
(Visit 7), Week 84 (Visit 8), Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation), 
and at the Post-Treatment visit (4 weeks post discontinuation of study drug).   
A full physical examination (including general appearance, head, eyes, ears, nose, mouth, throat, 
heart, thyroid, chest and lungs,  abdomen, extremities, neuromuscular system, skin, and lymph 
nodes) will be conducted at Screening/Baseline (Visit 1), Week 48 (Visit 5) and Week 96 (Visit 
9 – End of Treatment/Premature Discontinuation) visit. 
Physical exams may also be performed at any time during the study as clinically indicated. 
8.2.9. Pregnancy  
Serum beta chorionic gonadotropin (β-HCG) will be measured at all study visits (females only). 
8.2.10. Hematology Laboratory Assessment 
Hematology laboratory assessments will include white blood cell count with differential, 
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, total red cell count with morphology, and platelet count.  
These parameters will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 
24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 
84 (Visit 8), Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation), and at the 
Post-Treatment visit (4 weeks post discontinuation of study drug).  Hematology parameters will 
be analyzed by the central laboratory.  The Central Laboratory Manual should be consulted for 
collection, processing, and shipping details. 
8.2.11. Serum 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, globulin, albumin:globulin ratio, bilirubin (total, direct and indirect), creatine 
kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase, total 
cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, and 
cystatin C.  These parameters will be measured at Screening/Baseline on Visit 1, Week 12 (Visit 
2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 
7), Week 84 (Visit 8), Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation), and at 
the Post-Treatment visit (4 weeks post discontinuation of study drug).  Patients should have 
fasted for at least 8 hours prior to blood collection.  Biochemistry parameters will be analyzed by 
the central laboratory.  The Central Laboratory Manual should be consulted for collection, 
processing, and shipping details. 
8.2.12. Urinalysis 
Urinalysis will include analysis for pH, specific gravity, glucose, ketones, blood, protein, 
creatinine, urobilinogen, bilirubin, nitrite, and leukocyte esterase.  These parameters will be 
measured at Screening/Baseline on Visit 1, Week 12 (Visit 2), Week 24 (Visit 3), Week 36 (Visit 
4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), Week 84 (Visit 8), Week 96 (Visit 9 

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- End-of-Treatment/Premature Discontinuation), and at the Post-Treatment visit (4 weeks post 
discontinuation of study drug).  These parameters will be analyzed by the central laboratory.  
Urine samples will also be collected and shipped to central laboratory for assessment of urine 
protein, creatinine, osmolality, and urinalysis.  The Central Laboratory Manual should be 
consulted for collection, processing, and shipping details.   
8.2.13. Renal Ultrasound 
An ultrasound to examine the kidneys and collecting system will be performed at 
Screening/Baseline (Visit 1), Week 48 (Visit 5) and Week 96 (Visit 9 – End of 
Treatment/Premature Discontinuation) visit.  The ultrasound examination will be performed 
according to local standards and a final interpretation and report will be provided by a local 
qualified expert.  The findings will be captured in source documents and within the CRF.   
A follow-up renal ultrasound may also be performed at any time during the study as clinically 
indicated at the discretion of the investigator.  The PTC medical monitor must be informed via 
e-mail that an additional renal ultrasound was obtained and the serious adverse event reporting 
process should be followed, if applicable. 
8.2.14. 12-Lead ECG 
A 12-lead ECG will be obtained at Screening/Baseline (Visit 1), Week 48 (Visit 5), Week 96 
(Visit 9 – End of Treatment/Premature Discontinuation) visit, and at the Post-Treatment Visit 
(4 weeks post discontinuation of study drug).  The ECG will be performed and interpreted 
locally for clinical significance. The findings will be captured in source documents and with the 
CRF.   
A follow-up ECG may also be performed at any time during the study as clinically indicated at 
the discretion of the investigator.  The PTC medical monitor must be informed via e-mail that an 
additional ECG was obtained and the serious adverse event reporting process should be 
followed, if applicable. 
8.2.15. Study Drug Administration 
Patients should take study drug TID as described in Section 6.2.2  Study drug supply sufficient 
for each 12-week treatment period will be supplied to the patient at Screeing/Baseline (Visit 1), 
Week 12 (Visit 2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), 
Week 72 (Visit 7), and Week 84 (Visit 8).  Sufficient drug for 90 days (12 weeks + 6 days) will 
be provided at each of these visits so lessen the likelihood that patients will experience drug 
shortages due to inadvertent loss of some of the sachets or scheduling delays for return visits. 
8.2.16. Study Drug Compliance 
Study drug compliance will be assessed using a Subject Study Drug  Accountability Log (to be 
completed by the investigational site pharmacist or delegate site staff), which will document the 
return of unused sachets for compliance assessments.   
Patients or caregivers will return all unused sachets of study drug to the study site for full 
compliance assessments using the Subject Study Drug Accountability Log.  Clinic staff will 
record the study drug dosing information including the actual clock time of each dose when the 
patient is dosed in the clinic.   

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8.2.17. Adverse Events 
Adverse events must be assessed and documented at each clinic visit.  This information will be 
collected at Screening/Baseline (Visit 1) – following initiation of study drug, Week 12 (Visit 2), 
Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), 
Week 84 (Visit 8), Week 96 (Visit 9) and at the Post-Treatment Visit (4 weeks post 
discontinuation of study drug).  In addition, patients/caregivers will be encouraged to report 
adverse events of concern at any time in the intervals between visits. 
8.2.18. Concomitant Medications 
Information regarding any concomitant medications administered, as well as information 
regarding all non-drug therapies, will be collected throughout the study.  This information will be 
collected at Screening/Baseline (Visit 1) – following initiation of study drug, Week 12 (Visit 2), 
Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), 
Week 84 (Visit 8), Week 96 (Visit 9) and at the Post-Treatment Visit (4 weeks post 
discontinuation of study drug).   
8.2.19. Presence of Pseudomonas aeruginosa in Sputum  
The results of standard-of-care sputum cultures obtained by each subject’s treating CF physician 
will be collected throughout the study.  Available data, including the presence of Pseudomonas 
aeruginosa, will be collected  from each subject’s treating CF physician at Week 12 (Visit 2), 
Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 (Visit 7), 
Week 84 (Visit 8), and Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation). 
8.2.20. Spirometry 
Lung function will be assessed by spirometry using standardized equipment and procedures 
(please refer to the Study Manual for detailed instructions). Spirometry will be performed at all 
study visits.  Centralized review will be provided for all spirometry measurements. 
Consistent with usual practice, it is important that all subjects withhold the following 
medications prior to spirometry testing in order to obtain an accurate assessment of baseline lung 
function: 
• Short-acting beta agonists (SABAs) should not be administered within 4 hours prior to 
testing. 
• Long-acting beta agonists (LABAs) should not be administered within 12 hours prior to 
testing. 
Inhaled antibiotics prior to testing is permitted. If chronically used, and done for the baseline 
visit, the administration of inhaled antibiotic should be consistently administered before every 
study visit (as at the baseline visit). 
Use of SABAs, LABAs, and inhaled antibiotic will be captured in the central spirometry 
vendor’s system prior to start of testing.  
In exceptional circumstances where the subject’s lung function is too labile to tolerate the delay 
in the use of beta agonists, the investigator should confer with the PTC medical monitor to get 
approval to deviate from this requirement.  In this instance, the subject should have all 

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spirometry measurements performed after use of the prescribed beta agonist(s) at the appropriate 
interval(s). 
8.2.21. Pulmonary Exacerbation Rate  
Signs and symptoms associated with respiratory events that may constitute a pulmonary 
exacerbation will be collected and documented by the investigator or other qualified medical 
personnel on a Respiratory Event Form.  This assessment will be conducted on Visit 1, Week 12 
(Visit 2), Week 24 (Visit 3), Week 36 (Visit 4), Week 48 (Visit 5), Week 60 (Visit 6), Week 72 
(Visit 7), Week 84 (Visit 8), and Week 96 (Visit 9 - End-of-Treatment/Premature 
Discontinuation), and at the time of any unscheduled contact between the patient and the clinic.  
In addition to patient/caregiver and investigator discussion at scheduled study visits, 
patients/caregivers are encouraged to contact their investigator by telephone with all pulmonary 
exacerbation details for any events that occur between scheduled visits. 
8.2.22. CFQ-R 
The CFQ-R will be administered prior to performance of other study procedures with the 
exception of obtainment of informed consent.  The questionnaire will be administered at all 
study visits.   
8.2.23. Blood for Analysis of Pharmacokinetics  
Blood for trough ataluren concentrations will be collected at Week 24 (Visit 3), Week 48 (Visit 
5), Week 72 (Visit 7), and Week 96 (Visit 9 - End-of-Treatment/Premature Discontinuation 
immediately prior to the morning dose of study drug.  The Central Laboratory Manual should be 
consulted for collection, processing, and shipping details. 
Samples will be stored at the bioanalytical lab for analysis of ataluren parent drug using a 
validated high performance liquid chromatography with tandem mass spectrometry 
(HPLC/MS-MS) method.  Thereafter, samples will be retained at the bioanalytical lab for 
potential follow-up analyses of ataluren metabolites.    
8.3. Blood Collection Summary 
Every effort has been made to minimize blood drawing to the minimum required to monitor 
patient safety during the trial.  Assuming a 96-week treatment period and all visits completed as 
noted in Table 3, the maximum amount of blood to be drawn at a visit is ~12 mL and the total 
amount of blood to be drawn over the entire 96-week study period (including the Screening visit, 
the 96-week treatment period, and the 4-week follow-up period) is approximately 112 mL. 

