Clinical trial NCT02647359
Conditions: Aniridia
Sponsor: PTC Therapeutics
Start date: 2016-01-31; Completion date: 2021-01-22
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the effect of ataluren on Maximum Reading Speed as measured using the Minnesota Low Vision Reading Test (MNREAD) Acuity Charts in participants with nonsense mutation aniridia. This study involves a 4-week screening period, a 144-week treatment period (Stage 1: Weeks 1 to 48 \[double-masked treatment\] and Stage 2: Weeks 49 to 144 \[open label treatment\]), an optional 96-week open label extension sub-study, and a 4-week post-treatment follow-up period (either study completion or early termination). Participants that choose not to participate in the sub-study will be required to complete the post-treatment follow-up visit at the end of the Stage 2 open-label extension.

Detailed description:

Arms: arm 1: Participants will receive ataluren orally 3 times a day (TID) at a dose of 10 milligrams per kilogram (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 48 weeks in Stage 1 (double-masked period) and for additional 96 weeks in Stage 2 (open-label extension period). Participants, who complete Stage 2 and agree to continue in open-label sub-study, will continue to receive ataluren treatment at same dose as mentioned above, for 96 weeks or until commercial availability of ataluren for this indication, whichever is first, or until a positive risk-benefit assessment in this indication is not demonstrated. arm 2: Participants will receive placebo matching to ataluren TID orally in the morning, at midday, and in the evening for 48 weeks in Stage 1 (double-masked period) and ataluren orally TID at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for additional 96 weeks in Stage 2 (open-label extension period). Participants, who complete Stage 2 and agree to continue in open-label sub-study, will continue to receive ataluren treatment at same dose as mentioned above, for 96 weeks or until commercial availability of ataluren for this indication, whichever is first, or until a positive risk-benefit assessment in this indication is not demonstrated.
Interventions: intervention 1: Ataluren intervention 2: Placebo
Intervention descriptions: intervention 1: Ataluren oral suspension will be administered as per the dose and schedule specified in the respective arms. intervention 2: Placebo will be administered as per the schedule specified in the respective arm.

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
STAR:  A Phase 2, Multicenter, Randomized,  
Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of 
Ataluren (PTC124) for the Treatment of Nonsense Mutation Aniridia 
PTC124-GD-028-ANI 
17 DECEMBER 2019 
VERSION 7.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information:  This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc.  Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where 
required by applicable law) and should not be used for unauthorized purposes.  In the event of an actual or 
suspected breach of this obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #NCT02647359


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SYNOPSIS 
Name of 
Sponsor/Company:  
PTC Therapeutics, Inc. 
Name of Investigational 
Product:  
Ataluren 
Title of Study:  
STAR:  A Phase 2, Multicenter, Randomized, Double-Masked, 
Placebo Controlled Study of the Safety and Efficacy of Ataluren 
(PTC124) for the Treatment of Nonsense Mutation Aniridia 
Study Centers: 
 
Canada
Phase of Development:  
Phase 2 
Objectives:  
Primary Objective: 
The primary objective of this study is to evaluate the effect of ataluren 
on Maximum Reading Speed as measured using the Minnesota Low 
Vision Reading Test (MNREAD) Acuity Charts in subjects with 
nonsense mutation aniridia. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• 
Evaluate the effect of ataluren on the following: 
o Reading Accessibility Index 
o Best corrected visual acuity (BCVA) 
o Critical Print Size 
o Reading Acuity 
o Severity of corneal keratopathy 
o Iris area 
• 
Characterize the systemic and ocular safety profile of ataluren 
in subjects with nonsense mutation aniridia. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoints: 
Primary Endpoint: 
The primary endpoint of this study is the change from baseline 
(Visit 2/Day 1) to Week 48 in Maximum Reading Speed of OU as 
measured using the MNREAD Acuity Charts. 
Secondary Endpoints: 
The key secondary efficacy endpoints of this study are: 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading 
Accessibility Index of OU 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in BCVA 
Additional secondary efficacy endpoints of this study are as follows: 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in 
Maximum Reading Speed of OD and OS 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading 
Accessibility Index of OD and OS 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in Critical 
Print Size of OU, OD and OS 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading 
Acuity of OU, OD and OS 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in severity 
of corneal keratopathy 
• 
Change from baseline (Visit 2/Day 1) to Week 48 in iris area 
• 
Change from baseline (Visit 2/Day 1, Stage 1) to Week 240 
(End of Study Visit) in BCVA. Note: This endpoint will be 
assessed only for the cohort of subjects who enroll into the 
sub-study. 
The secondary safety endpoint of this study is the overall systemic and 
ocular safety profile of ataluren as determined by: 
• 
incidences of treatment-emergent adverse events 
• 
abnormal findings on laboratory assessments 
• 
vital signs 
• 
physical examinations 
• 
ophthalmoscopy 
• 
slit-lamp examination 
• 
visual field testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Description and 
Methodology 
This is a multicenter, stratified, randomized, double-masked, 
placebo-controlled study with a 4-week screening period, a 144-week 
treatment period, an optional 96-week open label sub-study, and a 
4-week post-treatment follow-up period (either study completion or 
early termination). 
Study Population:  
A minimum of 36 subjects with nonsense mutation aniridia who are 
≥2 years of age  
Main inclusion and 
exclusion criteria  
Inclusion criteria:  
Subjects who will be selected for this study must meet the following 
criteria: 
1. Evidence of signed and dated informed consent document(s) 
indicating that the study candidate (and/or a parent/legal guardian) 
has been informed of all pertinent aspects of the study.  Note: 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 ethics 
committee 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. Age ≥2 years and of either gender. 
3. Body weight ≥12 kg. 


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4. Documentation of the presence of a nonsense mutation in 1 allele 
of the PAX6 gene as determined by genotyping performed at a 
laboratory certified by the College of American Pathologists, or 
under the Clinical Laboratory Improvement Act/Amendment, or 
by an equivalent organization.  Note: Sponsor review of the 
genotyping documentation is required. 
5. Clinical diagnosis of aniridia. 
6. Willingness and ability to comply with scheduled visits, drug 
administration plan, study procedures, and study restrictions. 
7. Good general health, as determined at Visit 1 (Screening) by 
medical history and physical examination (including vital sign 
measurements). 
8. No clinically significant abnormality based upon laboratory 
assessments at Visit 1 (Screening), in the opinion of the 
investigator. 
9. Female subjects of childbearing potential are eligible for the study 
but must be willing to use adequate (at least 1 form of) 
contraceptive methods as described below during the study 
treatment period (starting from the day of first dose of study drug 
and ending 60 days after the last dose of study drug).  
Childbearing potential is defined as subjects who have 
experienced menarche and who are neither postmenopausal nor 
have been permanently sterilized. 
• 
Hormonal methods of contraception (including oral and 
transdermal contraceptives, injectable progesterone, 
progestin subdermal implants, progesterone-releasing 
intrauterine device [IUDs]) initiated at least 14 days prior 
to the first dose of study drug 
• 
Abstinence 
• 
Placement of a copper-containing IUD 
• 
Condom with spermicidal 
foam/gel/film/cream/suppository 
• 
Postmenopausal at least 12 months prior to first dose of 
study drug or permanently sterilized (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy) 
• 
Male partner who has had a vasectomy for at least 
3 months prior to the first dose of study drug 
10. Male subjects with partners of childbearing potential must agree to 
use adequate (at least 1 form of) contraception as described below 
during the study treatment period (starting from the day of first 
dose of study drug and ending 60 days after the last dose of study 
drug). 
• 
Abstinence 
• 
Vasectomy for at least 3 months prior to first dose of 
study drug or surgically sterile 
• 
Without a vasectomy, must use a condom with 
spermicidal foam/gel/film/cream suppository 


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Exclusion Criteria: 
The presence of any of the following conditions will exclude a subject 
from study enrollment: 
General exclusion criteria 
1. Subjects participating in any drug or device clinical investigation 
within 90 days prior to Visit 1 (Screening) or who anticipate 
participating in any other drug or device clinical investigation 
within the duration of this study. 
2. Exposure to ataluren within 90 days prior to Visit 1 (Screening). 
3. Surgery within 30 days prior to enrollment. 
4. Female subjects who are pregnant or breastfeeding.  Female 
subjects of childbearing potential must have a negative pregnancy 
test (beta-human chorionic gonadotropin) at screening and must 
use adequate (at least 1 form of) contraceptive methods. 
5. Active ocular infection or inflammation. 
6. Prior or ongoing medical condition (e.g., concomitant illness, 
alcoholism, drug abuse, psychiatric condition), medical history, 
physical findings, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the 
subject, makes it unlikely that the course of study drug 
administration or follow-up would be completed, or could impair 
the assessment of study results. 
7. Subjects with a positive result for hepatitis B, hepatitis C, or 
human immunodeficiency virus at Visit 1 (Screening). 
Drug therapies 
8. Ongoing warfarin, phenytoin, or tolbutamide therapy. 
9. Ongoing intravenous (IV) aminoglycoside or IV vancomycin use. 
10. Ongoing systemic cyclosporine therapy.  Note: Topical 
cyclosporine therapy is permitted. 
11. Known hypersensitivity to any of the ingredients or excipients of 
the study drug (polydextrose, polyethylene glycol 3350, 
poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl 
cellulose, vanilla, colloidal silica, or magnesium stearate). 
Ocular exclusion criteria  
12. 20/200 or worse visual acuity in the better eye with best 
correction. 
13. Subjects who are monocular. 
14. Subjects with a history of complications due to ocular surgery that 
could interfere with the study procedures or assessment of study 
endpoints. 
15. Subjects with any other significant ocular or systemic disease that 
the Investigator determines could interfere with the study. 


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Statistical analyses: 
Two separate analyses will be conducted, one for the double-masked 
phase (Day 1 through Week 48), and the second for the entire study 
(Day 1 through Week 240). For patients randomized to placebo, two 
baselines will be used, one at randomization (Visit 2, Day 1) and the 
other at first dose of open-label ataluren (Visit 4, 48 weeks) for the 
analyses outlined below.  
a) Analyses on the double-masked phase (Day 1 through Week 48).  
Both placebo and ataluren will be presented and comparison will be 
made through 48 weeks between these two treatment groups. For the 
analyses of the double-masked phase, assessments at randomization 
(Visit 2 [Day 1]) will serve as baseline. 
b) Analyses of the entire study (Visit 2, Day 1 through Week 240). 
Efficacy will be presented based on two different baselines for 
placebo, one baseline at randomization (Visit 2) and the other baseline 
at Week 48 when placebo subjects first take open-label ataluren. Three 
analysis groups will be presented:  
1) ataluren (all visits),  
2) placebo (all visits) with Visit 2 assessments serving as 
baseline, and  
3) combined groups with baseline at the first dose of ataluren 
(i.e., randomization -Visit 2 for ataluren patients and at the 
first dose of open-label ataluren (Visit 4, 48 weeks) for 
placebo patients).  
Safety data for the entire study will be presented for the combined 
group for patients receiving ataluren.  
By-subject listings will be created for each eCRF module.  Summary 
tables for continuous variables will contain the following statistics: N, 
mean, median, standard deviation, standard error, minimum, 
maximum, and 95% confidence interval (CIs), as appropriate.  
Summary tables for categorical variables will include N, percentage, 
and 95% CIs on the percentage.  Any CIs for proportions will be 
computed using normal approximation, if the number of the events is 
at least five.  Otherwise, CIs using an exact method will be provided.  
Graphical techniques will be used when such methods are appropriate 
and informative.  For safety summaries, CIs will not be presented, 
unless specified otherwise. 
Transformations of the data may be explored if warranted by the 
distribution of the data. 
Unless otherwise specified, all analyses will be two-sided at the 
0.05 level of significance. 
All analyses will be performed using SAS® (Version 9.0 or higher). 
 
 


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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC124-GD 
Therapeutic Area 
Genetic Disorders - Aniridia 
PTC Therapeutics Substance Identifier 
Ataluren (PTC124®) 
IND Number 
126792 
Included in clinical trials.gov Database 
NCT02647359 
Protocol Number 
PTC124-GD-028-ANI 
Protocol Version 
Version 7.0 
Protocol Version Date 
17 December 2019 
Protocol Phase 
Phase 2 
Protocol Title 
STAR: A Phase 2, Multicenter, Randomized, Double-
Masked, Placebo Controlled Study of the Safety and 
Efficacy of Ataluren (PTC124) for the Treatment of 
Nonsense Mutation Aniridia 
PTC Clinical Operations 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone (office):
 
Facsimile:
E-mail: 
PTC Medical Monitor 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone (office):
Facsimile:
E-mail:
PTC Biostatistician 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 USA 
Telephone:
Facsimile: 
E-mail:
 
 


PTC124-GD-028-ANI 
Clinical Protocol 
PTC THERAPEUTICS 
PROTOCOL APPROVAL SIGNATURES 
 
PTC Therapeutics, Inc. 
PTC Therapeutics, Inc. 
PTC Therapeutics, Inc. 
V7.0 
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Date 
/Je C f cf 
Date 
/ 
zo;q 
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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
 
I have read the protocol document and, on behalf of my institution, agree to comply with 
the protocol and all applicable regulations. 
 
 
 
 
 
Principal Investigator 
 
Date 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province: 
 
Country: 
 
Phone: 
 
Fax: 
 
Email: 
 
 
 


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TABLES OF CONTENTS 
SYNOPSIS ................................................................................................................................2 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ................................................8 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES .................................9 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE .............................10 
TABLES OF CONTENTS ....................................................................................................11 
LIST OF TABLES .................................................................................................................15 
LIST OF FIGURES ...............................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................16 
1 
OVERVIEW ..........................................................................................................18 
1.1 
Introduction ...........................................................................................................18 
1.2 
Study Design ..........................................................................................................19 
2 
BACKGROUND ...................................................................................................21 
2.1 
Disease Indication .................................................................................................21 
2.2 
Ataluren .................................................................................................................23 
2.2.1 
Therapeutic Rationale ..........................................................................................23 
3 
STUDY OBJECTIVES AND ENDPOINTS .......................................................28 
3.1 
Objectives ...............................................................................................................28 
3.1.1 
Primary Objective .................................................................................................28 
3.1.2 
Secondary Objectives ............................................................................................28 
3.1.3 
.........................................................................................28 
3.2 
Endpoints ...............................................................................................................29 
3.2.1 
Primary Endpoint .................................................................................................29 
3.2.2 
Secondary Endpoints ............................................................................................29 
3.2.3 
 .........................................................................................30 
4 
SUBJECT SELECTION CRITERIA .................................................................31 
4.1 
Overview ................................................................................................................31 
4.2 
Inclusion Criteria ..................................................................................................31 
4.3 
Exclusion Criteria .................................................................................................32 
5 
ENROLLMENT PROCEDURES .......................................................................34 
5.1 
Number of Subjects ...............................................................................................34 
5.2 
Subject Recruitment .............................................................................................34 
5.3 
Screening ................................................................................................................34 
5.4 
Randomization and Stratification .......................................................................34 
6 
STUDY DRUG ADMINISTRATION .................................................................35 
6.1 
Investigational Product .........................................................................................35 
6.1.1 
Ataluren .................................................................................................................35 
6.1.2 
Placebo ...................................................................................................................35 
6.1.3 
Packaging and Labeling .......................................................................................35 
6.1.4 
Study Drug Dispensing .........................................................................................35 


