Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis Nonsense mutation Premature stop codon PTC124 Ataluren
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 61
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine the long-term safety and tolerability of ataluren in participants with nonsense mutation cystic fibrosis (nmCF) who completed participation in the double-blind study PTC124-GD-009-CF (NCT00803205), as assessed by adverse events and laboratory abnormalities. The secondary objective of this study includes the assessment of the efficacy of ataluren, as measured by forced expiratory volume in 1 second (FEV1) and pulmonary exacerbation rate, and other safety parameters (for example, 12-lead electrocardiogram \[ECG\] measurements, vital signs).

Detailed description:

Arms:
arm 1: Participants will receive ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 192 weeks.

Interventions: intervention 1: Ataluren
Intervention descriptions: intervention 1: Ataluren will be administered per dose and schedule specified in the arm.

Protocol document:
Prot_001.pdf: 
CLINICAL PROTOCOL 
An Open-Label Safety and Efficacy Study for Patients with Nonsense 
Mutation Cystic Fibrosis Previously Treated with Ataluren (PTC124) 
Protocol Number PTC124-GD-023-CF 
08 February 2016 
Version 3.0 
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. 
NCT02107859


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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 
2013-005449-35 
Included in clinical trials.gov Database 
NCT02107859 
Protocol Number 
 
PTC124-GD-023-CF 
Protocol Version 
Version 3.0 
Protocol Version Date 
08 February 2016  
Protocol Phase 
Phase 3 
Protocol Title 
An Open-Label Safety and Efficacy Study for 
Patients with Nonsense Mutation Cystic Fibrosis 
Previously Treated with Ataluren (PTC124®) 
PTC Clinical Program Scientist 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Phone:
 
E-mail:
 
PTC Medical Monitor 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ  07080 USA 
Phone: 
 
Facsimile:
 
E-mail:
 
PTC Biostatistician 
 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Phone:
 
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. 
BACKGROUND .............................................................................................................................................. 12 
2.1. 
DISEASE INDICATION................................................................................................................................. 12 
2.2. 
ATALUREN (PTC124®)............................................................................................................................. 13 
2.2.1. 
Therapeutic Concept ............................................................................................................................ 13 
2.2.2. 
Chemical Description .......................................................................................................................... 14 
2.2.3. 
Clinical Studies .................................................................................................................................... 14 
2.2.3.1. 
Phase 1 Studies ............................................................................................................................... 14 
2.2.3.2. 
Phase 2a Studies ............................................................................................................................. 15 
2.2.3.3. 
Phase 3 Study .................................................................................................................................. 17 
2.2.3.3.1. 
Phase 3 Extension Study ............................................................................................................ 18 
3. 
STUDY OBJECTIVE AND ENDPOINTS .................................................................................................... 19 
3.1. 
OBJECTIVES ............................................................................................................................................... 19 
3.2. 
ENDPOINTS ................................................................................................................................................ 19 
4. 
SUBJECT SELECTION CRITERIA ............................................................................................................. 19 
4.1. 
OVERVIEW ................................................................................................................................................ 19 
4.2. 
INCLUSION CRITERIA ................................................................................................................................. 20 
4.3. 
EXCLUSION CRITERIA ............................................................................................................................... 20 
5. 
ENROLLMENT PROCEDURES .................................................................................................................. 22 
5.1. 
SOURCE AND NUMBER OF SUBJECTS ......................................................................................................... 22 
5.2. 
SCREENING AND STUDY DRUG DISPENSATION .......................................................................................... 22 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................................................................ 22 
6.1. 
STUDY DRUG SUPPLY ............................................................................................................................... 22 
6.1.1. 
Study Drug Packaging and Labeling ................................................................................................... 22 
6.1.2. 
Study Drug Storage .............................................................................................................................. 22 
6.1.3. 
Study Drug Dispensation ..................................................................................................................... 23 
6.1.4. 
Study Drug Preparation ....................................................................................................................... 23 
6.1.5. 
Study Drug Accountability ................................................................................................................... 23 
6.1.6. 
Overdose Precautions .......................................................................................................................... 24 
6.1.7. 
Inadvertent Exposure and Spill Precautions ....................................................................................... 24 
6.2. 
STUDY DRUG TREATMENT ........................................................................................................................ 24 
6.2.1. 
Study Drug Dosing .............................................................................................................................. 24 
6.2.2. 
Duration of Treatment ......................................................................................................................... 24 
6.2.3. 
Schedule of Administration .................................................................................................................. 24 
a Dosing times are examples and may be varied to suit each subject’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. ..... 25 
6.2.4. 
Instructions for Delays in Dosing ........................................................................................................ 26 
6.3. 
SAFETY MONITORING AND STUDY DRUG DOSE INTERRUPTION/MODIFICATION ....................................... 26 
6.3.1. 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and      Potential Drug 
Interruption/Modification .................................................................................................................................. 26 
6.3.2. 
Evaluation of Adverse Events or Laboratory Abnormalities ............................................................... 27 
6.3.3. 
Instructions for Resuming Ataluren Administration after an Interruption for Safety Concerns .......... 29 
6.3.4. 
Instructions for Discontinuation of Study Drug Administration for Safety Concerns ......................... 30 
7. 
CONCOMITANT AND SUPPORTIVE THERAPY .................................................................................... 30 
7.1. 
CONCOMITANT MEDICATIONS................................................................................................................... 30 
7.1.1. 
Therapy/Prophylaxis for CF-Related Conditions ................................................................................ 30 
7.1.2. 
Therapy for CF Pulmonary Exacerbations or Other CF Complications ............................................. 31 


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7.1.3. 
Drugs Metabolized by CYP2C8 or CYP2C9 ........................................................................................ 31 
7.1.4. 
Other Potential Interactions ................................................................................................................ 32 
7.1.5. 
Other Concomitant Medications .......................................................................................................... 32 
7.2. 
NON-DRUG THERAPY ................................................................................................................................ 33 
7.2.1. 
Physical and Respiratory Therapy ....................................................................................................... 33 
7.2.2. 
Dietary Restrictions ............................................................................................................................. 33 
7.2.3. 
Hydration ............................................................................................................................................. 33 
8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS ......................................................................... 33 
8.1. 
SCHEDULE OF EVENTS ............................................................................................................................... 33 
8.2. 
EXPLANATION OF STUDY PROCEDURES .................................................................................................... 37 
8.2.1. 
Screening and Week 1 Visits ................................................................................................................ 37 
8.2.2. 
Treatment Visits / Calls During Study ................................................................................................. 37 
8.2.2.1. 
End of Treatment ....................................................................................................................................... 37 
8.2.2.2. 
Post-Treatment Visits ................................................................................................................................. 37 
8.2.3. 
Informed Consent ................................................................................................................................. 37 
8.2.4. 
Clinical/Medication History ................................................................................................................ 37 
8.2.5. 
Vital Signs ............................................................................................................................................ 38 
8.2.6. 
Height, Weight, and Physical Examination ......................................................................................... 38 
8.2.7. 
Central Laboratory Assessments ......................................................................................................... 38 
8.2.7.1. 
Viral Screen and Pregnancy Laboratory Assessments ............................................................................... 38 
8.2.7.2. 
Adrenal Laboratory Assessment ................................................................................................................ 38 
8.2.7.3. 
Hematology Laboratory Assessment ......................................................................................................... 38 
8.2.7.4. 
Serum Biochemistry Laboratory Assessment ............................................................................................ 39 
8.2.7.5. 
Urinalysis ................................................................................................................................................... 39 
8.2.7.6. 
Pharmacokinetic Analysis (PK) ................................................................................................................. 39 
8.2.8. 
Renal Ultrasound ................................................................................................................................. 39 
8.2.9. 
12-Lead ECG ....................................................................................................................................... 39 
8.2.10. 
Ataluren Administration and Dispensation ..................................................................................... 40 
8.2.11. 
Ataluren Compliance ...................................................................................................................... 40 
8.2.12. 
Adverse Events ................................................................................................................................ 40 
8.2.13. 
Concomitant Medications ............................................................................................................... 40 
8.2.14. 
Spirometry ....................................................................................................................................... 41 
8.2.15. 
Pulmonary Exacerbation Rate ........................................................................................................ 41 
8.2.16. 
Presence of Pseudomonas aeruginosa in Sputum ........................................................................... 42 
8.3. 
BLOOD COLLECTION SUMMARY ................................................................................................................ 42 
9. 
ADVERSE EVENT ASSESSMENTS ............................................................................................................ 42 
9.1. 
ADVERSE EVENT DEFINITIONS .................................................................................................................. 42 
9.1.1. 
Adverse Events ..................................................................................................................................... 42 
9.1.2. 
Serious Adverse Events (SAEs) ............................................................................................................ 43 
9.1.3. 
Unexpected Adverse Events ................................................................................................................. 45 
9.2. 
ELICITING ADVERSE EVENT INFORMATION ............................................................................................... 45 
9.3. 
ADVERSE EVENT RECORDING ................................................................................................................... 45 
9.4. 
DESCRIBING ADVERSE EVENT RELATIONSHIP TO STUDY DRUG ............................................................... 46 
9.5. 
GRADING OF ADVERSE EVENT SEVERITY .................................................................................................. 46 
9.6. 
PREGNANCY .............................................................................................................................................. 47 
9.7. 
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS ..................................................................................... 47 
9.8. 
ADVERSE EVENT REPORTING PERIOD ....................................................................................................... 48 
9.9. 
INVESTIGATOR SITE ADVERSE EVENT REPORTING REQUIREMENTS .......................................................... 48 
9.10. 
PTC THERAPEUTICS ADVERSE EVENT REPORTING REQUIREMENTS ......................................................... 49 
10. 
WITHDRAWAL OF SUBJECTS................................................................................................................... 50 
11. 
STATISTICS AND DATA MANAGEMENT ............................................................................................... 50 
11.1. 
SAMPLE SIZE CALCULATION FOR THE PRIMARY ENDPOINT ...................................................................... 50 
11.2. 
POPULATION DEFINITION .......................................................................................................................... 51 


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11.2.1. 
As-Treated Population .................................................................................................................... 51 
11.2.2. 
Intent-to-Treat Population .............................................................................................................. 51 
11.3. 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................................ 51 
11.4. 
SPECIFIC STATISTICAL ANALYSES ............................................................................................................. 51 
11.4.1. 
Study Conduct and Subject Disposition .......................................................................................... 51 
11.4.2. 
Baseline Characteristics ................................................................................................................. 51 
11.4.3. 
Study Treatment Administration ..................................................................................................... 51 
11.4.4. 
Use of Concomitant Medication and Supportive Therapy .............................................................. 51 
11.4.5. 
Primary Variables ........................................................................................................................... 51 
11.4.5.1. 
Adverse Events .......................................................................................................................................... 51 
11.4.5.2. 
Laboratory Data ......................................................................................................................................... 52 
11.4.6. 
Secondary Variables ....................................................................................................................... 52 
11.4.6.1. 
12-Lead ECG and Other Safety Parameters ................................................................................... 52 
11.4.6.2. 
Spirometry ....................................................................................................................................... 52 
11.4.6.2.1. 
Change from Baseline in %-predicted FEV1 ........................................................................................ 52 
11.4.6.3. 
Pulmonary Exacerbation Rates .................................................................................................................. 52 
11.4.7. 
Tertiary Variables ........................................................................................................................... 53 
11.4.7.1. 
Spirometry ....................................................................................................................................... 53 
11.4.7.2. 
Weight and BMI .............................................................................................................................. 53 
11.4.8. 
Exploration of Correlations ............................................................................................................ 53 
12. 
STUDY COMMITTEES ................................................................................................................................. 53 
12.1. 
DATA MONITORING COMMITTEE .............................................................................................................. 53 
13. 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR ......................................................... 54 
13.1. 
COMPLIANCE WITH ETHICAL AND REGULATORY GUIDELINES .................................................................. 54 
13.2. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ....................................................... 54 
13.3. 
INFORMED CONSENT/ASSENT ................................................................................................................... 55 
13.4. 
CASE REPORT FORMS ................................................................................................................................ 55 
13.5. 
STUDY RECORDS ....................................................................................................................................... 56 
13.6. 
CONFIDENTIALITY ..................................................................................................................................... 56 
13.7. 
RETENTION OF RECORDS ........................................................................................................................... 57 
13.8. 
MONITORING AND AUDITING .................................................................................................................... 57 
13.9. 
TERMINATION OF THE STUDY .................................................................................................................... 58 
13.10. 
PUBLIC NOTIFICATION OF STUDY CONDUCT ........................................................................................ 58 
13.11. 
DISSEMINATION OF RESULTS ................................................................................................................ 58 
13.12. 
COMMUNICATION WITH REGULATORY AUTHORITIES ........................................................................... 59 
14. 
RATIONALE FOR STUDY DESIGN FEATURES ..................................................................................... 59 
14.1. 
PATIENT SELECTION .................................................................................................................................. 59 
14.1.1. 
General ........................................................................................................................................... 59 
14.1.2. 
Inclusion of Minors ......................................................................................................................... 59 
14.1.3. 
Safety Measurements....................................................................................................................... 61 
14.1.3.1. 
Safety Profiling .......................................................................................................................................... 61 
14.1.3.2. 
Study Drug Compliance ............................................................................................................................. 61 
14.1.4. 
Required Laboratory Values ........................................................................................................... 61 
14.1.5. 
Reproductive Considerations .......................................................................................................... 62 
14.1.6. 
Prior and Concomitant Therapies .................................................................................................. 62 
14.2. 
TREATMENT RATIONALE ........................................................................................................................... 63 
14.2.1. 
Schedule and Ataluren Dose Selection............................................................................................ 63 
14.2.2. 
Duration of Therapy........................................................................................................................ 63 
14.2.3. 
Safety Monitoring ............................................................................................................................ 63 
14.2.3.1. 
Renal Abnormalities .................................................................................................................................. 64 
14.2.3.1.1. 
Overview .............................................................................................................................................. 64 
14.2.3.1.2. 
Renal Monitoring Plan ......................................................................................................................... 65 
14.2.4. 
Hepatic Monitoring Plan ................................................................................................................ 67 
14.2.5. 
Blood Pressure Assessment ............................................................................................................. 67 


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14.2.6. 
Other Nonclinical Findings............................................................................................................. 67 
14.2.7. 
Other Abnormalities ........................................................................................................................ 68 
14.2.8. 
Actions to be Taken in Response to Safety Signals ......................................................................... 68 
14.2.9. 
Efficacy Measurements ................................................................................................................... 68 
14.2.9.1. 
Spirometry ................................................................................................................................................. 68 
14.2.9.2. 
Pulmonary Exacerbations .......................................................................................................................... 69 
14.2.9.3. 
Weight/Body Mass Index........................................................................................................................... 70 
14.2.10. 
Exposure Outcome Measures .......................................................................................................... 70 
14.2.10.1. 
Trough Ataluren Plasma Concentrations ................................................................................................... 70 
14.2.11. 
Timing of Assessments .................................................................................................................... 70 
14.3. 
STUDY COMMITTEES ................................................................................................................................. 70 
15. 
BENEFITS AND RISKS ................................................................................................................................. 71 
15.1. 
BENEFITS AND RISKS: NONCLINICAL ........................................................................................................ 71 
15.2. 
BENEFITS AND RISKS: CLINICAL ............................................................................................................... 72 
15.3. 
BENEFITS AND RISKS: SAFETY .................................................................................................................. 73 
15.4. 
BENEFIT/RISK CONCLUSIONS .................................................................................................................... 73 
16. 
BIBLIOGRAPHY ............................................................................................................................................ 75 
 LIST OF TABLES 
TABLE 1: 
SUGGESTED DAILY DOSING SCHEDULE ............................................................................................. 25 
TABLE 2: 
SAFETY MONITORING PARAMETERS AND ACTIONS TO BE TAKEN .................................................. 27 
TABLE 3: 
SCHEDULE OF EVENTS ........................................................................................................................ 34 
TABLE 4: 
RELATIONSHIP OF ATALUREN TO ADVERSE EVENT .......................................................................... 46 
TABLE 5: 
GRADING OF ADVERSE EVENT SEVERITY .......................................................................................... 47 
TABLE 6: 
INVESTIGATOR SITE REPORTING REQUIREMENTS FOR ADVERSE EVENTS...................................... 48 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
Area under the concentration-time curve 
BCRP 
Breast Cancer Resistant Protein 
ß-HCG 
Beta human chorionic gonadotropin 
BID 
Bis in die (2 times per day) 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
cAMP 
Cyclic adenosine monophosphate 
CD-ROM 
Compact disc read-only memory 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulations 
CFTR 
Cystic fibrosis transmembrane conductance regulator 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence interval 
CK 
Creatine kinase 
Cmax 
Maximum plasma concentration 
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 
HIV 
Human immunodeficiency virus 
HRQL 
Health-related quality of life 
ICH 
International Conference on Harmonization 
ICJME 
International Committee of Medical Journal Editors 
ICTRP 
WHO International Clinical Trials Registry Platform 
IL-8 
Interleukin 8 


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Abbreviation 
Definition 
IND 
Investigational New Drug (Application) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intention-to-treat 
IVR/IWR 
Interactive Voice Response/Interactive Web Response 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LABA 
Long-acting beta agonist 
LDL 
Low-density lipoprotein 
LOAEL 
Lowest-observed-adverse-effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NEL  
No-effect-level 
nmCF 
Nonsense mutation cystic fibrosis 
nmDBMD 
Nonsense mutation Duchenne/Becker muscular dystrophy 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
NOAEL 
No-observed-adverse-effect level 
OAT1 
Organic anion transporter 1  
OAT3 
Organic anion transporter 3 
OATP1B3 
Organic anion transporting polypeptide 1B3 
PK 
Pharmacokinetic(s) 
PTCAD 
PTC Therapeutics Awareness Date 
PTC124® 
Ataluren 
SABA 
Short-acting beta agonist 
SSC 
Study Steering Committee 
TID 
3 times per day 
TEPD 
Transepithelial Potential Difference 
T ½  
Plasma half-life 
ULN 
Upper limit of Normal 
WIRB 
Western Institutional Review Board 
 


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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.  Ivacaftor (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, double-blind, placebo-controlled study (PTC124-GD-009-CF; Study 009) of 
patients ≥6 years of age with nmCF receiving ataluren 10, 10, and 20 mg/kg for 48 weeks 
favored positive trends in the primary (relative change in %-predicted forced expiratory volume 
in 1 second [FEV1]) and secondary endpoint (pulmonary exacerbation rate over 48 weeks) of the 
trial compared to placebo [Rowe 2012].  Interim analysis of a subsequent Phase 3, open-label, 
extension study (PTC124-GD-009e-CF; Study 009e) lasting ~96 weeks supported the positive 
trends favoring ataluren vs placebo that were demonstrated in Study 009 [Kerem 2013].  
The primary objective of this study is to determine the long-term safety and tolerability of 10-, 
10-, 20-mg/kg ataluren in patients with nmCF that have completed participation in the double-
blind study (Study 009) as assessed by adverse events and laboratory abnormalities.  
The secondary objectives are to determine the efficacy and safety of ataluren as assessed by 
spirometry (forced expiratory volume in 1 second [FEV1]), pulmonary exacerbation rate, and 
other safety parameters (eg, 12-lead ECG measurements, vital signs).   
The tertiary objectives are to determine the efficacy of ataluren as assessed by other parameters 
of pulmonary function (FVC and FEF25-75), and changes in body weight and body mass index 
(BMI).  
It is planned that approximately 70 patients that completed participation in Study 009 will be 
enrolled into the study.  All participating sites must therefore have had at least 1 patient that 
completed participation in Study 009. It is anticipated that most eligible patients would have also 


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been enrolled in Study 009e, the 96-week open-label study that immediately proceeded Study 
009.  
Compliance with study medication will be assessed and use of concomitant therapies will be 
described.   
Planned interim safety analyses will be conducted by an independent data monitoring committee 
(DMC).  The first safety review will occur when ~35 patients have completed ≥32 weeks of 
treatment.  The second safety review will occur when ~35 patients have completed ≥64 weeks of 
treatment.     
 