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9. 
ADVERSE EVENT ASSESSMENTS 
9.1. Adverse Event Definitions 
9.1.1. Adverse Events 
An adverse event 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 adverse event 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 adverse events 
include the following: 
• All adverse events that are suspected or are not suspected to be due to study drug.   
• Overdose (administration of a study drug dose >4 times the highest 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 adverse events.  The outcome of the accident 
(hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
• Laboratory or ECG abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event 
(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 adverse events. 
• A pre-existing condition (eg, allergic rhinitis) must be noted on the appropriate CRF for 
Visit 1, but should not be reported as an adverse event unless the condition worsens or 
episodes increase in frequency during the adverse event reporting period.  Diagnostic and 
therapeutic non-invasive and invasive procedures, such as surgery, should not be reported as 
adverse events.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event.  For example, an acute 
appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event 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 

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adverse event.  Note that, as described in Section 9.1.2, any inpatient hospitalization 
occurring as the consequence of an adverse event during the study period should be reported 
as an SAE. 
Each adverse event is to be classified as serious or non-serious by the investigator using medical 
and scientific judgment.   
9.1.2. Serious Adverse Events (SAEs) 
A serious adverse event (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 should be reported as a serious adverse event whether it is a result of 
an event that started within the period covered by the on-study definition.  The reported 
adverse event should be the event that caused the death.  In addition, any adverse event 
resulting in death that occurs subsequent to the adverse event-reporting period and that the 
investigator assesses as possibly related to the study drug should also be reported as serious.   
• Life-threatening adverse event.  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 CF-related diagnostic procedures; other planned hospitalizations; or 
hospitalizations related only to progression of disease).  Please note that CF pulmonary 
exacerbations should be reported if they meet this criterion.  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. 
• 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. 
• A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly [including that in an aborted fetus]). 

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Except for CF pulmonary exacerbations, an event need not be reported as a SAE if it exclusively 
represents a relapse or an expected change or progression of the baseline CF.  This type of event 
need only to be reported as an adverse event.   
Note that any SAEs occurring within 4 weeks of the date of last dose should be reported to the 
CRO Pharmacovigilance Unit if the investigator becomes aware of them. 
In addition to serious adverse events, adverse events of special interest must be reported to the 
CRO Pharmacovigilance Unit within 24 hours.  Adverse events of special interest include the 
following: 
Laboratory abnormalities: 
• Serum cystatin C >1.33 x ULN  
• Serum creatinine > ULN for age 
• Serum BUN >1.5 x ULN 
• Urine dipstick with ≥2+ blood 
• Urine dipstick with ≥2+ protein 
Signs/symptoms: 
• Dysuria 
• Flank (renal) pain 
• Nephrolithiasis or other urinary tract calculi 
It should be noted that laboratory data sent to and analyzed by the Central Laboratory need not 
be reported through the CRO Pharmacovigilance Unit as these data will already be reported to 
PTC Therapeutics. Only those laboratory abnormalities meeting the protocol-defined criteria of 
an adverse event (ie, those that require clinical intervention or further investigation (beyond 
ordering a repeat [confirmatory] test), see Section 9.1.1) should be reported as adverse events in 
the appropriate CRF, whether they were analyzed by the central laboratory or another laboratory. 
9.1.3. Unexpected Adverse Events  
Unexpected adverse events 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 investigator brochure only referred to elevated hepatic enzymes or 
hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure only listed cerebral vascular 
accidents.  “Unexpected,” as used in this definition, also refers to an adverse event that is 
mentioned in the most current investigator brochure 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 investigator brochure provides a 
summary of the safety profile of ataluren based on available clinical information (also referred to 
as the reference safety information).   

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9.2. Eliciting Adverse Event Information 
Each study patient will be questioned about adverse events at each post-screening study visit or 
during any telephone contact with the patient or parent/caregiver.  The investigator is to report all 
directly observed adverse events and all adverse events spontaneously reported by the  patient or 
parent/caregiver at each scheduled clinic visit after study drug administration or during any 
telephone contact with the patient or parent/guardian caregiver.  The type of question asked 
should be open-ended, eg, “How have you/ your child been feeling?” or a similar type of query.   
9.3. Adverse Event Recording 
All adverse events (both serious and non-serious) that occur in patients during the adverse event 
reporting period must be recorded, whether or not the event is considered drug related.  In 
addition, any non-serious, known untoward event that occurs subsequent to the adverse event 
reporting period that the investigator assesses as possibly related to the investigational 
drug/product should also be recorded as an adverse event. 
All adverse events are to be recorded in the source documents and on the CRF 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 nonserious (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 
Classification of the event as serious or nonserious determines the reporting procedures to be 
followed.   
9.4. Describing Adverse Event Relationship to Study Drug 
Based on the considerations outlined in Table 5, the investigator should provide an assessment of 
the relationship of the adverse event to the study drug, ie, whether there is a reasonable 
possibility that the study drug caused the adverse event. 

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Table 4.  Relationship of Study Drug to Adverse Event 
Relationship 
Description 
Probable 
A clinical event in which a relationship to the study drug seems probable because of such 
factors as consistency with known effects of the drug; a clear temporal association with the 
use of the drug; improvement upon withdrawal of the drug; recurrence upon rechallenge with 
the drug; lack of alternative explanations for the event.   
Possible 
A clinical event occurring coincident with administration of the study drug and which may or 
may not be explained by concurrent disease or other drugs or chemicals.  Information on 
drug withdrawal or rechallenge may be lacking.   
Unlikely 
A clinical event with a temporal relationship to the study drug exposure that does not 
preclude causality but for which there is a clear alternate cause that is more likely to have 
caused the adverse event than study drug.  Such alternatives include a concomitantly 
administered drug, the 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 adverse event 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 adverse events will be graded using the CTCAE, Version 3.0 (refer to 
http://ctep.cancer.gov/forms/CTCAEv3.pdf).  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 adverse event.  For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 6. 
Table 5.  Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have a clinically 
significant effect on the patient’s overall health and well being, does not interfere with 
the patient’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 adverse event.  Severe 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. Pregnancy  
PTC Therapeutics should be notified in the event that a female patient in the study becomes 
pregnant at any time after the patient’s first dose of study drug.  Any such pregnancy occurring 
on-study or within 60 days of the last administration of study drug must be reported on a 
Pregnancy Notification Form (see the Study Manual for details).  This must be done whether or 

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not an adverse event has occurred and within 24 hours of awareness of the pregnancy.  The 
information submitted should include the anticipated date of birth or pregnancy termination.  
If possible, the investigator should follow the patient until completion of the pregnancy and 
notify the PTC Therapeutics medical monitor of the outcome within 5 days or as specified 
below.  The investigator will provide this information as a follow up to the initial Pregnancy 
Notification Form via the Pregnancy Outcome Form (see the Study Manual for details).   
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the investigator should follow the procedures for reporting 
serious adverse events, ie, report the event to the CRO Pharmacovigilance Unit and follow up by 
submission of appropriate adverse event CRFs (see Section 9.9). 
9.7. Follow-Up of Unresolved Adverse Events  
All adverse events 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 conducted within one 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 CRO 
Pharmacovigilance Unit should be informed via e-mail or fax.  A patient withdrawn from the 
study because of an adverse event 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.   
9.8. Adverse Event Reporting Period 
The first day of adverse event reporting will coincide with the day the first dose of study drug is 
administered.  The adverse event reporting period for this study ends with the 4-week (± 7 days) 
Post-Treatment Follow-up Visit, except as described in Section 9.7.  In addition, SAEs occurring 
in a patient after the study period should be reported to the sponsor if the investigator becomes 
aware of them. 
9.9. 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 adverse events are 
summarized in Table 6.  

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Table 6.  Investigator Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Complete AE and SAE portions of CRF and notify site IRB/IEC, 
as per local IRB/IEC requirements.  If unable to enter event in 
EDC, call the CRO Pharmacovigilance Unit or fax the back-up 
paper SAE report form to the CRO Pharmacovigilance Unit, 
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 CRO Pharmacovigilance Unit. 
Per CRF submission procedure 
Record and submit information on appropriate CRFs (eg, 
Medical History and Concomitant Medications CRFs) 
AESI 
Within 24 hours 
Complete AE and SAE portions of CRF and notify site IRB/IEC, 
as per local IRB/IEC requirements.  If unable to enter event in 
EDC, call the CRO Pharmacovigilance Unit or fax the back-up 
paper SAE report form to the CRO Pharmacovigilance Unit, 
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 CRO Pharmacovigilance Unit. 
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:  CRF = case report form, IRB/IEC = Institutional Review Board/Independent Ethics Committee,  
SAE = Serious Adverse Event 
 
For SAEs, in addition to completing the adverse event portion of the CRF, the SAE portion of 
the CRF must also be completed.  The SAE CRF must be completed within 24 hours of 
knowledge of the event.  If the site is unable to enter the event in the EDC system within 24 
hours, notification to the CRO Pharmacovigilance Unit should be conducted via telephone or fax 
using the back-up paper SAE report form.  Follow up information for the SAE should be entered 
on the SAE CRF or clearly documented on the back-up paper SAE report form, as applicable, 
upon receipt, and must also be sent to the site IRB/IEC, as required.  If a paper SAE report form 
is used to report follow up information, then it must be signed by the investigator.  The SAE 
CRF should be signed by the investigator only after the data on the form has been finalized.  Any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries) provided to the CRO Pharmacovigilance Unit should be redacted so that 
the subject’s name, address, and other personal identifiers are obscured.  Only the subject’s study 
number and initials are to be provided (in regions where the provision of such information is 
permitted).  The information in the adverse event and SAE portions of the CRF  must match or 
be reconciled.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same adverse event term should be used on both forms.   