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6.1.5 
Return of Study Drug ...........................................................................................36 
6.1.6 
Storage and Stability .............................................................................................36 
6.1.7 
Study Drug Accountability ...................................................................................36 
6.1.8 
Overdose Precautions ...........................................................................................37 
6.1.9 
Inadvertent Exposure and Spill Precautions ......................................................37 
6.2 
Study Drug Treatment ..........................................................................................37 
6.2.1 
Stratification and Randomization .......................................................................37 
6.2.2 
Drug Administration Plan ....................................................................................38 
6.2.3 
Schedule of Administration ..................................................................................38 
6.2.4 
Instructions for Delays in Dosing ........................................................................38 
6.2.5 
Study Drug Preparation and Storage ..................................................................38 
6.3 
Safety Monitoring and Ataluren Treatment Modification ...............................39 
6.3.1 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and 
Potential Drug Interruption/Modification ..........................................................39 
6.3.2 
Evaluation of Adverse Events or Laboratory Abnormalities ...........................39 
6.3.3 
Instructions for Resuming Study Drug Administration after an 
Interruption for Safety Concerns ........................................................................40 
6.3.4 
Instructions for Discontinuation of Study Drug Administration for Safety 
Concerns ................................................................................................................40 
7 
CONCOMITANT AND SUPPORTIVE THERAPY ........................................41 
7.1 
Concomitant Medications .....................................................................................41 
7.1.1 
Treatment for Aniridia-Related Conditions .......................................................41 
7.1.2 
Nephrotoxic Medications ......................................................................................41 
7.1.3 
Hydration ...............................................................................................................42 
7.1.4 
Other Concomitant Medications .........................................................................42 
7.1.5 
Drugs Metabolized by Cytochrome P450 Enzymes ...........................................42 
7.1.6 
Other Potential Drug Interactions .......................................................................43 
7.2 
Dietary Restrictions ..............................................................................................43 
8 
SCHEDULE OF EVENTS AND STUDY PARAMETERS ..............................44 
8.1 
Schedule of Events ................................................................................................44 
8.1.1 
Screening, Treatment and Follow-up Periods ....................................................47 
8.2 
Visit 8 (Week 144±28 Days – End of Treatment/Start of Sub-study ................55 
8.3 
Assessments ............................................................................................................58 
8.3.1 
Informed Consent .................................................................................................58 
8.3.2 
Medical and Ophthalmic History ........................................................................59 
8.3.3 
Serum Viral Screen ...............................................................................................59 
8.3.4 
Physical Examination ...........................................................................................59 
8.3.5 
Vital Signs ..............................................................................................................59 
8.3.6 
Height and Weight ................................................................................................59 
8.3.7 
Hematology Laboratory Assessment ...................................................................59 
8.3.8 
Biochemistry Laboratory Assessment .................................................................60 
8.3.9 
Pregnancy ..............................................................................................................60 
8.3.10 
Urinalysis ...............................................................................................................60 
8.3.11 
Study Drug Administration ..................................................................................60 
8.3.12 
Adverse Events ......................................................................................................60 
8.3.13 
Concomitant Medications .....................................................................................60 


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8.3.14 
 ..........................................................................61 
8.3.15 
MNREAD ...............................................................................................................61 
8.3.16 
Slit-Lamp Examination and Macro Photography .............................................61 
8.3.17 
Fundus Examination and Photography ..............................................................62 
8.3.18 
Optical Coherence Tomography ..........................................................................62 
8.3.19 
Humphrey Visual Field ........................................................................................62 
8.3.20 
Ophthalmoscopy ....................................................................................................62 
8.3.21 
Best Corrected Visual Acuity (BCVA) and Refraction .....................................62 
8.3.22 
 .............................................................................................63 
8.3.23 
 .............................................................................................63 
8.3.24 
......................................................................63 
8.3.25 
..........................63 
9 
ADVERSE EVENT ASSESSMENTS .................................................................64 
9.1 
Adverse Event Definitions ....................................................................................64 
9.1.1 
Adverse Events ......................................................................................................64 
9.1.2 
Serious Adverse Events ........................................................................................65 
9.1.3 
Unexpected Adverse Events .................................................................................66 
9.2 
Eliciting Adverse Event Information ..................................................................66 
9.3 
Adverse Event Recording .....................................................................................66 
9.4 
Describing Adverse Event Relationship to Study Drug.....................................67 
9.5 
Grading of Severity of Adverse Events ...............................................................68 
9.6 
Pregnancy ..............................................................................................................68 
9.7 
Follow-Up of Unresolved Adverse Events...........................................................69 
9.8 
Adverse Event Reporting Period .........................................................................69 
9.9 
Investigator Site Adverse Event Reporting Requirements ...............................69 
9.10 
PTC Therapeutics Adverse Event Reporting Requirements ............................70 
10 
WITHDRAWAL OF SUBJECTS .......................................................................71 
11 
STATISTICS .........................................................................................................71 
11.1 
Sample Size ............................................................................................................71 
11.2 
Analysis Populations .............................................................................................72 
11.3 
General Statistical Considerations ......................................................................72 
11.4 
Study Conduct .......................................................................................................73 
11.5 
Study Population ...................................................................................................73 
11.5.1 
Subject Disposition ................................................................................................73 
11.5.2 
Demography and Baseline Characteristics .........................................................73 
11.5.3 
Medical History and Prior Medication ...............................................................73 
11.6 
Extent of Exposure ................................................................................................73 
11.6.1 
Treatment Compliance .........................................................................................73 
11.7 
Efficacy ...................................................................................................................73 
11.7.1 
Primary Efficacy Endpoint ..................................................................................74 
11.7.2 
Secondary Efficacy Endpoints .............................................................................74 
11.7.3 
.........................................................................................74 
11.8 
Safety ......................................................................................................................75 
11.8.1 
Adverse Events ......................................................................................................75 
11.8.2 
Laboratory Parameters ........................................................................................75 


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11.8.3 
Other Parameters ..................................................................................................76 
11.9 
 .........................................................76 
11.10 
Concomitant Medication Use ...............................................................................76 
11.11 
Exploration of Correlations .................................................................................76 
11.12 
Subgroup Analyses ................................................................................................76 
11.13 
Multiplicity ............................................................................................................76 
12 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR .............77 
12.1 
Compliance with Ethical and Regulatory Guidelines ........................................77 
12.2 
Institutional Review Board/Independent Ethics Committee ............................77 
12.3 
Informed Consent/Assent .....................................................................................77 
12.4 
Electronic Case Report Forms .............................................................................78 
12.5 
Study Records ........................................................................................................78 
12.6 
Confidentiality .......................................................................................................79 
12.7 
Retention of Records .............................................................................................79 
12.8 
Monitoring and Auditing ......................................................................................79 
12.9 
Termination of the Study .....................................................................................80 
12.10 
Public Notification of Study Conduct ..................................................................80 
12.11 
Dissemination of Results .......................................................................................80 
12.12 
Communication with Regulatory Authorities ....................................................81 
13 
RATIONALE FOR STUDY DESIGN FEATURES ..........................................81 
13.1 
Subject Selection ...................................................................................................81 
13.1.1 
General ...................................................................................................................81 
13.1.2 
Reproductive Considerations ...............................................................................81 
13.1.3 
Prior and Concomitant Therapies .......................................................................81 
13.2 
Treatment Rationale .............................................................................................82 
13.2.1 
Ataluren Schedule and Dose Selection ................................................................82 
13.2.2 
Duration of Therapy .............................................................................................83 
13.2.3 
Selection of Outcome Measures ...........................................................................83 
14 
BENEFITS AND RISKS ......................................................................................86 
14.1 
Benefits and Risks: Non-Clinical .........................................................................86 
14.2 
Benefits and Risks: Clinical .................................................................................88 
14.2.1 
Justification for Inclusion of Minors ...................................................................88 
14.3 
Benefit/Risk Conclusions ......................................................................................89 
15 
REFERENCES ......................................................................................................90 
16 
APPENDICES .......................................................................................................93 
16.1 
Protocol Amendment History ..............................................................................93 
APPENDIX A 
 ...........................................95 
 
 
 


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LIST OF TABLES 
Table 1. 
Schedule of Events (Stage 1) ..............................................................................44 
Table 2. 
Schedule of Events (Stage 2) ..............................................................................45 
Table 3. 
Schedule of Events (Open-label Sub-study) .....................................................46 
Table 4. 
Relationship of Study Drug to Adverse Event .................................................67 
Table 5. 
Grading of Adverse Event Severity ...................................................................68 
Table 6. 
Investigator Site Requirements for Reporting Adverse Events .....................69 
 
LIST OF FIGURES 
Figure 1. STAR Aniridia Study Schematic .......................................................................20 
Figure 2. Ataluren Treatment Improves Eye Morphology in nmPAX6 Mutant Mice .25 
Figure 3. Ataluren Treatment Improves Retinal Histology in nmPAX6 Mutant Mice
 ..............................................................................................................................26 
Figure 4. Ataluren Treatment Improves Response to Light Stimulation 
(Electroretinographic) in nmPax6 Mutant Mice .............................................27 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
β-HCG 
Beta-human chorionic gonadotropin 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
BCRP 
Breast cancer resistant protein  
BCVA 
Best corrected visual acuity 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAP 
College of American Pathologists 
CD-ROM 
Compact disc read-only memory 
CFTR 
Cystic fibrosis transmembrane conductance regulator 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Act/Amendment 
Cmax 
Maximum concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EOS/ET 
End of study/ early termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCL 
Ganglion cell layer 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
Hz 
Hertz 
ICH 
International Council for Harmonisation 
INL 
Inner nuclear layer 
IPL 
Inner plexicon layer 
IRB/IEC 
Institutional review board/independent ethics committee 
IS 
Inner segments 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IV 
Intravenous 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
L 
Lens 
LEA 
LEA Symbols Visual Acuity Test System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmelonic acidemia 
MNREAD 
Minnesota Low Vision Reading Test (MNREAD) Acuity Charts 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MT 
Mutant 
nmCF 
Nonsense mutation cystic fibrosis 
nmDMD 
Nonsense mutation Duchenne muscular dystrophy 
nmPAX6 
Nonsense mutation PAX6 


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Term 
Definition 
OAT1 
Organic anion transporter 1 
OAT3 
Organic anion transporter 3 
OATP1B3 
Organic anion transporting polypeptide 1B3 
OCT 
Optical coherence tomography 
OD 
Oculus dexter (right eye) 
ONL 
Outer nuclear layers 
OS 
Oculus sinister (left eye) 
OS 
Outer segments 
OTC 
Over-the-counter 
OU 
Oculus unitas (both eyes) 
P 
Postnatal day 
P-gp 
P-glycoprotein 
PAX6 
Paired box 6 
Pax6Sey+/–  
Semidominant small eye mouse model of aniridia 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PTC124 
Ataluren 
qd 
One a day 
R 
Retina 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SYS 
Systemic ataluren (30 mg/kg qd) 
TID 
Three times a day 
UGT1A9 
UDP-glucuronosyltransferase 1-9 
WT 
Wild type 
 
 


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1 
OVERVIEW 
1.1 
Introduction 
Congenital aniridia, a familial condition with autosomal dominant inheritance, is a bilateral, 
panocular disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve 
(Valenzuela 2004, Netland 2011, Hingorani 2012, Chang 2014).  The vast majority of cases 
of aniridia are associated with mutations in the paired box 6 (PAX6) gene, which is located 
on chromosome 11p13 and regulates ocular development.  The phenotype is variable 
between and within families; however, affected individuals usually show little variability 
between the two eyes.  Individuals with aniridia characteristically show absence of iris, 
nystagmus, impaired visual acuity (usually 20/100 to 20/200), and foveal hypoplasia. 
Aniridia mainly manifests in the eye, but there are additional characteristics of aniridia, 
including obesity (Netland 2011) and impaired glucose tolerance and/or diabetes (Wen 2009) 
as PAX6 regulates not only eye development but also islet cell development (Yasuda 2002).  
PAX6 continues to be expressed through adulthood, contributing to maintenance of function 
in the eye and other tissues.  Individuals with isolated aniridia may show reduced olfaction 
and cognition, behavioral problems, or developmental delay. 
Many of the treatment methods used today for aniridia are ineffective.  Tinted or 
photochromic lenses may be used to reduce light sensitivity.  Surgical management of some 
of the visually disabling manifestations, such as cataract surgery or glaucoma shunt surgery, 
has provided improvement in eyesight visual acuity.  However, due to the structural defects, 
patients with aniridia often experience post-operative complications, including aniridic 
fibrosis syndrome, which together with limbal stem cell deficiency leads to decompensation 
of the cornea or aniridia-related keratopathy.  The eyesight vision of most aniridia patients 
progressively declines to the point of legal blindness. Corneal disease may be treated with 
lubricants, mucolytics, or punctual occlusion.  Corneal transplants, or keratoplasty, can be 
performed on patients with aniridia, but often produce only temporary vision improvements.  
The treatment of keratopathy associated with aniridia via amniotic membrane transplant has 
proven to be only a temporary solution for aniridia patients suffering from moderate 
keratopathy.  In patients with severe keratopathy who exhibit limbal insufficiency, treatment 
involves limbus transplant of lumbar cells.  Self-transplants are excluded since aniridia 
usually affects both eyes, therefore patients must receive allografts from compatible healthy 
relatives or cadavers and be treated with oral immunosuppression treatment post-transplant to 
alleviate the risk of rejection. 
Currently, there are no pharmacological approaches to the treatment of aniridia.  There is a 
high unmet medical need for a safe, convenient treatment targeting the underlying cause of 
this orphan genetic disorder. 
Nonsense mutations are the cause of congenital aniridia in ~40% of patients (Tzoulaki 2005).  
Nonsense mutations in deoxyribonucleic acid (DNA) correspond to premature stop codons in 
messenger ribonucleic acid (mRNA).  PTC Therapeutics, Inc., South Plainfield, NJ, USA, 
has discovered and developed ataluren, a novel, orally available, 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 those 
patients for whom a nonsense mutation causes aniridia. 


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Ataluren has demonstrated readthrough activity in a wide range of preclinical models of 
nonsense mutation diseases, including nonsense mutation aniridia.  In PAX6Sey+/– mice with a 
nonsense mutation in the mouse PAX6 gene, ataluren treatment during the postnatal period 
not only inhibited disease progression but also stably reversed corneal, lens, and retinal 
malformation defects and restored electrical and behavioral responses of the retina 
(Gregory Evans 2014).  Pharmacological activity of ataluren also has been documented in 
nonsense mutation choroideremia (Tracey-White 2014), nonsense mutation retinitis 
pigmentosa (Schwarz 2015), nonsense mutation Duchenne muscular dystrophy (nmDMD) 
(Welch 2007), nonsense mutation cystic fibrosis (nmCF) (Du 2008), and various other 
nonsense mutation genetic disorders.  In nonclinical neurological, respiratory, and 
cardiovascular safety pharmacology studies, ataluren has shown no adverse effects.  
Secondary pharmacodynamic assessments performed in vitro and in vivo have documented 
selective readthrough of premature stop codons without readthrough of normal stop codons.  
Toxicology studies in mice through 1 month, in rats through 6 months, and in dogs through 
1 year have indicated acceptable tolerability and support dosing in subjects ≥2 years old. 
Phase 1 clinical trials in which 62 healthy volunteers (ages 18 to 30 years) were administered 
ataluren at doses ranging from a single dose of 3 mg/kg to 50 mg/kg twice a day for 14 days 
demonstrated that oral ataluren can achieve target plasma concentrations associated with 
activity in preclinical testing.  Phase 2a studies in 77 subjects (ages 6 to 57 years) with nmCF 
receiving oral ataluren for periods of 14 days through 12 weeks demonstrated that oral 
ataluren is generally well tolerated and can generate production of apically localized 
epithelial cystic fibrosis transmembrane conductance regulator (CFTR) protein.  Phase 2a 
studies in 38 subjects (ages 5 to 17 years) with nmDMD administered oral ataluren through 
28 days confirm the ataluren safety profile and demonstrated evidence of pharmacodynamic 
activity, with improvements in muscle expression of dystrophin.  Phase 2b/3, 
placebo-controlled, 48 week studies in nmCF and nmDMD support the long-term safety of 
chronic ataluren administration and indicate that ataluren treatment is associated with clinical 
benefit (Bushby 2014, Kerem 2014).  In July 2014, the European Medicines Agency (EMA) 
conditionally approved ataluren for the treatment of nmDMD and it has been subsequently 
renewed five times. 
1.2 
Study Design 
This is a Phase 2, multicenter, stratified, randomized, double-masked, placebo-controlled 
study with a 4-week screening period, a 144-week treatment period, an optional 96-week 
open label sub-study, and a 4-week post-treatment follow-up period (either study completion 
or early termination).  A minimum of 36 subjects with nonsense mutation aniridia who are 
≥2 years of age are planned for enrollment into this study at investigator sites in US and 
Canada. 
During the 4-week screening period, subjects will be assessed for eligibility. 
Eligible subjects will enter the 144-week treatment period consisting of two stages: 
● 
Stage 1 (Weeks 1 to 48) during which subjects will receive either ataluren or 
placebo in a masked fashion; 
● 
Stage 2 (Weeks 49 to 144) during which subjects will receive open-label ataluren. 