2. 
BACKGROUND 
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 


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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 
[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 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 


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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/Becker muscular dystrophy (nmDBMD) 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 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.  This study aims to further evaluate the safety profile of ataluren in 
nmCF patients. 
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 readthrough of premature stop codons in mRNA.  
Chemical optimization, pharmacologic characterization, and toxicological evaluation have led to 
identification of ataluren as an orally bioavailable, small molecule with potential clinical utility 
in treating genetic disorders through induction of readthrough of nonsense mutations and 
production of full-length, functional proteins [Welch 2007, Du 2008].  In the subset of subjects 
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. 
Clinical Studies 
2.2.3.1. Phase 1 Studies 
Two Phase 1 safety and pharmacokinetic (PK) studies of ataluren were conducted in 62 healthy 
adult male and female volunteers ranging in age from 18 to 30 years (PTC124-GD-001-HV) 
[Hirawat 2007].  Single doses of ataluren administered orally at dose levels ranging from 3 
mg/kg to 100 mg/kg were palatable and generally well tolerated.  Mild adverse events of 


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headache, dizziness, nausea, vomiting, diarrhea, and stomach discomfort at dose levels of 150 
and 200 mg/kg appeared to be coincident with achieving the maximum concentration (Cmax).  
Elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 
observed in 1 subject receiving a single dose of 200 mg/kg.  With repeated doses through 
50 mg/kg/dose 2 times per day (BID), reversible, low-grade (<2 times the upper limit of normal) 
transaminase elevations were observed in some patients (PTC124-GD-002-HV).  No bilirubin 
increases were observed.  In addition, no notable BUN, creatinine, or urinalysis abnormalities 
were observed.  PK analyses indicated rapid oral absorption, generally dose-proportional PK, an 
effective plasma half-life (t1/2) in the range of 2 to 6 hours, and no relevant drug accumulation 
with repeated dosing.  The data also demonstrated that ataluren can be given with or without 
food and that trough plasma concentrations exceeding the ~2 µg/mL to ~10 µg/mL target values 
active in the mdx mouse model of nmDBMD might best be achieved with TID dosing after 
meals. 
In addition, a Phase 1 single-dose study of the absorption, metabolism, and excretion of 
radiolabeled ataluren was conducted in 7 healthy male subjects (PTC124-GD-010-HV).  This 
study documented that ataluren bioavailability is ≥50% following oral administration of a single 
20 mg/kg dose under fasting conditions.  An inactive acyl glucuronide of ataluren represented 
the sole plasma metabolite in humans.  Relative to unchanged ataluren, the ataluren acyl 
glucuronide plasma exposures were 6.2% for Cmax and 7.6% for area under the concentration 
versus time curve (AUC).  Based on available data, relative exposures to ataluren acyl 
glucuronide in the toxicology species were as high as or higher than in humans.  Excretion data 
indicated that 47.3% of the administered radioactive dose is recovered in the feces and 55.1% 
was recovered in the urine.  In feces, parent drug accounted for ~0.4% and various minor 
metabolites were present due to metabolism by fecal microorganisms.  In the urine, unchanged 
ataluren and ataluren acyl glucuronide accounted for <1% and 49%, respectively, of the 
administered dose. 
2.2.3.2. Phase 2a Studies 
Phase 2a studies in adult patients with nmCF were conducted in the United States and in Israel 
(PTC124-GD-003-CF, PTC124-GD-005-CF), and in children with nmCF in Europe (PTC124-
GD-006-CF) [Clancy 2006, Kerem 2008a, Sermet-Gaudelus 2008].  These studies were similar 
in design and were performed as open-label, dose-ranging, challenge-dechallenge-rechallenge 
evaluations of the activity, safety, and PK of ataluren in patients with nmCF.  Participants with 
analyzed data from these studies totaled 47 adult patients (18 through 57 years of age) and 
30 pediatric patients (6 through 18 years of age).  All patients received ataluren in 2 repeated 
28-day cycles, each comprising 14 days on therapy and 14 days off therapy.  In one cycle, 
participants received ataluren TID at morning, midday, and evening doses of 4-, 4-, 8-mg/kg and 
in the other cycle, they received ataluren TID at doses of 10-, 10-, 20-mg/kg.  
TEPD testing was used to assess total transepithelial chloride transport as the primary outcome 
measure.  This parameter constitutes an integrated evaluation of the presence and surface 
localization of full-length, functional, membrane-associated CFTR.  The results in the studies in 
Israel and Europe indicated statistically significant improvements in TEPD chloride transport, 
the percentage of patients with a chloride transport response (improvements of ≥-5 mV relative 
to baseline), and the proportion of patients with a chloride transport value in the normal range 
(equal to or more electrically negative than -5.0 mV).  Responses were observed in multiple stop 
types (including Q493X, G542X, R553X, W846X, W882X, E1104X, R1162X, W1282X, and 


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3849+10kB C→T).  Changes in pharmacodynamic parameters were not clearly dose-dependent 
although persistence of effects may have been greater at the 10-, 10-, 20-mg/kg dose level.  In 
contrast, a Phase 2 study (PTC124-GD-003-CF) conducted in adults in 5 centers in the United 
States did not show significant improvements in total chloride response in nmCF patients 
[Clancy 2006].  Positive trends in pulmonary function changes were observed during ataluren 
administration. Sweat chloride concentration, measured over 2 weeks in the trial conducted in 
Israel, showed no improvement with ataluren administration. 
Across all studies and both dose levels, treatment-emergent adverse events were consistent with 
background CF-related sinus, pulmonary, or gastrointestinal symptoms.  No drug-related serious 
adverse events were reported.  The only notable event was the occurrence of mild dysuria in 
several patients with the morning void; no drug, uric acid, or calcium oxalate crystals; hematuria; 
pyuria; or other abnormalities were detected in urine from these subjects.  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 subjects’ physical examinations, vital sign measurements, or electrocardiograms (ECGs).  
Treatment-emergent laboratory abnormalities showed no obvious dose dependency and none of 
these events was considered clinically relevant.  Compliance was very good; on average, patients 
received >95% of the planned ataluren doses and no patient discontinued ataluren due to an 
adverse event. 
Ataluren has also been tested in Israel in an open-label, extension study in patients with nmCF 
(PTC124-GD-005e-CF) [Kerem 2008b].  The study was designed to evaluate the activity, safety, 
and ataluren plasma concentrations associated with 3 months of continuous treatment in the same 
patients who were enrolled in the previous Phase 2a study performed in Israel.  In this extension 
study, 19 patients were assigned to respective morning, midday, and evening doses of either 4-, 
4-, 8-mg/kg (n=11) or 10-, 10-, 20-mg/kg (n= 8) based on the investigator interpretation of the 
best chloride transport response previously observed in the Phase 2a study.  Patients who had not 
experienced a chloride transport response in the previous Phase 2a study were allocated to the 
10-, 10-, 20-mg/kg dose level.  Patients were to receive 84 consecutive days (12 weeks) of 
treatment with ataluren followed by 28 days of post-treatment follow-up. 
The results indicated statistically significant, time-dependent improvements in TEPD chloride 
transport, the percentage of patients with a chloride transport response (improvements of ≥-5 mV 
relative to baseline), and the proportion of patients with a chloride transport value in the normal 
range (equal to or more electrically negative than -5.0 mV).  Changes in pharmacodynamic 
parameters were not clearly dose-dependent.  However, 2 patients who had not experienced a 
chloride transport normalization at either dose level in the previous Phase 2a study showed 
normalization over 3 months in this extension study.  In addition, 2 patients who had not 
experienced a chloride transport response at either dose level in the previous Phase 2a study 
showed a response in this extension study.  Statistically significant, time-dependent 
improvements in CF-related cough were also evident, particularly at the higher dose level of 10-, 
10-, 20-mg/kg.  Positive trends over time in pulmonary function were also observed. 
Across both dose levels, treatment-emergent adverse events were primarily consistent with 
CF-related sinus, pulmonary, or gastrointestinal symptoms and no clearly dose-dependent 
increases in frequency or severity of adverse events were evident.  Three patients (2 at the lower 
dose level and 1 at the higher dose level) noted mild dysuria.  One patient receiving the higher 
dose level with a history of CF-related distal intestinal obstruction syndrome (DIOS) developed 


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constipation and dehydration on Day 80 of ataluren dosing; the event was considered possibly 
related to ataluren and was deemed serious because the patient was hospitalized for rehydration.  
There were no safety concerns identified in subjects’ physical examinations, vital sign 
measurements, or ECGs.  Repeated measurements of basal serum ACTH and cortisol 
concentrations during the 84 days of dosing showed no evidence of insufficiency of 
corticosteroid production.  There was no evidence of hyperkalemia that would suggest 
hypoaldosteronism.  One patient receiving the 10-, 10-, 20-mg/kg dose level of ataluren had 
unexplained treatment-emergent Grade 1 serum creatinine concentrations throughout the study; 
there were no urine abnormalities and the finding resolved upon cessation of treatment.  Two 
patients discontinued ataluren early.  One patient withdrew consent on Day 52 due to a transient 
Grade 1 increase in liver transaminase levels.  The other patient, who had almost completed the 
84-day course of dosing, developed DIOS on Day 80 (described above) and did not resume 
ataluren administration after resolution of her DIOS-related symptoms. 
Hour 0 (trough) and Hour 3 plasma concentrations relative to the first daily dose were evaluated 
at monthly intervals.  Ataluren showed generally stable concentrations over time, achieving 
mean trough concentrations of ≥2 µg/mL at the 4-, 4-, 8-mg/kg dose level, and of ≥5 µg/mL at 
the 10-, 10-, 20-mg/kg dose level.   
2.2.3.3. Phase 3 Study 
Ataluren was tested in a 48-week, double-blind, placebo-controlled study PTC124-GD-009-CF 
(Study 009) comparing ataluren to placebo in nmCF patients [Rowe 2012]. Eligible patients 
≥6 years of age with nmCF and %-predicted FEV1 between 40-90% were randomized to receive 
ataluren 10-, 10-, 20-mg/kg orally TID or placebo for 48 weeks. Primary and secondary 
endpoints were %-predicted FEV1 change from baseline at 48 weeks and pulmonary 
exacerbations, respectively. Tertiary endpoints included nasal TEPD, sweat chloride, and chest 
CT scan.  The trial enrolled 238 patients, ages six years and older, at multiple sites in North 
America, Europe, and Israel. Patients were randomly assigned to one of two treatment arms: 
ataluren (10 mg/kg morning, 10 mg/kg midday, 20 mg/kg evening) or placebo (morning, 
midday, evening).  
The primary endpoint, the relative change from baseline in %-predicted FEV1 at 48 weeks 
showed a positive trend favoring ataluren versus placebo, and a larger effect in the patients not 
receiving chronic inhaled antibiotics.  The effect of inhaled antibiotics was largely attributable to 
the use of inhaled aminoglycosides.  In the intent-to-treat population, there was a 3% difference 
in the relative change from baseline in %-predicted FEV1 between the ataluren and placebo 
groups at Week 48 (-2.5% change on ataluren vs -5.5% change on placebo; p=0.124).  The 
relative decline in FEV1 of -5.5% in the placebo arm over 48 weeks is indicative of the severity 
of nmCF patients.  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). 
The study was stratified by age, baseline FEV1, and the use of chronic inhaled antibiotics.  A 
statistically significant effect (nominal p=0.0072) was seen between treatment and use of inhaled 
antibiotics at baseline, indicating that inhaled antibiotics was a significant confounder of the 
overall results.  A substantial treatment effect was seen in the patients not receiving chronic 
inhaled antibiotics at baseline; the Week 48 difference between the ataluren and placebo arms in 
FEV1 was 6.7% (-0.2% change on ataluren vs -6.9% change on placebo).  This difference in 


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treatment effect was driven by the use of inhaled 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 antibiotics, the pulmonary exacerbation rate in the ataluren group was 43% lower 
than the rate in the placebo group; 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.  
The endpoints of nasal TEPD and sweat chloride, which were included in the study as 
biomarkers, failed to discriminate active treatment from placebo.   
The CT scan score, which was included in Study 009 as an exploratory endpoint, failed to 
discriminate active treatment from placebo over the 48-week study duration.  Specifically, there 
was no appreciable change in CT scan scores in the placebo group, despite significant decrease 
in %-predicted FEV1, suggesting that this outcome measure may not have been sufficiently 
sensitive to detect clinical changes over 48 weeks in this trial.  
Safety results indicate that ataluren was generally well tolerated.  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 14.2.3.1).  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.  
2.2.3.3.1. Phase 3 Extension Study 
Ataluren was also further tested in an international open-label, extension study in patients with 
nmCF (PTC124-GD-009e-CF).  Subjects that completed the Phase 3 study (Study 009) were 
eligible for enrollment.  The primary objective of this 96-week study (n=191) was to evaluate the 
long-term safety of ataluren in nmCF patients, at the planned daily dose level of 10-, 10-, 20- 
mg/kg of ataluren.  Secondary objectives were to determine the long-term effect of ataluren on 
pulmonary function; pulmonary exacerbations, medical interventions; health-related quality of 
life (HRQL); general well-being; compliance with ataluren therapy; and ataluren plasma 
exposure.  During the first 48 weeks of the trial, study assessments were performed at clinic 
visits every 4 to 8 weeks, depending upon the type of outcome measure.  During the final 
48 weeks of the trial, study assessments were performed at clinic visits every 8 to 16 weeks, 
depending upon the type of outcome measure. The results of this study are pending. 
  


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3. 
STUDY OBJECTIVE AND ENDPOINTS 
3.1. Objectives 
The primary objective of this study is to determine the long-term safety and tolerability of 10-, 
10-, 20- mg/kg ataluren in patients with nmCF who completed participation in the double-blind 
study (Study 009) as assessed by adverse events and laboratory abnormalities. 
The secondary objectives are to determine the efficacy and safety of ataluren as assessed by 
spirometry (FEV1), pulmonary exacerbation rate, and other safety parameters (eg, 12-lead ECG 
measurements, vital signs). 
The tertiary objectives are to determine the efficacy of ataluren as assessed by other parameters 
of pulmonary function (FVC and FEF25-75), and changes in body weight BMI. 
3.2. Endpoints 
Primary 
• Safety profile characterized by type, frequency, severity, timing, and relationship to 
ataluren of any adverse events, and laboratory abnormalities 
Secondary 
• Change from baseline to end of treatment in spirometric performance as measured by 
FEV1 
• Rate of pulmonary exacerbations, as assessed by modified Fuchs (primary definition), 
and Fuchs and expanded Fuchs criteria 
• Change from baseline in other safety parameters (eg, 12-lead ECG measurements, vital 
signs) 
Tertiary 
• Change from baseline to end of treatment in spirometric performance as measured by 
FVC and FEF25-75 
• Change from baseline to end of treatment in body weight and BMI 
 
4. 
SUBJECT SELECTION CRITERIA 
4.1. Overview 
This clinical study can fulfill its objectives only if appropriate patients are enrolled.  The 
following eligibility criteria are designed to select patients for whom study participation is 
considered appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.  Eligibility 
criteria may not be waived and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) audit or a regulatory authority inspection.  Any questions 
regarding a subject’s eligibility should be discussed with the PTC Therapeutics medical monitor 
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4.2. Inclusion Criteria 
Subjects must meet all of the following conditions to be eligible for enrollment into the study: 
1. Evidence of signed and dated informed consent/assent document(s) indicating that the 
subject (and/or 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 subject should be followed. 
2. Evidence of completed participation in the double-blind study, PTC124-GD-009-CF 
(Study 009). 
3. Body weight ≥16 kg. 
4. Performance of a valid, reproducible spirometry test using the study-specific spirometer 
during the screening period.  Note: An FEV1 value within a pre-specified range is not 
required for eligibility. 
5. Confirmed screening laboratory values within the central laboratory ranges.  Note: 
Confirmation should be performed for out-of-range values during the screening period 
to determine if the abnormality is real or artifactual.  Values used to establish eligibility 
should be obtained during the screening period, and should generally be the most 
recent measurement obtained. All screening laboratory results must be received, 
reviewed and deemed acceptable for study participation before a subject is enrolled into 
the study.  
6. In male and female subjects 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 60-day follow-up period. 
7. Willingness and ability to comply with all study procedures and assessments, including 
scheduled visits, drug administration plan, laboratory tests, and study restrictions.  Note: 
The Investigator should consider any psychological, social, familial, or geographical 
factors that might preclude adequate study participation. 
4.3. Exclusion Criteria 
The presence of any of the following conditions will exclude a subject from study enrollment: 
1. Known hypersensitivity to any of the ingredients or excipients of ataluren (polydextrose, 
polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, 
hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate). 
2. Any change (initiation, change in type of drug, dose modification, schedule modification,    
interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen 
for CF or for CF-related conditions within 4 weeks prior to screening or between 
screening and randomization. Note: A subject can be enrolled who is using inhaled 
medications such as aztreonam, colistin, dornase-alfa, hypertonic saline, 
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Expected cycling of inhaled aztreonam or inhaled colistin is permitted.  Other than for 
treatment of CF pulmonary exacerbations, subjects should remain on a stable medical 
regimen of treatment/prophylaxis for CF-related conditions to avoid confounding 
interpretation of study results. 
3. Chronic use of systemic, tobramycin within 4 weeks prior to screening.  
4. Exposure to another investigational drug within 4 weeks prior to screening.  Note: 
Subjects receiving another investigational drug as part of a pre-approval expanded 
access program for that drug may participate with the prior consent of the 
PTC Therapeutics medical monitor. 
5. Ongoing participation in any other therapeutic clinical trial.  Note: Subjects receiving 
another investigational drug as part of a pre-approval expanded access program for 
that drug may participate with the prior consent of the PTC Therapeutics medical 
monitor. 
6. Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection 
(including viral illnesses) within 3 weeks prior to screening or between screening and 
randomization.  Treatment with intravenous antibiotics within 3 weeks prior to screening. 
7. Treatment with intravenous antibiotics within 3 weeks prior to screening. 
8. Ongoing immunosuppressive therapy (other than corticosteroids). 
9. Ongoing warfarin, phenytoin, or tolbutamide therapy. 
10. History of solid organ or hematological transplantation.  
11. Major complications of lung disease (including massive hemoptysis, pneumothorax, or 
pleural effusion) within 8 weeks prior to screening. 
12. Known portal hypertension. 
13. Positive hepatitis B surface antigen, hepatitis C antibody test, or human 
immunodeficiency virus (HIV) test.  Note: Subjects who are hepatitis C antibody 
positive but do not have active hepatitis C as documented by normal serum bilirubin; 
ALT and AST; and negative hepatitis C RNA test during the screening period may be 
eligible for inclusion.  Subjects with hepatitis C with elevated serum bilirubin, ALT, or 
AST and negative hepatitis C RNA test may be eligible if the abnormalities are 
attributed to other causes by a gastroenterologist or hepatologist. 
14. Pregnancy or breast-feeding. 
15. Current smoker or a smoking history of ≥10 pack-years (number of cigarette packs/day × 
number of years smoked). 
16. Prior or ongoing medical condition (eg, concomitant illness, alcoholism, drug abuse, 
psychiatric condition), medical history, physical findings, ECG findings, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the safety of the 
subject, makes it unlikely that the course of treatment or follow-up would be completed, 
or could impair the assessment of study results. 