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In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is to 
document his/her first awareness of the adverse event and report the event within 24 hours after 
learning of it.  
The CRO contact information for reporting serious adverse events and adverse events of special 
interest is provided below and may also be found in the Investigator File and the back-up paper 
SAE report form. 
PPD North America, EU, and Israel 
Toll-Free: 
   
Safety Fax Number: 
 
In addition, each site will be provided with a Verizon, country-specific calling code.  
9.10. PTC Therapeutics Adverse Event Reporting Requirements 
For regulatory reporting purposes, the event is classified as related if the investigator or 
PTC Therapeutics determines that the event is possibly or probably related to the study drug (see 
Section 9.4).  An adverse event will be considered expected if the protocol or investigator 
brochure indicates that such an event of similar or greater severity has already been observed in 
association with use of the study drug.   
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.  The event is classified as related if the investigator or PTC 
Therapeutics determines that the event is possibly or probably related to the study drug (see 
Section 9.4).  An adverse event will be considered expected if the protocol or investigator 
brochure indicates that such an event of similar or greater severity has already been observed in 
association with use of the study drug.  If notification of an adverse event requiring expedited 
reporting to investigators is received, PTC Therapeutics or its designated representative will 
contact each investigator site participating in this study by e-mail, fax, and/or overnight mail 
such that the investigator can promptly notify the site IRB/IEC, as applicable, per their local 
requirements.  The PTC Therapeutics Awareness Date (PTCAD) is the date the regulatory 
reporting clock begins and the date is considered Day 0.  The initial expedited safety report will 
be provided as required according to local regulations after the earliest date PTC Therapeutics or 
an agent of PTC Therapeutics (eg, a site monitor) becomes aware of an adverse event (eg, within 
7 calendar days for deaths or life-threatening events or within 15 calendar days for other 
reportable events from the PTCAD). 

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10. WITHDRAWAL OF PATIENTS  
All patients who receive study drug should remain in the study whenever possible.  However: 
• The patient has the right to withdraw consent and discontinue study drug at any time. 
• If the patient’s condition substantially worsens after initiating study drug, the patient will be 
carefully evaluated by the investigator in consultation with the PTC Therapeutics medical 
monitor.  The patient will be withdrawn from treatment if continuing would place them at 
risk. 
• Upon consultation with the PTC Therapeutics medical monitor, the investigator may 
withdraw the patient from study drug, if, in the investigator’s clinical judgment, it is not in 
the patient’s best interest to continue.   
• If the patient becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements.  In this event, the patient should be withdrawn from study 
treatment when the circumstances surrounding noncompliance increase risk to the patient or 
are anticipated to substantially compromise the interpretation of study results. 
• The patient will be withdrawn from treatment if he is unable to tolerate study drug. 
• This study may be discontinued by the relevant regulatory authority and/or PTC Therapeutics 
at any time. 
• This study may be stopped upon ataluren marketing authorization within the relevant 
country. 
The date study drug is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the eCRF.  The PTC medical monitor (and designee) should be 
informed via e-mail of when a patient is discontinues study drug. 
When study drug is discontinued (regardless of the reason), the investigator should encourage 
that all of the evaluations required at the End of Treatment Visit be performed and that any 
additional evaluations 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. STATISTICS AND DATA MANAGEMENT  
11.1. Sample Size Calculation  
The sample size for this extension study is not based upon any formal statistical hypothesis, but 
its upper bound is determined by the requirement that patients must have participated in the 
previous Phase 3 study of ataluren (PTC124-GD-021-CF) in which ~ 208 patients are expected 
to be enrolled. 
11.2. Study Population Definition 
11.2.1. As-Treated Population 
The as-treated population consists of all subjects who took at least one dose of ataluren.  This 
population will be used to analyze safety and treatment administration. 
11.2.2. Evaluable Populations 
In general, evaluable populations consist of all as-treated subjects who have sufficient data to 
assess the measure of interest (eg, ataluren plasma concentrations).  These populations may be 
evaluated in the analysis of other endpoints. 
11.3. General Statistical Considerations 
By-subjects listings will be created for each CRF module.  Summary tables for continuous 
variables will contain the following statistics: n, mean, standard deviation, standard error, 95% 
confidence intervals (CIs) on the mean, median, minimum, and maximum.  Summary tables for 
categorical variables will include N, n, percentage, and 95% CIs on the percentage.  Where 
applicable, the summary data (mean, standard error) will be presented in graphical form of 
against time of visit.   
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
All analyses will be performed based on all observed data. For the efficacy endpoints, eg, FEV1, 
FVC, FEF25-75, and pulmonary exacerbation, the analyses will be performed for 48-week 
completers and the whole study completers as well. 
11.4. Specific Statistical Analyses  
11.4.1. Study Conduct and Subject Disposition 
The number and percentage of subjects in each of the analyzed study populations and the 
subjects completing 96 weeks of planned assessments and those of all planned assessments 
during the study will be described.  The number and percentage of subjects who prematurely 
discontinue from the study will also be reported.  
Reasons for screening failures, reasons for discontinuation, and time of withdrawal from the 
study will be described. 
11.4.2. Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized in frequency tables and 
descriptive statistics will be provided for quantitative variables.    

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11.4.3. Study Treatment Administration 
For each subject, ataluren administration will be described, inclusive of duration of therapy, dose 
modifications, dose delays and omissions, and reasons for any deviations from planned therapy. 
11.4.4. Use of Concomitant Medication and Supportive Therapy 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification 
(ATC) codes.  The number and percentage of subjects who received specific concomitant 
medications and supportive therapy will be summarized descriptively for each drug within each 
drug class.  Multiple drug usage by a subject in the same category will be counted only once.  
The by-subject listings of concomitant medication will be presented. 
11.4.5. Primary Variables  
11.4.5.1        Adverse Event 
Adverse events will be classified using the MedDRA classification system.  The severity of 
adverse events will be graded according to the CTCAE, Version 3.0, whenever possible.   
A treatment-emergent adverse event is defined as an adverse event that occurs or worsens in 
severity in the period extending from the day of a subject’s first ataluren dose in this study to 4 
weeks after the last ataluren dose in this study. 
The number and percentage of subjects experiencing a specific adverse event will be tabulated 
by body system and MedDRA term.  A subject having the same event more than once will be 
counted only once.  Adverse events will be summarized by worst CTCAE grade within a subject.  
Exposure-adjusted incidence rate will be reported. 
Adverse events classified as CTCAE Grade 3 or higher; study-drug-related events; hepatic, and 
renal events leading to special diagnostic evaluations; events leading to discontinuation from 
treatment; SAEs; and AESIs will be considered with special attention. 
11.4.5.2  
Laboratory Data 
Hematological, serum biochemistry, urine data, and their changes (only for continuous 
laboratory parameters) from baseline will be summarized descriptively for each visit.  
Hematological, serum biochemistry, and urine data will be graded according to CTCAE severity 
grade when applicable.  For parameters for which a CTCAE scale does not exist, the frequency 
of subjects with values below, within, and above the normal ranges will be summarized.  
Summary tables will be presented for each relevant assay to show the number of subjects by 
severity grade with corresponding percentages.  Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during the time period of interest.   
Separate listings and tables will be created for assessment of hepatic and renal parameters. 
11.4.6. Secondary Variables  
11.4.6.1      Spirometry 
Both absolute change and relative change in %-predicted FEV1 from Baseline at each visit will 
be summarized descriptively.  Pediatric equations for calculating %-predicted FEV1 [Wang 
1993] will be used from 6 to <16 years of age for female subjects and from 6 to <18 years of age 
for male subjects.  For males or females >18 years of age, an adult equation for calculating 