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Eligible subjects will be randomized in a masked 2:1 fashion to either ataluren or placebo.  
Randomization will be stratified by age:  ≤10 years versus >10 years.  Masked study drug 
will be dosed three times a day (TID): 10 mg/kg in the morning, 10 mg/kg at midday, and 
20 mg/kg in the evening for 48 weeks.  Subjects (or parent/legal guardian) will record each 
dose on a diary card provided by PTC Therapeutics.   
After completion of the Stage 1 (Week 48), subjects will be eligible for an additional 
96 weeks of open-label ataluren treatment.  Subjects who received ataluren during Stage 1 
will continue to receive ataluren; subjects who had been randomized to placebo will receive 
ataluren during Stage 2. 
There will be an optional sub-study at the end of the Stage 2 Open-Label Extension. Subjects 
will be able to consent to receive an additional 96 weeks of ataluren treatment, returning to 
the clinic every 24 weeks. The assessments to be conducted are outlined in the schedule of 
events.  Subjects that choose not to participate in the sub-study will be required to complete 
the Post-treatment follow-up visit at the end of the Stage 2 Open-Label Extension. The start 
of the sub-study will require prior approval of a protocol amendment from applicable IRBs 
and will continue for 96 weeks or until commercial availability of ataluren for this indication, 
whichever is first, or until a positive risk-benefit assessment in this indication is not 
demonstrated. 
After the subject’s last dose of ataluren, there will be a 4-week post-treatment follow-up 
period.  Analyses of the double-masked phase will be conducted after the last subject has 
completed Week 96. 
A schematic of the study design is provided in Figure 1. 
Figure 1. 
STAR Aniridia Study Schematic 
 
 


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2 
BACKGROUND 
2.1 
Disease Indication 
Aniridia, a familial condition with autosomal dominant inheritance, is a bilateral panocular 
disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve.  Aniridia 
is caused by mutations in the PAX6 gene, which is located on chromosome 11p13 and 
regulates ocular development.  The phenotype is variable between and within families; 
however, affected individuals usually show little variability between the two eyes.  
Individuals with aniridia characteristically show absence of iris, nystagmus, impaired visual 
acuity (usually 20/100 to 20/200), and foveal hypoplasia.  Milder forms of aniridia with 
subtle iris architecture changes, good vision, and normal foveal structure do occur.  Other 
abnormalities include corneal changes, glaucoma, cataract, lens subluxation, strabismus, 
optic nerve coloboma and hypoplasia, and occasionally microphthalmia. 
Aniridia is inherited as an autosomal dominant trait caused by mutations including nonsense 
mutations (premature stop codons), frameshift insertions and deletions, and splice mutations 
in the PAX6 gene located on chromosome 11p13.  The PAX6 gene is a transcriptional 
regulator that is expressed in the iris tissue and other ocular tissues derived from neural crest 
cells. 
Reduction in visual acuity (usually 20/100–20/200), a universal abnormality associated with 
aniridia, usually starts at birth and is caused by foveal hypoplasia or optic nerve hypoplasia.  
As the patient reaches adulthood visual acuity progressively declines due to the occurrence of 
cataracts, nystagmus, amblyopia, glaucoma, and corneal keratopathy.  Most children with 
aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with 
nystagmus (usually apparent by six weeks of age).  Congenital glaucoma rarely occurs in 
aniridia; in such cases, a large corneal diameter and corneal edema may be the presenting 
findings.  Cataracts develop at a young age in 50 to 85% of aniridia patients usually prior to 
20 years of age. 
Ocular manifestations of aniridia are described below: 
● 
Iris.  The most obvious ocular abnormality is iris hypoplasia.  The severity varies 
from a nearly normal iris to almost complete iris absence in which a small stump 
of residual iris tissue is visible on gonioscopy, anterior segment optical coherence 
tomography (OCT), or ultrasound biomicroscopy.  In less extreme cases, the pupil 
size may be normal, but there may be loss of the iris surface architecture or 
presence of iris transillumination.  Other iris changes include partial iris defects 
(resembling a coloboma) or eccentric or misshapen pupils and iris ectropion. 
● 
Lens.  Congenital lens opacities are common. Often there is persistent 
vascularization of the anterior lens capsule (tunica vasculosa lentis) or remnants of 
the pupillary membrane.  The lens opacities are rarely dense enough to require lens 
extraction in infancy, but visually significant lens opacities eventually develop in 
50% to 85% of affected individuals, often in the teens or early adulthood. 


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● 
 
 
 
 
 
 
● 
Cornea.  Keratopathy (corneal degeneration) is a relatively late manifestation with 
multifactorial causes including limbal stem cell abnormalities and abnormal 
wound healing occurring in approximately 80% of the eyes of aniridia patients and 
causes visual disturbances in 26% of eyes.  Changes vary from mild peripheral 
vascularization to pan-corneal vascularization, opacification, and keratinization. 
● 
Fovea.  Foveal hypoplasia is usually (but not always) present.  Findings include 
reduced foveal reflex, macular hypopigmentation, and crossing of the usual foveal 
avascular zone by retinal vessels.  OCT images can clearly delineate the absence 
of normal foveal architecture. 
● 
Optic nerve.  Optic nerve hypoplasia (i.e., the optic nerve head appears 
abnormally small) may occur in aniridia patients, as well as optic nerve coloboma. 
● 
Retina.  Retinal detachment may occur, probably as a consequence of a high 
myopia or previous intraocular surgery.  Very rarely, primary retinal 
manifestations such as an exudative vascular retinopathy or chorioretinal 
degeneration may occur. 
● 
Other ocular manifestations.  Affected individuals may have significant 
refractive errors and may develop a secondary strabismus (squint, eye 
misalignment). 
Aniridia mainly manifests in the eye, but there are additional characteristics of 
aniridia, including effects on hearing and the central nervous system as well as 
obesity and glucose intolerance.  Systemic manifestations associated with aniridia 
are described below: 
● 
Central nervous system.  Individuals with isolated aniridia may show reduced 
olfaction and cognition, behavioral problems, or developmental delay. 
● 
Hearing.  Central auditory processing difficulties (from abnormal 
interhemispheric transfer) present in some individuals may cause hearing 
difficulties.  This finding is particularly important in the context of associated 
visual impairment. 
● 
Obesity.  Patients with aniridia are significantly more likely to be classified as 
overweight or obese compared with siblings without aniridia.  The high prevalence 
of obesity in aniridic patients may be related to endocrine pancreatic function, 
which is influenced by PAX6 gene expression. 
● 
Glucose Intolerance.  PAX6 regulates not only eye development but also islet cell 
development.  In patients with aniridia, PAX6 mutations are associated with 
impaired glucose tolerance and/or diabetes. 


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Aniridia is diagnosed via a clinical examination entailing slit lamp examination, fundoscopy, 
iris fluorescein angiography, OCT, and high-frequency ultrasound biomicroscopy.  Gene 
sequencing is performed to identify the disease-causing mutation. 
Many of the treatment methods used today for aniridia are ineffective.  Surgical management 
of some of the visually disabling manifestations, such as cataract surgery or glaucoma shunt 
surgery, has provided improvement in eyesight.  However, due to the structural defects, 
aniridia patients often experience post-operative complications, including aniridic fibrosis 
syndrome, which leads to decompensation of the cornea or aniridia-related keratopathy.  The 
eyesight of most aniridia patients progressively declines to the point of legal blindness.  
Corneal transplants, or keratoplasty, can be performed on patients with aniridia, but often 
produce only temporary vision improvements.  The treatment of keratopathy associated with 
aniridia via amniotic membrane transplant has proven to be only a temporary solution for 
aniridia patients suffering from moderate keratopathy.  In patients with severe keratopathy 
who exhibit limbal insufficiency, treatment involves limbus transplant of lumbar cells.  
Self-transplants are excluded since aniridia usually affects both eyes, therefore patients must 
receive allografts from compatible healthy relatives or cadavers and be treated with oral 
immunosuppression treatment post-transplant to alleviate the risk of rejection. 
2.2 
Ataluren 
2.2.1 
Therapeutic Rationale 
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 PAX6 tells the ribosomes to halt 
production of the protein before the full-length protein is completed.  The resulting truncated 
PAX6 is too short to serve its necessary function and causes disease. 
Drugs with translation-modifying mechanisms of action, such as the aminoglycoside 
antibiotics (e.g., gentamicin), can modulate the effects of nonsense mutations in experimental 
systems.  By binding to the ribosomes, such agents permit the ribosomes to reinterpret the 
nonsense mutation stop signal in mRNA such that they can move through the obstruction by 
inserting an amino acid and continuing the translation process to produce a full-length 
functional protein.  In experimental animal systems and in pilot clinical studies in nmCF, 
treatment with high concentrations of gentamicin has restored production of functional CFTR 
(Clancy 2001, Du 2002, Wilschanski 2003).  Similarly, preclinical and clinical studies in 
nmDMD have demonstrated gentamicin-induced restoration of dystrophin, the structural 
protein that is defective in that disease (Barton-Davis 1999, Politano 2003).  Nonsense 
suppression also has been documented in a number of ocular disorders (Wang 2015).  
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 


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of safer and more conveniently administered, low-molecular-weight, synthetic compounds 
with the ability to promote readthrough of disease-causing nonsense mutations. 
PTC Therapeutics, Inc. is a biopharmaceutical company involved in the discovery and 
development of new therapies for genetic diseases.  PTC Therapeutics has conducted a drug 
discovery program with the objective of finding and developing new agents that overcome 
the effects of nonsense mutations.  A high-throughput screening program identified sets of 
novel, non-aminoglycoside chemical structures that selectively induce ribosomal 
read-through of premature stop codons in mRNA.  Chemical optimization, pharmacologic 
characterization, and toxicological evaluation led to identification of ataluren as an orally 
bioavailable, small molecule with potential clinical utility in treating genetic disorders 
through induction of read-through of nonsense mutations and production of full-length, 
functional proteins (Welch 2007, Du 2008, Gregory-Evans 2014).  In the subset of patients 
whose disease is mediated by a nonsense mutation, ataluren may offer an effective therapy 
by restoring critical protein production for aniridia and other disabling and life-threatening 
genetic disorders. 
In July 2014, the EMA conditionally approved ataluren for the treatment of nmDMD and it 
has been subsequently renewed five times. 
2.2.1.1 
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 Class 2 
compound, possessing low aqueous solubility (<31 g/mL) but high permeability across 
gastrointestinal epithelium, consistent with its high oral bioavailability.  The drug is 
manufactured and formulated under current Good Manufacturing Practices (cGMP) and is 
provided as a vanilla-flavored, white to off-white granules for oral suspension. 
2.2.1.2 
Nonclinical Studies 
Refer to the Ataluren Investigator Brochure for a detailed presentation of efficacy 
pharmacology, safety pharmacology, toxicology, and pharmacokinetic (PK) data from 
ataluren nonclinical studies.  A study of ataluren in a nonclinical model of aniridia is 
described below. 
Ataluren was evaluated in the small-eye mouse model of nonsense mutation aniridia 
(PAX6Sey+/-) (Gregory-Evans 2014).  Aniridia in the small eye mouse model is caused by a 
naturally occurring nonsense mutation in the mouse PAX6 gene. 
Treatment with ataluren caused an increase in the PAX6 protein by 90% in the corneal and 
retinal epithelium protein lysates compared to wild-type mice (Figure 2) as measured by 
enzyme-linked immunosorbent assay.  A mouse model containing a splice-site mutation in 
PAX6 (PAX6Sey-1Neu) did not show a response to ataluren therapy, demonstrating that 
ataluren is specific to nonsense mutation-mediated disease. 


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Dramatic improvements in the eye morphology were observed in mice treated for 10 days by 
subcutaneous injection (30 mg/kg qd) compared to untreated mice.  Untreated nmPAX6 
mutant eyes at postnatal day 4 (P4) (Figure 2, lower left panel) showed thickening of the 
cornea, the appearance of a lenticular stalk in which the underdeveloped lens was attached to 
the cornea, and thickening of the retina with abnormal in-folding at the ciliary margin and by 
P14 (Figure 2, lower middle panel) there is progressive in-folding of the retina and an 
abnormally small lens is observed.  In contrast, when ataluren was administered by 
subcutaneous injection at 30 mg/kg qd for 10 days (P4 to P14) retinal in-folding was 
prevented and the size of the lens increased by 70% (Figure 2, lower right panel). 
Figure 2. 
Ataluren Treatment Improves Eye Morphology in nmPAX6 Mutant Mice 
 
Abbreviations: L, lens; Mt, mutant; nmPAX6, P, Postnatal day; r, retina; Wt, wild type 
Effect of ataluren treatment on eye morphology in nmPAX6 mice (1) administered once daily subcutaneously 
(30 mg/kg) for 10 days.  The black arrow-head indicates the lenticular stalk; the black arrow indicates the cornea; 
and the asterisk indicates the ciliary margin. 
In addition to the morphological improvements, mice treated with ataluren showed 
improvements in the thickness of the retinal layers (Figure 3) and higher packing density of 
photoreceptor nuclei. 


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Figure 3. 
Ataluren Treatment Improves Retinal Histology in nmPAX6 Mutant Mice 
 
Abbreviations: GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS, inner segments; 
nmPAX6, nonsense mutation PAX6; ONL, outer nuclear layers; OS, outer segments, PAX6Sey+/-, semidominant 
small eye mouse model of aniridia 
Retinal sections from wild-type systemically-treated PAX6 mutant mice (30 mg/kg subcutaneous injection from 
P4-14) and untreated nmPAX6 mice, showing the photoreceptor inner segments (IS) and outer segments (OS) 
are shorter in treated mice (n=6).  The outer nuclear layers (ONL) are more densely packed in the treated mice 
compared with those in the wild-type mice.  All the retinal layers in the untreated mice are thinner than normal.  
Dramatic improvements in the response to light as measured by electroretinograms were 
observed in mice treated for 46 days by subcutaneous injection (30 mg/kg qd) compared to 
untreated mice (Figure 4: compare Trace 2 [mutant untreated] to Trace 3 [subcutaneous 
administration 30 mg/kg daily P14-P60]).  Dramatic improvements were also observed in 
mice administered the topical formulations for 46 days (Figure 4: compare Trace 4 
[1% ataluren twice a day P14-P60] to Trace 2). 
 
 


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Figure 4. 
Ataluren Treatment Improves Response to Light Stimulation 
(Electroretinographic) in nmPax6 Mutant Mice 
 
Abbreviations: ANOVA, analysis of variance; Hz, hertz; MT, mutant; nmPAX6, nonsense mutation PAX6; 
P, postnatal day; PAX6Sey+/-, semidominant small eye mouse model of aniridia; qd, one a day; SC, 
subcutaneous; SYS, systemic ataluren (30 mg/kg qd); WT, wild type 
Electroretinographic analyses in response to light stimulation. (A) Restoration of light sensitivity in 
Pax6Sey+/– eyes measured at P60. Trace 1 shows wild-type mice with systemic ataluren. Trace 2 shows 
untreated Pax6Sey+/– mouse responses. Trace 3 shows Pax6Sey+/– mice with systemic ataluren. a,a-wave 
maximum from baseline; b, b-wave maximum from baseline. (B) Quantification of scotopic and photopic b-wave 
responses (n = 6). Significance determined by 1-way ANOVA with Tukey post-hoc tests *P<0.05; **P<0.01.). 
As shown above (Figure 4), treatment with ataluren resulted in increased response of the 
retina to light stimulation, demonstrating that the PAX6 protein produced was functional.  
The optokinetic tracking response was measured to determine changes in behavioral response 
mediated through the retina-brain circuitry as an approximation for visual acuity.  These 
results support the previous observations that ataluren treatment improves the morphology of 
the eye and the response of the retina to light by demonstrating that PAX6 protein is 
produced and is functional as measured by optokinetic tracking. 
Taken together, these results demonstrate that ataluren treatment of the nonsense mutation 
small eye enables readthrough of the nonsense codon in the PAX6 mRNA producing 
full-length functional PAX6 protein.  The increased PAX6 protein results in the reversal of 
the congenital ocular malformation associated with the disease.  These results demonstrate 
that ataluren has the potential to be a promising treatment for the underlying cause of 
aniridia. 