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5. 
ENROLLMENT PROCEDURES 
5.1. Source and Number of Subjects 
Approximately 70 subjects will be enrolled following completion of participation in the double-
blind study PTC124-GD-009-CF (Study 009). 
5.2. Screening and Study Drug Dispensation 
The investigator must inform each 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 subject number used in the PTC124-GD-009-CF study shall be retained for use in this study.  
This subject number must be used for subject identification on all study related documents (case 
report forms [CRFs], laboratory samples, etc.).  
Any questions regarding the eligibility of a patient should be discussed with the PTC 
Therapeutics medical monitor.   
The relevant site staff will need to supply the Interactive Voice Response/Interactive Web 
Response (IVR/IWR) system with the information required by the system (eg, site number, 
subject number, subject weight in kilograms) to permit study drug dispensation. 
 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
6.1. Study Drug Supply 
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 is packaged in aluminium-foil, child-resistant sachets (packets), and supplied in dose 
strengths containing 125-, 250-, or 1000-mg of the active drug substance.   
Ataluren will be supplied free of charge to the investigator site by PTC Therapeutics for 
appropriate distribution to the subjects/caregivers.  It is intended that ataluren will be provided in 
sufficient supply for a 16-week study period.   However, in the event of pending commercial 
availability of ataluren, drug may be supplied for a treatment period of less than 16 weeks.  
Resupply may be obtained via the IVR/IWR system. 
6.1.1. 
Study Drug Packaging and Labeling 
Sachets and cartons will be color coded to indicate dosage strength (125 mg – yellow, 250 mg – 
pink, 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.  
6.1.2. 
Study Drug Storage 
Sachets of ataluren will be shipped to the investigational sites, and stored and monitored at room 
temperature (~15 to 30°C).  The available stability data from representative samples support the 
use of the drug product for 48 months when stored at room temperature.   


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Study personnel must ensure that all ataluren supplies are 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 other site personnel supply 
study product to other investigators or clinics, or allow the supplies to be used other than as 
directed by this protocol. 
6.1.3. 
Study Drug Dispensation 
Dosing of ataluren will be based on milligrams of drug per kilogram of subject body weight at 
Screening (Visit 1) and will be calculated to allow for dosing with 1 or 2 of the 3 available sachet 
dose strengths (125- or 250- or 1000-mg of ataluren).   
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
ataluren in 16-week increments according to the dosing schedule and IVR/IWR directions.     
Because of potential changes in subject body weight over time, at Week 32 (Visit 4), Week 64 
(Visit 6), Week 96 (Visit 8), Week 128 (Visit 10) and Week 160 (Visit 12) a dose adjustment 
may be made 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.   
6.1.4. 
Study Drug Preparation 
Once at the investigational site and/or with the subject/caregiver, ataluren sachets should be 
stored at room temperature, away from the reach of children until time of reconstitution.  One (1) 
or 2 of the 3 available sachet dose strengths (125-, 250-, or 1000-mg of ataluren) will be used to 
prepare each dose. The powder in the sachet may be mixed with water, milk (skim, 1% fat, 2% 
fat, whole milk, chocolate milk, 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, or 3 tablespoons of semi-solid food.  The prepared dose should be mixed well 
before administration.  The amount of the liquid or semi-solid food can be increased based on 
subject preference.  
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 (if kept at room temperature). 
Detailed written drug mixing and dosing instructions will be provided to the subject/caregiver 
when ataluren supplies are dispensed.  A copy of these instructions will be maintained in the 
investigator site study file.   
6.1.5. 
Study Drug Accountability 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all ataluren shipped by PTC Therapeutics or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all ataluren.  Current 
reconciliation and dispensing records must also be maintained that include the date and amount 
of ataluren dispensed, relevant batch numbers, and subject’s assigned study number.  Subjects 
should return all unused sachets of ataluren to the investigational site at the end of each 16-week 
treatment period for inventory.  The CRF will serve as the source document for drug supply to 
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Depending upon the decision of PTC Therapeutics, unused clinical supplies must be destroyed or 
returned to PTC Therapeutics (or its designee) after the study is completed and drug 
accountability has been verified by the monitor.  Records documenting the date of study drug 
destruction or shipping, relevant batch numbers, and amount destroyed or shipped should be kept 
in the investigator site study file.  
6.1.6. 
Overdose Precautions 
For any subject experiencing an overdose (administration of an ataluren dose >4.0 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).   
6.1.7. 
Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, ataluren does not appear to be acutely toxic or 
genotoxic at levels that are likely to result from inadvertent exposure to the contents of the 
packet, if opened.  Based on general experience with the drug during manufacturing, it does not 
appear that exposure to formulated ataluren is likely to be irritating to skin or eyes.  However, 
personnel handling the drug should use reasonable precautions to avoid eye contact, skin contact, 
inhalation, or ingestion of the material in the packets.  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. 
Study Drug Dosing 
Dosing of ataluren will be based on milligrams of drug per kilogram of subject body weight at 
Screening (Visit 1).  All subjects will receive approximately 10-, 10-, 20-mg/kg ataluren TID for 
~192 weeks.  At Week 32 (Visit 4), Week 64 (Visit 6), Week 96 (Visit 8), Week 128 (Visit 10) 
and Week 160 (Visit 12)  dose adjustment may be made based on the subject’s body weight at 
that visit.  
6.2.2. 
Duration of Treatment 
Study duration will be 192 weeks.  If ataluren becomes commercially available or the clinical 
development of ataluren in nmCF is discontinued prior to the 192 weeks, subjects will be 
discontinued from the study.  The actual duration of ataluren treatment under this protocol will 
be subject to the provisions in Section 10. 
6.2.3. 
Schedule of Administration 
As noted in Table 1, 3 doses should be taken per day – the 1st dose in the morning, the 2nd dose 
during the middle of the day (mid-day), and the 3rd dose in the evening.  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 


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morning and mid-day doses, ~6 hours (±1 hour) between mid-day and evening doses, and 
~12 hours (±1 hour) between the evening dose and the morning dose on the next day.   
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 subject’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. 


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6.2.4. 
Instructions for Delays in Dosing 
Dosing delays should be handled as follows: 
• If dosing of ataluren is delayed by ≤1 hour, the planned dose should be taken with no 
changes to the subsequent dose schedules.   
• If ataluren dosing is delayed by >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.   
• If ataluren dosing is delayed by >4 hours, the dose should not be taken.  Ataluren 
administration may continue but the missed dose should not be taken and the planned 
timing of subsequent study drug dosing should not be altered.      
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 
Subjects must be monitored closely for adverse events or laboratory abnormalities during the 
course of the study.   
Renal abnormalities will be followed closely in this study given findings that have occurred in an 
international, multicenter, double-blind, placebo-controlled Phase 3 trial evaluating ataluren in 
patients ≥6 years of age with nonsense mutation cystic fibrosis (PTC124-GD-009-CF; as 
described in Section 14.2.3.1 and in the Ataluren Investigator Brochure).   
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 ataluren 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.pdf) for 
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 ataluren immediately, 
for interrupting ataluren after confirmation of a value beyond the threshold, or for continuing 
ataluren 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 ataluren 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, Confirma 
Abnormal Value, 
and Then Start 
Work-Up 
Stop Study Drug After  
Confirminga Abnormal 
Value,  
and Then Start Work-Up 
Continue Study Drug,  
Confirma Abnormal 
Value,  
and then Start 
Work-Up 
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 
--- 
Urine protein: urine 
creatinine (spot) 
--- 
>0.40 mg:mg 
--- 
Urine blood (by 
dipstick) 
4+ (in absence of 
menstruation) 
3+ (in absence of 
menstruation) 
2+ (in absence of 
menstruation) 
a Laboratory abnormalities may be confirmed immediately or 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, 
Ca2+ = calcium, GGT = gamma glutamyl transferase, HCO3- = bicarbonate, K+ = potassium, Mg2+ = magnesium, 
Na+ = sodium, ULN = upper limit of normal 
It should be noted that blood samples for cortisol, renin and aldosterone determinations will be 
obtained as necessary during the study, for patients with 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, 


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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. 
Laboratory evaluation for adrenal function (cortisol, renin and aldosterone) will be performed at 
study baseline 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 subjects 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 Table 6).  Once it has been documented that a subject 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.  Subjects 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 subjects 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 subjects with multiple 
stones at first presentation, in subjects 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.  


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• 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 subject 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 subject should 
be evaluated for possible underlying causes of stone disease, including hypercalcemia, 
hypercalciuria, hyperuricosuria, hypocitraturia, hyperoxaluria, and urine volume. 
6.3.3. 
Instructions for Resuming Ataluren Administration after an Interruption for 
Safety Concerns 
In deciding whether to re-institute ataluren 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 ataluren 
• The subject’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 ataluren treatment.  If the investigator considers the 
hepatic or renal event that led to ataluren interruption to be probably related to ataluren, 
restarting ataluren is not advised.  In this case, the subject should be discontinued from the study 
(see Sections 6.3.4 and 10).  If the investigator considers the hepatic or renal event that prompted 
ataluren interruption to be possibly related or unlikely related to ataluren, the investigator should 
use best judgment in determining whether to restart ataluren.  If the hepatic or renal event is 
considered unrelated to ataluren, re-institution of ataluren is recommended.   
If the investigator believes it is appropriate to do so and the PTC Therapeutics medical monitor 
has been consulted, ataluren may be re-initiated.  If the event was determined to be unrelated to 
ataluren, the treatment may be resumed at full dose.  Otherwise, if the drug is resumed, it should 
be initially re-initiated at half of the original dose.  The appropriate clinic staff should instruct the 
subject/caregiver about the revised number of study drug sachets to be used per dose according 
to the new schedule.  Re-challenge at half dose should be initiated only as a bridge to full dosing. 
If a subject cannot tolerate the full dose, they should be discontinued from study participation.  
If further evaluation reveals that the adverse event that led to dose reduction was not related to 
the ataluren, the dose should be escalated to the original dose level.  The appropriate clinic staff 
should instruct the subject/caregiver about the revised number of ataluren sachets to be used per 
dose according to the schedule provided by the IVR/IWR system.   
If after dose reduction, the subject experiences a recurrence of a previous abnormality that led to 
ataluren dose interruption or experiences the new occurrence of an unacceptable adverse event or 
laboratory abnormality, the investigator should interrupt ataluren and confer with the 


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PTC Therapeutics medical monitor regarding the potential need to discontinue ataluren 
permanently. 
6.3.4. 
Instructions for Discontinuation of Study Drug Administration for Safety 
Concerns 
If after appropriate consideration of ataluren interruption/modification and consultation with the 
PTC Therapeutics medical monitor, it is not appropriate for a subject to continue with study 
treatment, then ataluren should be permanently discontinued.  If permanent discontinuation of 
ataluren is the result of an SAE, then a follow-up SAE report form should be completed (see 
Section 9.7).  In the case of a treatment discontinuation due to an adverse event that is not an 
SAE, the PTC Therapeutics medical monitor should be notified (see Section 10).  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 case report 
form (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. 
 
7. 
CONCOMITANT AND SUPPORTIVE THERAPY 
7.1. Concomitant Medications 
Other than ataluren, any treatments (including prescription and non-prescription drugs, health 
foods, herbal remedies, self-prescribed drugs, street drug, tobacco products, or alcohol) taken by a 
subject from the screening period through the  4-Week Post-Treatment Follow-Up Visit 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 subjects 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.  If considered necessary for the subject’s 
wellbeing, 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 drug other than 
ataluren should take into account subject safety, the medical need, the potential for drug 
interactions, the possibility for masking symptoms of a more relevant underlying event, and 
whether use of a concomitant medication will compromise the outcome or integrity of the study.   
For subjects 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 subjects who 
are on CF-specific therapy/prophylaxis at baseline, a stable regimen should be maintained during  
ataluren treatment while participating in this clinical trial.  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, subjects who do require initiation, interruption, dose 
modification, or substitution of CF treatment may remain on ataluren therapy. 


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7.1.2. 
Therapy for CF Pulmonary Exacerbations or Other CF Complications 
Subjects 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 subjects 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 subjects 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.  Subjects requiring IV therapy with a glycopeptide antibiotic (eg, 
vancomycin), should be closely monitored in an appropriate setting, such as a hospital.  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 subjects receiving any type of 
potentially nephrotoxic agents, antibiotic drug levels, and renal function should be closely 
monitored.  Creatinine and BUN should be measured prior to initiating aminoglycosides or other 
potentially nephrotoxic therapy, and at least twice a week during the course of such antibiotic 
treatment, where possible.  The antibiotic trough level, creatinine and BUN should be measured 
within 24 to 48 hours of administration of the first antibiotic dose, and further antibiotic dosing 
should be based on these results.  Trough levels should also be measured at intervals during the 
course of antibiotic treatment, where possible.  Additionally, subjects 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 subjects experiencing nausea, vomiting, diarrhea, fever, or laboratory 
evidence of dehydration.  Treatment with ataluren may be resumed no earlier than 2 days after 
administration of nephrotoxic antibiotics has ceased.  
In subjects receiving non-nephrotoxic systemic antibiotics, creatinine and BUN should be 
measured at least once per week, where possible during the course of treatment for a pulmonary 
exacerbation. 
It should be emphasized to subjects/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. 
7.1.3. 
Drugs Metabolized by CYP2C8 or CYP2C9 
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.   


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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 subjects 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 subjects who require anticoagulation during the study, use of an alternative 
form of anticoagulation (eg, fractionated heparin) should be considered.  Phenytoin is 
metabolized by CYP2C9 and concomitant use with ataluren may be of potential concern.  For 
subjects who require anticonvulsant therapy during the study, use of alternative anticonvulsant 
drugs should be considered.   
The metabolism of losartan to its active metabolite may, in part, be mediated by CYP2C9.  
However, concomitant use of losartan and inhibitors of CYP2C9 have not been examined.  
Because this drug does not have a narrow therapeutic window, the potential for mild to moderate 
changes in activity does not require a dose modification. 
7.1.4. 
Other Potential 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 
(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. 
7.1.5. 
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.  Subjects 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.   
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator.  The decision to 
authorize the use of any other drug(s) should take into account subject safety, the medical need, 
the potential for drug interactions, the possibility for masking symptoms of a more relevant 
underlying event, and whether use of a concomitant medication will compromise the outcome or 
integrity of the study.    
Subjects/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 subject during 
the course of the study and the reason for use will be recorded in the source documents and in the 
concomitant medication CRF. 


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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 subjects 
participating in the study.  Respiratory care guidelines as suggested by the American Thoracic 
Society/European Thoracic Society should be followed [ATS 2004].   
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 subjects 
receiving ataluren, it is important to encourage study subjects to maintain adequate hydration 
throughout the study.  Subjects 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 subjects who are experiencing nausea, vomiting, diarrhea, fever, or laboratory 
evidence of dehydration. 
 
8. 
SCHEDULE OF EVENTS AND STUDY PARAMETERS 
8.1. Schedule of Events 
The types and timing of data to be recorded are summarized in Table 3.  Please see Section 8.2 
for cross-referenced explanations of the study procedures outlined.  