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%-predicted FEV1 [Hankinson 1999] will be used.  Each %-predicted FEV1 will be based on the 
height value obtained at the same study visit.  The changes from baseline to each post-baseline 
visit will be analyzed using paired t-tests.  
Above analyses will be repeated for FVC and FEF25-75. 
11.4.6.2     Pulmonary Exacerbation  
A modified Fuchs’ exacerbation is defined as an event requiring treatment with or without IV 
antibiotics for any 4 of the following 12 symptoms: change in sputum; new or increased 
hemoptysis; increased cough; increased dyspnea; fatigue; temperature >38°C; anorexia; sinus 
pain; change in sinus discharge; change in physical examination of the chest; decrease in 
pulmonary function by 10 percent or more from a previously recorded value; or radiographic 
changes indicative of pulmonary function [Fuchs 1994].  Modified Fuchs’ (primary definition) 
exacerbation incidence will be summarized descriptively for each visit.  Other pulmonary 
exacerbation definitions, including Fuchs and expanded Fuchs, will also be summarized. 
11.4.7. Tertiary Variables  
11.4.7.1  Vital Signs, Renal Ultrasound, 12-Lead ECG, and Other Safety 
Parameters 
Vital signs (height, weight, BMI, systolic and diastolic blood pressure, pulse rate, pulse 
oximetry, and body temperature) and ECG will be listed and summarized by visit and overall. 
Physical examination findings will be listed. Where appropriate, changes from baseline at each 
visit will be presented by visit and overall.   
The results of an ultrasound to examine the kidneys and collecting system will be listed and 
abnormal results will be noted and investigated in terms of their relation to other relevant subject 
outcome measurement.  
11.4.7.2.   Ataluren Plasma Concentrations 
Ataluren plasma concentrations will be summarized via n, mean, standard deviation, standard 
error, median, minimum, and maximum, CV% mean, geometric mean, and CV% geometric 
mean for each visit.  The relationship between ataluren plasma concentrations and selected 
efficacy and safety outcomes will be explored.   
11.4.7.3.   CFQ-R 
Changes in CFQ-R domains will be summarized descriptively for each visit. The CFQ-R 
respiratory domain will be the major HRQL parameter. 
11.4.7.4  Respiratory Events 
Incidences, rates, and durations of interventions (eg, antibiotic use and hospitalization) and 
disruptions to daily living (eg, missed school or work) resulting from pulmonary symptoms will 
be summarized descriptively. The rate and durations will be adjusted forsubject exposure. 
 
 

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12. STUDY COMMITTEES 
A DMC, operating autonomously from the sponsor, the clinical investigators, and the Study 
Steering Committee (SSC), 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 at least 
2 physicians experienced in treating patients with CF, a nephrologist, and a biostatistician.  The 
DMC will be chaired by one of these 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.  The DMC will formally interact with the SSC through the 
sharing of meeting minutes.  Informal interactions between the DMC and SSC will be limited.  
The DMC will operate under a charter developed as a collaborative document between the DMC 
and PTC Therapeutics.  The primary responsibility of the DMC is to protect the safety and 
welfare of patients participating in this clinical study and to ensure the integrity of the clinical 
study.   
In general, the DMC will be responsible for: 
• Examining accumulated data at pre-specified points during the course of the study in order to 
make recommendations concerning continuation, termination, or modification of the study 
• Reviewing major study design modifications prior to implementation of those modifications 
• Reviewing the general progress of the study regarding  such issues as patient accrual, study 
conduct, and protocol deviations 
• Providing expert advice to PTC Therapeutics on an ad hoc basis regarding matters such as 
safety concerns or diagnostic evaluations in individual patients 
Based on the results of its deliberations, the DMC can recommend continuation of the study 
unchanged, study interruption, study termination, modification of the study, or alteration in the 
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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. 
13.2. Institutional Review Board/Independent Ethics Committee 
Prior to enrollment of patients into the study, as required by the Food and Drug Administration 
(FDA) and other regulatory authorities, the protocol and informed consent document will be 
reviewed and approved by an appropriate IRB/IEC.  By signing the Statement of Investigator 
Form (FDA Form 1572), the investigator assures that approval of the study protocol will be 
obtained from the IRB/IEC and that all aspects of the IRB/IEC review will be conducted in 
accordance with current regulations.  Amendments to the protocol will be subject to the same 
IRB/IEC review requirements as the original protocol.  Only changes necessary to eliminate 
apparent immediate hazards to the 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 adverse events, or any other information that may affect the safe use of 
the drug during the course of the study, per local IRB/IEC requirements.   
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 or the sponsor shall submit a progress report, at least once yearly, to the 
IRB/IEC, as applicable, according to local regulations.  A copy of any progress report submitted 
by the investigator must be provided to PTC Therapeutics. PTC Therapeutics will provide to the 
investigator a copy of any progress report submitted to the IRB/IEC.  As soon as possible after 
completion or termination of the study, the investigator will submit a final report to the IRB/IEC, 
as applicable, and to PTC Therapeutics.  This report should include the following: 
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 adverse events.  PTC Therapeutics will assist the investigator in the preparation of this 
report, as needed. 
If this study is performed under a grant from the US government, PTC Therapeutics will also 
submit the protocol and informed consent documents to the company’s IRB of record 
(Western Institutional Review Board [WIRB], Olympia, WA).  PTC Therapeutics or its designee 
will be responsible for all interactions with WIRB relating to the study, including submission of 
protocol documents, consent forms, and amendments; submission of adverse event reports and 
annual reports; receipt of approval notices; and exchange of other correspondence.   
13.3. Informed Consent/Assent 
By signing the Statement of Investigator (FDA Form 1572), the investigator assures that 
informed consent/assent will be obtained from each patient and/or parent/legal guardian prior to 

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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 
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/guardian signature on the 
informed consent form should be obtained at the investigator site in the presence of the 
investigator or a qualified representative (eg, sub-investigator).  Where applicable, the 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 or paper CRF, as applicable, is required and must be completed for each enrolled 
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 contract research organization (CRO) for this study.  After the 
investigator or the investigator’s designees (eg, research coordinators) have been appropriately 
trained, they will be given access to the EDC system and will enter the data required by the 
protocol into the EDC system.  Any change of data will be made via the EDC system, with all 
changes tracked by the system to provide an audit trail.   
With an electronic signature, the investigator certifies that the data are complete and accurate 
prior to database lock.  This electronic signature serves to attest that the information contained in 
the eCRFs is true.  After database lock, the investigator site will retain read-only access to their 
respective eCRF data (as entered in the EDC system) for a period of up to 6 months following 
database lock.  The investigator will have opportunity to review CD-ROM and/or paper copies of 
eCRF data against the read-only data (serving as a contemporaneous and independent copy of 
CRF).  At all times, the principal investigator has final responsibility for the accuracy and 
authenticity of all clinical data entered onto the CRFs and/or reported to PTC Therapeutics from 
the investigator site.   
13.5. Study Records 
During the study, the investigator will maintain adequate records for the study, including the 
following: 

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• Medical records 
• Source document records detailing the progress of the study for each patient 
• Laboratory reports 
• A CD-ROM or paper copies of the data that have been captured in the EDC for each patient 
• Signed informed consent forms 
• Delegation of Responsibility/Authority Log 
• Ataluren drug accountability, reconciliation and disposition records 
• Relevant equipment maintenance and calibration records 
• Correspondence with the IRB/IEC 
• Adverse event reports 
• 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 
or other regulatory authorities.   
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.   
Attention is drawn to the regulations promulgated by the FDA under the Freedom of Information 
Act providing, in part, that information furnished to clinical investigators and the IRB/IEC will 
be kept confidential by the FDA only if maintained in confidence by the clinical investigator and 
the IRB/IEC.  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.  In other countries where this clinical trial is conducted, the investigator and the 
sponsor will comply with the local data protection requirements, as applicable. 
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 

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EDC for each patient (electronic equivalents of CRFs), and detailed records of study drug 
disposition.  All records and documents pertaining to the study (including but not limited to those 
outlined in Section 13.5) 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 or another institution.  
Precautions should be taken to ensure the integrity, security, and protection of these documents 
from damage or loss at all times during and after completion of the study. 
13.8. Monitoring and Auditing  
In accordance with 21 Code of Federal Regulations (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, applicable FDA and 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 patients will be kept in strict confidence and will not appear on 
eCRFs or other records provided to or retained by PTC Therapeutics.  The 
investigator/institution guarantees direct access to source documents by PTC Therapeutics and 
appropriate regulatory authorities. 
The investigator 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 the FDA and/or other 
regulatory authorities.  The Investigational New Drug (IND) regulations also require the 
investigator to allow authorized representatives of the FDA to inspect and make copies of the 
same records.   
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.   
13.9. Termination of the Study 
PTC Therapeutics reserves the right to discontinue the study prior to inclusion of the intended 
number of patients.  The investigator, after consultation with the PTC Therapeutics medical 
monitor, reserves the right to discontinue the study at the investigator site for safety reasons at 
any time.   
After a decision to terminate the study, investigators must contact all patients who are continuing 
their participation in the study and must do so within a time-period set by PTC Therapeutics.  As 

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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 Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
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.  Information from 
ClinicalTrials.gov is provided to other publically available and/or electronically linked databases, 
including the WHO International Clinical Trials Registry Platform (ICTRP).   
The protocol will also be listed in the EU Clinical Trials Register, the EU clinical trials database, 
as extracted from EudraCT.  The information provided by PTC Therapeutics is a component of 
its application to a national medicines regulatory authority for authorization to conduct the 
study.  The information from PTC Therapeutics is loaded into the EudraCT database by the 
national medicines regulatory authority.   
PTC Therapeutics will ensure that information on the websites 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 investigator 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 or other regulatory authorities.  Such information may be disclosed as deemed 
necessary by PTC Therapeutics. 
PTC Therapeutics intends that the data from this study will be presented and published.  The 
PTC Therapeutics staff under the direction of the PTC Therapeutics chief medical officer in 
collaboration with the investigator will be responsible for writing presentations and manuscripts 
for publication.  Investigators will not be allowed to publish or present the data from this study 
without prior agreement with PTC Therapeutics.   
13.12. Communication with Regulatory Authorities 
PTC Therapeutics will assume responsibility for regulatory interactions with the FDA, the 
European Medicines Agency (EMA), and/or other regulatory authorities.  In this regard, 
PTC Therapeutics will maintain an IND for ataluren in support of the study.  In fulfilling this 
responsibility, PTC Therapeutics (or a designee) will collect, assemble, and communicate all 
required regulatory documents (eg, Form FDA 1572, 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 adverse event reporting to regulatory authorities as described in Section 9.10. 