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2.2.1.3 
Clinical Studies 
In total, >1036 subjects, including healthy volunteers as well as subjects with several 
nonsense mutation genetic disorders, have been exposed to ataluren in Phase 1 
(Hirawat 2007), Phase 2 (Kerem 2008, Sermet-Gaudelus 2010, Wilschanski 2011, 
Finkel 2013) and Phase 3 (Bushby 2014, Kerem 2014) clinical studies.  Refer to the Ataluren 
Investigator Brochure for a detailed presentation of safety, efficacy, and PK data from these 
clinical studies. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objective 
The primary objective of this study is to evaluate the effect of ataluren on Maximum Reading 
Speed as measured using the Minnesota Low Vision Reading Test (MNREAD) Acuity 
Charts in subjects with nonsense mutation aniridia. 
3.1.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Evaluate the effect of ataluren on the following: 
o Reading Accessibility Index 
o Best corrected visual acuity (BCVA) 
o Critical Print Size 
o Reading Acuity 
o Severity of corneal keratopathy 
o Iris area 
• Characterize the systemic and ocular safety profile of ataluren in subjects with 
nonsense mutation aniridia. 
3.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2 
Endpoints 
3.2.1 
Primary Endpoint 
The primary endpoint of this study is the change from baseline (Visit 2/Day 1) to Week 48 in 
Maximum Reading Speed of OU as measured using the MNREAD Acuity Charts. 
3.2.2 
Secondary Endpoints 
The key secondary efficacy endpoints of this study are: 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OU 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in BCVA 
Additional secondary efficacy endpoints of this study are as follows: 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Maximum Reading Speed of 
OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Critical Print Size of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Acuity of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in severity of corneal 
keratopathy 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in iris area 
● 
Change from baseline (Visit 2/Day 1, Stage 1) to Week 240 (End of Study Visit) 
in BCVA. Note: This endpoint will be assessed only for the cohort of subjects who 
enroll into the sub-study. 
The secondary safety endpoint of this study is the overall systemic and ocular safety profile 
of ataluren as determined by: 
● 
incidences of treatment-emergent adverse events 
● 
abnormal findings on laboratory assessments 
● 
vital signs 
● 
physical examinations 
● 
ophthalmoscopy 


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● 
slit-lamp examination 
● 
visual field testing 
3.2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
SUBJECT SELECTION CRITERIA 
4.1 
Overview 
The following eligibility criteria are designed to select subjects 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 or designee prior to enrollment. 
Subjects that complete the parent study will be eligible to participate in the sub-study. The 
principal investigator (PI) or sub-investigator will discuss the possibility of participation 
directly with study subjects and/or parent/legal guardian in the clinic. 
4.2 
Inclusion Criteria 
Subjects who will be selected for this study must meet the following criteria: 
1. 
Evidence of signed and dated informed consent document(s) indicating that the 
study candidate (and/or a parent/legal guardian) has been informed of all pertinent 
aspects of the study.  Note: 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 ethics 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. 
Age ≥2 years and of either gender. 
3. 
Body weight ≥12 kg. 
4. 
Documentation of the presence of a nonsense mutation in 1 allele of the PAX6 
gene as determined by genotyping performed at a laboratory certified by the 
College of American Pathologists (CAP), or under the Clinical Laboratory 
Improvement Act/Amendment (CLIA), or by an equivalent organization.  Note: 
Sponsor review of the genotyping documentation is required. 
5. 
Clinical diagnosis of aniridia. 
6. 
Willingness and ability to comply with scheduled visits, drug administration plan, 
study procedures, and study restrictions. 
7. 
Good general health, as determined at Visit 1 (Screening) by medical history and 
physical examination (including vital sign measurements). 
8. 
No clinically significant abnormality based upon laboratory assessments at Visit 1 
(Screening), in the opinion of the investigator. 


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9. 
Female subjects of childbearing potential are eligible for the study but must be 
willing to use adequate (at least 1 form of) contraceptive methods as described 
below during the study treatment period (starting from the day of first dose of 
study drug and ending 60 days after the last dose of study drug).  Childbearing 
potential is defined as subjects who have experienced menarche and who are 
neither postmenopausal nor have been permanently sterilized. 
○ 
Hormonal methods of contraception (including oral and transdermal 
contraceptives, injectable progesterone, progestin subdermal implants, 
progesterone-releasing intrauterine devices [IUDs]) initiated at least 14 days 
prior to the first dose of study drug 
○ 
Abstinence 
○ 
Placement of a copper-containing IUD 
○ 
Condom with spermicidal foam/gel/film/cream/suppository 
○ 
Postmenopausal at least 12 months prior to first dose of study drug or 
permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy) 
○ 
Male partner who has had a vasectomy for at least 3 months prior to the first 
dose of study drug 
10. Male subjects with partners of childbearing potential must agree to use adequate 
(at least 1 form of) contraception as described below during the study treatment 
period (starting from the day of first dose of study drug and ending 60 days after 
the last dose of study drug). 
○ 
Abstinence 
○ 
Vasectomy for at least 3 months prior to first dose of study drug or surgically 
sterile 
○ 
Without a vasectomy, must use a condom with spermicidal 
foam/gel/film/cream suppository 
4.3 
Exclusion Criteria 
The presence of any of the following conditions will exclude a subject from study 
enrollment: 
General exclusion criteria 
1. 
Subjects participating in any drug or device clinical investigation within 90 days 
prior to Visit 1 (Screening) or who anticipate participating in any other drug or 
device clinical investigation within the duration of this study. 
2. 
Exposure to ataluren within 90 days prior to Visit 1 (Screening). 
3. 
Surgery within 30 days prior to enrollment. 


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4. 
Female subjects who are pregnant or breastfeeding.  Female subjects of 
childbearing potential must have a negative pregnancy test (beta-human chorionic 
gonadotropin [β-HCG]) at screening and must use adequate (at least 1 form of) 
contraceptive methods. 
5. 
Active ocular infection or inflammation. 
6. 
Prior or ongoing medical condition (e.g., concomitant illness, alcoholism, drug 
abuse, psychiatric condition), medical history, physical findings, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the safety of 
the subject, makes it unlikely that the course of study drug administration or 
follow-up would be completed, or could impair the assessment of study results. 
7. 
Subjects with a positive result for hepatitis B, hepatitis C, or human 
immunodeficiency virus at Visit 1 (Screening). 
Drug therapies 
8. 
Ongoing warfarin, phenytoin, or tolbutamide therapy. 
9. 
Ongoing intravenous (IV) aminoglycoside or IV vancomycin use. 
10. Ongoing systemic cyclosporine therapy.  Note: Topical cyclosporine therapy is 
permitted. 
11. Known hypersensitivity to any of the ingredients or excipients of the study drug 
(polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, 
crospovidone XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or 
magnesium stearate). 
Ocular exclusion criteria  
12. 20/200 or worse visual acuity in the better eye with best correction. 
13. Subjects who are monocular. 
14. Subjects with a history of complications due to ocular surgery that could interfere 
with the study procedures or assessment of study endpoints. 
15. Subjects with any other significant ocular or systemic disease that the Investigator 
determines could interfere with the study. 


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5 
ENROLLMENT PROCEDURES 
5.1 
Number of Subjects 
A minimum of 36 subjects with nonsense mutation aniridia who are ≥2 years of age will be 
enrolled into this study at investigative sites in the US and Canada. 
5.2 
Subject Recruitment 
Subjects will be recruited from aniridia populations who receive care at or are referred to the 
investigational site for evaluation.  The PI or sub-investigator will discuss the possibility of 
participation directly with study candidates and/or parent/legal guardian in the clinic and who 
may be appropriate subjects for the study. 
Subjects will be recruited for the sub-study from the parent study.  
5.3 
Screening 
The investigator must inform each study candidate and/or parent/legal guardian of the nature 
of the study, explain the potential risks, and obtain written informed consent/assent from the 
study candidate and/or the parent(s)/legal guardian (as required by local regulations) prior to 
performing any study related screening procedures.  Once written informed consent/assent 
has been obtained, screening procedures for determination of eligibility can be initiated. 
At the time the study candidate signs the informed consent a site representative should access 
the Interactive Voice Response/Interactive Web Response (IVR/IWR) system to indicate that 
a candidate is being screened.  The caller will need to supply the IVR/IWR system with 
information, including the following: 
● 
Site number as previously assigned by PTC Therapeutics 
● 
Subject initials (as allowed by local regulations) 
● 
Subject date of birth (as allowed by local regulations) 
● 
Age 
● 
Date of Screening (Visit 1) 
● 
Documentation of the presence of a nonsense mutation in of the PAX6 gene 
● 
Subject body weight (in kilograms) 
The IVR/IWR will use this information to maintain a central screening log documenting that 
screening occurred.  The screening subject number must be used for subject identification on 
all study related documents (electronic case report forms [eCRFs], clinic notes, laboratory 
samples, etc.). Upon successful completion of the call and confirmation of all subject 
eligibility requirements, the subject may proceed to Baseline procedures. 
5.4 
Randomization and Stratification 
The IVR/IWR system will register each subject with a unique subject identification number 
(a 3-digit site number followed by a 3-digit subject number [3-digit stratum number + 3-digit 
randomization number]).  The subject may be enrolled and begin ataluren or placebo 
administration after confirmation of eligibility has been received from the IVR/IWR system. 


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6 
STUDY DRUG ADMINISTRATION 
6.1 
Investigational Product 
6.1.1 
Ataluren 
Masked ataluren (treatment through Week 48) as well as open-label ataluren (treatment from 
Week 49 to Week 144 and during the sub-study) will be provided as granules for oral 
suspension with a white to off-white powder appearance.  The drug substance and drug 
product are manufactured under cGMP conditions.  The formulation includes matrix and 
suspending agents, surfactants, and various excipients that aid in the manufacturing process.  
The granules for oral suspension are packaged in aluminum-foil, child-resistant sachets 
(packets) and supplied in dose strengths containing 125, 250, or 1000 mg of the active drug 
substance.  For administration, the powder in the sachet may be mixed with water, fruit juice, 
fruit punch, or milk (skim, 1% fat, 2% fat, whole milk, chocolate milk, soy milk, or 
lactose-free milk), or semi-solid food (yogurt, pudding, or applesauce). 
6.1.2 
Placebo 
A white to off-white granule placebo formulation will be provided for oral suspension.  The 
placebo formulation has been manufactured under cGMP conditions.  The dry granules and 
the liquid suspension of the drug match the active formulation in appearance, odor, and taste.  
The placebo formulation contains excipients similar to those used in the active product.  The 
placebo is packaged in the same aluminum-foil, child-resistant sachets using weights and 
volumes to match each of the 125, 250, and 1000 mg dose strengths of active drug sachets. 
6.1.3 
Packaging and Labeling 
Drug kits will be provided, each of which contains 90 sachets of one of the dose strengths 
(125, 250, or 1000 mg or matching placebo).  Sachets and cartons will be color coded to 
indicate dosage strength (125 mg – yellow, 250 mg – pink, 1000 mg – blue). 
Each kit will have a unique kit ID number.  During Stage 1, labeling for active drug and 
placebo will be identical.  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. 
Open-label ataluren will be provided during Stage 2 and during the sub-study. 
6.1.4 
Study Drug Dispensing 
During the parent study (masked Stage 1 and open-label Stage 2) and the sub-study, dosing 
of ataluren will be based on milligrams of drug per kilogram of subject body weight and will 
be adjusted to allow for dosing with up to 2 of the available sachet dose strengths (125 mg, 
250 mg, and/or 1000 mg).  The sachet dose strengths and number of sachets to be taken per 
dose will be calculated and provided by the IVR/IWR system. 


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The clinic staff (e.g., pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IVR/IWR system directions.  At the time of randomization, the 
IVR/IWR system will provide the clinic staff with the subject randomization number and the 
kit ID numbers designating the kits to be dispensed.  Multiple kits may be dispensed at a 
single visit (maximum of two different strengths). 
The clinic staff (e.g., pharmacist or other qualified person) will write the subject number on 
each kit that is dispensed. A 180-day supply (2 kits each containing 90 sachets; 24 weeks + 
6 days) of study drug will be provided for each two 24-week study periods of Stage 1, the 
four 24-week study periods of Stage 2, and the four 24-week study periods during the sub-
study. 
Because of potential changes in subject body weight over time, at Week 24 (Visit 3) and 
every 24 weeks thereafter, a dose adjustment will 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. 
6.1.5 
Return of Study Drug 
Subjects and/or parents/caregivers should return all remaining ataluren (all unused sachets) to 
the study site at each onsite study visit.  The Study Drug Administration Record will serve as 
the source document for drug supply to the subjects and will document the return of any 
unused drug for compliance assessments. 
6.1.6 
Storage and Stability 
Kits containing sachets of study drug will be stored at controlled room temperature 
(~15 to 30°C).  The available stability data from representative samples support the use of the 
drug product for 48 months when stored at room temperature.  The stability of the clinical 
study samples or representative samples may be monitored, as appropriate, to support the 
clinical study. 
6.1.7 
Study Drug Accountability 
Study personnel must ensure that all ataluren supplies are kept in a temperature-monitored, 
secure locked area with access limited to authorized personnel.  Ataluren must not be used 
outside the context of this protocol.  Under no circumstances should the investigator or site 
personnel supply ataluren to other investigators or clinics or allow the ataluren supplies to be 
used other than as directed by this protocol. 
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 dispensing records must also be maintained that include the subject’s assigned study 
number, date and amount of ataluren dispensed, and relevant lot and sachet numbers. 
Unused clinical supplies must be destroyed or returned to PTC Therapeutics or its designee.  
Records documenting the date of study drug destruction or shipping, relevant sachet 
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6.1.8 
Overdose Precautions 
For any subject experiencing an overdose (administration of an ataluren dose >4 times the 
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 or designee must be contacted if an overdose occurs, 
and the overdose must be reported as an adverse event (AE) according to Section 9.1.1 (or as 
a serious adverse event [SAE] if it meets the applicable criteria for an SAE in Section 9.1.2). 
6.1.9 
Inadvertent Exposure and Spill Precautions 
Reference can be made to the Ataluren Investigator Brochure for current information on 
inadvertent exposures and spill precautions. 
6.2 
Study Drug Treatment 
6.2.1 
Stratification and Randomization 
After a subject has completed the necessary screening assessments and has been confirmed to 
be eligible by the investigator, the subject can be randomized into the study. 
During Stage 1, a minimum of 36 eligible subjects will be stratified by age group (≤10 years 
old versus >10 years old) and then be randomized in a 2:1 ratio to 1 of 2 possible treatment 
assignments: 
• Ataluren (10, 10, 20 mg/kg) 
• Placebo 
The first dose of study drug will be administered in the clinic and the date and time of 
administration will be recorded.  At the end of each Stage, the last dose of study drug will be 
taken on the evening before the clinic visit (i.e., the night before the Visit 4/Week 48 [end of 
Stage 1], the night before Visit 8 (EOS/ET)/Week 144 [end of Stage 2], and the night before 
Visit 12 (end of Sub-study)/Week 240). 
6.2.1.1 
Masked Dosing 
During Stage 1, the identity of the treatments will be concealed by the use of a placebo that is 
matched to the active drug in appearance, taste, odor, packaging, labeling, and schedule of 
administration.  Unmasking will only occur in the case of subject emergencies before study 
completion and at the conclusion of the study.  Except for emergency unmasking, individual 
subjects, subjects/caregivers, and site personnel will not be informed of the randomized 
treatment assignments until the implications of revealing such data for the overall ataluren 
clinical development program have been determined by PTC Therapeutics. 