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Table 3: 
Schedule of Events 
Study Period 
Screening 
Ataluren Treatment 
Study Week 
Week  
-4 to -1 
Week 1 
Week 8 
(Phone 
Call) 
Week 16 
Week 24 
(Phone 
Call) 
Week 32 
Week 40 
(Phone 
Call) 
Week 48  
Week 56 
(Phone 
Call) 
Study Day 
-28 to -1 
1 
(+7 days) 
56 (±7 
days) 
112 (±7 
days) 
168 (±7 
days) 
224 (±7 
days) 
280 (±7 
days) 
336 (±7 
days) 
392 (±7 
days) 
Visit / Call 
1 
2 
2a 
3 
3a 
4 
4a 
5 
5a 
Informed Consent  
X 
 
 
 
 
 
 
 
 
IVR/IWR System Screening 
X 
 
 
 
 
 
 
 
 
Clinical and Medication History  
X 
 
 
 
 
 
 
 
 
Vital Signs (including pulse oximetry)  
X 
X 
 
X 
 
X 
 
X 
 
Height 
X 
X 
 
X 
 
X 
 
X 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
Physical Examination 
X 
As clinically indicated 
X 
As clinically 
indicated 
Serum Viral Screen  
X 
 
 
 
 
 
 
 
 
β-HCGa 
X 
X 
 
X 
 
X 
 
X 
 
Cortisol, Renin, and Aldosterone 
X 
As clinically indicated 
Biochemistryb 
X 
X 
 
X 
 
X 
 
X 
 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
Urinalysis  
X 
X 
 
X 
 
X 
 
X 
 
Ataluren PK (trough) 
 
 
 
X 
 
X 
 
X 
 
Renal Ultrasound 
X 
As clinically indicated 
12-Lead ECG  
X 
 
 
X 
 
X 
 
X 
 
Ataluren Administration in Clinic 
 
Xc 
 
 
 
 
 
 
 
Ataluren Dispensation 
 
X 
 
X 
 
X 
 
X 
 
Review Ataluren Compliance  
 
 
 
X 
 
X 
 
X 
 
Adverse Events 
Xd 
X 
 
X 
 
X 
 
X 
 
Concomitant Medication / 
Non-Drug Therapy 
X 
X 
 
X 
 
X 
 
X 
 
Spirometry 
X 
X 
 
X 
 
X 
 
X 
 
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Presence of P. aeruginosa in Sputum 
X 
X 
 
X 
 
X 
 
X 
 
 


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Table 3: 
Schedule of Events - Continued 
Study Period 
Ataluren Treatment 
Study Week 
Week 64 
Week 72 
(Phone 
Call) 
Week 
80 
Week 88 
(Phone 
Call) 
Week 96 
 Week 104 
(Phone 
Call) 
Week 
112 
Week 120 
(Phone 
Call) 
Week 128 
Week 136 
(Phone 
Call) 
Study Day  
448  
(+7 days) 
504  
(±7 days) 
560  
(±7 
days) 
616  
(±7 days) 
672  
(±7 days) 
728  
(±7 days) 
784  
(±7 days) 
840  
(±7 days) 
896  
(±7 days) 
952  
(±7 days) 
Visit / Call 
6 
6a 
7 
7a 
8 
8a  
9 
9a 
10 
10a 
Vital Signs (including pulse 
oximetry)  
X 
  
X 
  
X 
  
X 
  
X 
  
Height 
X 
  
X 
  
X 
  
X 
  
X 
  
Weight 
X 
  
X 
  
X 
  
X 
  
X 
  
Physical Examination 
As clinically indicated 
X 
As clinically indicated 
Serum Viral Screen  
  
  
  
  
  
  
  
  
  
  
β-HCGa 
X 
  
X 
  
X 
  
X 
  
X 
  
Cortisol, Renin, and Aldosterone 
As clinically indicated 
Biochemistryb 
X 
  
X 
  
X 
  
X 
  
X 
  
Hematology 
X 
  
X 
  
X 
  
X 
  
X 
  
Urinalysis  
X 
  
X 
  
X 
  
X 
  
X 
  
Ataluren PK (trough) 
X 
  
X 
  
X 
  
X 
  
X 
  
Renal Ultrasound 
As clinically indicated 
12-Lead ECG  
X 
  
X 
  
X 
  
X 
  
X 
  
Ataluren Administration in Clinic 
  
  
  
  
  
  
  
  
  
  
Ataluren Dispensation 
X 
  
X 
  
X 
  
X 
  
X 
  
Review Ataluren Compliance  
X 
  
X 
  
X 
  
X 
  
X 
  
Adverse Events 
X 
  
X 
  
X 
  
X 
  
X 
  
Concomitant Medication / 
X 
  
X 
  
X 
  
X 
  
X 
  
Non-Drug Therapy 
Spirometry 
X 
  
X 
  
X 
  
X 
  
X 
  
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Presence of P. aeruginosa in Sputum 
X 
  
X 
  
X 
  
X 
  
X 
  
 


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Table 3: 
Schedule of Events - Continued 
Study Period 
Ataluren Treatment 
4-Week Post- 
Treatment 
Follow-Up 
(End of Study) 
Study Week 
Week 144 
Week 152 
(Phone Call) 
Week 160 
Week 168 
(Phone Call) 
Week 176 
Week 184 
(Phone Call) 
Week 192 
EOT/ 
Early D/Cf 
Study Day  
1008  
(±7 days) 
1064  
(±7 days) 
1120  
(±7 days) 
1176  
(±7 days) 
1232  
(±7 days) 
1288  
(±7 days) 
1344  
(±7 days) 
1372  
(±7 days) 
Visit / Call 
11 
11a 
12 
12a 
13 
13a 
14 
15 
Vital Signs (including pulse oximetry)  
X 
  
X 
  
X 
  
X 
X 
Height 
X 
  
X 
  
X 
  
X 
X 
Weight 
X 
  
X 
  
X 
  
X 
X 
Physical Examination 
X 
As clinically indicated 
X 
X 
Serum Viral Screen  
  
  
  
  
  
  
  
  
β-HCGa 
X 
  
X 
  
X 
  
X 
X 
Cortisol, Renin, and Aldosterone 
As clinically indicated 
Biochemistryb 
X 
  
X 
  
X 
  
X 
X 
Hematology 
X 
  
X 
  
X 
  
X 
X 
Urinalysis  
X 
  
X 
  
X 
  
X 
X 
Ataluren PK (trough) 
X 
  
X 
  
X 
  
X 
  
Renal Ultrasound 
As clinically indicated 
12-Lead ECG  
X 
  
X 
  
X 
  
X 
X 
Ataluren Administration in Clinic 
  
  
  
  
  
  
  
  
Ataluren Dispensation 
X 
  
X 
  
X 
  
  
  
Review Ataluren Compliance  
X 
  
X 
  
X 
  
X 
  
Adverse Events 
X 
  
X 
  
X 
  
X 
X 
Concomitant Medication / 
Non-Drug Therapy 
X 
  
X 
  
X 
  
X 
X 
Spirometry 
X 
  
X 
  
X 
  
X 
X 
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
  
Presence of P. aeruginosa in Sputum 
X 
  
X 
  
X 
  
X 
  
a Testing for female subjects only. 
b Ideally, subjects should have fasted for at least 8 hours prior to blood collection. 
c Clinic staff will administer the first dose of study drug at Study Day 1 (Visit 2). 
d Adverse events (AEs) should be elicited from subjects at all study visits; however, any untoward medical occurrences collected at Screening will be used to assess study eligibility only and will not be 
reported as AEs in the CRF.   
e Includes completion of the Respiratory Event Form (REF). 
f Patients that do not complete ≥192 Weeks of treatment will be considered prematurely discontinued. 
Abbreviations: β-HCG = human chorionic gonadotropin, D/C = discontinuation, ECG = electrocardiogram, EOT = end of treatment, IVR/IWR = Interactive Voice Response/Interactive Web Response, 
PK = pharmacokinetics 


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8.2. Explanation of Study Procedures 
8.2.1. 
Screening and Week 1 Visits 
No study-related procedures should be performed prior to the signature of the informed 
consent/assent document(s).  Thereafter, subjects should undergo the initial set of 
screening procedures as noted in Table 3, including registration in the IVR/IWR system.  If a 
subject has successfully completed the necessary screening assessments and has been confirmed 
as eligible by the investigator, the Week 1 visit for the subject can be conducted and ataluren 
treatment may be initiated immediately.  The subject/caregiver will receive a 16-week supply of 
study drug before leaving the clinic.  Instructions regarding appropriate study drug storage, 
compliance, preparation, and administration will also be provided. 
8.2.2. 
Treatment Visits / Calls During Study 
Each subject will subsequently return to the clinical research facility for on-site visits every 16 
weeks (112 ± 7 days) over 192 weeks of treatment.  In addition, phone calls will be conducted 
between on-site visits approximately 8 weeks (56 ± 7 days) after the previous on-site visit.   
8.2.2.1. 
End of Treatment  
Each subject will return to the clinical research facility at Week 192 (Visit 14) for the End of 
Treatment (EOT) Visit.  However, study duration may be altered (either extended or terminated), 
if clinically appropriate according to interim study results.  In this case, the timing of the EOT 
Visit will be adjusted appropriately.  If the subject discontinues prematurely (ie, before Week 
192 (Visit 14)) and the last visit to the investigational site occurred >4 weeks previously, the 
procedures that would normally be performed at Week 192 (Visit 14) should be performed 
before the subject leaves the study as a Premature Discontinuation Visit.  However, if the subject 
discontinues prematurely and the date of the last dose of ataluren was ≥4 weeks prior to 
discontinuation, the subject should return for the 4-Week Post-Treatment Follow-up Visit only. 
8.2.2.2. 
Post-Treatment Visits 
All subjects, including those who discontinue study drug prematurely, will return to the 
investigational site 4 weeks (+7 days) after the last dose of ataluren for a 4-Week Post-Treatment 
Follow-up Visit.  Please refer to Section 10 for further details regarding subject withdrawal 
procedures.  The end of trial will be defined as the date the last subject completes the last study 
visit, which is expected to be the 4-Week Post-Treatment Follow-up Visit. 
8.2.3. 
Informed Consent 
The investigator or sub-investigator must inform each prospective subject of the nature of the 
study, explain the potential risks, and obtain written informed consent/assent from the subject 
and/or the parent/legal guardian prior to performing any study-related screening procedures.  
Subjects will be re-consented with the appropriate age-related documents as needed, if required 
by local regulations. 
8.2.4. 
Clinical/Medication History 
The investigator or a qualified designee should review the patient’s clinical history, including 
details relating to CF and any other medical conditions.  Information regarding clinical history 
and current medications must be captured on the medical history and prior/concomitant 
medication CRFs, respectively.  In particular, details regarding any inhaled aminoglycoside use 


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within 6 months prior to study entry should be documented.  In addition, history of Pseudomonas 
aeruginosa infection, history of renal insufficiency, and history of exocrine pancreatic 
insufficiency should also be collected.  
8.2.5. 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, pulse oximetry, and body 
temperature) will be monitored at Screening (Visit 1) through Week 196 (Visit 15 - Post-
Treatment Visit; 4 weeks post discontinuation of study drug).  Pulse rate, pulse oximetry and 
blood pressure determinations will be performed with the subject in a sitting position after a 
5-minute rest.   
8.2.6. 
Height, Weight, and Physical Examination  
Height (in cm) and weight (in kg) will be measured at Screening (Visit 1) through Week 196 
(Visit 15- Post-Treatment Visit; 4 weeks post discontinuation of study drug) at each clinic visit 
as outlined in Table 3. 
A full physical examination (including evaluation of the cardiovascular system, chest and lungs, 
thyroid, abdomen, nervous system, skin and mucosae, musculoskeletal system, eyes, ears, nose, 
mouth, throat, spine, lymph nodes, and extremities) will be conducted at Screening (Visit 1), 
Week 48 (Visit 5),  Week 96 (Visit 8), Week 144 (Visit 11), Week 192 (Visit 14/End of 
Treatment), and Week 196 (Visit 15 - Post-Treatment Visit; 4 weeks post discontinuation of 
study drug). 
Physical exams may also be performed at any time during the study as clinically indicated. 
8.2.7. 
Central Laboratory Assessments  
All laboratory samples will be analyzed by a central laboratory.  Please refer to the Central 
Laboratory Manual for instructions regarding collection, processing, and shipment of all 
laboratory samples. 
Please refer to Section 8.3 for a summary of blood draw volume requirements for this study.  
8.2.7.1. 
Viral Screen and Pregnancy Laboratory Assessments 
The following serum laboratory parameters will be measured at Screening (Visit 1): hepatitis B 
surface antigen, hepatitis C antibody, human immunodeficiency virus (HIV).  
Serum beta chorionic gonadotropin (β-HCG) will be measured at all study visits (females only).  
8.2.7.2. 
Adrenal Laboratory Assessment 
Plasma adrenal laboratory assessments will include cortisol, renin, and aldosterone. These 
parameters will be measured at Screening (Visit 1) and as clinically indicated during the study in 
subjects who develop evidence of adrenal dysfunction. 
8.2.7.3. 
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 all study visits.   


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8.2.7.4. 
Serum Biochemistry Laboratory Assessment 
Serum 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 all study visits.  Ideally, subjects should 
have fasted for at least 8 hours prior to blood collection. 
8.2.7.5. 
Urinalysis 
Urinalysis assessments will include pH, specific gravity, glucose, ketones, blood, protein, 
creatinine urobilinogen, bilirubin, nitrite, and leukocyte esterase.  These parameters will be 
measured at all study visits.   
8.2.7.6. 
Pharmacokinetic Analysis (PK) 
A plasma PK trough sample will be collected prior to the morning ataluren administration at 
Week 16 (Visit 3), Week 32 (Visit 4), Week 48 (Visit 5), Week 64 (Visit 6), Week 80 (Visit 7), 
Week 96 (Visit 8), Week 112 (Visit 9), Week 128 (Visit 10), Week 144 (Visit 11), Week 160 
(Visit 12), Week 176 (Visit 13), and Week 192 (Visit 14/End of Treatment).  These samples will 
be sent to a central bioanalytical laboratory for analysis of ataluren trough levels. Please refer to 
the Lab Manual for instructions regarding the collection, processing and shipment of all PK 
samples to the bioanalytical laboratory  
8.2.8. 
Renal Ultrasound 
An ultrasound to examine the kidneys and collecting system will be performed at Screening 
(Visit 1) in order to obtain a baseline assessment for each subject.  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 results of such ultrasounds must also be 
included in the CRF.  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. 
8.2.9. 
12-Lead ECG 
A 12-lead electrocardiogram (ECG) will be obtained at Screening (Visit 1), Week 16 (Visit 3), 
Week 32 (Visit 4), Week 48 (Visit 5), Week 64 (Visit 6), Week 80 (Visit 7), Week 96 (Visit 8), 
Week 112 (Visit 9), Week 128 (Visit 10), Week 144 (Visit 11), Week 160 (Visit 12), Week 176 
(Visit 13), Week 192 (Visit 14/End of Treatment), and Week 196 (Visit 15 - Post-Treatment 
Visit; 4 weeks post discontinuation of study drug).  The central reading provided by a certified 
vendor will serve as the official study result.  Starting in the second year of the study, after Week 
56, ECGs will be read locally at investigational sites and interpreted for clinical significance.  
The findings will be captured in source documents and within the CRF.   


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Additional ECGs may be performed at any time during the study as clinically indicated at the 
discretion of the investigator.  However, the PTC medical monitor must be informed via e-mail 
that an additional ECG was obtained.  
8.2.10. Ataluren Administration and Dispensation   
Subjects should take ataluren TID as described in Section 6.2.3.  Study drug supply sufficient for 
each 16-week treatment period will be supplied to the subject/caregiver at Study Day 1 (Visit 2) 
and each subsequent on-site visit through Week 176 (Visit 13).  Sufficient drug for 120 days (16 
weeks + 8 days) will be provided at each of these visits to lessen the likelihood that subjects will 
experience drug shortages due to inadvertent loss of study drug or scheduling delays for return 
visits. 
Clinic staff will administer the first dose of the study drug at Study Day 1 (Visit 2).  Subjects 
should remain in the study center for at least 30 minutes to determine that no immediate 
untoward reactions occurred after ataluren administration. 
8.2.11. Ataluren Compliance 
Subjects/caregivers will return all unused sachets of ataluren to the study site.  A Study Drug 
Administration Record (to be completed by the investigational site pharmacist or designated 
personnel) will document the return of unused sachets for compliance assessments at Week 16 
(Visit 3), Week 32 (Visit 4), Week 48 (Visit 5), Week 64 (Visit 6), Week 80 (Visit 7), Week 96 
(Visit 8), Week 112 (Visit 9), Week 128 (Visit 10), Week 144 (Visit 11), Week 160 (Visit 12), 
Week 176 (Visit 13), and Week 192 (Visit 14/End of Treatment).  Clinic staff will record the 
ataluren dosing information including the actual clock time of the first dose administered in the 
clinic.   
8.2.12. Adverse Events 
Adverse events must be assessed and documented at each clinic visit.  This information will be 
collected at Week 1 (Visit 2) through Week 196 (Visit 15 - Post-Treatment Visit; 4 weeks post 
discontinuation of study drug).  In addition, subjects/caregivers will be encouraged to report 
adverse events of concern at any time in the intervals between visits.  Refer to Section 9 for 
additional information regarding adverse event collection and reporting.  
8.2.13. Concomitant Medications 
Information regarding any concomitant medications administered, as well as information 
regarding all non-drug therapies, will be collected throughout the study.  Specifically, start and 
stop dates for all inhaled antibiotics used during the study must be captured in the CRF.  This 
information will be collected at Screening (Visit 1), Week 1 (Visit 2), Week 16 (Visit 3), Week 
32 (Visit 4), Week 48 (Visit 5), Week 64 (Visit 6), Week 80 (Visit 7), Week 96 (Visit 8), Week 
112 (Visit 9), Week 128 (Visit 10), Week 144 (Visit 11), Week 160 (Visit 12), Week 176 (Visit 
13), Week 192 (Visit 14/End of Treatment) and Week 196 (Visit 15 - Post-Treatment Visit; 4 
weeks post discontinuation of study drug).  In addition, subjects/caregivers will be encouraged to 
report any change in concomitant medications at any time in the intervals between visits.  Please 
refer to Section 7 for additional information regarding concomitant medications and other 
supportive (ie, non-drug) therapies. 


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8.2.14. Spirometry 
Lung function will be assessed by spirometry using standardized equipment and procedures.  
Spirometry will be performed at Screening (Visit 1), Week 1 (Visit 2), Week 16 (Visit 3), Week 
32 (Visit 4), Week 48 (Visit 5), Week 64 (Visit 6), Week 80 (Visit 7), Week 96 (Visit 8), Week 
112 (Visit 9), Week 128 (Visit 10), Week 144 (Visit 11), Week 160 (Visit 12), Week 176 (Visit 
13),Week 192 (Visit 14/End of Treatment) and Week 196 (Visit 15 - Post-Treatment Visit; 4 
weeks post discontinuation of study drug). 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 obtain 
approval to deviate from this requirement.  In this instance, the subject should have all 
spirometry measurements performed after use of the prescribed beta agonist(s) at the appropriate 
interval(s).  
8.2.15. 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 at Screening (Visit 
1), Week 1 (Visit 2), Week 16 (Visit 3), Week 32 (Visit 4) and Week 48 (Visit 5), Week 64 
(Visit 6), Week 80 (Visit 7), Week 96 (Visit 8), Week 112 (Visit 9), Week 128 (Visit 10), Week 
144 (Visit 11), Week 160 (Visit 12), Week 176 (Visit 13), and Week 192 (Visit 14/End of 
Treatment).  Information regarding pulmonary exacerbations will also be collected via phone call 
in between on-site visits (ie, Week 8, Week 24, Week 40, Week 56, Week 72, Week 88, Week 
104, Week 120, Week 136, Week 152, Week 168 and Week 184), and at the time of any 
unscheduled contact between the subject and the clinic.   
In addition to subject/caregiver and investigator discussion at scheduled study visits and phone 
calls, subjects/caregivers are encouraged to contact their investigator by telephone with all 
pulmonary exacerbation details for any events that occur between scheduled visits or phone calls. 


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8.2.16. 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 Screening (Visit 1), 
Week 1 (Visit 2), Week 16 (Visit 3), Week 32 (Visit 4), and Week 48 (Visit 5), Week 64 (Visit 
6), Week 80 (Visit 7), Week 96 (Visit 8), Week 112 (Visit 9), Week 128 (Visit 10), Week 144 
(Visit 11), Week 160 (Visit 12), Week 176 (Visit 13), and Week 192 (Visit 14/End of 
Treatment). 
8.3. Blood Collection Summary 
Assuming a 192-week treatment period and all visits completed as noted in Table 3, the 
maximum amount of blood to be drawn at a single visit is approximately 18.0 mL, which occurs 
at the Screening visit only.  The maximum blood to be drawn at subsequent visits (Visits 2-15) is 
approximately 9.0 mL or less.  The total amount of blood to be drawn over the entire study 
period (including the Screening visit, the 192-week treatment period, and the 4-week follow-up 
period) is approximately 144.0 mL.  
 
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 subject who is administered ataluren 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 ataluren.   
• Overdose (administration of an ataluren dose >4.0 times the highest intended total daily 
dose level for this protocol [>160 mg/kg/day]). 
• All reactions from medication misuse, abuse, withdrawal, sensitivity, or toxicity 
• All reactions that result from medication errors or uses of ataluren outside what is 
described in the protocol. 
• Apparently unrelated illnesses, including the worsening of a pre-existing 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. 