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14.  RATIONALE FOR STUDY DESIGN FEATURES  
14.1. Patient Selection 
14.1.1 Overview 
Since this protocol describes an open-label extension study, enrollment is limited to the patients 
who successfully complete the double-blind, placebo-controlled Phase 3 study 
(PTC124-GD-021-CF).  The eligibility criteria are designed to enable enrollment of patients who 
are sufficiently well (both in terms of CF and in terms of concomitant illness) to safely 
participate in study procedures and provide interpretable results.  Consistent with GCP 
guidelines, patients and/or parent must provide informed consent/assent before initiation of any 
study procedures.  To minimize missing data and premature discontinuations, patients must have 
the personal and family resources to comply with study procedures and restrictions.  In addition, 
patients must not have serious concomitant conditions that would compromise safety, 
compliance, or evaluation. 
14.1.2 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 many of the patients likely to be 
enrolled in this study limits reproductive risks.  However, restriction on eligibility relating to 
willingness to avoid unprotected sexual intercourse in any patients known to be sexually active is 
included as a general precaution.  Because it is unknown if ataluren is excreted in breast milk, 
lactating female patients who are breast-feeding are excluded from participation. 
14.1.3 Concomitant Therapies 
Ataluren has not proved allergenic in studies performed to date, but review of known allergies to 
excipients contained in the formulation is prudent.  The restriction on concurrent involvement in 
other therapeutic clinical trials is intended to avoid confounding effects.   
14.1.4 Safety Profiling  
As is conventional, safety will be characterized in terms of the type, incidence, timing, severity, 
drug-relatedness, and seriousness of adverse events and laboratory abnormalities.  For 
consistency of interpretation, adverse events will be coded using the MedDRA, the severity of 
these events and laboratory abnormalities will be graded using the well-defined CTCAE, Version 
3.0, and concomitant medications will be coded with the WHODRUG dictionary.   
14.1.5 Study Drug Compliance  
Evaluation of study drug compliance provides context for assessments of pharmacological 
activity, safety, and PK, and may offer a general indication of patient acceptance of therapy, 
integrating factors of tolerability, palatability, and convenience.  The compliance of the patient 
will be verified by counting unused drug study sachets.   
14.1.6 Trough Ataluren Plasma Concentrations 
Collection of plasma for ataluren concentrations is important for confirming maintenance of 
exposure over time.  Having these data may allow correlations of exposure with measures of 
efficacy and toxicity.  Because the ataluren PK profile has been well characterized in existing 
Phase 2a and Phase 3 studies in patients with CF, plasma sampling will be limited to before 

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dosing relative to the morning dose at each clinic visit.  This will provide information regarding 
ataluren trough concentrations.  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.  
Plasma samples will be retained for potential later analyses of ataluren metabolites or 
corticosteroid parent drug and metabolites.    
14.1.7 Timing of Assessments 
The timing of study assessments is appropriate in the context of a chronic study, permitting 
inclusion of 8 post-baseline evaluations during the study period, ensuring that time trends can be 
adequately assessed and that sporadically missing data do not have a substantial impact on data 
analysis.  The visit frequency also give consideration the need for many patients to travel 
considerable distances to study sites and that sites may achieve limiting capacity to accomplish 
study visits and data flow once multiple patients are being followed simultaneously at a single 
site.   
Study activities have been mapped across the study as outlined in the Schedule of Events (see 
Table 3). 
14.2. Treatment and Safety Monitoring Plan 
14.2.1. Schedule and Dose Selection 
Dosing based on body weight will continue to be employed.  Such dosing reduces variability in 
exposure by accommodating differences in patient size across the span of ages in patients who 
will participate in the clinical study program.   
The schedule of drug administration is derived directly from Phase 1 PK modeling and from 
Phase 2 exposure information.  The intent of administering two 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. 
14.2.2. Duration of Therapy 
This open-label study is expected to generate at least 96 weeks of safety information.  This 
information will supplement safety data obtained from the randomized, placebo-controlled, 
double-blind study (PTC124-GD-021-CF), which has a planned treatment duration of 48 weeks. 
14.2.3. Safety Monitoring Overview  
In response to the occurrence of renal toxicology findings in the mouse and renal laboratory 
abnormalities in prior ataluren studies, the renal safety monitoring plan utilized for the previous 
Phase 3 study is also appropriate for renal monitoring of this study population.  Thresholds for 
evaluation and intervention have been established for other types of adverse events or laboratory 
abnormalities observed in the study, including hepatic abnormalities.  The intent is to protect 
patients, obtain a thorough assessment of any clinically relevant adverse events or laboratory 
abnormalities, and to offer recommendations for interruption and dose modification of study 
drug in response to potential safety signals.  The nature of these risks and the measures to 
monitor for them will be reflected in the informed consent form. 

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As noted in Section 6.3.1, patients must be monitored closely for adverse events or laboratory 
abnormalities during the course of the study.  Section 6.3.1 provides information on actions to be 
taken in the event that abnormalities are noted on specified monitoring studies.  Thresholds are 
provided for interrupting study drug immediately, for interrupting study drug after confirmation 
of a value beyond the threshold, or for continuing study drug while evaluating for potential 
drug-related toxicity. 
14.2.4. Renal Monitoring Plan  
Renal findings were seen in mice receiving one or two doses through 26 weeks of dosing with 
ataluren.  A no-observed-adverse-effect level (NOAEL) for the renal toxicity findings in mice 
has not been identified; the lowest observed adverse effect level (LOAEL) = 75 mg/kg/day.  
Exposure in mice at 75 mg/kg/day is 0.3-fold the exposure in patients administered ataluren at 
the morning, midday, and evening doses of 10, 10 and 20 mg/kg/day, respectively.  The renal 
finding was seen primarily in the distal nephron and involved some degenerative changes 
(apoptosis) and regenerative changes (proliferation of renal epithelium) accompanied by tubular 
dilatation and proteinaceous material within the tubules.  Rarely the tubules were mineralized.  
Fibrosis was not seen after 1 month of dosing, but an interstitial renal fibrosis was observed in 
the 26-week carcinogenicity study in mice.  The finding was occasionally accompanied by 
individual increases in serum blood urea nitrogen (BUN) and/or creatinine, but a dose 
relationship for these parameters was not observed.  The kidney findings were partially to 
completely reversible as soon as 2 to 6 weeks after cessation of dosing.  The renal toxicity was 
observed in mice only, and has not been seen in rats dosed for 24 months or in dogs dosed for 
52 weeks despite achievement of exposures in rats and dogs that were comparable to or greater 
than those observed in mice.   
In the Phase 3 clinical trial (Study 009), serious adverse events related to renal dysfunction, 
which occurred only in the ataluren arm, included 3 patients with acute renal failure, 3 patients 
with renal failure, and 1 patient with hypercreatininemia. These events were characterized by 
elevated creatinine (Grade 1 to Grade 4), which resolved over days to weeks. Only 1 patient 
experienced symptoms of renal dysfunction (transient oliguria).  All 7 events were associated 
with concomitant systemic treatment with potentially nephrotoxic antibiotics (eg, 
aminoglycosides, vancomycin) that were generally administered as treatment for pulmonary 
exacerbations.  No patient required dialysis.  One patient was unblinded and 1 patient chose not 
to continue study drug treatment; the remaining 5 of 7 patients restarted study medication and 
continued study participation without recurrent creatinine elevations.  This issue was recognized 
during the conduct of the study and changes were made in the protocol (eg, prohibition of 
concomitant use of potentially nephrotoxic agents), which successfully addressed the issue. 
Non-serious creatinine elevations occurred predominantly in the ataluren arm and were transient, 
generally mild, and resolved with or without interruption of study medication.  The incidence of 
treatment emergent nephrolithiasis was similar in the ataluren and placebo groups. 
Non-serious episodes of creatinine elevation in Study 009 occurred predominantly in the ataluren 
arm and were transient, generally mild, and resolved with or without interruption of study 
medication. However, there was no clinically meaningful difference in creatinine between the 
ataluren and placebo arms at Week 48, indicating that there was no cumulative effect of these 
transient elevations on renal function. The incidence of treatment-emergent nephrolithiasis was 
similar in the ataluren and placebo groups. 