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Emergency unmasking should only occur after the PI deems the subject’s emergency 
warrants the unmasking of the treatment.  Unmasking of the treatment can only be performed 
by the PI in the IVR/IWR system.  Unmasking instructions are provided in the IVR/IWR 
system instruction manual. 
6.2.1.2 
Open-Label Dosing 
After completion of the Stage 1 (Week 48), subjects will be eligible for an additional 
96 weeks of open-label ataluren treatment.  Subjects who received ataluren during Stage 1 
will continue to receive ataluren; subjects who had been randomized to placebo will receive 
ataluren during Stage 2. Upon completion of the parent study, subjects will be eligible to 
continue receiving open-label ataluren for an additional 96 weeks in the sub-study. 
6.2.2 
Drug Administration Plan 
Study drug (masked ataluren or placebo [during Stage 1] as well as open-label ataluren 
[during Stage 2 and the sub-study]) will be administered TID.  The dose level to be 
administered is: 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening. 
6.2.3 
Schedule of Administration 
Throughout the study (i.e., during the parent study and the sub-study), study drug should be 
taken TID – the 1st dose (10 mg/kg) in the morning, the 2nd dose (10 mg/kg) at mid-day, and 
the 3rd dose (20 mg/kg) in the evening.  Intervals for dosing should be ~6 hours (±1 hour) 
between morning and mid-day doses, ~6 hours (±1 hour) between mid-day and evening 
doses, and ~12 hours (±1 hour) between evening doses and the morning dose on the next day. 
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. 
6.2.5 
Study Drug Preparation and Storage 
Once at the investigational site and/or with the subject/caregiver, study drug sachets should 
be stored at room temperature, away from the reach of children until time of reconstitution 
and should only be opened at the time of dose preparation.  The full contents of the sachets 
should be mixed with at least 30 mL (1 ounce) of liquid (water, milk, fruit juice, fruit punch), 
or 3 tablespoons of semi-solid food (yogurt, pudding, or applesauce). The prepared dose 
should be mixed well before administration.  The amount of the liquid can be increased based 
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Each prepared dose is best administered immediately after preparation.  The prepared dose 
should be discarded if not consumed within 24 hours of preparation (if kept refrigerated), or 
within 3 hours of preparation (if kept at room temperature). 
The clinic staff will instruct each subject or parent/caregiver on the specific number of 
sachets to be taken from each kit for each dose and will provide detailed oral directions 
regarding drug preparation.  In addition, detailed written drug mixing and dosing instructions 
will be provided to the subject or parent/caregiver when drug supplies are dispensed.  A copy 
of these instructions will be maintained in the investigator site study file. 
6.3 
Safety Monitoring and Ataluren Treatment 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. 
For adverse events or laboratory abnormalities, the investigator will use judgment in 
determining whether the event or abnormality is clinically significant, whether diagnostic 
evaluation is warranted, and whether potential interruption of study drug treatment is 
appropriate.  In general, life-threatening (Grade 4) or severe (Grade 3) adverse events or 
laboratory abnormalities should be considered clinically significant, although recurrent or 
persistent moderate events (Grade 2) may also be considered clinically significant in certain 
circumstances.  Reference should be made to the Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0 for grading the severity of adverse events and laboratory 
abnormalities. 
6.3.2 
Evaluation of Adverse Events or Laboratory Abnormalities 
The PTC Therapeutics medical monitor or designee 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. 
Clinical evaluations for potential hepatic and renal toxicities may include the following: 
• Hepatic:  The medical history, hepatitis screening results, all clinical blood 
values (particularly serum bilirubin, gamma-glutamyl transferase [GGT], 
aspartate aminotransferase [AST], and alanine aminotransferase [ALT] values), 
and all concomitant medications should be reviewed.  Depending upon changes 
observed, the recommended diagnostic workup may include more frequent 
monitoring or further evaluations for viral hepatitis and immune disorders; tests 
for cholelithiasis; or abdominal ultrasound, computed tomography, magnetic 
resonance imaging (MRI), or other imaging methods. 
• Renal:  The medical history, all clinical blood and urine renal values, serum 
electrolytes, medications, and potential pre- or post-renal conditions should be 
reviewed.  Depending upon the changes observed, recommended diagnostic 
workup may include further evaluations of blood or urine; tests of glomerular 


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filtration rate, concentrating ability, or other renal functions; computed 
tomography, MRI, or other imaging methods; and/or renal biopsy. 
6.3.3 
Instructions for Resuming Study Drug Administration after an Interruption 
for Safety Concerns 
In deciding whether to re-institute study drug after a dose interruption for any clinically 
significant safety concern, the investigator in consultation with PTC Therapeutics should 
consider factors such as the following: 
• Type and severity of the adverse event or laboratory abnormality 
• The potential causal relationship of study drug 
• The subject’s status in terms of aniridia and other health conditions 
• The ability to monitor for recurrence of the event 
If further evaluation reveals that the adverse event that led to dose interruption was not 
related to the study drug, study drug may be restarted. 
If the subject experiences a recurrence of a previous abnormality that led to study drug dose 
interruption or experiences the new occurrence of an unacceptable adverse event or 
laboratory abnormality, the investigator should interrupt study drug and confer with the 
PTC Therapeutics medical monitor or designee regarding the potential need to discontinue 
study drug permanently. 
6.3.4 
Instructions for Discontinuation of Study Drug Administration for Safety 
Concerns 
If after appropriate consideration of study drug interruption/modification and consultation 
with the PTC Therapeutics medical monitor or designee, it is not appropriate for a subject to 
continue with study treatment, then study drug should be permanently discontinued.  If 
permanent discontinuation of study drug 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 or designee 
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 eCRF.  The End of Treatment Visit eCRF 
should be completed and appropriate follow-up (at ~4 weeks as per protocol or until recovery 
from or stabilization of the adverse event, whichever comes last) should be instituted 


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7 
CONCOMITANT AND SUPPORTIVE THERAPY 
7.1 
Concomitant Medications 
Other than the study drug, any treatments (including prescription and non-prescription drugs, 
health foods, herbal remedies, self-prescribed drugs, street drug, tobacco products, or alcohol) 
taken by a subject from the screening period through the 4-Week End of Treatment 
Follow-Up are considered concomitant medications.  Information regarding all concomitant 
medications will be collected and documented in the concomitant medication page of the 
eCRF. 
7.1.1 
Treatment for Aniridia-Related Conditions 
Surgery for aniridia-related conditions (e.g., glaucoma, cataract) during this study is 
permitted. 
Study subjects may receive supportive care medications (e.g., drops, lubricants) consistent 
with local best practices and guidelines.  The use of topical cyclosporine is permitted. 
7.1.2 
Nephrotoxic Medications 
Renal abnormalities were observed in a Phase 3 trial evaluating ataluren in subjects ≥6 years 
of age with nmCF who were receiving concomitant IV aminoglycosides (as described in the 
Ataluren Investigator Brochure).  Caution should therefore be exercised during concomitant 
use of study drug and potentially nephrotoxic agents. 
In subjects who require treatment for serious infections, investigators should substitute other 
antibiotics for systemic aminoglycosides when clinically appropriate.  If IV aminoglycosides 
or other nephrotoxic antibiotics (e.g., vancomycin) are administered, study drug must be 
interrupted during the course of antibiotic therapy.  Subjects requiring IV aminoglycoside or 
vancomycin therapy should be closely monitored in an appropriate setting, such as a hospital.  
In subjects receiving such agents, antibiotic drug levels and serum creatinine and blood urea 
nitrogen (BUN) should be monitored closely as follows: 
• Creatinine and BUN should be measured: 
○ 
Prior to initiating IV aminoglycoside or vancomycin therapy 
○ 
Within 24 to 48 hours of the first antibiotic administration (and further 
antibiotic dosing should be based on these results) 
○ 
At least twice a week during the course of antibiotic treatment 
• Antibiotic trough levels should be measured: 
○ 
Within 24 to 48 hours of the first antibiotic administration (and further 
antibiotic dosing should be based on these results) 
○ 
At intervals during the course of antibiotic treatment.  


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7.1.3 
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. 
7.1.4 
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” (e.g., 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 eCRF. 
7.1.5 
Drugs Metabolized by Cytochrome P450 Enzymes 
As the primary route of ataluren metabolism is via glucuronidation by 
UDP-glucuronosyltransferase 1-9 (UGT1A9), clinically significant interactions between 
ataluren and co-administered drugs metabolized by cytochrome P450 enzymes (CYPs) are 
unlikely.  In particular, ataluren is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, 
CYP2D6, and CYP3A4/5, and does not have induction potential on the major CYP enzymes. 
In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug 
interactions mediated by these enzymes are not expected according to the criteria described 
in the EMA guideline on the investigation of drug interactions (EMA 2012).  As an added 
measure of safety, however, investigators should pay specific attention to use of drugs that 
are known substrates of these enzymes, particularly when such drugs may have a low 
therapeutic index. 


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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 [e.g., 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 (e.g., 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. 
7.1.6 
 Other Potential Drug Interactions 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and of breast cancer resistant 
protein (BCRP).  Coadministration with rifampin, a strong inducer of metabolic enzymes, 
including UGT1A9 and CYP3A4, did not affect exposure of ataluren in healthy subjects.  No 
dose adjustment is required when ataluren is co-administered with UGT1A9-inducing 
medications. Caution should be exercised when ataluren is co-administered with drugs that 
are inhibitors of BCRP (e.g., cyclosporine, eltrombopag, gefitinib), as these drugs may affect 
ataluren plasma concentrations, e.g.  Note: Topical cyclosporine therapy is permitted. 
In vitro data indicate that ataluren is an inhibitor of organic anion transporter 1 (OAT1), 
organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 
(OATP1B3).  Caution should be exercised when ataluren is co-administered with e.g. OAT1, 
OAT3, or OATP1B3 (e.g., oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, 
bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) because of the risk 
of increased plasma concentration of these drugs. 
The investigator is encouraged to consult the PTC medical monitor or designee with 
questions relating to specific drugs and their potential for interactions with ataluren. 
7.2 
Dietary Restrictions 
There are no specific dietary restrictions in the study. 


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8 
SCHEDULE OF EVENTS AND STUDY PARAMETERS 
8.1 
Schedule of Events 
The types and timing of data to be recorded are summarized in Table 1 (Stage 1, double-masked 
period),  Table 2 (Stage 2, open-label period), and Table 3 (open-label sub-study). 
Table 1. 
Schedule of Events (Stage 1) 
Protocol Activities 
Screening 
Double-Masked Treatment 
Day±Window 
Week 
-28 
-4 
1a 
1 
169±28 24 
337±28 48/End of 
Stage 1b 
Visit 
1 
2 
3 
4 
Informed consent 
X 
 
 
 
Medical and ophthalmic historyc 
X 
 
 
 
Serum viral screen 
X 
 
 
 
Physical exam 
X 
X 
 
X 
Height and weight 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
Hematology, biochemistry, urinalysis 
X 
 
X 
X 
Serum β-HCGd 
X 
X 
X 
X 
Study drug and diary dispensing 
 
X 
X 
X 
Study drug administration 
 
X 
X 
X 
Study drug compliance and return 
 
 
X 
X 
Collect diary  
 
 
X 
X 
Adverse events 
 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
MNREAD 
 
X 
 
X 
 
 
X 
X 
X 
Slit-lamp examinatione  
 
X 
X 
X 
Slit-lamp photography 
 
X 
X 
X 
OCT  
 
X 
X 
X 
Fundus photography 
 
X 
X 
X 
Humphrey visual fields 
 
X 
 
X 
BCVA and refractionf 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
blood sample for plasma PKg 
 
If feasible  
(i.e., during surgery for glaucoma, cataracts, etc.) 
Abbreviations: β-HCG, beta-human chorionic gonadotropin, BCVA, best corrected visual acuity, 
ETDRS, early treatment diabetic retinopathy study; LEA, LEA Symbols Visual Acuity Test System, 
MNREAD, Minnesota Low Vision Reading Acuity Charts, OCT, optical coherence tomography, 
PK, pharmacokinetic(s) 
a All study and laboratory assessments on the first day of treatment must be done prior to in-clinic 
administration of the first dose.  
b Open-label study drug administration will start at the end of Stage 1 (Visit 4/Week 48). 
c Should include capture of available historical values for ocular assessments included in this study, such as 
visual acuity, 
, etc. 
d Sample taken only for female subjects of childbearing potential. 
e Slit-lamp examination should precede 
 measurement.   
f BCVA and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an 
age-appropriate alternative (e.g., LEA). 
g 
 
 


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Table 2. 
Schedule of Events (Stage 2) 
Protocol Activities 
Open-Label Treatment 
End of 
Treatmenta 
Follow-Upb 
Day± 
Window 
Week 
505±28 
72 
673±28 
96 
841±28 
120 
1009±28 
144 
28 Days 
Post End 
of 
Treatment 
±7 
148 
Visit 
5 
6 
7 
8 
9 
Physical exam 
 
X 
 
X 
X 
Height and weight 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
X 
Hematology, 
biochemistry, 
urinalysis 
X 
X 
X 
X 
X 
β-HCGc 
X 
X 
X 
X 
 
Study drug and diary 
dispensing 
X 
X 
X 
 
 
Study drug 
administration 
X 
X 
X 
 
 
Study drug 
compliance and return 
X 
X 
X 
X 
 
Collect diary  
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
MNREAD 
 
X 
 
X 
 
Slit-lamp examination 
d 
X 
X 
X 
X 
 
Slit-lamp photography 
X 
X 
X 
X 
 
OCT 
X 
X 
X 
X 
 
Fundus photography 
X 
X 
X 
X 
 
Humphrey visual field 
 
X 
 
X 
 
BCVA and refractione 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 blood 
sample for plasma 
PKf 
If feasible  
(e.g., during surgery for glaucoma, cataracts, etc.) 
 
Abbreviations: β-HCG, beta-human chorionic gonadotropin; BCVA, best corrected visual acuity; LEA, LEA 
Symbols Visual Acuity Test System; MNREAD, Minnesota Low Vision Reading Acuity Charts; OCT, optical 
coherence tomography; PK, pharmacokinetic(s) 
a Refer to Table 3 for the schedule of events for subjects participating in the sub-study for Visits 8-13. 
b This visit is only required for subjects not participating in the sub-study. 
c Sample taken only for female subjects of childbearing potential. 
d Slit-lamp examination should precede 
 measurement.   
e BCVA and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an 
age-appropriate alternative (e.g., LEA). 
f 
 
 


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Table 3. 
Schedule of Events (Open-label Sub-study) 
Protocol Activities 
Open-Label Treatment 
End of Study/
Early 
Termination 
Follow-Up 
Week 
144 ±28 
days 
168±28 
days 
192±28 
days 
216±28 
days 
240 ±28 days 
28 Days 
(4 weeks) 
Post EOS/ET 
(Week 
244±7days) 
Visit 
8 
9 
10 
11 
12 
13 
Informed consent 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
X 
Height and weight 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
X 
X 
Hematology, biochemistry, 
urinalysis 
X 
X 
X 
X 
X 
X 
β-HCGa 
X 
X 
X 
X 
X 
 
Study drug and diary 
dispensing 
X 
X 
X 
X 
 
 
Study drug administration 
X 
X 
X 
X 
 
 
Study drug compliance and 
return 
X 
X 
X 
X 
X 
 
Collect diary  
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
MNREAD 
X 
X 
X 
X 
X 
 
Slit-lamp examination b 
X 
 
 
 
 
 
Slit-lamp photography 
X 
 
 
 
 
 
OCT 
X 
 
 
 
 
 
Fundus photography 
X 
 
 
 
 
 
Humphrey visual field 
X 
 
 
 
X 
 
BCVA and refractionc 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
  
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
Schedule next visit 
X 
X 
X 
X 
X 
 
Abbreviations: β-HCG, beta-human chorionic gonadotropin; BCVA, best corrected visual acuity; 
EOS/ET, end of study/early termination; ETDRS, early treatment diabetic retinopathy study; LEA, LEA 
Symbols Visual Acuity Test System; MNREAD, Minnesota Low Vision Reading Acuity Charts; OCT, optical 
coherence tomography 
a Sample taken only for female subjects of childbearing potential. 
b Slit-lamp examination should precede 
 measurement.   
c BCVA and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an 
age-appropriate alternative (e.g., LEA). 