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• 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 subject 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 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 ataluren administration), 
including deaths due to disease progression.  Any death occurring later than 4 weeks 
following the last dose need not be reported as a serious adverse event unless 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 ataluren 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 subject 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 (excluding 
hospitalizations for administration of ataluren, procedures required by the study protocol, 


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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 subject 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 subject 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). 
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 unless 
hospitalization is required.  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 


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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 
ataluren 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 ataluren, 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).   
9.2. Eliciting Adverse Event Information 
Each study subject will be questioned about adverse events at each study visit or during any 
telephone contact with the subject or parent/guardian caregiver.  The investigator is to report all 
directly observed adverse events and all adverse events spontaneously reported by the 
subject/caregiver at each scheduled clinic visit after ataluren administration or during any 
telephone contact with the subject/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 subjects 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 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 non-serious (see Section 9.1) 
• Relationship to ataluren (see Section 9.4) 
• Severity of the event (see Section 9.5) 


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• Onset date  
• Resolution date, or date of death  
• Action taken 
• Outcome of the event 
Classification of the event as serious or non-serious determines the reporting procedures to be 
followed.   
9.4. Describing Adverse Event Relationship to Study Drug 
Based on the considerations outlined in Table 4, 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. 
Table 4: 
Relationship of Ataluren to Adverse Event 
Relationship 
Description 
Probable 
A clinical event in which a relationship to ataluren 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 ataluren 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 ataluren exposure that does not preclude 
causality but for which there is a clear alternate cause that is more likely to have caused 
the adverse event than study drug.  Such alternatives include a concomitantly 
administered drug, the subject’s disease state, other medical conditions, or 
environmental factors. 
Unrelated 
A clinical event, for which a relationship to ataluren seems improbable because of 
factors such as inconsistency with known effects of the ataluren, lack of a temporal 
association with ataluren administration, lack of association of the event with ataluren 
withdrawal or rechallenge, and/or presence of alternative explanations for the event.  
Alternative explanations might include a known relationship of the adverse event to a 
concomitant drug, medical history of a similar event, the subject’s disease state, other 
medical conditions, or environmental factors. 
9.5. Grading of Adverse Event Severity 
The severity of adverse events will be graded using the CTCAE, Version 3.0 (refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/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 5. 


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Table 5: 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have 
a clinically significant effect on the subject’s overall health and well-being, 
does not interfere with the subject’s usual function, and is not likely to 
require medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects clinical 
status, and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and 
likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
Note the distinction between the seriousness and the severity of an adverse event.  Severity is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed in Section 9.1.2.   
9.6. Pregnancy 
PTC Therapeutics should be notified in the event that a female subject in the study becomes 
pregnant at any time after the subject’s first dose of ataluren.  Any such pregnancy occurring 
on-study or within 60 days of the last administration of ataluren must be reported on a Pregnancy 
Notification Form).  This must be done whether or 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 subject 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  
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 provided within one additional calendar week.  The investigator 
should consider protocol guidelines and use his/her discretion in ordering additional tests as 
necessary to monitor the resolution of such events.  In the event of additional investigations, the 
CRO Pharmacovigilance Unit should be informed via e-mail or fax.  A subject 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 subject has discontinued from the study, 
and additional investigations may be requested by the medical monitoring team.   


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9.8. Adverse Event Reporting Period 
The first day of adverse event reporting will coincide with the day the first dose of ataluren 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 subject 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) determines the reporting 
procedures to be followed.  Investigator site reporting requirements for adverse events are 
summarized in Table 6. 
Table 6: 
Investigator Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
SAE 
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 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  Subject name, address, and other personal identifiers should be redacted from all study documents prior to 
submission. 
Abbreviations:  AESI = adverse events of special interest; 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 


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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.   
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 PTC Therapeutics Safety Department or assigned designee (such as a 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. 
PTC Therapeutics, Inc. 
Safety Lead: 
 
Phone: 
 
SAE Fax number: 
 
E-mail: 
 
 
In addition, each site will be provided with a Verizon, country specific, calling code. 
 
9.10. PTC Therapeutics Adverse Event Reporting Requirements 
As the sponsor of the study, PTC Therapeutics is responsible for reporting certain safety 
information, particularly SAEs and subject deaths related to participation in the study, to each 
investigator in an expedited manner.  If notification of an 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 SUBJECTS  
All subjects who receive ataluren should remain in the study whenever possible.  However: 
• The subject has the right to withdraw consent and discontinue ataluren at any time. 
• If the subject’s condition substantially worsens after initiating ataluren, the subject will 
be carefully evaluated by the investigator in consultation with the PTC Therapeutics 
medical monitor.  The subject 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 subject from ataluren treatment, if, in the investigator’s clinical judgment, it 
is not in the subject’s best interest to continue.   
• If the subject becomes significantly noncompliant with ataluren administration, study 
procedures, or study requirements, the subject should be withdrawn, particularly when 
the circumstances surrounding noncompliance increase risk to the subject or are 
anticipated to substantially compromise the interpretation of study results. 
• The subject will be withdrawn from treatment if he/she is unable to tolerate ataluren. 
• If the subject becomes eligible to participate in another ataluren nmCF clinical trial 
program initiated by PTC Therapeutics, and elects to enroll in said study, they will be 
withdrawn from this study. 
• This study may be discontinued by the relevant regulatory authority and/or PTC 
Therapeutics at any time. 
The date ataluren is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the CRF.  The PTC medical monitor (and designee) should be informed 
via e-mail of when a subject discontinues ataluren. 
When ataluren 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 subject is free of untoward 
effects.  The subject should be encouraged to seek appropriate follow-up for any continuing 
health problems.   
A subject who completes the study through Week 192 (Visit 14-End-of-Treatment/Premature-
Discontinuation) and is then lost to follow-up during the follow-up period will not be considered 
to have prematurely withdrawn. 
 
11. STATISTICS AND DATA MANAGEMENT  
11.1. Sample Size Calculation for the Primary Endpoint 
The pool of patients potentially eligible for this study is described by the inclusion criteria.  The 
sample size is determined by how many patients satisfy all inclusion/exclusion criteria upon 
applying for study participation, not by any formal statistical analysis. 


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11.2. Population Definition 
11.2.1. 
As-Treated Population 
The as treated population consists of all subjects who received at least 1 dose of ataluren.  This 
population will be evaluated in the analyses of safety and treatment administration. 
11.2.2. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population consists of all subjects who have at least 1 post-baseline 
efficacy assessment.  This population will be evaluated in the analysis of efficacy. 
11.3. General Statistical Considerations 
By-subject 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 by time 
of visit.   
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
11.4. Specific Statistical Analyses  
11.4.1. 
Study Conduct and Subject Disposition 
Subjects who prematurely discontinue from the study will be reported.  Reasons for screening 
failures and early discontinuations, reasons for study discontinuation, and time of withdrawal 
from the study will be described. 
11.4.2. 
Baseline Characteristics 
Subject characteristics at entry and in each phase of the study will be summarized in frequency 
tables and descriptive statistics will be provided for quantitative variables.    
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.  Type and timing of specific concomitant medications (and non-drug therapies) 
will be listed and summarized.     
11.4.5. 
Primary Variables 
11.4.5.1. Adverse Events 
Adverse events will be classified using the MedDRA classification system.  The severity of 
adverse events will be graded by the investigator 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 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. 


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The frequency of subjects experiencing a specific adverse event will be tabulated by treatment 
group, body system, and MedDRA term.  In the by-subject analysis, a subject having the same 
event more than once will be counted only once.  Adverse events will be summarized by worst 
CTCAE grade.    
Adverse events classified as CTCAE Grade 3 or higher; study-drug-related events; adrenal, 
hepatic, and renal events leading to special diagnostic evaluations; events leading to 
discontinuation from treatment; and SAEs will be considered with special attention. 
11.4.5.2. Laboratory Data 
Hematological, serum biochemistry, adrenal assessments, and urine data and their changes (only 
for continuous laboratory parameters) from baseline will be summarized by visit.  
Hematological, serum biochemistry, adrenal assessments, 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.   
Shift tables for hematology, serum biochemistry, adrenal assessments, and urine data will also be 
presented showing change in CTCAE severity grade from baseline to each visit.  For parameters 
for which a CTCAE scale does not exist, shift tables will be presented showing change in results 
from baseline (normal, low and high [or abnormal]) to each visit (normal, low and high [or 
abnormal]).  
Separate listings and tables will be created for assessment of adrenal, hepatic, and renal 
parameters based on the conditions listed in Section 6.3.1.   
11.4.6. 
Secondary Variables 
11.4.6.1. 12-Lead ECG and Other Safety Parameters 
ECG and vital sign data will be listed and summarized by visit.  Physical examination findings 
will be listed.  Where appropriate, changes from baseline at each visit will be presented.   
11.4.6.2. Spirometry 
11.4.6.2.1. Change from Baseline in %-predicted FEV1 
A secondary variable analysis will evaluate relative change in %-predicted FEV1 from Baseline 
to Week 192.  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 %-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 in the variable from baseline to each post-baseline 
visit will be summarized descriptively.  The changes from baseline to each post-baseline visit 
will be analyzed using paired t-tests. 
11.4.6.3. Pulmonary Exacerbation Rates  
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 


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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 rates 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. Spirometry 
FVC and FEF25-75 will be analyzed with the same methods used in the analysis of FEV1. 
11.4.7.2. Weight and BMI 
Weight and BMI will be summarized by visit.  Change from baseline to post-baseline 
measurements will also be summarized. 
11.4.8. 
Exploration of Correlations 
Correlations between subject characteristics and outcome measures, and correlations among 
outcomes measures may be explored using regression models or other appropriate techniques.   
 
12. STUDY COMMITTEES 
12.1. 
Data Monitoring Committee 
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 subjects 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 
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• Reviewing the general progress of the study regarding such issues as subject accrual, 
study conduct, and protocol violations 
• Providing expert advice to PTC Therapeutics on an ad hoc basis regarding matters such 
as safety concerns or diagnostic evaluations in individual subjects 
Interim safety analyses are planned when ~35 subjects have completed >32 weeks of treatment 
and when ~35 subjects have completed >64 weeks of treatment.  Additional interim safety 
analyses may be performed based on the discretion of the DMC and will be described in the 
DMC charter. 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 DMC monitoring plan.  
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 Declaration of Helsinki and 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 subjects 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 
subjects evaluated, the number of subjects who discontinued (and the reasons for 
discontinuation), the number of subjects who completed the study, and the results of the study, 


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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 
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.   


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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 the 
CRF).  At all times, the principal investigator has final responsibility for the accuracy and 
authenticity of all clinical data entered onto the eCRFs and/or reported to PTC Therapeutics from 
the investigator site.   
13.5. Study Records 
During the study, the investigator will maintain adequate records for the study, including the 
following: 
• Medical records  
• Source document records detailing the progress of the study for each subject 
• Laboratory reports 
• A CD-ROM or paper copies of the data that have been captured in the EDC for each 
subject 
• 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 subject 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 subjects enrolled in this study.  These 
regulations also allow the same records to be inspected by authorized representatives of the FDA 
or other regulatory authorities.   
13.6. Confidentiality 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information.  The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs, paper CRFs, or other records provided to or retained 
by PTC Therapeutics (or its authorized designee).  The names and identities of the subjects need 
not be divulged; however, the records must nevertheless be inspected.  This will be accomplished 
by redacting the subject’s name and replacing the name with the subject’s study identification 
number on any record provided to or retained by PTC Therapeutics.  The informed consent form 
must include appropriate statements explaining these requirements.   


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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 but not limited to the 
documents listed in Section 13.5, as well as the identity of all participating subjects (sufficient 
information to link CRFs and clinic records).  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. These records will be maintained by the investigator until notified by 
PTC Therapeutics that record retention is no longer required.   
The investigator must obtain written permission from PTC Therapeutics before disposing of any 
records.  In order to avoid any possible errors, the investigator will contact PTC Therapeutics 
prior to the destruction of any study records.  The investigator will promptly notify 
PTC Therapeutics in the event of accidental loss or destruction of any study records.  If the 
investigator relocates, retires, or for any reason withdraws from the study, the study records may 
be transferred to an acceptable designee, such as another investigator, another institution, or to 
PTC Therapeutics.   
13.8. Monitoring and Auditing  
In accordance with 21 Code of Federal Regulations (CFR) Part 312.56 and/or relevant ICH 
guidelines, PTC Therapeutics or a designee will periodically inspect all CRFs (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 CRFs; 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 subjects in this study.  The names and identities of all 
research subjects will be kept in strict confidence and will not appear on CRFs or other records 
provided to or retained by PTC Therapeutics.  The investigator/institution guarantees direct 
access to source documents by PTC Therapeutics or its designee 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 
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It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections, and that sufficient time is devoted to the 
process.   
13.9. Termination of the Study 
PTC Therapeutics reserves the right to discontinue the study prior to inclusion of the intended 
number of subjects.  The investigator, after consultation with the PTC Therapeutics medical 
monitor, reserves the right to discontinue the study at the investigator site for safety reasons at 
any time.   
After a decision to terminate the study, investigators must contact all subjects who are currently 
participating in the study and must do so within a time-period set by PTC Therapeutics.  As 
directed by PTC Therapeutics, all study materials must be collected and all electronic data entry 
forms completed to the greatest extent possible. 
13.10.  Public Notification of Study Conduct 
Consistent with 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 
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for publication.  Investigators will not be allowed to publish or present the data from this study 
without prior agreement with the PTC Therapeutics Publications Committee.   
13.12.  Communication with Regulatory Authorities 
PTC Therapeutics will be responsible for regulatory interactions with the FDA, the European 
Medicines Agency (EMA), and/or other regulatory authorities, as required.  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 for notification or for approval, as applicable (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. 
 
14. RATIONALE FOR STUDY DESIGN FEATURES  
14.1. Patient Selection 
14.1.1. General 
This study is an open-label safety and tolerability study in previously treated ataluren patients 
with nmCF, that have successfully completed their participation in the Phase 3 double-blind 
study, PTC124-GD-009-CF.  Consistent with GCP guidelines, patients and/or parents/guardians 
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.   
The assessment and evaluation of the overall safety profile of ataluren in nmCF patients is 
developed with safety endpoints considered as having a logical possible connection to the 
disease, testing that can be performed on the study population, are unlikely to have limitations 
due to floor or ceiling effects or confounding factors, can be accurately and reproducibly 
assessed, offer standardized simplicity in performance and analysis, can be interpreted relative to 
normative data, and provide data in a useful timeframe.  The efficacy and safety results of Study 
009 and the open-label extension Study 009e have also been considered in the selection of the 
secondary endpoints of this study. 
14.1.2. Inclusion of Minors   
Inclusion of both children and adults in this protocol is appropriate and necessary.  Based on past 
experience in multiple randomized clinical trials [Fuchs 1994, Ramsey 1999, Saiman 2003, 
Elkins 2006], including the double-blind study of ataluren in nmCF [Rowe 2012],  there is strong 
precedence for this approach.  The benefit-risk ratio is enhanced by inclusion of only children 
with FEV1 values ≤ 90% of predicted, weighting enrollment toward those who are already 
experiencing CF-related pulmonary compromise.  In addition, this ratio is enhanced by the 
known severity of the disease phenotype in patients with CF caused by nonsense mutations 
[Shoshani 1992, Cystic Fibrosis Genotype-Phenotype Consortium 1993, Kerem 1996, de Gracia 
2005, McKone 2006], the generally favorable safety profile of ataluren, and the limited 


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population of patients with nonsense-mutation-mediated disease (10% of the total CF 
population). 
Inclusion of children as well as adults will allow an understanding of how age-dependent  
disease characteristics may affect treatment outcomes.  A total of 65 (86.7%) patients <18 years 
of age completed Study 009 and are eligible for this open-label extension study.  Participation of 
these younger patients in this extension study will allow further exploration of the influence of 
age on safety and efficacy outcomes.  Study participants will now be at least 9 years of age, 
enhancing the ability of participants to reliably perform protocol procedures [Loeb 2008] and 
will have nomogram data describing %-predicted FEV1 values [Wang 1993]. 
Participants in this trial have the potential for direct benefit from treatment with ataluren, which 
justifies the known and potential risks.  Substantial nonclinical and clinical safety experience 
provides appropriate risk-benefit information that supports the conduct of this study.  This 
information is detailed in the Investigator Brochure and is summarized in Section 9.8 of the 
Investigator Brochure.  The potential risks (real and theoretical) have been weighed against the 
expected benefits for the children enrolled in the clinical trial.  It is believed that the balance of 
risks versus expected benefits will be positive for the clinical trial.  In Phase 2 clinical studies, 
including those conducted in nmDMD, a population almost entirely comprised of children, 
ataluren has demonstrated comparable pharmacodynamic activity, safety, and PK profiles in 
children and adults with CF [Clancy 2006, Kerem 2008, Sermet-Gaudelus 2008].  The drug has 
also shown pharmacodynamic activity and was generally well tolerated at even higher dose 
levels in children with DMD [Bönnemann 2007]. 
This study includes a comprehensive safety monitoring plan.  The safety monitoring plan builds 
on the safety observations from previous nonclinical and clinical studies in order to protect study 
participants and more fully define the potential risk profile of ataluren.  During study conduct, 
patients will be monitored closely for adverse clinical and laboratory events.  This protocol 
clearly defines the actions to be taken if adverse events occur.  Procedures have been established 
for defining adverse events, eliciting adverse event information, recording adverse events, 
evaluating the relationship of adverse events to the study drug, grading the severity of adverse 
events, following up on unresolved adverse events, and reporting adverse events.  These 
procedures are fully detailed in Section 9.  Additional risk/benefit information that becomes 
available during the conduct of the study will be provided to each investigative site as a “letter to 
the investigator” or safety alert.  In addition, pain and discomfort will be prevented as much as 
possible, and investigations will be limited to a minimum necessary to provide meaningful data 
and performed using size/age appropriate material and devices. 
Because the level of risk may evolve over time, during the trial and with evolving knowledge, 
safety will be monitored by a data monitoring committee (DMC) (refer to Section 12.1).  The 
oversight of an independent DMC provides an added measure of risk mitigation for study 
participants.  The DMC will provide recommendations to PTC Therapeutics about the evolving 
risks and benefits observed in the course of the study and any modifications required during the 
course of the study.  DMC members will be responsible for reviewing study conduct, protecting 
subject well-being, and reviewing the quality and integrity of the data in the study.  The 
investigative sites will be informed of all DMC recommendations that relate to subject safety and 
any modifications to the study that may affect the willingness of study subjects to continue with 
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14.1.3. Safety Measurements 
14.1.3.1. 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, and other 
safety assessments.  For consistency of interpretation, adverse events will be coded using the 
MedDRA and the severity of these events and laboratory abnormalities will be graded using the 
well-defined CTCAE, Version 3.0.  Version 3.0 will remain the reference for this study to 
facilitate comparison with safety data from previously conducted ataluren trials.  Concomitant 
medications will be coded with the WHODRUG dictionary.  ECG data will be evaluated in 
accordance with the relevant ICH ECG guidance. 
14.1.3.2. 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 subject acceptance of therapy, 
integrating factors of tolerability, palatability, and convenience.  The compliance of the subject 
will be verified by counting used ataluren sachets.  
14.1.4. Required Laboratory Values 
The required laboratory values for eligibility are necessary in order to implement the safety 
monitoring plan described in Section 6.3. 
Minimal reversible serum transaminase elevations (ALT, AST) have been observed in healthy 
volunteers receiving ataluren (Section 2.2.3.1) [Hirawat 2007].  However, because such findings 
have not been prominent in prior nmCF clinical trials testing (Section 2.2.3), and because many 
patients with CF may have chronic elevations in serum ALT, AST, and GGT, it is not practical 
to exclude all patients with such abnormalities.  Therefore, candidates with Grade 1 elevations in 
serum ALT, AST, or GGT values at screening may be enrolled.  Patients with more severe 
elevations in these parameters or with chronic active hepatitis infections will be excluded.  The 
requirement that subjects have a screening serum albumin ≥3.0 g/dL (in conjunction with 
exclusion for those with known portal hypertension) avoids accrual of those who have 
profoundly unstable hepatic or nutritional status.   
Mild nephrosis in mice has been observed in toxicology studies.  Renal findings in Study 009 
included episodes of creatinine elevations and nephrolithiasis.  Overall, treatment-emergent renal 
adverse events were seen more frequently in the ataluren arm; cases of reversible Grade 3-4 
creatinine elevations were observed in the ataluren arm, which were associated with the 
treatment of exacerbations with nephrotoxic systemic antibiotics and, in some cases, 
dehydration.  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.  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 new onset nephrolithiasis was similar in 
both arms (5 patients [4.2%] on ataluren vs 4 patients [3.4%] on placebo). 
Thus, ultrasound will be performed in each subject during screening to establish an anatomic 
baseline against which to compare any future renal findings and subjects must have adequate 
baseline renal function as established by serum markers (cystatin C, creatinine, BUN), urine 