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The renal monitoring program included in this protocol considers nonclinical and clinical 
findings with ataluren and past experience with known nephrotoxicants.  Concomitant use of 
potentially nephrotoxic antibiotics with ataluren is prohibited.  A focus is placed on 
well-established clinical indictors of renal dysfunction for making diagnostic decisions and 
prompting treatment interruptions/ modifications in individual patients.  The rationale for each of 
the decision-making parameters is discussed below.     
• Serum Creatinine:  Given the widespread clinical familiarity with serum creatinine as a 
marker of renal dysfunction and as a monitoring tool for nephrotoxins in clinical practice 
[Gilead 2002, Gilead 2006, Novartis 2005], characterization of serum creatinine provides an 
appropriate frame of reference relative to other experiences.   
• Serum Cystatin C:  An alternative to assessing GFR based on serum creatinine, serum 
cystatin C offers advantages in the assessment of renal function in the context of this 
protocol.  Cystatin C is a low-molecular-weight {~13 kDa) proteinase inhibitor derived from 
all cells that is filtered by the glomerulus and degraded in the renal tubules [Herget-Rosenthal 
2007].  The serum cystatin C concentration is almost solely dependent upon GFR and 
appears relatively unaffected by muscle mass or other conditions.  An additional advantage is 
that circulating cystatin C changes more rapidly in response to multiple types of renal injury 
than creatinine [Herget-Rosenthal 2007].  Methods for measuring cystatin C are standardized 
and the correlations between serum cystatin C and GFR have been derived and confirmed in 
large studies involving healthy children and adults and those with renal dysfunction 
[Dharnidharka 2002, Grubb 2005, Zappitelli 2007].  Based on these considerations, values of 
serum cystatin above 1.33 mg/L should prompt diagnostic evaluation and 
interruption/modification of study drug if required per protocol. 
• Serum Blood Urea Nitrogen: Considering its role in maintaining urine-concentrating 
ability, urea has major importance in renal physiology and its clinical measurement as a 
marker of renal dysfunction is long established.  In the context of nephrotoxicity, elevations 
in BUN suggest disruption of tubular integrity [Vonderscher 2007].  In the nonclinical mouse 
studies of ataluren in which nephrosis were observed, BUN was elevated in some of the 
affected animals, confirming that this marker should also be measured in clinical studies of 
ataluren.  Monitoring serum BUN, like monitoring creatinine, provides an additional frame 
of reference relative to other markers assessed within this study and in other studies of 
known nephrotoxicants.  However, an elevation in BUN is not a specific signal of renal 
tubular injury, but also may reflect compromised renal tubular blood flow due to depressed 
cardiac output, medications, or dehydration [Guignard 2004, Stevens 2007].  For these 
reasons, a BUN increase ≥1.5 x ULN should prompt a review of potential pre-renal, renal, 
and post-renal causes for the abnormality as well as consideration of potential 
interruption/modification of study drug dosing. 
• Renal Ultrasound: In considering the markers to be used for decision-making within the 
study, renal ultrasound is proposed because it is the central imaging modality for assessing 
the anatomy of the kidneys and urinary tract in children.  The test can detect changes in 
kidney size, assess parenchymal cystic or mass lesions, evaluate the renal vasculature, and 
assess the collecting system [Avni 2004].  Renal ultrasound is a routine component of 
diagnostic algorithms for follow-up of serum or urinary abnormalities suggesting renal 
dysfunction [Barratt 2004] and will be among the diagnostic testing performed for this 

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protocol as part of the assessment for such findings.  It is safe, painless and convenient, 
providing advantages over contrast-enhanced computed tomography (CT) scanning (which 
has contrast-mediated nephrotoxicity and radiation risks) and magnetic resonance imaging 
(MRI) (which requires contrast administration and potential sedation in young children).  
Obtaining a baseline ultrasound enhances the sensitivity of subsequent ultrasonography, 
offering context for any potential abnormalities emerging during study drug treatment.  An 
end-of-study ultrasound offers further reassurance that the kidneys remain anatomically 
normal at the completion of this protocol. 
14.2.5. Hepatic Monitoring Plan 
CF-related hepatobiliary obstruction and inflammation may result in serum transaminase 
elevations.  Consequently, it is not practical to exclude patients with modestly increased serum 
AST, ALT, or GGT concentrations from enrollment in the Phase 3 study, and monitoring for 
hepatotoxicity in patients with preexisting disease must rely on observing changes from baseline 
in these parameters while also looking for increases in bilirubin.  Consistent with well-
established guidelines [Abboud 2007] applied in this disease setting, even modest (Grade 2) 
alterations in bilirubin should prompt interruption of study drug, once abnormal value is 
confirmed (per Table 2).  
In the Phase 2a experience with ataluren in nmCF, reductions in serum markers of hepatic injury 
(particularly ALT) were observed [Clancy 2006], although no significant changes were seen in a 
larger-scale Phase 3 study.  Since no significant changes in hepatic serum markers were observed 
in the Phase 3 study, these markers are not included in this protocol as efficacy assessments.  
Therefore, the hepatic monitoring in this study is being performed as part of the general safety 
monitoring.   
14.2.6. Blood Pressure Assessment 
During the Phase 2b double-blind study of ataluren in nmDMD (PTC124-GD-007-DMD), 
6 patients – all receiving corticosteroids – had hypertension (or increased blood pressure) 
reported as adverse events (0 for ataluren 20-, 20-, 40-mg/kg, 5 for ataluren 10-, 10-, 20-mg/kg, 
and 1 for placebo.  During the double-blind Phase 3 study of nmCF (Study 009), changes in 
systolic and diastolic blood pressure were small and not clinically meaningful.  No substantial 
shifts in systolic or diastolic blood pressure from below to above the 95th and/or 99th percentile 
(adjusted for age and height) from baseline to Week 48 were observed in the ataluren group.  In 
this study, blood pressure will be monitored via standardized procedure at each visit.   
14.2.7. Other Nonclinical Findings 
Single lipomatous, non metastatic tumors, determined to be malignant hibernomas originating in 
brown adipose tissue were identified in 6 rats during a 26 week toxicity study.  In a second 
26-week rat study, no malignant hibernomas were observed in any dose group, including the 
high dose group (1200 mg/kg/day).  The exact correlative relevance of this finding is unclear 
given the lack of reproducibility in rats, the different physiology of brown fat in rats relative to 
humans [Cannon 2004, Iatropoulos 2004], the very young age of the rats used in these studies, 
the lack of ataluren genotoxicity, and the extreme rarity and generally benign course of 
hibernomas in humans [Furlong 2001].   
Urinary bladder tumors were observed in 3/60 females at the high dose of 300 mg/kg/day in the 
24-month carcinogenicity study in rats.  This dose exceeded the maximum tolerated dose 

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(MTD), based on an average 23% reduction in body weight gain in comparison to vehicle 
controls throughout the study.  In addition, the proposed mode of urinary bladder tumor 
formation (presence of calculi) in rats is not considered relevant to humans.  Mean steady state 
exposures in female rats at the mid-dose of 100 mg/kg/day and in male rats at the high-dose of 
300 mg/kg/day were 4 and 6 times, respectively, the steady state exposure in patients 
administered ataluren at the morning, midday and evening doses of 10-, 10-, and 20-mg/kg/day, 
respectively. 
Long-term post-treatment follow-up safety data currently available, some for over 7 years, from 
the patients dosed with ataluren to date in the clinical studies, indicate no increased risk of 
tumors. Long-term outcomes will be collected by completion of long-term health surveys after 
completion of ataluren or through a post-approval registry. 
14.2.8. Other Abnormalities 
Recommendations for interruption of dosing are provided in Section 6.3.1, with the general 
intent that a Grade 4 (life-threatening) event should result in immediate cessation of study drug 
while awaiting confirmation of the abnormal laboratory value, a Grade 3 (severe) event may 
require confirmation of the abnormal laboratory value before cessation of dosing, and a Grade 2 
(moderate) event may prompt further evaluation while study drug dosing continues.  It is 
intended that these recommendations be viewed flexibly; the type and context for any adverse 
event or laboratory abnormality must be considered in taking action.   
14.2.9. Actions to be Taken in Response to Safety Signals 
The intent of the recommendations to investigators regarding response to safety signals is to 
encourage a medically appropriate and consistent approach to adverse events and 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 the PTC Therapeutics medical monitor (or qualified designee) to obtain guidance and to 
ascertain whether similar events are being seen at other investigator sites.  The availability of 
advice from medical experts retained by PTC Therapeutics is intended to provide a uniformly 
high level of consultation in support of the investigators and the PTC Therapeutics medical 
monitor.   
The dose interruption and modification provisions are designed to balance a primary concern for 
patient safety with the potential for observing efficacy in circumstances under which a patient 
experiencing an adverse event may still be able to continue on therapy at a lower study drug 
dose.  Interruption of therapy is advocated as the primary response in order to determine 
reversibility of the adverse finding. 
14.2.10. 
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 (eg, inhaled 
aminoglycosides) 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.  
Precluding the accrual of patients who are participating in another therapeutic clinical trial 
prevents potential conflicts between protocols relating to assessments of efficacy and safety, or 
conduct of study procedures.     