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8.1.1 
Screening, Treatment and Follow-up Periods 
No study-related procedures should be performed prior to the signing of the informed 
consent/assent document(s).  Screening evaluations for the study will be performed at the 
clinical research facility as needed. 
Study participants will report to the clinic on the morning of each on-site visit and will 
remain in the clinic until released by the investigator after all the study-related procedures 
have been completed and the subject has been instructed regarding drug storage, 
reconstitution, and administration. 
Subjects must return to the clinic for follow-up assessment at 4 weeks after the last dose of 
study drug. 
8.1.1.1 
Stage 1: Visit 1 (Screening, 4 Weeks Prior to Baseline Visit 2) 
The Screening Visit (Visit 1) will occur 4 weeks prior to Baseline Visit 2.  Screening 
procedures will proceed as follows:  
● 
Obtain written informed consent/assent 
● 
Determine if the subject meets the preliminary eligibility criteria: 
○ 
Documentation of the presence of a nonsense mutation in 1 allele of the 
PAX6 gene as determined by genotyping performed at a laboratory certified 
by the CAP, or under the CLIA, or by an equivalent organization.  Note: 
Sponsor review of genotyping documentation is required prior to 
randomization. 
○ 
Collect demographic information 
○ 
Collect current and relevant medical history and ophthalmic history 
○ 
Identify concomitant medications used 
○ 
BCVA and refraction 
If the subject meets the preliminary eligibility criteria, the following assessments will be 
performed: 
● 
Ophthalmoscopy 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 3 - 
5 minutes 
● 
Physical examination 
● 
Height (in centimeters) and weight (in kilograms) will be measured at each clinic 
visit  
● 
Blood draw for clinical laboratory evaluations: 
○ 
Serum β-HCG, as applicable (sample taken only for female subjects of 
childbearing potential) 
○ 
Hematology and biochemistry 


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○ 
Serum viral screen 
● 
Urinalysis 
● 
Schedule Visit 2 
8.1.1.2 
Visit 2 (Baseline, Week 1 ±1 Day) 
After the 4-week Screening period, subjects who continue to meet all eligibility criteria will 
complete the Baseline Visit (Visit 2/Week 1) as follows: 
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Physical examination 
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - Slit-lamp examination should precede 
 
 measurement   
○ 
Slit-lamp photography.  The Reading Center manual should be referenced for 
detailed instructions regarding macro photography 
○ 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions 
○ 
Humphrey visual fields 
○ 
 
○ 
 
 
○ 
MNREAD 
● 
Blood draw for clinical laboratory evaluations 
○ 
 
○ 
Serum β-HCG, as applicable (sample taken only for female subjects of 
childbearing potential) 


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● 
Dispense masked study drug and Study Drug Dosing Diary, and review 
administration instructions 
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
○ 
The first dose of study drug should be administered in the clinic after 
completion of all other assessments and procedures required at this visit 
● 
Schedule Visit 3 
8.1.1.3 
Visit 3 (Week 24 ±28 Days) 
The subject will return to the site for visit 3.  Visit 3 will proceed as follows: 
● 
Record any adverse events occurring since administration of first dose at last visit, 
and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - Slit-lamp examination should precede 
 
 measurement.   
○ 
Slit-lamp photography.  The Reading Center manual should be referenced for 
detailed instructions regarding macro photography. 
○ 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions. 
○ 
 


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○ 
 
 
 
● 
Blood draw for clinical laboratory evaluations 
○ 
 
○ 
Serum β-HCG, as applicable (sample taken only for female subject of 
childbearing potential) 
○ 
Hematology and biochemistry 
● 
Urinalysis 
 
 
 
 
 
 
● 
Dispense masked study drug and Study Drug Dosing Diary 
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule Visit 4 
8.1.1.4 
Visit 4 (Week 48 ±28 Days [End of Stage 1/Start of Stage 2])   
The subject will return to the site for visit 4.  Visit 4 will proceed as follows: 
● 
Record any adverse events occurring since last visit, and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Physical examination 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - Slit-lamp examination should precede 
 
 measurement   


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○ 
Slit-lamp photography.  The Reading Center manual should be referenced for 
detailed instructions regarding macro photography 
○ 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions 
○ 
Humphrey visual fields 
○ 
 
○ 
 
 
○ 
MNREAD 
● 
Blood draw for clinical laboratory evaluations 
○ 
  
○ 
Serum β-HCG, as applicable (sample taken only for female subject of 
childbearing potential) 
○ 
Hematology and biochemistry 
● 
Urinalysis 
 
 
 
 
 
 
● 
Dispense open-label ataluren and Study Drug Dosing Diary 
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule the Visit 5 
8.1.1.5 
Visit 5 (Week 72 ±28 Days) 
Procedures at Visit 5, will proceed as follows: 
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 


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● 
 
● 
Ophthalmoscopy examination 
● 
BCVA and refraction 
● 
Slit-lamp examination - Slit-lamp examination should precede 
 
measurement. 
● 
Slit-lamp photography. The Reading Center manual should be referenced for 
detailed instructions regarding macro photography 
● 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed. The Reading Center manual should be referenced 
for detailed instructions 
● 
 
● 
 
 
● 
Blood draw for clinical laboratory evaluations 
● 
 
● 
Serum β-HCG, as applicable (sample taken only for female subject of childbearing 
potential) 
● 
Hematology and biochemistry 
● 
Urinalysis 
● 
 
   
● 
 
 
● 
Dispense open-label ataluren and Study Drug Dosing Diary  
● 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule Visit 6 
8.1.1.6 
Visit 6 (Week 96 ±28 Days) 
The subject will return to the site for visit 6.  Visit 6 will proceed as follows: 
● 
Record any adverse events occurring since last visit, and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Physical examination 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  


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● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - Slit-lamp examination should precede 
 
 measurement. 
○ 
Slit-lamp photography.  The Reading Center manual should be referenced 
for detailed instructions regarding macro photography 
○ 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions 
○ 
Humphrey visual fields 
○ 
 
○ 
 
 
 
○ 
MNREAD 
● 
Blood draw for clinical laboratory evaluations 
○ 
 
○ 
Serum β-HCG, as applicable (sample taken only for female subject of 
childbearing potential) 
○ 
Hematology and biochemistry 
● 
Urinalysis 
● 
 
 
○ 
 
 
● 
Dispense open-label ataluren and Study Drug Dosing Diary, and review 
administration instructions  
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule Visit 7 


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8.1.1.7 
Visit 7 (Week 120 ±28 Days) 
The subject will return to the site for visit 7.  Visit 7 will proceed as follows: 
● 
Record any adverse events occurring since last visit, and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
○ 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - slit-lamp examination should precede 
 
 measurement 
○ 
Slit-lamp photography. The Reading Center manual should be referenced for 
detailed instructions regarding macro photography 
○ 
OCT/Fundus photography - anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions 
○ 
 
○ 
 
 
  
● 
Blood draw for clinical laboratory evaluations 
○ 
 
○ 
Serum β-HCG, as applicable (sample taken only for female subject of 
childbearing potential) 
○ 
Hematology and biochemistry 
● 
Urinalysis 
● 
 
 
○ 
 
 


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● 
Dispense open-label ataluren and Study Drug Dosing Diary  
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule Visit 8 (EOS/ET) 
8.2 
Visit 8 (Week 144±28 Days – End of Treatment/Start of Sub-study 
The subject will return to the site for Visit 8 (Week 144).  Additionally, any subject who 
discontinues early from the parent study should complete the Visit 8 assessments and return 
in 4 weeks for follow-up assessments. 
This visit will be considered the end of the parent study and the beginning of the sub-study. 
Subjects should have taken their final dose of study drug for the parent study the night before 
the clinic visit. 
Visit 8 will proceed as follows: 
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Physical examination 
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
Slit-lamp examination - Slit-lamp examination should precede 
 
 measurement.   
○ 
Slit-lamp photography.  The Reading Center manual should be referenced for 
detailed instructions regarding macro photography. 
○ 
OCT/Fundus photography - Anterior and posterior segment OCT and fundus 
photography will be performed.  The Reading Center manual should be 
referenced for detailed instructions. 
○ 
Humphrey visual fields 
○ 
 


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○ 
 
 
 
○ 
MNREAD 
● 
Blood draw for clinical laboratory evaluations: 
○ 
Hematology and biochemistry 
○ 
Serum β-HCG, as applicable (sample taken only for female subjects of 
childbearing potential) 
○ 
 
● 
Urinalysis 
● 
No study drug will be dispensed at this visit for subjects that do not consent to the 
sub-study. Subjects not continuing into the sub-study should return to the clinic in 
4-weeks (±7 days) for their Follow-up visit.  
For all subjects that choose to participate in the open-label sub-study, in addition to the Visit 8 
assessments listed above, the following will need to be completed: 
● 
Obtain written informed consent/assent 
● 
Dispense open-label ataluren and Study Drug Dosing Diary, and review 
administration instructions 
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule Visit 9 in 24 weeks ±28 days 
8.2.1.1 
Sub-study Visits 9, 10, and 11 (Weeks 168, 192, and 216 ±28 Days) 
During the sub-study, subjects will return to the site every 24 weeks (±28 days).  The 
following will be performed at Visits 9, 10, and 11:  
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 – 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 


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○ 
 
 
○ 
MNREAD 
● 
Blood draw for clinical laboratory evaluations: 
○ 
Hematology and biochemistry 
○ 
Serum β-HCG, as applicable (sample taken only for female subjects of 
childbearing potential) 
● 
Urinalysis 
● 
Dispense open-label ataluren and Study Drug Dosing Diary, and review 
administration instructions 
○ 
TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Schedule next visit in 24 weeks ±28 days 
8.2.1.2 
Visit 12 (Week 240 ±28 Days – End of Study/Early Termination Visit) 
This visit will be considered the end of sub-study and should be completed for all subjects. 
Subjects participating in the sub-study who terminate the study before Visit 12 should 
complete the Visit 12 assessments at the time of early termination. Subjects should take their 
final dose of study drug the night before the clinic visit. 
Visit 12, End of Study/Early Termination Visit will proceed as follows: 
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Collect any unused study drug 
● 
Study Drug Dosing Diary review and collection: The diary will be collected and 
reviewed  
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 - 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
Ophthalmoscopy examination 
○ 
BCVA and refraction 
○ 
 
 
○ 
MNREAD 
○ 
Humphrey visual fields 
● 
Blood draw for clinical laboratory evaluations: 


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○ 
Hematology and biochemistry 
○ 
Serum β-HCG, as applicable (sample taken only for female subjects of 
childbearing potential) 
● 
Urinalysis 
● 
No study drug will be dispensed at this visit 
● 
Schedule Follow-up Visit in 4 weeks ±7 days 
8.2.1.3 
Follow-up Visit (4 Weeks Post End of Study/Early Termination Visit ±7 Days) 
Follow-up should occur 4 weeks (±7 days) after the End of Study/Early Termination visit. 
Additionally, any subject who discontinues early from the parent study or the sub-study 
should complete this visit. The Follow-up visit will proceed as follows: 
● 
Record any adverse events occurring since last visit and any that occur during this 
visit 
● 
Record any changes in concomitant medications 
● 
Physical examination 
● 
Height and weight 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and 
body temperature): performed after the subject has been in a sitting position for 
3 – 5 minutes 
● 
Complete the following ophthalmological assessments: 
○ 
Ophthalmoscopy examination 
● 
Blood draw for clinical laboratory evaluations 
○ 
Hematology and biochemistry 
● 
Urinalysis 
8.3 
Assessments 
All assessment should be completed as per the Schedules of Events:  
Table 1 (Stage 1, double-masked period), Table 2 (Stage 2, open-label period), and Table 3 
(open-label sub-study). 
8.3.1 
Informed Consent 
The investigator/study staff member must inform each study candidate of the nature of the 
study, explain the potential risks, and obtain written informed consent at Visit 1 (Screening) 
and Visit 8 (if participating in the sub-study) from the study candidate and/or parent(s)/legal 
guardian (as required by local regulations) prior to performing any study-related activities. 


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8.3.2 
Medical and Ophthalmic History 
The investigator or a qualified designee will review the subject’s clinical and ophthalmic 
history at Visit 1 (Screening), including details relating to aniridia and any other medical 
conditions.  Information regarding clinical history and current medications must be captured 
on the medical history and prior/concomitant medication eCRFs, respectively.  Ophthalmic 
history may include capture of available historical values for ocular assessments included in 
this study, such as visual acuity or 
.  Any historical ocular assessments to 
be collected will only come from three most recent examinations that have occurred within 
the last two (2) years. Ocular assessments would include the date of the exam, 
 
, cup/disc ratios, visual acuities, as well as if previous fundus photos were 
captured and any associated PI comments/notes on the photos. 
8.3.3 
Serum Viral Screen 
Tests to be conducted at Visit 1 (Screening) include hepatitis B surface antigen, hepatitis C 
antibody, and human immunodeficiency virus.  The study manual should be referenced for 
collection, processing, and shipping information. 
8.3.4 
Physical Examination 
The physical examination (including general appearance, head, eyes, ears, nose, mouth, 
throat, heart, thyroid, chest and lungs, abdomen, extremities, neuromuscular system, skin, 
and lymph nodes) will be conducted. 
Physical examinations may also be performed at any time during the study as clinically 
indicated. 
8.3.5 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature) will be monitored at each clinic visit and should be performed after the subject 
has been in a sitting position for 3 - 5 minutes. 
8.3.6 
Height and Weight 
Height (in cm) and weight (in kg) will be measured at each clinic visit. 
8.3.7 
Hematology Laboratory Assessment 
Hematology laboratory assessments will include white blood cell count with differential, 
hemoglobin, hematocrit, other red cell parameters, and platelet count.  Your institute’s local 
laboratory’s manual should be referenced for specimen collection, processing, storing, and/or 
shipping information. 


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8.3.8 
Biochemistry Laboratory Assessment 
Biochemistry laboratory assessments will include sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, 
bilirubin (total, direct, and indirect), AST, ALT, GGT, creatine kinase, lactate 
dehydrogenase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, and cystatin C. Your institute’s local laboratory’s manual should be 
referenced for specimen collection, processing, storing, and/or shipping information. 
8.3.9 
Pregnancy 
Serum β-HCG will be measured only in females of childbearing potential.  Childbearing 
potential is defined as subjects who have experienced menarche and who are neither 
postmenopausal nor have been permanently sterilized. 
8.3.10 
Urinalysis 
Urinalysis will include analysis for pH, specific gravity, glucose, ketones, blood, protein, 
bilirubin, nitrite, and leukocyte esterase.  A test for urobilinogen should be performed if the 
bilirubin test is abnormal. Your institute’s local laboratory’s manual should be referenced for 
specimen collection, processing, storing, and/or shipping information. 
8.3.11 
Study Drug Administration 
Refer to Section 6.2. 
8.3.12 
Adverse Events 
Systemic and ocular adverse events must be assessed and documented at each scheduled 
clinic visit, beginning at Visit 2.  If the subject does not visit the clinic on the scheduled day, 
a telephone call to the subject by qualified site personnel is required to assess adverse events.  
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an adverse event should be obtained when 
clinically indicated.  Subjects must be followed for adverse events for at least 28 days after 
the last dose of ataluren administration, or until any drug-related adverse events and/or 
ongoing SAEs have resolved or become stable, whichever is later. 
8.3.13 
Concomitant Medications 
Concomitant medication information will be collected and documented at each scheduled 
clinic visit.  Any concomitant drugs (prescribed or over-the-counter, which include vitamin 
and herbal supplements) used during the course of the study and the reason for their use will 
be recorded.  Information regarding the timing, type, and amount will be recorded in an 
eCRF.  Excluded drug therapies to consider during screening are listed in the exclusion 
criteria in Section 4.3.  


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8.3.14 
 
 
 
 
 
8.3.15 
MNREAD 
Standard MNREAD Acuity Charts will be used to assess Reading Acuity, Critical Print Size, 
Maximum Reading Speed, and Reading Accessibility Index.   
Reading speed is a strong predictor of visual ability and vision-related quality of life for 
patients with vision loss (Hazel 2000). For this reason, reading performance has been used as 
an outcome measure in clinical trials for judging the effectiveness of treatments 
(Mahmood 2015). 
The Reading Accessibility Index summarizes an individual’s access to text over the range of 
print sizes found in everyday life. The Reading Accessibility Index relies on a simple 
calculation: averaging the reading speed measured over the 10 largest print sizes on the 
MNREAD and normalizing it by the mean value for a group of normally sighted young 
adults (Calabrese 2016). The Reading Accessibility Index is a single-valued measure that 
depends on both the range of accessible print sizes for a subject, and the subject’s speed of 
reading within this range. Because the Reading Accessibility Index is normalized by the 
value for a group of normally sighted young adults (aged 18–39 years), a Reading 
Accessibility Index of 1.0 represents normal performance for this age group. Values less than 
1.0 mean reduced accessibility to printed text within the range of print size encountered in 
daily life (Calabrese 2016).  
The MNREAD Acuity Charts are continuous-text reading-acuity charts suitable for 
measuring reading acuity and reading speed of normal and low-vision patients.  The study 
manual should be referenced for detailed instructions. 
The reading level of the MNREAD Acuity Charts is approximately 2nd to 3rd grade level. It 
is estimated that subjects around the age of 8 years or older will be able to complete this 
assessment. Any subject less than the age of 8 years old will not be required to have this 
study assessment administered. 
Three charts will be utilized for the MNREAD testing; one chart will be used for OD, one 
chart for OS, and the third chart for OU. It is imperative that the charts used for the 
monocular and binocular testing be changed out to decrease the likelihood of memorization 
of the text sentences by the subject. 
8.3.16 
Slit-Lamp Examination and Macro Photography 
Slit lamp examination and macro photography will be performed on the lids, conjunctiva, 
limbus, cornea, anterior chamber, vitreous, and lens without pupil dilation.  The Reading 
Center manual should be referenced for detailed instructions regarding macro photography. 