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markers (protein and blood), and serum electrolytes (Na+, K+, HCO3-, Mg2+, Ca2+, and 
phosphate). 
During the Phase 2b double-blind study of ataluren in nmDMD (PTC124-GD-007-DMD), mean 
total cholesterol and triglycerides were in the upper range of normal at baseline and increased on 
study, reaching borderline high or high values.  Baseline mean cholesterol and triglycerides 
values were higher in patients receiving systemic corticosteroid therapy.  During the treatment 
period, increases in mean cholesterol levels were observed in patients receiving systemic 
corticosteroid therapy, more prominently in ataluren-treated patients than in the placebo arm.  In 
patients not receiving systemic corticosteroid therapy, mean cholesterol levels increased 
similarly across all 3 treatment arms (placebo, 10-, 10-, 20-mg/kg TID, and 20-, 20-, 40-mg/kg 
TID), and mean triglyceride levels increased minimally in ataluren-treated patients.  Similar 
changes were not seen in the double-blind study for nmCF (Study 009).  In that study, low 
cholesterol levels were observed prior to treatment in >40% of patients across both treatment 
arms.  No ataluren-treated patients shifted from normal cholesterol at baseline to high cholesterol 
at Week 48.  Shifts from normal triglycerides at baseline to high triglycerides at Week 48 were 
observed in both treatment arms, and were somewhat higher in placebo.  Despite the lack of 
effect of ataluren on total cholesterol and triglycerides in nmCF, total cholesterol and 
triglycerides will continue to be monitored throughout this study. 
14.1.5. 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. 
14.1.6. Prior and Concomitant Therapies 
Conventional supportive therapies will be permitted; however, efforts will be made to avoid use 
of concomitant medications that might confound interpretation of study results or pose a safety 
risk.  Ataluren has not proved allergenic in studies performed to date, but review of known 
allergies to excipients containing in the formulation is prudent.  Concomitant use of potentially 
nephrotoxic 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, inhaled aminoglycoside use cannot occur within four 
months prior to the Screening Visit, and it is strongly recommended that alternative agents be 
utilized for CF treatment/prophylaxis. 
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, 


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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.  
Physicians and subjects are encouraged to avoid the use of extraneous drugs or alternative 
therapies in order to minimize the possibility that drug-drug interactions might occur.  In 
particular, physicians are advised to closely monitor subjects when drugs of low therapeutic 
index that are cleared by CYP2C9 (eg, phenytoin or warfarin) are administered concomitantly 
with ataluren. 
14.2. 
Treatment Rationale 
14.2.1. Schedule and Ataluren Dose Selection 
Dosing based on body weight will continue to be employed.  Such dosing reduces variability in 
exposure by accommodating differences in subject size across the span of ages in subjects 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 subjects, thus enhancing 
compliance.   
14.2.2. 
Duration of Therapy 
Duration of therapy in this study is intended to provide approximately 4 years of additional 
safety data for nmCF patients that have completed Study 009, and as a secondary outcome, to 
provide additional long-term efficacy data in this population.  Study duration may be expanded 
to include multiple years, if so determined by PTC Therapeutics. 
14.2.3. 
Safety Monitoring  
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 
subjects, obtain a thorough assessment of any clinically relevant adverse events or laboratory 


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abnormalities, and to offer recommendations for interruption and dose modification of ataluren 
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. 
As noted in Section 6.3, subjects must be monitored closely for adverse events or laboratory 
abnormalities during the course of the study.  Section 6.3 provides information on actions to be 
taken in the event that abnormalities are noted on specified monitoring studies.  Thresholds are 
provided for interrupting ataluren immediately, for interrupting ataluren after confirmation of a 
value beyond the threshold, or for continuing ataluren while evaluating for potential drug-related 
toxicity. 
14.2.3.1. Renal Abnormalities 
14.2.3.1.1. Overview 
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 Phase 1 studies in healthy volunteers and Phase 2 studies in patients with DMD and cystic 
fibrosis, renal laboratory abnormalities have been infrequent.   
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. 


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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.  
14.2.3.1.2. Renal Monitoring Plan 
• 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 was 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 ataluren dosing. 
• Urine Protein:Creatinine: Proteinuria can be an early marker for renal injury in 
experimental models [Amin 2004] and is commonly observed with even modest clinical 
decreases in renal function [National Kidney Foundation 2002].  Glomerular disease (eg, 
diabetic nephropathy) is often associated with albuminuria due to defects in exclusion of 
plasma proteins in the glomerular filtrate.  Tubular injury (eg, as observed in mice 


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receiving ataluren) more often leads to increases in low-molecular-weight proteins (eg, 
beta-2 microglobulin, β2-microglobulin, α1-microglobulin retinol-binding protein, 
lysozyme) as tubular protein catabolism is compromised or proteins of injury are 
produced [Guignard 2004, Stevens 2007].  Because mice that developed nephrosis while 
receiving ataluren had proteinaceous material in the renal tubules on histological 
examination, monitoring of urine protein in humans receiving ataluren is additionally 
warranted.   
Traditional methods of urine protein screening are only semiquantitative, are relatively 
insensitive, and are confounded by exogenous substances and subjective interpretation 
[Kim 2007].  The presence of urinary protein may be masked in dilute urine or 
exaggerated in concentrated urine.  For these reasons, a quantitative method of accessing 
proteinuria is planned in this study, specifically urinary protein concentration relative to 
urinary creatinine concentration [Ginsberg 1983, Schwab 1987].  These methods of 
screening, using spot urine samples, have been found to be as accurate as and more 
practical than quantification of urine protein during a 24-hour collection.  Values for 
protein:creatinine of ≥0.2 mg/dL:mg/dL have been established as abnormal [Morgenstern 
2003].  Follow-up methods such as urine electrophoresis may be useful in discriminating 
among the types of proteins present and may suggest a site of injury (eg, an 
albumin-specific pattern with glomerular damage versus a diffuse multiple 
low-molecular-weight protein pattern with tubular damage) [Stevens 2007].  Confirmed 
proteinuria should prompt consideration of interruption/modification of study drug 
dosing. 
• Urine Blood:  Blood in the urine may indicate pathology of the renal parenchyma or of 
the urinary collecting system (eg, ureters, bladder, and urethra).  Like proteinuria, 
hematuria is commonly found in patients with minimal changes in GFR due to renal 
(particularly glomerular) dysfunction [National Kidney Foundation 2002].  Confirmed, 
persistent evidence of urinary blood by dipstick and/or microscopic examination will 
prompt further evaluation.  Ultrasound or other imaging can evaluate for a potential renal 
cause for bleeding.  Urology consultation can be obtained to assess for post-renal sources 
of hematuria.  Clotting function and use of drugs that may impair platelet function will be 
reviewed.  Confirmed, persistent hematuria in the absence of a post-renal source of 
bleeding or a bleeding diathesis will prompt potential interruption/modification of 
ataluren dosing. 
• Serum Electrolytes: Assessments of serum electrolytes (sodium, chloride, potassium, 
bicarbonate, magnesium, calcium, and phosphorus) provide information regarding renal 
function that may supplement more primary assessments.  Derangements in serum 
concentrations may reflect altered tubular handling of these ions.  With worsening renal 
function, hyperphosphatemia and hypocalcemia may develop and reductions in serum 
bicarbonate or elevations in potassium may suggest an impaired ability of proximal 
tubules or collecting ducts to maintain acid-base balance [National Kidney Foundation 
2002].  Given the cardiovascular and neurological consequences of severe derangements 
of serum potassium, calcium, or magnesium, evaluation of these ions is important to 
avoid potential secondary complications.  Because transient Grade 1 alterations in the 
concentrations of electrolytes are very unlikely to be associated with significant 


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secondary side effects, alterations to ≥Grade 2 are considered appropriate to prompt 
potential interruption/modification of ataluren 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 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. 
14.2.4. Hepatic Monitoring Plan 
CF-related hepatobiliary obstruction and inflammation can 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 hepatotoxicity 
monitoring should focus special attention on any increases in bilirubin [Abboud 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 
much larger-scale Phase 3 studies of ataluren.  Since no significant changes in hepatic serum 
markers were observed in the Phase 3 studies, these markers are not included in this protocol as 
efficacy assessments.  Therefore, the hepatic monitoring of this study is for monitoring of 
general safety thresholds specific to the nmCF population. 
14.2.5. 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 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.  Nonetheless, 
blood pressure will be monitored via standardized procedures at each visit.   
14.2.6. 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 


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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 
(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 from the patients dosed with 
ataluren to date in the clinical studies, some for over 7 years indicate no increased risk of tumors. 
Long-term outcomes will be collected by completion of long-term health surveys or in a post-
approval registry). 
14.2.7. Other Abnormalities 
Recommendations for interruption of dosing are provided in Section 6.3, 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.   
14.2.8. 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 
subject safety with the potential for observing efficacy in circumstances under which a subject 
experiencing an adverse event may still be able to continue on ataluren therapy at a lower dose.  
Interruption of therapy is advocated as the primary response in order to determine reversibility of 
the adverse finding.   
14.2.9. Efficacy Measurements 
14.2.9.1. 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 


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principal means of assessing both the level of dysfunction and the effects of intervention has 
been spirometry [Ramsey 1994].  Because the initial pulmonary defect in CF is obstructive, 
FEV1 has commonly been evaluated.  Rates of decline in FEV1 are correlated with survival 
[Corey 1997] and have prognostic significance for mortality [Kerem 1992]; the relative risk of 
death is doubled with each 10% decrement in the %-predicted FEV1.  The more rapid declines in 
FEV1 in patients with pancreatic-insufficient disease and in women are correlated with shorter 
survival in these subgroups [Corey 1997, Kerem 1992], providing internal corroboration of the 
predictive import of FEV1 within the available data.  The statistical relationship between FEV1 
values and survival appears to strengthen as patients grow older [Schlucter 2002], reaching a 
zenith at ages ≥15 years.   
A clinically meaningful FEV1 treatment effect has been established.  Data from patients with 
chronic obstructive pulmonary disease suggest that a >4% change in %-predicted FEV1 can be 
detected symptomatically [Redelmeier 1996].  In CF, the experience with dornase-alfa, inhaled 
tobramycin, azithromycin, and hypertonic saline demonstrate respective relative improvements 
in %-predicted FEV1 over 6 to 12 months of 5.7%, 10%, 6.2%, and 3.2%, respectively, 
compared to patients receiving placebo [Fuchs 1994, Ramsey 1999, Saiman 2003, Elkins 2006].  
In the previous double-blind study of ataluren (Study 009), the subgroup of patients not receiving 
chronic inhaled tobramycin showed a 5.7% difference in the relative change of %-predicted 
FEV1 the ataluren arm when compared to placebo.  Hence, FEV1 was selected as a secondary 
endpoint of this study, to further assess the effect of ataluren on pulmonary performance. 
In order to maximize uniformity of testing, data collection, and analysis for this study, an 
experienced CRO 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 and 
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. 
14.2.9.2. Pulmonary Exacerbations 
The approach to CF pulmonary exacerbations to be taken in this study evolves from that used in 
the study of hypertonic saline [Elkins 2006], ie, by characterizing exacerbations as those 
presenting symptomatically (whether or not antibiotics are given) and  those requiring 
intervention (with oral or parenteral antibiotics).  As in the previous open-label Phase 3 
extension 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 [Rowe 2012].   
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 
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Subjects 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 or 
scheduled phone calls.  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. 
14.2.9.3. Weight/Body Mass Index 
Patients with CF are generally underweight compared to healthy individuals of the same gender 
and age [Rabin 2004].  Assessment of body weight and BMI during the course of this Phase 3 
study is planned.  While changes in these parameters are quite nonspecific, they constitute 
simple-to-assess outcomes of general well-being.  
14.2.10. 
Exposure Outcome Measures  
14.2.10.1. 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 subjects with CF, plasma sampling will be limited to before 
dosing.  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.    
14.2.11. Timing of Assessments 
The timing of study assessments are considered adequate for safety and efficacy monitoring and 
the design builds upon the results of previous ataluren Phase 3 studies.  The 16-week interval 
takes into account time for full cycling of concomitant medications, ie, inhaled non-
aminoglycoside antibiotics.  
Study activities have been mapped across the study (as outlined in Sections 8.1) and within each 
study visit (as described in Section 8.2).  The intent is to minimize variability by maintaining a 
timely, clear and consistent approach to evaluations for each subject, across subjects at a site, and 
across sites.  At the beginning of each visit, discussion of subject health status and adverse 
events, concomitant medication usage, and compliance permits investigators and clinic staff to 
determine early in the visit if medical events or other problems have developed that require 
additional diagnostic testing or subject counseling.  The clustering and sequencing of study 
procedures considers practical, subject convenience, and staff convenience factors while seeking 
to minimize subject time in the clinic.   
14.3. 
Study Committees 
Inclusion of the SSC and a DMC of independent experts incorporates a high level of 
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 


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expert assistance in these disciplines that should enhance the review of any potential safety 
signals relating to the kidneys.   
 
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 


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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 
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 
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 Section 2.2).   
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 (-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, supported by TEPD results in the 
previous Phase 2 clinical trials, demonstrate the beneficial effect of ataluren in patients with 


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nmCF.  Ataluren thus offers an important advance in the genetic-based treatment of nmCF in 
patients aged 6 years and older.  The increased effect seen in patients not receiving chronic 
inhaled tobramycin makes benefit more likely in this subgroup, who will be enrolled in this 
study, further supports the potential for the benefit of ataluren therapy. 
15.3. 
Benefits and Risks: 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 subjects’ 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 
14.2.3.1).  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, clinical trials in nmDMD have demonstrated that the adverse-event profile of 
ataluren was comparable to that of placebo.  In the double-blind 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.   


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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 to ataluren.  Appropriate monitoring and laboratory evaluation, as detailed in Section 
14, is incorporated in this protocol in order to mitigate any risks to study participants.  The 
current trial (Study 023) is feasible and will provide additional safety and efficacy data of 
ataluren in nmCF.  


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Vonderscher J.  Biomarker of drug-induced kidney injury: qualification for regulatory decision-
making.  Institute of Medicine of the National Academies: Forum on Drug Discovery, 
Development, and Translation Workshop – Emerging Safety Science. 2007 Apr. 
http://www.iom.edu/Object.File/Master/42/665/Vonderscher.pdf. 
von Unruh GE, Voss S, Sauerbruch T, Hesse A.  Dependence of oxalate absorption on the daily 
calcium intake.  J Am Soc Nephrol. 2004 Jun;15(6):1567-73. 
Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary function between 6 and 18 
years of age. Pediatr Pulmonol. 1993 Feb;15(2):75-88. 
Welch EM, Wong W, Peltz, SP. Translation termination: It’s not the end of the story. In 
Sonenberg N, Hershey JWB, and Matthews M, eds. Translational control of gene expression. 
2000 Cold Spring Harbor Press, New York: 467-485. 
Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta 
CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, 
Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, 
Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, 
Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 
targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. 
Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: Scriver CR, Beaudet AL, 
Sly WS, Valle D, eds. The metabolic basis of inherited disease. 8th ed. Vol. 3. New York: 
McGraw-Hill, 2001:5121-5188. 
Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, 
Bebok Z, Shushi L, Kerem B, Kerem E.  Gentamicin-induced correction of CFTR function in 
patients with cystic fibrosis and CFTR stop mutations.  N Engl J Med. 2003 Oct 9;349(15):1433-
41. 
Zappitelli M, Joseph L, Gupta IR, Bell L, Paradis G.  Validation of child serum creatinine-based 
prediction equations for glomerular filtration rate. Pediatr Nephrol. 2007 Feb;22(2):272-81. 
 