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Concomitant use of potentially nephrotoxic systemic antibiotics (eg, aminoglycosides and 
vancomycin) with ataluren is prohibited. 
Aminoglycosides, eg, tobramycin, are theorized to ribosomally interfere with ataluren’s 
mechanism of action.  In previous Phase 3 studies of ataluren, notable differences in treatment 
effect have been observed in ataluren-treated patients that had been concomitantly treated with 
chronic inhaled aminoglycosides (eg, tobramycin) vs patients that were not administered chronic 
inhaled aminoglycosides (eg, tobramycin), which have a ribosomal-binding mechanism of 
action.  An in vitro experiment confirmed this ribosomal mechanistic interference theory [Study 
Report PTC124-12030].  For these reasons, chronic use of inhaled aminoglycoside use cannot 
occur during study participation.  Short regimens (up to 3 months total) are permitted for 
eradication of newly acquired Pseudomonas aeruginosa infection but must be completed during 
the first 12 weeks of treatment.  Prohibition of the use of inhaled aminoglycosides in the last 12 
weeks of study treatment is intended to minimize the possible interference with ataluren at Week 
48, the time point at which efficacy is primarily determined in this study.  Eradication protocols 
that have been reported to have eradication success similar to 3 months of  tobramycin inhalation 
solution (TIS) should be considered, including protocols requiring only 28 days of TIS therapy 
[Ratjen 2009] or use of alternative antibiotics such as inhaled sodium colistimethate plus oral 
ciprofloxacin for 3months [Proesmans 2013].  Furthermore, similar outcomes were seen in CF 
patients assigned to inhaled colistin/oral ciprofloxacin or to inhaled tobramycin/oral 
ciprofloxacin [Tacetti 2012].  Patients requiring Pseudomonas aeruginosa eradication protocols 
that require inhaled tobramycin in the last 12 weeks of the study must be withdrawn from study 
participation.  Use of eradication using non-aminoglycoside antibiotics may occur at any time 
during the study.  There is no prohibition of the use of inhaled vancomycin.  Specific start and 
stop dates for all inhaled antibiotics used during the study must be captured in the eCRF.   
In vitro studies have suggested that ataluren is potentially an inhibitor of cytochrome P450 
(CYP) 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 breast cancer resistant protein (BCRP).  Caution should be exercised 
when ataluren is co-administered with drugs that are inducers of UGT1A9 (eg, phenobarbital, 
rifampin), or inhibitors of BCRP (eg, cyclosporine, eltrombopag, geftinib).   
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 1 
(OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3).  Caution should be exercised when ataluren is co-administered with drugs that are 
substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, or OATP1B3 (eg, 
oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, valsartan, pravastatin, 
rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased concentration of these 
drugs. 
14.3. Study Committees 
Inclusion of an SSC comprising PTC Therapeutics clinical/biostatistical personnel and 
committed disease experts and a DMC of independent experts incorporates a high level of 

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collaborating skill in the design and conduct of the trial with a substantial degree of impartial 
oversight in analysis of trial results.  Inclusion of a nephrologist on the DMC provides access to 
expert assistance in these disciplines that should enhance the review of any potential safety 
signals relating to the kidneys. 
14.4. Efficacy measurements 
14.4.1. Spirometry 
Progressive pulmonary dysfunction is the major source of disability and shortened survival 
associated with CF, and reversing such dysfunction is an essential therapeutic goal.  The 
principal means of assessing both the level of dysfunction and the effects of intervention has 
been spirometry [Ramsey 1994].   
In order to maximize uniformity of testing, data collection, and analysis for this study, an 
experienced vendor has been engaged to provide a single spirometry system.  This system 
ensures that all sites are provided with a study-specific spirometer for collection of pulmonary 
function data. In addition, the system establishes standard operating procedures for spirometry 
performance, requiring that spirometric effort is sufficient and that each test is valid consistent 
with American Thoracic Society/European Respiratory Society guidelines [Miller 2005a, Miller 
2005b].  The system is preprogrammed to generate data normalized for gender, age, and height 
using well-established nomograms for children [Wang 1993], and adults [Hankinson 1999].  
Flow-volume loops and derived data are transferred to a central site for expert over-reading and 
interpretation.  Data capture, transmission, and storage are performed electronically using secure 
systems that are compliant with FDA 21 CFR Part 11.Advances in electronic spirometric 
evaluation and data capture permit a unified approach to pulmonary function testing in order to 
enhance the consistency and accuracy of test performance. 
14.4.2. Pulmonary Exacerbations  
Decreasing exacerbation frequency has been considered an important outcome of treatment in 
CF, and has been an endpoint documenting drug efficacy in prior randomized clinical trials 
[Fuchs 1994, McCoy 1996, Ramsey 1999, Quan 2001, Saiman 2003, Elkins 2006].  As in the 
previous double-blind study, the modified Fuchs definition (ie, presence of at least 4 of 12 
Fuchs’ signs and symptoms without the requirement for treatment with antibiotics) will be the 
primary definition used [Kerem 2014]. 
A respiratory event collection form has been developed to collect CF pulmonary exacerbation 
information from the physician perspective.  These data will be collected by the investigator or 
other qualified medical personnel at clinic visits and any unscheduled visits as appropriate.  
Patients will also be instructed to contact their physician by telephone during or immediately 
after an exacerbation has occurred to describe any events that occur between on-site visits.  This 
form is designed to systematically characterize health-care provider observations related to 
exacerbations, and to allow categorization and scoring consistent with Fuchs or Rosenfeld CF 
exacerbation definitions.  The data generated from these forms will provide the basis for 
recording incidence and rate of pulmonary exacerbations, which will be assessed in this study 
14.4.3. HRQL and the CFQ-R  
The CFQ-R has been most extensively developed HRQL instrument in CF and is available in 
multiple languages.  The CFQ-R comprises 44 items, including 7 generic scales of physical 

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functioning, role functioning, vitality, health perceptions, emotional functioning, and social 
functioning, and 5 CF specific scales of respiratory and digestive symptoms, body image, eating 
disturbances, and treatment burden.  Variations of the CFQ-R can be employed in children from 
6 to 13 years of age (CFQ child), parents with young children with CF (CFQ parent), and 
adolescents ≥14 years of age (CFQ teen/adult).  The instrument has undergone large multicenter 
validation program within the centers of the CF TDN [Quittner 2005].   
The focus of attention will be on changes in the respiratory scale as the most direct assessment of 
ataluren treatment effect.  Changes in other HRQL domains (eg, emotional or social functioning) 
are likely to be less directly affected by drug therapy. 
14.4.4. Weight/Body Mass Index  
Patients with CF are almost universally underweight when compared to healthy individuals of 
the same gender and age.  Contributing factors include malabsorption due to pancreatic 
insufficiency and high work of breathing [Zemel 1996].  There is an association between 
worsening lung function and malabsorption, and evidence that nutritional intervention may 
improve pulmonary function [Milla 2004].   
Given this knowledge, assessment of body weight and BMI during the course of this Phase 3 
extension study is planned.  While changes in these parameters are quite nonspecific, they 
constitute simple-to-assess outcomes of general well-being that complement data obtained from 
other efficacy measures. 
14.4.5. Hepatobiliary Markers 
Patients with CF can experience hepatobiliary inflammation [Colombo 2007], manifest as 
abnormalities of liver-derived serum enzymes such as serum ALT or AST in ~15% of patients 
with the disease [Goss 2007].  Oral bile acid therapy is available, but is variably used, and its 
influence on CF-associated hepatic disease progression or serum transaminase values is unclear 
[Colombo 2007].  In the Phase 2a experience with ataluren, reductions in serum markers of 
hepatic injury (particularly ALT) were observed [Clancy 2006], although no significant changes 
were seen in Study 009.  Assessing these markers as extrapulmonary manifestations of CF is 
planned in this study. 
14.4.6. New Pseudomonas Aeruginosa Lung Infection  
In addition to the treatment of persistent Pseudomonas aeruginosa lung infection with inhaled 
antibiotics recommend by both European and CF treatment guidelines [Mogaygel 2013, 
Heijerman 2009] a growing body of evidence suggests that treatment of early Pseudomonas 
aeruginosa infection may be warranted, leading to a recommendation for early eradication 
therapy by the European Cystic Fibrosis Society [Heijerman 2009].  To investigate the extent to 
which ataluren may influence the occurrence of new Pseudomonas aeruginosa lung infection, the 
incidence of the occurrence of new positive cultures will be calculated. These airway cultures 
will be collected using the procedures and at a frequency (eg, quarterly) consistent with local 
standard of care.  To limit reporting bias, the presence of Pseudomonas aeruginosa-positive 
cultures will be specifically elicited from the investigator.    