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Slit lamp examination (without pupil dilation) will be done for both eyes of the subjects for 
this study. Both the Haag-Streit and Zeiss slit lamp biomicroscopes are acceptable for study 
use and it is at the Investigator’s discretion which manufacturer’s brand will be used during 
the study; however, the same slit lamp biomicroscope must be used for assessing the anterior 
segment for all subjects enrolled and for all study visits throughout the trial. 
It is recommended that the slit lamp examinations for an individual subject be performed by 
the same personnel using the same slit lamp for each study visit. 
8.3.17 
Fundus Examination and Photography 
Fundus examination and photography should be performed after testing visual acuity, slit 
lamp examination and macro photography. 
A fundus exam will be performed of the retina, macula, and choroid.  The largest cup-to-disc 
ratio measured should be entered on to the electronic case report form (eCRF).  The Reading 
Center manual should be referenced for detailed instructions regarding fundus photography. 
8.3.18 
Optical Coherence Tomography  
Optical Coherence Tomography will be performed.  The Reading Center manual should be 
referenced for detailed instructions. 
8.3.19 
Humphrey Visual Field 
Vision field testing will be performed by a Duke certified study technician. Humphrey visual 
field will be assessed. The Reading Center manual should be referenced for detailed 
instructions. 
8.3.20 
Ophthalmoscopy 
Ophthalmoscopic examination of the fundus will be performed using an indirect binocular 
ophthalmoscope. The largest cup to disc ratio measured should be entered on to the eCRF for 
each eye.  Any abnormalities of the macula, vessels, periphery and disc are to be recorded. 
The study manual should be referenced for detailed instructions. 
8.3.21 
Best Corrected Visual Acuity (BCVA) and Refraction 
BCVA and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study 
(ETDRS).  
Refraction and testing of BCVA must be performed before the subject’s eyes are dilated and 
prior to fundus photography and OCT imaging. Manifest refraction must precede the BCVA 
testing. For this study, it is estimated that children at the age of 6 or older will be able to be 
tested with a subjective refraction and ETDRS charts.  
Age-appropriate alternative visual acuity chart (e.g., LEA symbols) will be used for any 
subject under the age of 6; however, the same chart should be used throughout the duration 
of the study.   
The study manual should be referenced for detailed instructions. 


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9 
ADVERSE EVENT ASSESSMENTS 
9.1 
Adverse Event Definitions 
9.1.1 
Adverse Events 
An adverse event is any untoward medical occurrence associated with the use of a drug 
(investigational medicinal product) in humans, whether or not it is considered related to the 
drug.  An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease in a study subject who is administered 
study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as adverse events 
include the following: 
● 
All adverse events that are suspected or are not suspected to be due to study drug. 
● 
Overdose (administration of a study drug dose >4 times the intended total daily 
dose level for this protocol [>160 mg/kg/day]) of study drug. 
● 
All reactions from medication misuse, abuse, withdrawal, sensitivity, or toxicity. 
● 
All reactions that result from medication errors or uses of the study drug outside 
what is described in the protocol. 
● 
Apparently unrelated illnesses, including the worsening of a preexisting illness. 
● 
Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as two separate adverse events.  The 
outcome of the accident (hip fracture secondary to the fall) should be recorded in 
source documents. 
● 
Abnormalities in physiological testing or physical examination findings that 
require clinical intervention or further investigation (beyond ordering a repeat 
[confirmatory] test). 
● 
Laboratory 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 (e.g., 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 (e.g., allergic rhinitis) must be noted on the appropriate 
eCRF 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 


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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 
An SAE is an untoward medical occurrence or effect associated with the use of a study drug 
at any dose, regardless of whether it is considered to be related to the study drug, which 
results in one of the following: 
• Death (i.e., all deaths on treatment or within 4 weeks after last study drug 
administration), including deaths due to disease progression.  Any death occurring 
later than 4 weeks following the last dose need not be reported as an SAE unless it 
is a result of an event that started within the period covered by the on-study 
definition.  The reported adverse event should be the event that caused the death.  
In addition, any adverse event resulting in death that occurs subsequent to the 
adverse event-reporting period and that the investigator assesses as possibly 
related to the study drug should also be reported as serious. 
• Life-threatening adverse event.  This is an event that, in the view of either the 
investigator or the sponsor, places the 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 (e.g., 
excluding hospitalizations for administration of the study drug, procedures 
required by the study protocol, or aniridia-related diagnostic procedures; other 
planned hospitalizations; or hospitalizations related only to progression of 
disease).  Treatments in the emergency room for procedures such as hydration 
that do not require admitting the subject to the hospital and observational 
durations in the emergency room for less than 24 hours are not considered serious. 
• Persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions, not related to aniridia. 
• 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 


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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]). 
An event need not be reported as a SAE if it exclusively represents a relapse or an expected 
change or progression of the baseline aniridia.  This type of event need only to be reported as 
an adverse event. 
Note that any SAEs occurring after the end of the subject’s participation in the study should 
be reported to the sponsor if the investigator becomes aware of them. 
9.1.3 
Unexpected Adverse Events 
Unexpected adverse events are defined as those events that were not previously reported with 
study drug as referenced in the most current investigator’s 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’s 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’s brochure as occurring 
with the class of drugs or as anticipated from the pharmacological properties of the study 
drug but is not specifically mentioned as occurring with the medicinal product. 
For the purposes of considering expectedness, the ataluren investigator’s 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 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject or parent/guardian in case of a child.  In 
addition, each study subject will be questioned about adverse events at each scheduled clinic 
visit after study drug administration or during any telephone contact with the subject or 
parent/guardian in case of a child.  The type of question asked should be open-ended, e.g., 
“How has 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 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. 


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All adverse events are to be recorded in the source documents and on the eCRF using concise 
medical terminology; whenever possible terms contained in the Medical Dictionary for 
Regulatory Activities (MedDRA) should be employed.  In addition, the following 
information should be recorded: 
● 
Indication of whether the event is serious or non-serious (see Section 9.1.2) 
● 
Relationship to study drug (see Section 9.4) 
● 
Severity of the event (see Section 9.5) 
● 
Onset date 
● 
Resolution date, or date of death 
● 
Action taken 
● 
Outcome of the event 
Classification of the event as serious or 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, i.e., whether there is a 
reasonable possibility that the study drug caused the adverse event. 
Table 4. 
Relationship of Study Drug to Adverse Event  
Relationship 
Description 
Probable 
A clinical event in which a relationship to the study drug seems probable because 
of such factors as consistency with known effects of the drug; a clear temporal 
association with the use of the drug; improvement upon withdrawal of the drug; 
recurrence upon re-challenge with the drug; lack of alternative explanations for 
the event. 
Possible 
A clinical event occurring coincident with administration of the study drug and 
which may or may not be explained by concurrent disease or other drugs or 
chemicals.  Information on drug withdrawal or re-challenge may be lacking. 
Unlikely 
A clinical event with a temporal relationship to the study drug exposure that does 
not preclude causality but for which there is a clear alternate cause that is more 
likely to have caused the adverse event than study drug.  Such alternatives 
include a concomitantly administered drug, the subject’s disease state, other 
medical conditions, or environmental factors. 
Unrelated 
A clinical event, for which a relationship to the study drug seems improbable 
because of factors such as inconsistency with known effects of the study drug, 
lack of a temporal association with study drug administration, lack of association 
of the event with study drug withdrawal or re-challenge, 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. 


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9.5 
Grading of Severity of Adverse Events 
The severity of adverse events will be graded using the CTCAE Version 4.0 (refer to the 
Study Manual).  For each episode, the highest severity grade attained should be reported. 
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal) to describe the maximum intensity of the adverse event.  For purposes of consistency 
with the CTCAE, these intensity grades are defined in Table 5. 
Table 5. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected 
to have a clinically significant effect on the subject’s overall health 
and well-being, does not interfere with the subject’s usual function, 
and is not likely to require medical attention 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affects 
clinical status, and may require medical intervention 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical 
status and likely requires medical intervention and/or close follow up 
Grade 4 
Life-threatening 
Sign or symptom results in a potential threat to life 
Grade 5 
Fatal 
Sign or symptom results in death 
Note the distinction between the seriousness and the severity of an 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 9.2. 
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 study drug.  Any such pregnancy 
occurring on-study or within 60 days of the last administration of study drug must be 
reported on a Pregnancy Notification Form (see Study Manual for details).  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 or designee of the outcome within 5 days or as 
specified below.  The investigator will provide this information as a follow up to the initial 
Pregnancy Notification Form via the Pregnancy Outcome Form (see the Study Manual for 
details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in 
an aborted fetus]), the investigator should follow the procedures for reporting SAEs, i.e., 
report the event to the PTC Therapeutics Safety Department or designee and follow up by 
submission of appropriate adverse event eCRFs (see Section 9.8). 


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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 PTC Therapeutics Safety Department or designee 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. 
9.8 
Adverse Event Reporting Period 
The first day of adverse event reporting will coincide with the day the first dose of study drug 
is administered.  The adverse event reporting period for this study ends with the 4-week 
post-treatment follow-up visit (+7 days) after the end of study or end of treatment, 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 9.1.2) determines the 
reporting procedures to be followed.  Investigator site reporting requirements for adverse 
events are summarized in Table 6. 
Table 6. 
Investigator Site Requirements for Reporting Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Fax or e-mail to the PTC Therapeutics Safety Department 
or designee 
Within 24 hours 
Fax report or document scan on designated SAE report 
form to the PTC Therapeutics Safety Department or 
designee and to site IRB/IEC, as per local IRB/IEC 
requirements 
Within 5 calendar 
days 
Photocopies or document scan of relevant eCRFs (e.g., 
adverse event form, medical history form, concomitant 
drug/therapy form) and source documentsa (e.g., 
progress notes, nurses’ notes, laboratory and diagnostic 
test results, discharge summaries) to the PTC 
Therapeutics Safety Department or designee 
Per eCRF submission 
procedure 
Record and submit information on appropriate eCRFs 
Nonserious 
Per eCRF submission 
procedure 
Record and submit information on appropriate eCRFs 
Abbreviations: eCRF, electronic case report form; IRB/IEC, Institutional Review Board/Independent Ethics 
Committee; SAE, Serious Adverse Event 
a Subject name, address, and other personal identifiers should be obscured. 


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For SAEs, in addition to completing the adverse event eCRF, the SAE report form must also 
be completed.  The SAE report form should be signed by the investigator; however, if the 
investigator is unable to sign at the time of the event or within 24 hours, the form should be 
signed by the clinical staff member reporting the SAE (e.g., the study coordinator).  The SAE 
report form must be faxed or emailed to the PTC Therapeutics Safety Department or 
designee and to the site IRB/IEC (if required by local regulations) within 24 hours.  Follow-
up information to the SAE should be clearly documented as “follow up” in the SAE report 
form and must also be faxed or emailed to the same parties.  All follow up SAE report forms 
for the event must be signed by the investigator.  Any source documents (e.g., progress notes, 
nurses’ notes, laboratory and diagnostic test results, discharge summaries) provided to the 
sponsor must 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 
eCRF and the SAE report form(s) must match or be reconciled.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same 
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 (e.g., if a subject initially seeks treatment elsewhere or if not brought to the 
attention of the investigator), 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 / designee contact information for reporting SAEs 
is provided below.  This information is also provided in the Study Manual and in the SAE 
report form. 
PTC Therapeutics Safety Department 
E-mail: 
 
SAE Fax Line: 
   
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 per 
their local requirements.  The initial expedited safety report will be provided as required 
according to local regulations (e.g., within 15 days) after the earliest date PTC Therapeutics 
or an agent of PTC Therapeutics (e.g., a site monitor) becomes aware of an adverse event.  
This awareness date is the date the regulatory reporting clock begins, and the date is 
considered Day 0. 


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10 
WITHDRAWAL OF SUBJECTS 
All subjects who receive study drug should remain in the study whenever possible.  
However: 
• The subject has the right to withdraw consent and discontinue study drug at any 
time. 
• If the subject’s condition substantially worsens after initiating study drug, the 
subject will be carefully evaluated by the investigator.  The subject will be 
withdrawn from treatment if continuing would place them at risk. 
• The investigator may withdraw the subject from study drug, 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 study drug administration, 
study procedures, or study requirements.  In this event, the subject should be 
withdrawn from study drug when the circumstances surrounding noncompliance 
increase risk to the subject or are anticipated to substantially compromise the 
interpretation of study results. 
• The subject may be withdrawn from this study in circumstances where the 
masking is intentionally or accidentally broken. 
• This study may be discontinued by the relevant regulatory authority, IRB/EC, 
and/or PTC Therapeutics at any time. 
The date study drug is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the eCRF.  The PTC medical monitor (and designee) should be 
informed via e-mail of when a subject discontinues study drug. 
When study drug is discontinued (regardless of the reason), the investigator is expected to 
capture all of the evaluations required at the EOS/ET Visit and any additional evaluations 
should be completed that may be necessary to ensure that the subject is free of untoward 
effects.  The subject should be encouraged to seek appropriate follow-up for any continuing 
health problems. 
11 
STATISTICS 
11.1 
Sample Size 
The study is planned to enroll a minimum of 36 subjects with nonsense mutation aniridia 
who are ≥2 years of age.  This number of subjects should provide adequate information to 
evaluate the safety of ataluren in this population.  For a statistical hypothesis test for any 
efficacy endpoint, the study will have 60% power to detect an effect size (i.e., standardized 
mean difference) of 0.85, or 80% power to detect an effect size of 1.06, at the 0.05 
significance level (two-sided). 


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11.2 
Analysis Populations 
Intent-to-Treat (ITT) Population / Safety Population: This population will include all 
randomized subjects who receive at least 1 dose of study drug. 
Efficacy Analysis Populations: For each efficacy outcome measure, this population will 
include all subjects who have a baseline value and at least 1 post-baseline value. 
11.3 
General Statistical Considerations 
Two separate analyses will be conducted, one for the double-masked phase (Day 1 through 
Week 48), and the second for the entire study (Day 1 through Week 240). For patients 
randomized to placebo, two baselines will be used, one at randomization (Visit 2, Day 1) and 
the other at first dose of open-label ataluren (Visit 4, 48 weeks) for the analyses outlined 
below.  
a) Analyses on the double-masked phase (Day 1 through Week 48).  
Both placebo and ataluren will be presented and comparison will be made through 48 weeks 
between these two treatment groups. For the analyses of the double-masked phase, 
assessments at randomization (Visit 2 [Day 1]) will serve as baseline. 
b) Analyses of the entire study (Visit 2, Day 1 through Week 240). 
Efficacy will be presented based on two different baselines for placebo, one baseline at 
randomization (Visit 2) and the other baseline at Week 48 when placebo subjects first take 
open-label ataluren. Three analysis groups will be presented:  
1. 
ataluren (all visits),  
2. 
placebo (all visits) with Visit 2 assessments serving as baseline, and  
3. 
combined groups with baseline at the first dose of ataluren (i.e., 
randomization -Visit 2 for ataluren patients and at the first dose of open-label 
ataluren (Visit 4, 48 weeks) for placebo patients).  
Safety data for the entire study will be presented for the combined group for patients 
receiving ataluren.  
By-subject listings will be created for each eCRF module.  Summary tables for continuous 
variables will contain the following statistics: N, mean, median, standard deviation, standard 
error, minimum, maximum, and 95% confidence interval (CIs), as appropriate.  Summary 
tables for categorical variables will include N, percentage, and 95% CIs on the percentage.  
Any CIs for proportions will be computed using normal approximation, if the number of the 
events is at least five.  Otherwise, CIs using an exact method will be provided.  Graphical 
techniques will be used when such methods are appropriate and informative.  For safety 
summaries, CIs will not be presented, unless specified otherwise. 
Transformations of the data may be explored if warranted by the distribution of the data. 
Unless otherwise specified, all analyses will be two-sided at the 0.05 level of significance. 
All analyses will be performed using SAS® (Version 9.0 or higher). 


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11.4 
Study Conduct 
All protocol deviations will be listed and summarized. 
11.5 
Study Population 
Frequency distributions or summary statistics of data pertaining to subject disposition, 
demographics, baseline characteristics, and medical history will be tabulated. 
11.5.1 
Subject Disposition 
The disposition of subjects, including the number of subjects screened, the number of 
subjects enrolled, the number of subjects who received at least one dose of study drug, and 
the number of subjects who discontinued study drug during each of the two stages, as well as 
the reasons for premature termination of study drug, will be tabulated.  Screening failure 
might also be summarized. 
11.5.2 
Demography and Baseline Characteristics 
Demographic and baseline characteristics of subjects will be summarized descriptively by 
means and standard deviations for continuous variables, and by frequency distributions for 
categorical variables.  Summaries will be presented for the ITT population only. 
11.5.3 
Medical History and Prior Medication 
Medical history and prior medication information will be summarized. 
11.6 
Extent of Exposure 
The extent of exposure to ataluren treatment is defined as the last dose date minus the first 
dose date + 1 day.  The frequency will be presented according to the duration ranges in each 
Stage (i.e., Stage 1 [double-masked dosing] or Stage 2 [open-label dosing]): <24 weeks, 
>24 to <48 weeks, >48 to <72 weeks, >72 to <96 weeks, >96 to <120 weeks, >120 to 
<144 weeks, ≥144 to <168 weeks, ≥168 to <192 weeks, ≥192 to <216 weeks, and ≥216 to 
≥240 weeks.  The number r of subjects in each category as well as the mean duration 
(in days) will also be presented. 
11.6.1 
Treatment Compliance 
Study drug compliance will be assessed by analysis of unused study drug reported.  This 
information will be used to describe and summarize compliance by treatment arm.  
Compliance will be assessed in terms of the percentage of drug actually taken relative to the 
amount that should have been taken during the study. 
11.7 
Efficacy 
All efficacy analyses will be performed in the ITT population. 