SAP_000.pdf: 
Protocol: PTC124-GD-023-CF 
Statistical Analysis Plan 
PTC Therapeutics, Inc. – Confidential 
Version 1.0 
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STATISTICAL ANALYSIS PLAN 
Version 1.0 
 14 July 2017 
Protocol PTC124-GD-023-CF 
An Open-Label Safety and Efficacy Study for Patients with Nonsense 
Mutation Cystic Fibrosis Previously Treated with Ataluren (PTC124®) 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc.  Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where 
required by applicable law) and should not be used for unauthorized purposes.  In the event of an actual or 
suspected breach of this obligation, PTC Therapeutics, Inc. should be notified promptly. 
NCT02107859


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APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
  
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Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
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Protocol: PTC124-GD-023-CF 
 
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CONTENTS 
 
OVERVIEW ....................................................................................................................................................... 6 
 
STUDY OVERVIEW ........................................................................................................................................ 6 
 
STUDY DESIGN ............................................................................................................................................ 6 
 
STUDY OBJECTIVES ................................................................................................................................... 11 
 
Primary Objective ................................................................................................................................ 11 
 
Secondary Objectives ........................................................................................................................... 11 
 
Tertiary Objectives .............................................................................................................................. 11 
 
STUDY ENDPOINTS .................................................................................................................................... 11 
 
Primary Endpoint ................................................................................................................................ 11 
 
Secondary Endpoints ........................................................................................................................... 11 
 
Tertiary Endpoints ............................................................................................................................... 11 
 
Other Endpoints ................................................................................................................................... 11 
 
SAMPLE SIZE ............................................................................................................................................. 12 
 
STUDY POPULATIONS ................................................................................................................................ 12 
 
AS-TREATED POPULATION ........................................................................................................................ 12 
 
INTENTION-TO-TREAT (ITT) POPULATION ................................................................................................ 12 
 
STATISTICAL AND ANALYTICAL PROCEDURES ............................................................................... 12 
 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................................ 12 
 
CONTROL OF THE MULTIPLICITIES ............................................................................................................ 12 
 
MISSING DATA HANDLING ........................................................................................................................ 13 
 
MULTIPLE CENTERS .................................................................................................................................. 13 
 
SUBJECT DISPOSITION ............................................................................................................................... 13 
 
Accounting for Subjects ....................................................................................................................... 13 
 
Protocol Deviations ............................................................................................................................. 13 
 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................................................................. 13 
 
MEDICAL HISTORY .................................................................................................................................... 13 
 
PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES ................................................................... 13 
 
STUDY TREATMENT ADMINISTRATION AND COMPLIANCE ........................................................................ 14 
 
PRIMARY ANALYSES ................................................................................................................................. 14 
 
Adverse Events ................................................................................................................................ 14 
 
Clinical Laboratory Evaluations ..................................................................................................... 16 
 
SECONDARY ANALYSES ............................................................................................................................ 18 
 
Vital Signs ....................................................................................................................................... 18 
 
Electrocardiographic Analyses ....................................................................................................... 18 
 
Change from Baseline in %-predicted FEV1 ................................................................................... 19 
 
Pulmonary Exacerbation Rates ....................................................................................................... 20 
 
TERTIARY ANALYSES ................................................................................................................................ 20 
 
FVC ................................................................................................................................................. 20 
 
Body Weight, Height, and BMI ....................................................................................................... 20 
 
PHARMACOKINETICS ANALYSES ............................................................................................................... 20 
 
INTERIM ANALYSES .................................................................................................................................. 20 
 
DATA HANDLING ......................................................................................................................................... 21 
 
BASELINE .................................................................................................................................................. 21 
 
ANALYSIS VISITS ...................................................................................................................................... 21 
 
REPEATED MEASUREMENTS IN SPIROMETRY DATA .................................................................................. 21 


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ABSOLUTE AND RELATIVE CHANGE FROM BASELINE ............................................................................... 21 
 
MISSING DATES OF AE AND PRIOR AND CONCOMITANT MEDICATIONS .................................................... 21 
 
Missing Date Information for Adverse Events ..................................................................................... 21 
 
Missing Date Information for Prior or Concomitant Medications ...................................................... 22 
 
PULMONARY EXACERBATION DEFINITIONS .............................................................................................. 24 
 
ANALYSIS CHANGES FROM PROTOCOL .............................................................................................. 26 
 
BIBLIOGRAPHY ............................................................................................................................................ 27 
 TABLES 
TABLE 1.  SCHEDULE OF EVENTS .................................................................................................................................... 7 
TABLE 2.  SAFETY MONITORING PARAMETERS AND ACTIONS TO BE TAKEN............................................................... 17 
 


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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 
BUN 
Blood urea nitrogen 
CDC 
Centers for Disease Control and Prevention 
CF 
Cystic fibrosis 
CI 
Confidence interval 
CK 
Creatine kinase 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
FEF25-75 
Forced expiratory flow between 25% and 75% of expiration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GGT 
Gamma-glutamyl transferase 
ITT 
Intent-to–treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QT 
Ventricular depolarization-repolarization (interval on ECG) 
QTc 
QT interval corrected for heart rate 
REF 
Respiratory Event Form 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
ULN 
Upper limit of normal 
WHODRUG 
World Health Organization Drug (dictionary) 
 
 


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OVERVIEW 
This statistical analysis plan (SAP) details the statistical methods to be used in the analyses and 
presentation of the data collected in Study PTC124-GD-023-CF (Study 023). Preparation of this 
SAP incorporates statistical design elements present in the study protocol version 3.0 (dated 03 
February 2016). Where conflicts exist between this SAP and the study protocol, the information 
contained in this SAP supersedes the protocol. Any refinements to the SAP will be incorporated 
by amendment before the databases are locked.    
 
STUDY OVERVIEW 
 
Study Design 
Study 023 is a Phase 3, international, multicenter, long-term safety study of ataluren in patients 
with nmCF that have completed participation in the double-blind study PTC124-GD-009-CF 
(Study 009).  
It is planned that approximately 70 patients that completed participation in Study 009 will be 
enrolled into the study.  All participating sites must therefore have had at least 1 patient that 
completed participation in Study 009.  It is anticipated that most eligible patients would have 
also been enrolled in PTC124-GD-009e-CF (Study 009e), the 96-week open-label study that 
immediately proceeded Study 009. Eligible subjects will receive oral ataluren administered 3 
times per day (TID) at respective morning, midday, and evening doses of 10-, 10-, and 20-mg/kg 
for ~192 weeks. The detailed schedule of assessments are displayed in Table 1. 
Planned interim safety analyses will be conducted by an independent data monitoring committee 
(DMC).  The first safety review will occur when ~35 patients have completed ≥32 weeks of 
treatment.  The second safety review will occur when ~35 patients have completed ≥64 weeks of 
treatment.     
The study will be terminated prematurely according to company’s strategic decision on March 2, 
2017. All subject who are on-going by then will be discontinued. 
 


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Table 1.  Schedule of Events 
Study Period 
Screening 
Ataluren Treatment 
Study Week 
Week  
-4 to -1 
Week 1 
Week 8 
(Phone 
Call) 
Week 16 
Week 24 
(Phone 
Call) 
Week 32 
Week 40 
(Phone 
Call) 
Week 48  
Week 56 
(Phone 
Call) 
Study Day 
-28 to -1 
1 
(+7 days) 
56 (±7 
days) 
112 (±7 
days) 
168 (±7 
days) 
224 (±7 
days) 
280 (±7 
days) 
336 (±7 
days) 
392 (±7 
days) 
Visit / Call 
1 
2 
2a 
3 
3a 
4 
4a 
5 
5a 
Informed Consent  
X 
 
 
 
 
 
 
 
 
IVR/IWR System Screening 
X 
 
 
 
 
 
 
 
 
Clinical and Medication History  
X 
 
 
 
 
 
 
 
 
Vital Signs (including pulse oximetry)  
X 
X 
 
X 
 
X 
 
X 
 
Height 
X 
X 
 
X 
 
X 
 
X 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
Physical Examination 
X 
As clinically indicated 
X 
As clinically 
indicated 
Serum Viral Screen  
X 
 
 
 
 
 
 
 
 
β-HCGa 
X 
X 
 
X 
 
X 
 
X 
 
Cortisol, Renin, and Aldosterone 
X 
As clinically indicated 
Biochemistryb 
X 
X 
 
X 
 
X 
 
X 
 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
Urinalysis  
X 
X 
 
X 
 
X 
 
X 
 
Ataluren PK (trough) 
 
 
 
X 
 
X 
 
X 
 
Renal Ultrasound 
X 
As clinically indicated 
12-Lead ECG  
X 
 
 
X 
 
X 
 
X 
 
Ataluren Administration in Clinic 
 
Xc 
 
 
 
 
 
 
 
Ataluren Dispensation 
 
X 
 
X 
 
X 
 
X 
 
Review Ataluren Compliance  
 
 
 
X 
 
X 
 
X 
 
Adverse Events 
Xd 
X 
 
X 
 
X 
 
X 
 
Concomitant Medication / 
Non-Drug Therapy 
X 
X 
 
X 
 
X 
 
X 
 
Spirometry 
X 
X 
 
X 
 
X 
 
X 
 
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Presence of P. aeruginosa in Sputum 
X 
X 
 
X 
 
X 
 
X 
 
 


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Table 1.  Schedule of Events - Continued 
Study Period 
Ataluren Treatment 
Study Week 
Week 64 
Week 72 
(Phone 
Call) 
Week 
80 
Week 88 
(Phone 
Call) 
Week 96 
 Week 104 
(Phone 
Call) 
Week 
112 
Week 120 
(Phone 
Call) 
Week 128 
Week 136 
(Phone 
Call) 
Study Day  
448  
(+7 days) 
504  
(±7 days) 
560  
(±7 
days) 
616  
(±7 days) 
672  
(±7 days) 
728  
(±7 days) 
784  
(±7 days) 
840  
(±7 days) 
896  
(±7 days) 
952  
(±7 days) 
Visit / Call 
6 
6a 
7 
7a 
8 
8a  
9 
9a 
10 
10a 
Vital Signs (including pulse 
oximetry)  
X 
  
X 
  
X 
  
X 
  
X 
  
Height 
X 
  
X 
  
X 
  
X 
  
X 
  
Weight 
X 
  
X 
  
X 
  
X 
  
X 
  
Physical Examination 
As clinically indicated 
X 
As clinically indicated 
Serum Viral Screen  
  
  
  
  
  
  
  
  
  
  
β-HCGa 
X 
  
X 
  
X 
  
X 
  
X 
  
Cortisol, Renin, and Aldosterone 
As clinically indicated 
Biochemistryb 
X 
  
X 
  
X 
  
X 
  
X 
  
Hematology 
X 
  
X 
  
X 
  
X 
  
X 
  
Urinalysis  
X 
  
X 
  
X 
  
X 
  
X 
  
Ataluren PK (trough) 
X 
  
X 
  
X 
  
X 
  
X 
  
Renal Ultrasound 
As clinically indicated 
12-Lead ECG  
X 
  
X 
  
X 
  
X 
  
X 
  
Ataluren Administration in Clinic 
  
  
  
  
  
  
  
  
  
  
Ataluren Dispensation 
X 
  
X 
  
X 
  
X 
  
X 
  
Review Ataluren Compliance  
X 
  
X 
  
X 
  
X 
  
X 
  
Adverse Events 
X 
  
X 
  
X 
  
X 
  
X 
  
Concomitant Medication / 


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Non-Drug Therapy 
X 
  
X 
  
X 
  
X 
  
X 
  
Spirometry 
X 
  
X 
  
X 
  
X 
  
X 
  
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Presence of P. aeruginosa in Sputum 
X 
  
X 
  
X 
  
X 
  
X 
  
 
Table 1.  Schedule of Events - Continued 
Study Period 
Ataluren Treatment 
4-Week Post- 
Treatment 
Follow-Up 
(End of Study) 
Study Week 
Week 144 
Week 152 
(Phone Call) 
Week 160 
Week 168 
(Phone Call) 
Week 176 
Week 184 
(Phone Call) 
Week 192 
EOT/ 
Early D/Cf 
Study Day  
1008  
(±7 days) 
1064  
(±7 days) 
1120  
(±7 days) 
1176  
(±7 days) 
1232  
(±7 days) 
1288  
(±7 days) 
1344  
(±7 days) 
1372  
(±7 days) 
Visit / Call 
11 
11a 
12 
12a 
13 
13a 
14 
15 
Vital Signs (including pulse oximetry)  
X 
  
X 
  
X 
  
X 
X 
Height 
X 
  
X 
  
X 
  
X 
X 
Weight 
X 
  
X 
  
X 
  
X 
X 
Physical Examination 
X 
As clinically indicated 
X 
X 
Serum Viral Screen  
  
  
  
  
  
  
  
  
β-HCGa 
X 
  
X 
  
X 
  
X 
X 
Cortisol, Renin, and Aldosterone 
As clinically indicated 
Biochemistryb 
X 
  
X 
  
X 
  
X 
X 
Hematology 
X 
  
X 
  
X 
  
X 
X 
Urinalysis  
X 
  
X 
  
X 
  
X 
X 
Ataluren PK (trough) 
X 
  
X 
  
X 
  
X 
  
Renal Ultrasound 
As clinically indicated 
12-Lead ECG  
X 
  
X 
  
X 
  
X 
X 


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Ataluren Administration in Clinic 
  
  
  
  
  
  
  
  
Ataluren Dispensation 
X 
  
X 
  
X 
  
  
  
Review Ataluren Compliance  
X 
  
X 
  
X 
  
X 
  
Adverse Events 
X 
  
X 
  
X 
  
X 
X 
Concomitant Medication / 
Non-Drug Therapy 
X 
  
X 
  
X 
  
X 
X 
Spirometry 
X 
  
X 
  
X 
  
X 
X 
Respiratory Event Evaluatione 
X 
X 
X 
X 
X 
X 
X 
  
Presence of P. aeruginosa in Sputum 
X 
  
X 
  
X 
  
X 
  
a Testing for female subjects only. 
b Ideally, subjects should have fasted for at least 8 hours prior to blood collection. 
c Clinic staff will administer the first dose of study drug at Study Day 1 (Visit 2). 
d Adverse events (AEs) should be elicited from subjects at all study visits; however, any untoward medical occurrences collected at Screening will be used to assess study eligibility only and will not be 
reported as AEs in the CRF.   
e Includes completion of the Respiratory Event Form (REF). 
f Patients that do not complete ≥192 Weeks of treatment will be considered prematurely discontinued. 
Abbreviations: β-HCG = human chorionic gonadotropin, D/C = discontinuation, ECG = electrocardiogram, EOT = end of treatment, IVR/IWR = Interactive Voice Response/Interactive Web Response, 
PK = pharmacokinetic


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Study Objectives  
 
Primary Objective 
The primary objective of this study is to determine the long-term safety and tolerability of 10-, 
10-, 20- mg/kg ataluren in patients with nmCF who completed participation in the double-blind 
study (PTC124-GD-009-CF) as assessed by adverse events and laboratory abnormalities. 
 
Secondary Objectives 
The secondary objectives are to determine the efficacy and safety of ataluren as assessed by 
spirometry (FEV1), pulmonary exacerbation rate, and other safety parameters (eg, 12-lead ECG 
measurements, vital signs). 
 
Tertiary Objectives 
The tertiary objectives are to determine the efficacy of ataluren as assessed by other parameters 
of pulmonary function (FVC and FEF25-75), and changes in body weight BMI. 
 
 
Study Endpoints 
 
Primary Endpoint 
• Safety profile characterized by type, frequency, severity, timing, and relationship to 
ataluren of any adverse events, and laboratory abnormalities 
 
Secondary Endpoints 
• Change from baseline to end of treatment in spirometric performance as measured by 
FEV1 
• Rate of pulmonary exacerbations, as assessed by modified Fuchs (primary definition),  
Fuchs and expanded Fuchs criteria 
• Change from baseline in other safety parameters (eg, 12-lead ECG measurements, vital 
signs) 
 
Tertiary Endpoints 
• Change from baseline to end of treatment in spirometric performance as measured by 
FVC and FEF25-75 
• Change from baseline to end of treatment in body weight and BMI 
 
 
Other Endpoints 
• Study drug extent of exposure and characterization of investigator-prescribed dosing 
modifications 


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• Study drug compliance as assessed by a subject daily diary and by quantification of used and 
unused study drug 
• Incidence of concomitant therapies 
 
 
 Sample Size 
Approximately 70 patients that completed participation in Study 009 will be enrolled into the 
study.  The sample size is not determined by statistical power. 
 
STUDY POPULATIONS 
 
As-Treated Population 
 The As-Treated population consists of all subjects who received at least 1 dose of ataluren.  This 
population will be evaluated in the analyses of safety and treatment administration. 
 
Intention-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) population consists of all subjects who have at least 1 post-baseline 
efficacy assessment.  This population will be evaluated in the analysis of efficacy. 
 
STATISTICAL AND ANALYTICAL PROCEDURES 
 
General Statistical Considerations 
By-subject listings will be created for each CRF module. Summary tables for continuous 
variables will contain the following statistics: n, mean, standard deviation, standard error, and 
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 by time 
of visit. 
The baseline value used in each analysis will be the last (most recent) non-missing pretreatment 
value, except as noted for spirometry data. 
Unless otherwise specified, all applicable analyses will be 2-sided at the 0.05 level of 
significance.  
All analyses and tabulations of data will be performed using SAS (Version 9.1 or higher).   
 
Control of the Multiplicities 
Since all analyses are descriptive in this study, there is no need to control the multiplicity. 


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Missing Data Handling 
In general, the missing data in safety endpoints will not be imputed, unless specified otherwise. 
The imputation rules of missing start/stop dates in adverse events and prior/concomintant 
medications/therapies will be documented in Section 5.5.  
 
Multiple Centers 
Study centers from different countries will be pooled by geographic region (North America [US 
and Canada], Europe, and Other [ie, Australia, Israel, Argentina, and Brazil]). The number of 
subjects in each region will be reported.  
 
Subject Disposition 
 
Accounting for Subjects 
Subject enrollment status will be summarized by country and site for the As-Treated population. 
The number and percentage of subjects will also be reported by all enrolled subjects, the ITT 
population, and the As-Treated population.  The number of subjects at each scheduled visit will 
be tabulated for the As-Treated population.  For the As-Treated population, the number of 
completers, subjects who discontinue prematurely from the study, and reasons of discontinuation 
will be tabulated. In addition, reasons of screening failures will be summarized and listed. 
 
Protocol Deviations 
All major protocol deviations will be summarized by type for the ITT population. A listing of 
major and minor protocol deviations will be provided. 
 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized for ITT and As-Treated 
populations. 
The continuous baseline characteristics include age (years), baseline height (cm), baseline weight 
(kg), baseline BMI (kg/m2), %-predicted FEV1 at screening and baseline. The categorical 
baseline characteristics include gender, race, region, age group (<18 vs ≥18 years), baseline %-
predicted FEV1 group (<65% vs ≥65%), presence of pancreatic insufficiency, chronically 
infected Pseudomonas aeruginosa, and diabetes in medical history.  
 
Medical History 
The medical history will be summarized by the system organ class and preferred term. The 
listing of medical history will be provided as well. 
 
Prior and Concomitant Medications and Procedures 
Prior medications will be defined as those medications that were used prior to the first dose of 
study treatment.  Concomitant medications will be defined as those medications that were used 
during the study treatment period.  If the start date of a medication is missing and the end date is 


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prior to study start, the medication will be deemed prior. If the end date is after study start or is 
also missing, the drug will be deemed concomitant.  If the end date is missing or the medication 
is ongoing, the medication will be considered concomitant. If the medication start date is 
completely missing and end date is missing or ongoing, the medication will be considered both 
prior and concomitant. Prior and concomitant therapies will be defined similarly. 
Prior and concomitant medications will be coded by means of the World Health Organization 
Drug Dictionary (WHODRUG) into Anatomical-Therapeutic-Chemical classification (ATC) 
codes. Subject incidence of prior and concomitant medications will be tabulated by ATC level 2 
and preferred term for the As-Treated population. Subjects will only count once for each ATC or 
preferred term in the event that they have multiple records of the same ATC or preferred term in 
the database.  
Prior and concomitant non-drug therapies will be coded and analyzed similarly.  
 
Study Treatment Administration and Compliance 
The study treatment duration in weeks is defined as (last dose date – first dose date +1)/7 and 
will be summarized overall. This duration is irrespective of the dose interruptions. 
The drug compliance of a specific time period is defined as 100*(number of sachets taken during 
the period/number of planned sachets during the period). It will be summarized for overall 
treatment duration. The percentages will take into account physician-prescribed reductions and 
interruptions.   
The number and percentage of subjects having dose interruptions and dose changes will be 
summarized using descriptive statistics for overall treatment duration.   
The above analyses will be performed for the As-Treated population. 
 