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15. BENEFITS AND RISKS 
15.1 
Benefits and Risks: Nonclinical 
In cellular assays and animal models of genetic disease, ataluren demonstrated the ability to 
specifically and selectively enable readthrough of mRNA containing a premature stop codon, 
inducing production of full-length protein that localizes to the appropriate cellular location and is 
functionally active.  Ataluren consistently enabled mRNA readthrough and functional full-length 
protein production from mRNAs that contain a premature stop codon without promoting 
readthrough of normal stop codons.   
Ataluren was shown to be selective for translation.  Ataluren did not alter levels of mRNA with 
premature stop codons or wild type mRNA demonstrating that ataluren does not modify 
transcription or mRNA stability.  In cell-free translation assays, ataluren functions at the level of 
translation and not transcription.  Ataluren does not produce a functional protein by promoting 
readthrough of premature stop codons due to frameshift mutations (insertions or deletions) or of 
mRNAs harboring multiple sequential premature stop codons.  Ataluren is selective for 
premature stop codons and does not promote readthrough of normal stop codons.     
Toxicokinetic data were obtained in toxicity studies conducted in mice, rats, rabbits, and dogs.  
Consistent with the short t½, there was no accumulation of drug in plasma upon repeated daily 
dosing.  In all species, ataluren exposure increased with increasing dose, but the increase was 
generally less than dose proportional.  There were no sex-related differences in ataluren exposure 
in dogs, but in rats and mice, exposure was slightly higher in females than in males.  The major 
metabolite seen in mice, rats and dogs was ataluren acyl glucuronide; exposure to this metabolite 
in the toxicology species at LOAELs, NOAELs, and NELs in the toxicology program was 
greater than the exposure observed in humans administered the clinical dose of 10-, 10- and 20-
mg/kg/day at morning, midday, and evening, respectively.  Ataluren is highly bound (> 97%) to 
plasma proteins in all species, including human.  Ataluren is neither a substrate for nor an 
inhibitor of p-glycoprotein.  Enzyme inhibition studies with human liver microsomes showed 
that ataluren has a very weak potential for direct inhibition of CYP2C8 and CYP2C9.  Enzyme 
induction evaluations in human hepatocytes showed that ataluren did not induce the activities of 
CYP450 enzymes.  However, there were slight increases in the activities of CYP2C8 and 
CYP2C9 only with the highest incubated ataluren concentration of 400 μM.  It was concluded 
that the increased activities of CYP2C8 and CYP2C9 were not clinically significant or relevant.  
Therefore, ataluren is not expected to decrease exposure to drugs that are eliminated via 
metabolism by these CYP enzymes. 
Ataluren was evaluated in safety pharmacology studies and found to have no effects on the 
cardiovascular system, respiratory system, or central nervous system.  In the toxicology program, 
the major findings observed were species-specific, ie, observed in one toxicology species only.  
These findings included kidney findings in mice (nephrosis, predominantly in the distal nephron, 
reversible following cessation of dosing) and adrenal gland cortical findings in dogs 
(lymphohistiocytic infiltrates with focal parenchymal cell degeneration in regions responsible for 
synthesis of glucocorticoids).  Chronic studies were conducted in weanling rats and dogs to 
support dosing in children as young as 2 years of age.  Ataluren was not genotoxic, and was not 
teratogenic in rats and rabbits.   In rats and rabbits, fetal toxicity was observed only at materno-
toxic doses.  Ataluren had no effect on the fertility of male and female rats.  In rats, postnatal 
developmental effects were observed only at materno-toxic doses.  Maternal administration of 

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ataluren in rats had no effect on F1 reproduction or F2 embryo/fetal development.  Ataluren did 
not increase the incidence of tumors in a 26-week carcinogenicity study in Tg.rasH2 mice. 
Tumors observed in rats in the toxicology program occurred at exposures that exceeded clinical 
exposure and were not considered relevant to humans.  The structurally identified process 
impurities of the ataluren drug substance were qualified in rats at doses 29- to 33-fold higher  
than would be administered in the clinic at the proposed morning, midday, and evening doses of 
10-, 10- and 20-mg/kg/day, respectively.  Ataluren is a small molecular weight compound, and 
therefore, is not expected to produce anti-drug antibodies.  Ataluren had no effect on the immune 
system in the toxicology program and in the clinical trials; therefore, immunotoxicity studies 
were not performed with ataluren. 
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 in patients as young as 2 years of age. 
The nonclinical evaluation of ataluren presented in this summary support its use for the treatment 
of nmCF. 
15.2 
Benefits and Risks: Clinical Efficacy 
Multiple Phase 2 and Phase 3 trials have now shown the potential benefit and safety of ataluren 
in the treatment nmCF in adults and children.  Ataluren activity was demonstrated with TEPD 
testing in 2 separate Phase 2 trials (further details are provided in the ataluren Investigator 
Brochure).   
Clinical benefit was further explored in the multicenter Phase 3 double-blind study (Study 009). 
In this 48-week study positive trends favoring ataluren were seen in the primary endpoint, the 
relative change from baseline in %-predicted FEV1 at 48 weeks, which demonstrated a 3% 
difference between ataluren and placebo (-2.5% change on ataluren vs -5.5% change on placebo; 
p=0.124).  An analysis of the relative change from baseline in %-predicted FEV1 across all 
post-baseline study visits demonstrated an average difference between ataluren and placebo of 
2.5% (-1.8% average change on ataluren vs -4.3% average change on placebo; p= 0.0478).  A 
larger effect was seen in the patients not receiving chronic inhaled antibiotics.  The effect of 
inhaled antibiotics was largely attributable to the use of inhaled aminoglycosides (ie, 
tobramycin).  In patients not receiving chronic inhaled tobramycin at baseline, the Week 48 
difference between the ataluren and placebo arms in the relative change of %-predicted was 
5.7% (-0.7% change on ataluren vs -6.4% change on placebo difference in FEV1). 
The secondary endpoint, the rate of pulmonary exacerbations (ie, the number of pulmonary 
exacerbations in 48 weeks) also showed a positive trend in favor of ataluren, with the rate in the 
ataluren group being 23% lower than the placebo group (p=0.0992).  In the patients not receiving 
chronic inhaled tobramycin, the pulmonary exacerbation rate in the ataluren group was 40% 
lower than the rate in the placebo group.  These results show a consistent treatment effect of 
ataluren on both pulmonary function and exacerbation rates.  
Collectively, the FEV1 and pulmonary exacerbation data demonstrate the beneficial effect of 
ataluren in patients with nmCF aged 6 years and older.  The increased effect seen in patients not 
receiving chronic inhaled tobramycin makes benefit more likely in these patients, who constitute 
the study population of this trial. 

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15.3 
Benefits and Risks: Clinical Safety 
Safety results indicate that ataluren was generally well tolerated.  Across all studies, the most 
common treatment-emergent adverse events were consistent with background CF-related sinus, 
pulmonary, or gastrointestinal symptoms.  Notable in the Phase 2 and 3 trials was the occurrence 
of mild dysuria in several patients.  Resolution was successfully achieved with increased 
hydration.  No clearly dose-dependent increases in frequency or severity of adverse events were 
evident.  There were no safety concerns identified in patients’ physical examinations, vital sign 
measurements, or electrocardiograms (ECGs). 
In Study 009, the overall incidence of adverse events through Week 48 was similar in the 
ataluren and placebo groups.  The most common adverse events were typical for CF and 
included pulmonary exacerbation, cough, and upper respiratory tract infection, which occurred at 
similar frequencies in the ataluren and placebo arms.  Most of the serious adverse events, those 
requiring hospitalization, were pulmonary exacerbations unrelated to study treatment and some 
patients experienced creatinine elevations that occurred at Grades 3 and 4 in connection with 
concomitant treatment with systemic aminoglycosides (further details are provided in Section 
14.2.4).  Therefore, the Study 009 protocol was amended to prohibit the concomitant use of these 
antibiotics with ataluren, and to encourage patients to maintain adequate hydration.  Non-serious 
episodes of creatinine elevation occurred predominantly in the ataluren arm and were transient, 
generally mild, and resolved with or without interruption of study medication. 
In addition, in clinical trials in nmDMD the adverse-event profile of ataluren was comparable to 
that of placebo.  In the double-blind Phase 2b study of nmDMD, six patients – all receiving 
corticosteroids - had hypertension (or increased blood pressure) reported as adverse events (0 for 
ataluren 20-, 20-, 40-mg/kg, 5 for ataluren 10-, 10-, 20-mg/kg, and 1 for placebo), although 
similar events were not seen in the nmCF studies.  Mean total cholesterol and triglycerides were 
in the upper range of normal at baseline and increased, reaching borderline high or high values.  
The values tended to stabilize early in the study and did not increase further with continued 
treatment.  Small increases in mean serum creatinine, BUN, and cystatin C were observed.  
Similarly, the values tended to stabilize early in the study and did not increase further with 
continued treatment.  
Collectively, the safety data from clinical trials demonstrate that ataluren has a favorable safety 
profile for the treatment of patients with nmCF. 
15.4 
Benefit/Risk Conclusions 
Cystic fibrosis (CF) is a disabling and life-threatening genetic disorder resulting from mutations 
in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR 
dysfunction leads to multiple organ dysfunction starting in early childhood.  An urgent unmet 
medical need exists for a therapy that addresses the underlying cause of nmCF, a condition for 
which no approved treatment exist.  Ataluren 10-, 10-, 20-mg/kg represents the first disease-
modifying therapy for 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 nmCF. 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 021e) is feasible and will provide additional safety and efficacy data of 
ataluren in nmCF.  

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Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol 
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