Primary Analyses 
All primary analyses will be performed for the As-Treated population. 
 
Adverse Events 
Adverse events will be classified by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA Version 17.0). In order to remain 
consistent in the adverse event data collected in previous trials, the severity of adverse events 
will be graded by the investigator according to the CTCAE, Version 3.0 whenever possible. The 
adverse event CTCAE/severity grades include Grade 1 (Mild), Grade 2 (Moderate), Grade 3 
(Severe), Grade 4 (Life-threatening), and Grade 5 (Fatal). The relationship of study drug to 
adverse event has 4 categories: probable, possible, unlikely and unrelated. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event that occurs or 
worsens in the period extending from the day of a subject’s first dose of study drug to 4 weeks 
after the last dose of study drug in this study. In the following analyses, a subject having the 
same event more than once will be counted only once. Adverse events will be summarized by 
worst CTCAE/severity grade.  


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Total numbers of AEs, TEAEs and serious AEs (SAE) and the number and percentage of 
subjects experiencing ≥1 TEAE, ≥1 SAE, discontinuation due to AE, and death will be tabulated. 
The number and percentage of subjects with TEAEs and SAEs will be by Relationship to study 
drug and CTCAE/severity, respectively. 
The number and percentage of subjects experiencing a specific TEAE will be tabulated  
1) by SOC, and PT  
2) by SOC, PT, and CTCAE/severity grade  
3) by SOC in the descending order of the SOC frequency in ataluren group,  
4) by PT in the descending order of  the PT frequency in ataluren group. 
The following TEAEs will be analyzed similarly:  
1) by SOC, and PT and  
2) by SOC, PT, and CTCAE/severity grade. 
• Possibly or probably treatment-related TEAEs 
• Serious TEAEs and possibly or probably treatment-related serious TEAEs 
• TEAEs leading to discontinuation from treatment 
• Adrenal, hepatic and renal TEAEs and possibly or probably treatment-related adrenal, 
hepatic and renal TEAEs leading to special diagnosis evaluation  
• TEAEs with CTCAE/severity grade ≥3 and possibly or probably treatment-related 
TEAEs with CTCAE/severity grade ≥3 
• Common TEAEs (subject frequency of ≥5%) 
Listings of death, serious AEs, AEs leading to discontinuation from treatment, and adrenal, 
hepatic and renal AEs leading to special diagnostic evaluations will be provided. Renal AEs for 
subjects not using nephrotoxic concomitant medications, subjects using nephrotoxic concomitant 
medications, and subjects with postbaseline creatinine > 1.5*ULN will also be listed, separately. 
The drug exposure adjusted TEAE incidence rate will be summarized by SOC and PT, where the 
incidence rate of the TEAE per 100 patient-year = (number of events/number of patient-years) 
*100. The number of patient-years is defined as the sum of the number of days on study drug of 
all patients divided by 365.25.  
In addition, the number of subjects with clinical laboratory abnormalities, abnormal vital signs, 
and abnormal electrocardiogram reported as TEAE will be summarized. 
Non-serious TEAE will be displayed by SOC and PT. The common non-serious TEAE (subject 
frequency of ≥5%) will also be displayed by SOC and PT. 
Numbers of occurrence of serious TEAE and the numbers of occurrence of non-serious TEAE 
will be summarized by SOC and PT, separately. 


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Clinical Laboratory Evaluations 
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 all study visits. 
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 all study visits. Ideally, subjects should have 
fasted for at least 8 hours prior to blood collection.  
Urinalysis assessments will include pH, specific gravity, glucose, ketones, blood, protein, 
creatinine, urobilinogen, bilirubin, nitrite, and leukocyte esterase. These parameters will be 
measured at all study visits. 
Hematology, serum biochemistry, and urinalysis data and their changes from baseline (only for 
continuous laboratory parameters) will be summarized by visit. Maximal and minimal change 
from baseline in each parameter will also be summarized.  
Shift tables for hematology, serum biochemistry, and urinalysis will also be presented showing 
change in CTCAE severity grade from baseline to each visit.  For parameters for which a 
CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline (normal, low, and high [or abnormal]) to each visit (normal, low, and high [or 
abnormal]).   
Frequency tables will be presented for safety monitoring parameters to show the number and 
percentages of subjects by severity grade categories defined in Table 2. If a CTCAE grade does 
not exist, abnormal results will be summarized by protocol-defined thresholds as noted in Table 
2.  Subjects will be characterized only once for a given assay, based on their worst severity grade 
observed during the time period of interest.   
By-subject listings will be provided for viral screen (hepatitis B surface antigen, hepatitis C 
antibody, human immunodeficiency virus (HIV)), Serum beta chorionic gonadotropin (β-HCG), 
and CFTR gene sequencing in addition to the above mentioned clinical laboratory tests.   
As necessary, laboratory abnormalities will be described by duration of study drug exposure, by 
dose, by age group, by sex, by race, by weight, and for special populations (eg, antibiotic use). 
 


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Table 2.  Safety Monitoring Parameters and Actions To Be Taken 
 
Organ System and 
Laboratory Parameter 
Stop Study Drug Immediately, 
Confirma Abnormal Value, 
and Then Start Work-Up 
Stop Study Drug After  
Confirminga Abnormal Value,  
and Then Start Work-Up 
Continue Study Drug,  
Confirma Abnormal Value,  
and then Start Work-Up 
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 
--- 
Urine protein: urine 
creatinine (spot) 
--- 
>0.40 mg:mg 
--- 
Urine blood (by dipstick) 
4+ (in absence of menstruation) 
3+ (in absence of menstruation) 
2+ (in absence of menstruation) 
a Laboratory abnormalities may be confirmed immediately or 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, Ca2+ = calcium, GGT = gamma glutamyl 
transferase, HCO3- = bicarbonate, K+ = potassium, Mg2+ = magnesium, Na+ = sodium, ULN = upper limit of normal 
I


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Secondary Analyses 
 
 
Vital Signs 
Vital sign parameters include systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
heart rate (bpm), pulse oximetry (%), and body temperature (oC). Vital sign assessments and the 
changes from baseline for each parameter will be summarized by visit for the As-Treated 
population. Maximal and minimal change from baseline in each parameter will also be 
summarized.  
Weight gain and loss will be tabulated for the following categories: normal change from 
baseline, weight gain (5-<10%), weight gain (10-<20%) (Grade 2), weight gain (>=20%) 
(Grade 3), weight loss (5-<10%) (Grade 1), weight Loss (10-<20%) (Grade 2), and weight loss 
(>=20%) (Grade 3). 
For adults (≥18 years of age), blood pressure parameters will be programmatically flagged for 
Stage 1 hypertension (systolic: ≥140 to <160 mmHg, diastolic: ≥90 to <100 mmHg), Stage 2 
hypertension (systolic: ≥160 mmHg, diastolic: ≥100 mmHg), and hypotension (systolic: <90 
mmHg, diastolic: <60 mmHg) [USDHHS 2003].  For children and adolescents (<18 years of 
age), blood pressure parameters will be programmatically evaluated based upon height- and 
age-specific nomograms, and categorized by percentile (<95%, ≥95% to <99%, and ≥99%) 
[USDHHS 2005].  A summary of the number and percent of subjects by systolic and diastolic 
blood pressure categories of <95%, ≥95% to <99%, and ≥99% as defined as follows. 
<95%: for age <18 years old, SBP <95% and DBP <95%; for age ≥18 years old, SBP <140 
mmHg and DBP <90 mmHg. 
≥95% to <99%: for age <18 years old, SBP ≥95% to <99% or DBP ≥95% to <99%; for age ≥18 
years old, SBP ≥140 to <160 mmHg or DBP ≥90 to <100 mmHg. In addition, none of SBP and 
DBP meets the following criteria of ≥99%. 
≥99%: for age <18 years old, SBP ≥99% or DBP ≥99%; for age ≥18 years old, SBP ≥160 mmHg 
or DBP ≥100 mmHg. 
Shift tables will be presented showing change in results from baseline using above <95%, ≥95% 
to <99%, and ≥99% categories. 
As necessary, vital signs will be described by duration of study drug exposure, by dose, by age 
group, by sex, by race, by weight, and for special populations (eg, antibiotic use).   
 
Electrocardiographic Analyses 
The assessments and change from baseline in electrocardiographic (ECG) parameters (e.g., RR, 
PR, QRS, QT, heart rate, QTcB, and QTcF) will be summarized by visit for the As-Treated 
population. Maximal and minimal change from baseline in each parameter will also be 
summarized. 


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Standard ECG intervals will be determined. The QT interval will be corrected by both the 
Bazett’s and Fridericia’s method as follows: 
Bazett’s:  QTcB = QT / (RR)1/2 
Fridericia: QTcF = QT / (RR)1/3 
The QTc data obtained by using the Bazett and Fridericia corrections will be categorized 
separately into the following classifications and summarized by visit: 
• QTc interval >450 msec and ≤480 msec 
• QTc interval >480 msec and ≤500 msec 
• QTc interval >500 msec 
The change of the QTc values obtained by using the Bazett and Fridericia corrections will also 
be categorized separately as follows and summarized by visit: 
• QTc interval increases from baseline by >30 msec and ≤60 msec 
• QTc interval increases from baseline by >60 msec 
QTc data will be presented in shift tables from baseline to each visit based on the categories: 
<450 msec, 450-480 msec, >480 msec. 
The number and percentages of subjects with abnormal ECG parameter assessments will be 
tabulated by visit. Below list the abnormal criteria for the parameters:  
• Heart rate > 140 bpm or < 50 bpm for age > 17 (or <60 for age 13-17, or <75 for age 6-
12 and/or increase/decrease by > 30 bpm for heart rate;  
• PR > 250 and/or increase by > 50 ms for PR interval;  
• QRS > 120ms and/or increase by > 20 ms for QRS duration;  
• QT, QTcB or QTcF > 500 ms and/or increase by > 60 ms for QT interval and its 
corrections. 
Shift tables for the interpretation of the 12-lead ECG results (“normal”, “abnormal, clinically 
insignificant”, “abnormal, potentially clinically significant”) will be presented by treatment 
group to show the change in results from baseline (“normal”, “abnormal, clinically 
insignificant”, “abnormal, potentially clinically significant”) to each visit (“normal”, “abnormal, 
clinically insignificant”, “abnormal, potentially clinically significant”).   
 
Change from Baseline in %-predicted FEV1 
The descriptive statistics of %-predicted FEV1, absolute, and relative change in %-predicted 
FEV1 will be summarized for each visit for the ITT population.  The highest FEV1 assessment at 
each visit will be included into the analyses. 


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Pulmonary Exacerbation Rates 
The descriptive statistics of the 48-week pulmonary exacerbation rates based on different 
definitions in Section 5.6 will be reported for the ITT population. The number of subjects with 0, 
≥1, ≥2, and ≥3 pulmonary exacerbations based on different definitions will also be tabulated as 
well.  
 
Tertiary Analyses 
 
FVC  
The absolute change in FVC will be analyzed using descriptive statistics for each visit for the 
ITT population. 
 
Body Weight, Height, and BMI  
Descriptive statistics on change from baseline in the body weight (kg), height (cm), and BMI 
will be displayed at each visit for the As-Treated population. 
The change in weight or height percentiles calculated by using Centers for Disease Control and 
Prevention (CDC) growth chart [CDC] will be analyzed similarly for subjects < 18 years old at 
baseline. 
 
Pharmacokinetics Analyses 
The ataluren plasma concentrations collected prior to the morning dose will be listed.  
For ataluren plasma concentrations, those that are below the limit of quantification will be 
identified by “BQ” in listings.  Those values that are missing will be left blank in listings.   
 
Interim Analyses 
Interim safety analyses are planned when ~35 subjects have completed >32 weeks of treatment 
and when ~35 subjects have completed >64 weeks of treatment.  Additional interim safety 
analyses may be performed based on the discretion of the DMC and will be described in the 
DMC charter. 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 DMC monitoring plan.  
The planned interim analysis will be based on the DMC Charter focusing on the safety review.  
 
 


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DATA HANDLING  
 
Baseline 
In general, Baseline is defined as the last non-missing valid assessment prior to or on the date of 
the first dose. However, Baseline for FEV1, %-predicted FEV1 , FVC, or FEF25-75 is the average 
of the corresponding valid assessments at Screening and Week 1 visit if they met ATS criteria. 
 
Analysis Visits 
Analysis visits are the scheduled visits in the protocol, unless specified otherwise. They are not 
derived via visit window mapping. Baseline is derived as noted in Section 5.1. Final Visit is 
derived as the last non-missing on-treatment visit during the study for each subject and included 
into the by-visit summary analyses. Early termination visit should also be derived as the visit 
right after the non-missing scheduled visit. For example, if the subject discontinued after Week 
8, the early termination visit should be derived as Week 16.  
 
Repeated Measurements in Spirometry Data 
If there are multiple valid assessments in spirometry data at a particular visit, the highest value 
will be chosen for analysis.   
 
Absolute and Relative Change from Baseline 
The absolute change from baseline at each post-baseline visit is calculated as (post-baseline 
value – Baseline), while the relative change (%) from baseline at each post-baseline visit is 
calculated as (post-baseline value – Baseline)/Baseline×100.  
 
Missing Dates of AE and Prior and Concomitant Medications 
 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date is incomplete (ie, 
partially missing) for adverse events. 
Missing day and month 
• If the year is same as the year of the date of the first dose of double-blind study drug, then the 
day and month of the date of the first dose of double-blind study drug will be assigned to the 
missing fields. 
• If the year is prior to the year of the date of the first dose double-blind study drug, then 
December 31 will be assigned to the missing fields. 
• If the year is after the year of the date of the first dose double-blind study drug, then January 
1 will be assigned to the missing fields. 


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Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only  
• If the month and year are same as the year and month of the date of the first dose double-
blind study drug, then the date of the first dose double-blind study drug will be assigned to 
the missing day. 
• If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (ie, partial 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a subject, impute the start date first. 
 
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose of 
double-blind study drug, then the day and month of the date of the first dose of double-blind 
study drug will be assigned to the missing fields. 
• If the year of the incomplete start date is prior to the year of the date of the first dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose of double-
blind study drug, then January 1 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 


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Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of double-blind study drug, then the day of the date of the first dose of 
double-blind study drug will be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of double-blind study drug or 
if both years are the same but the month is before the month of the date of the first dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 
• If either the year is after the year of the date of the first dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the first dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
 
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of double-blind study drug is missing, replace it with the last visit date or data cut-off date 
if the subject is on-going. If the imputed stop date is before the start date (imputed or non-
imputed start date), then the imputed stop date will be equal to the start date. 
Missing day and month 
• If the year of the incomplete stop date is the same as the year of the date of the last dose of 
double-blind study drug, then the day and month of the date of the last dose of double-blind 
study drug will be assigned to the missing fields. 
• If the year of the incomplete stop date is prior to the year of the date of the last dose of 
double-blind study drug, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the date of the last dose of double-
blind study drug, then January 1 will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
Missing day only  
• If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of double-blind study drug, then the day of the date of the last dose of 
double-blind study drug will be assigned to the missing day. 
• If either the year is before the year of the date of the last dose of double-blind study drug or if 
both years are the same but the month is before the month of the date of the last dose of 
double-blind study drug, then the last day of the month will be assigned to the missing day. 


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• If either the year is after the year of the date of the last dose of double-blind study drug or if 
both years are the same but the month is after the month of the date of the last dose of 
double-blind study drug, then the first day of the month will be assigned to the missing day. 
 
Pulmonary Exacerbation Definitions 
A respiratory event evaluation form has been developed to collect CF pulmonary exacerbation 
information from the physician perspective. This form is designed to systematically characterize 
health-care provider observations related to exacerbations, and to allow categorization and 
scoring consistent with Fuch’s or Rosenfeld CF exacerbation definitions. The data generated 
from these forms will provide the basis for recording incidence and rate of pulmonary 
exacerbations. 
The following 12 Fuchs’ signs and symptoms will be assessed in the definitions of Fuch’s, 
modified Fuch’s, and expanded Fuch’s exacerbation. 
1. Increased cough 
2. Change in sputum volume, color, or consistency 
3. New or increased hemoptysis 
4. Increased dyspnea during moderate exertion,  during mild exertion, or at rest 
5. Sinus pain or tenderness 
6. Change in sinus discharge 
7. Malaise, fatigue, or lethargy 
8. Anorexia or weight loss 
9. Temperature above 38°C 
10.  Change in findings on chest examination 
11.  Relative 10% decrease in %-predicted FEV1 
12.  Chest radiography results consistent with pulmonary infection 
The modified Fuchs exacerbation is defined as the presence of at least 4 of 12 Fuchs’ signs and 
symptoms without the requirement for treatment with antibiotics [Rowe 2012].  
The expanded Fuchs exacerbation is defined as the presence of at least 4 of 12 Fuchs’ signs and 
symptoms requiring treatment with any form of antibiotic treatment [inhaled, oral, or 
intravenous]. This antibiotic treatment is defined either as the addition of new antibiotics or an 
increase in the dose of an existing antibiotics within 14 days of the pulmonary exacerbation 
start/stop date. 
The classic Fuchs exacerbation is defined as the presence of at least 4 of 12 Fuchs’ signs and 
symptoms requiring treatment with parenteral antibiotics. This antibiotic treatment is defined 
either as the addition of new antibiotics or an increase in the dose of an existing antibiotics 
within 14 days of the pulmonary exacerbation start/stop date. 


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Pulmonary exacerbation based on investigator’s assessments is recorded in the conclusion of 
respiratory event evaluation form. 
 
 


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ANALYSIS CHANGES FROM PROTOCOL  
Due to the premature termination of the study, the time of withdrawal from the study analysis 
has been removed compared to current protocol version 3.0. The paired t-test on FEV1 and the 
summary of FEF25-75 have also been removed.  On the other hand, the drug exposure adjusted 
incidence rate of TEAEs has been added. Summary of occurrence of TEAE has been added as 
well. 


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BIBLIOGRAPHY  
Centers for Disease Control and Prevention. CDC Growth Charts. Available at: 
http://www.cdc.gov/growthcharts/percentile_data_files.htm. 
Rowe SM, Sermet-Gaudelus I, Konstan M, Kerem E, Wilschanski M, DeBoeck K et al. Results 
of the Phase 3 Study of Ataluren in Nonsense Mutation Cystic Fibrosis (nmCF). Pediatric 
Pulmonology 2012 Sep; 47(S35): 290 (abst #193) 
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, 
Lung, and Blood Institute, National High Blood Pressure Education Program. The Seventh 
Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment 
of High Blood Pressure. NIH Publication No. 03-5233. Bethesda, MD: National Heart, Lung, 
and Blood Institute.  Revised December 2003. 
U.S. Department of Health and Human Services, National Institutes of Health, National Heart, 
Lung, and Blood Institute, National High Blood Pressure Education Program. The Fourth Report 
on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents. NIH Publication No. 05-5268. Bethesda, MD: National Heart, Lung, and Blood 
Institute.  Revised May 2005.