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11.7.1 
Primary Efficacy Endpoint 
The primary endpoint is change from baseline (Visit 2/Day 1) to Week 48 in Maximum 
Reading Speed of OU as measured using the MNREAD Acuity Charts. 
To assess the treatment effect on the Maximum Reading Speed (OU) at Week 48, change 
from baseline will be analyzed using Analysis of Covariance (ANCOVA) with age and 
baseline Maximum Reading Speed (OU) as covariates, and treatment as a factor.  The 
p-value of testing treatment difference will be provided. Significance level is 0.05 two-sided.  
11.7.2 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints of this study are: 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OU 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in BCVA 
Additional secondary efficacy endpoints of this study are as follows: 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Maximum Reading Speed of 
OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Critical Print Size of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Acuity of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in severity of corneal 
keratopathy 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in iris area 
● 
Change from baseline (Visit 2/Day 1, Stage 1) to Week 240 (End of Study Visit) 
in BCVA. Note: This endpoint will be assessed only for the cohort of subjects who 
enroll into the sub-study. 
All secondary efficacy endpoints will be analyzed similarly as the primary endpoint. 
A summary of the efficacy endpoints listed above will also be provided by visit to assess the 
trend. 
11.7.3 
 
 
 
 


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11.8 
Safety 
All safety presentations will be based on the safety population and will be based only on data 
included in the analysis period of interest 
Adverse event and SAE summaries will also be presented for the following periods: 
● 
Through Week 48 (double-masked phase) 
● 
Through End of Treatment (entire study, including the sub-study)  
Additional frequency tables summarizing the occurrence of adverse events and SAEs after 
the end of the analysis period of interest will also be provided.  All AEs and SAEs will be 
summarized by treatment arm, as defined in Section 11.2.  Marked laboratory abnormalities 
will also be descriptively summarized.  No statistical tests will be performed for AEs or 
laboratory marked abnormalities. 
11.8.1 
Adverse Events 
Adverse events are recorded by the investigators on the Serious and Non-Serious Adverse 
Event page(s) of the eCRF.  All investigators are required to report the nature, the onset and 
resolution date, intensity, action taken, treatment required for event, and to express their 
opinion regarding the relationship between the AE and the study medication. 
Summary information (the number and percent of subjects by treatment) will be tabulated 
for: 
● 
Treatment-emergent adverse events, including clinical and laboratory adverse 
events 
● 
Treatment-emergent and treatment-related adverse events 
● 
Treatment-emergent adverse events by severity 
● 
SAEs 
● 
Adverse events leading to discontinuation 
● 
Ocular adverse events  
Summaries will be presented by System Organ Classes and Preferred Terms.  The 
frequencies of adverse events displayed will be the crude rates that represent the number of 
subjects experiencing adverse events divided by the total number of subjects. 
11.8.2 
Laboratory Parameters 
Changes in clinical laboratory tests from baseline (last measurement prior to entering the 
study at Visit 2, and, in addition, for placebo subjects last measurement prior to receiving 
open-label ataluren at Visit 4) and laboratory marked abnormalities (laboratory adverse 
events) using pre-defined abnormality criteria will be descriptively summarized.  For 
laboratory adverse events, the severity will be graded by CTCAE, when possible.  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. In the by-subject analysis, a 
subject having the same abnormality more than once will be counted only once based on the 
worst severity grade observed. 


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11.8.3 
Other Parameters 
Height, weight, vital signs, physical examination, ophthalmoscopy, slit-lamp examination, 
and visual fields will be summarized descriptively.    
11.9 
 
 
 
 
11.10 
Concomitant Medication Use 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary into Anatomical-Therapeutic-Chemical classification codes.  The type and timing 
(between each visit) of use of specific concomitant medications will be listed and 
summarized. 
The frequency, timing (between each visit), type, and amount of any other therapies for 
aniridia will be considered with special interest. 
11.11 
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. 
11.12 
Subgroup Analyses 
Data will be summarized within subject subgroups of interest based on potentially relevant 
demographic, genetic, and clinical factors, such as age, nonsense mutation stop codon type 
(UGA, UAG, UAA), nonsense mutation exon location, and/or baseline efficacy parameters. 
11.13 
Multiplicity 
The key secondary endpoints will be tested sequentially in the order of Reading Accessibility 
Index and then BCVA at the two-sided significance level 0.05. For example, if the 
hypothesis for the primary endpoint, Maximum Reading Speed of OU, is rejected at 
0.05 level, then Reading Accessibility Index will be tested at 0.05 level. Further, if the 
hypothesis for Reading Accessibility Index is rejected at 0.05 level, then BCVA will be 
tested at 0.05 level. If the hypothesis for the primary endpoint is not rejected at 0.05 level, 
then no hypothesis testing will be performed for the key secondary endpoints. 


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12 
OBLIGATIONS OF THE INVESTIGATOR AND THE SPONSOR 
12.1 
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 (The World Medical Association 2008) and the International 
Council for Harmonisation (ICH) GCP guideline (International Council for Harmonisation 
1996). 
12.2 
Institutional Review Board/Independent Ethics Committee 
Prior to enrollment of subjects into the study, as required by regulatory authorities, the 
protocol and informed consent document will be reviewed and approved by an appropriate 
IRB/IEC.  By signing the protocol, the investigator assures that approval of the protocol will 
be obtained from the IRB/IEC and that all aspects of the IRB/IEC review will be conducted 
in accordance with current regulations.  Amendments to the protocol will be subject to the 
same IRB/IEC review requirements as the original protocol.  Only changes necessary to 
eliminate apparent immediate hazards to the 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. 
A letter documenting the IRB/IEC approval and a list of the names and titles of the IRB/IEC 
members must be received by PTC Therapeutics prior to the initiation of the study.  All 
correspondence with the IRB/IEC should be retained in the investigator’s study file. 
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to PTC Therapeutics.  As soon as possible after completion or termination of 
the study, the investigator will submit a final report to the IRB/IEC and to PTC Therapeutics.  
This report should include the dates of initiation and completion of the study, a description of 
any changes in study procedures or amendments to the protocol, any deviations from the 
protocol, the number and type of subjects evaluated, the number of subjects who 
discontinued (and the reasons for discontinuation), the number of subjects who completed the 
study, and the results of the study, including a description of any adverse events.  
PTC Therapeutics will assist the investigator in the preparation of this report, as needed. 
12.3 
Informed Consent/Assent 
By signing the protocol, the investigator assures that informed consent/assent will be 
obtained from each subject and/or parent/legal guardian prior to performing any study-related 
activities and that the informed consent/assent will be obtained in accordance with current 
regulations. 
The investigator or sub-investigator will give each subject 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 subject and/or parent/guardian in a language in which the subject or parent/guardian is 
fluent.  This information must be provided to the subject or parent/guardian prior to 
undertaking any study-related procedure.  Adequate time should be provided for the subject 


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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 subject and/or parent/guardian 
may have about the study.  The subject and/or parent/guardian should be able to ask 
additional questions as and when needed during the conduct of the study.  The subject’s 
and/or parent(s)/guardian signature (as required by local regulations) on the informed consent 
form should be obtained at the investigator site in the presence of the investigator or a 
qualified representative (e.g., sub-investigator).  Where applicable, the subject will sign an 
age-appropriate assent form. 
Each subject 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 subject information must not be changed without prior approval by 
PTC Therapeutics and the IRB/IEC. 
12.4 
Electronic Case Report Forms  
An eCRF is required and must be completed for each subject, with all required study data 
accurately recorded such that the information matches the data contained in medical records 
(e.g., physicians’ notes, nurses’ notes, clinic charts, and other study-specific source 
documents).  The eCRFs exist within a web-based electronic data capture (EDC) system 
managed by the data management contract research organization for this study.  After the 
investigator or the investigator’s designees (e.g., research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system.  Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail. 
With an electronic signature, the investigator certifies that the data are complete and accurate 
prior to database lock.  This electronic signature serves to attest that the information 
contained in the eCRFs is true.  After database lock, the investigator site will receive a 
CD-ROM and/or paper copies of the subject data for archiving at the investigator site.  At all 
times, the principal investigator has final responsibility for the accuracy and authenticity of 
all clinical data entered onto the eCRFs and/or reported to PTC Therapeutics from the 
investigator site. 
12.5 
Study Records 
During the study, the investigator will maintain adequate records for the study, including 
medical records, source document records detailing the progress of the study for each 
subject, laboratory reports, a CD-ROM or paper copy of the data that have been captured in 
the EDC for each subject (eCRFs), paper CRFs, signed informed consent forms, ataluren 
disposition records, correspondence with the IRB/IEC, adverse event reports, and 
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 
Food and Drug Administration (FDA), Health Canada, or other regulatory authorities. 


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12.6 
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. 
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. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or PTC Therapeutics, the 
investigator agrees to keep accurate and complete records, including the identity of all 
participating subjects (sufficient information to link eCRFs and clinic records), all original 
signed informed consent forms, CD-ROM or paper copies of the data that have been captured 
in the EDC for each subject (eCRFs), and detailed records of ataluren disposition.  All 
records and documents pertaining to the study (including but not limited to those outlined in 
Section 12.5) will be maintained by the investigator until notification is received from PTC 
Therapeutics that the records no longer need to be retained. 
The investigator must obtain written permission from PTC Therapeutics before disposing of 
any records.  In order to avoid any possible errors, the investigator will contact PTC 
Therapeutics prior to the destruction of any study records.  The investigator will promptly 
notify PTC Therapeutics in the event of accidental loss or destruction of any study records.  
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to PTC Therapeutics. 
12.8 
Monitoring and Auditing 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH 
guidelines, PTC Therapeutics or a designee will periodically inspect all eCRFs (see 
Section 12.4 ), study documents, research facilities, and clinical laboratory facilities 
associated with this study at mutually convenient times, before, during, and after completion 
of the study.  As required by applicable regulations (Responsibilities of Sponsors and 
Investigators), the monitoring visits provide PTC Therapeutics with the opportunity to 
evaluate the progress of the study; verify the accuracy and completeness of data in the 
eCRFs; ensure that all protocol requirements, other relevant regulations, and investigator’s 
obligations are being fulfilled; and resolve any inconsistencies in the study records.  This 
includes inspection of all documents and records required to be maintained by the 
investigator, including but not limited to medical records (office, clinic, or hospital) for the 
subjects in this study.  The names and identities of all research subjects will be kept in strict 


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confidence and will not appear on eCRFs or other records provided to or retained by 
PTC Therapeutics.  The investigator/institution guarantees direct access to source documents 
by PTC Therapeutics and appropriate regulatory authorities. 
The 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 regulatory 
authorities.  The GCP regulations also require the investigator to allow authorized 
representatives of the regulatory authorities to inspect and make copies of the same records. 
It is important that the investigator and relevant institutional personnel are available during 
the monitoring visits and possible audits or inspections and that sufficient time is devoted to 
the process. 
12.9 
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 
continuing their participation in the study and must do so within a time-period set by 
PTC Therapeutics.  As directed by PTC Therapeutics, all study materials must be collected, 
and all electronic data entry forms completed to the greatest extent possible. 
12.10 
Public Notification of Study Conduct 
Consistent with requirements of the International Committee of Medical Journal Editors as a 
condition of consideration for publication of study results, PTC Therapeutics will be 
responsible for ensuring that this protocol is listed at the World Health Organization 
International Clinical Trials Registry Platform, European Union Clinical Trials Registry, and 
at ClinicalTrials.gov.  PTC Therapeutics will also be responsible for ensuring that 
information at these 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. 
12.11 
Dissemination of Results 
The information developed during the conduct of this clinical study is considered 
confidential by PTC Therapeutics.  This information may be disclosed as deemed necessary 
by PTC Therapeutics. 
To allow for the use of the information derived from this clinical study and to ensure 
compliance with current regulations, the investigator is obliged to provide PTC Therapeutics 
with complete test results and all data developed in this study.  The information obtained 
during this study may be made available by PTC Therapeutics to other physicians who are 
conducting similar studies and to the FDA, Health Canada, or other regulatory authorities.  
Such information may be disclosed as deemed necessary by PTC Therapeutics. 


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PTC Therapeutics intends for the data from this study to be presented and published.  The 
PTC Therapeutics staff under the direction of the PTC Therapeutics Chief Medical Officer or 
designee in collaboration with the investigator will be responsible for writing presentations 
and manuscripts for publication.  Investigators will not be allowed to publish or present the 
data from this study without prior agreement with PTC Therapeutics. 
12.12 
Communication with Regulatory Authorities 
PTC Therapeutics (or designee) will assume responsibility for regulatory interactions with 
the FDA, Health Canada, and/or other regulatory authorities.  In fulfilling this responsibility, 
PTC Therapeutics (or a designee) will collect, assemble, and communicate all required 
regulatory documents (e.g., investigator financial disclosure forms, protocol and protocol 
amendments, investigator’s brochure, 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. 
13 
RATIONALE FOR STUDY DESIGN FEATURES 
13.1 
Subject Selection 
13.1.1 
General 
This study is a randomized, double-masked, placebo-controlled safety and efficacy study of 
ataluren in subjects with nonsense mutation aniridia.  Consistent with GCP guidelines, 
parents/guardians and subjects must provide informed consent/assent before initiation of any 
study procedures.  To minimize missing data and premature discontinuations, subjects must 
have the personal and family resources to comply with study procedures and restrictions.  In 
addition, subjects must not have serious concomitant conditions that would compromise 
safety, compliance, or evaluation. 
13.1.2 
Reproductive Considerations 
Ataluren is not genotoxic, did not affect fertility in male and female rats, and was not 
teratogenic in rats and rabbits.  In addition, lack of sexual maturity in many of the subjects 
likely to be enrolled in this study limits reproductive risks.  However, restriction on eligibility 
relating to willingness to avoid unprotected sexual intercourse in any subjects known to be 
sexually active is included as a general precaution.  Because it is unknown if ataluren is 
excreted in breast milk, lactating female subjects who are breast-feeding are excluded from 
participation. 
13.1.3 
Prior and Concomitant Therapies 
Surgery for aniridia-related conditions is permitted during the study. 
Conventional supportive therapies will be permitted; however, efforts will be made to avoid 
use of concomitant medications that might confound interpretation of study results (e.g., 
aminoglycosides) or pose a safety risk.  Ataluren has not proved allergenic in studies 
performed to date, but review of known allergies to excipients contained in the formulation is 
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As the primary route of ataluren metabolism is via glucuronidation by UGT1A9, clinically 
significant interactions between ataluren and co-administered drugs metabolized by CYPs are 
unlikely.  In particular, ataluren is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, 
CYP2D6, and CYP3A4/5, and does not have induction potential on the major CYP enzymes. 
In vitro, ataluren is a weak inhibitor of CYP2C8 and CYP2C9, but in vivo drug-drug 
interactions mediated by these enzymes are not expected according to the criteria described 
in the EMA guideline on the investigation of drug interactions (EMA 2012).   
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. 
Based on in vitro studies, ataluren is also not expected to be an inhibitor or a substrate of 
P-glycoprotein (P-gp)-mediated transport. 
Note: Topical cyclosporine therapy is permitted. 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, OAT1, OAT3 and OATP1B3.  
Caution should be exercised when ataluren is co-administered with drugs that are substrates 
of OAT1, OAT3, or OATP1B3 (e.g., oseltamivir, acyclovir, ciprofloxacin, captopril, 
furosemide, bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) 
because of the risk of increased concentration of these drugs. 
Other restrictions relating to recent use of experimental drugs or surgery allow candidates 
sufficient time to recover before proceeding to ataluren dosing.  Restrictions against 
enrollment of subjects expected to have major surgical procedures during the course of the 
study or who have substantial respiratory or cardiac compromise are intended to avoid safety 
problems or gaps in ataluren administration in subjects who require intensive supportive care. 
Please refer to the IB for the latest information on prohibited medications.   
13.2 
Treatment Rationale 
13.2.1 
Ataluren Schedule and Dose Selection 
Dosing based on body weight will be employed.  Such dosing is common in pediatrics and 
reduces variability in exposure by accommodating differences in subject size across the span 
of ages of the subjects who will participate in the clinical study. 
The schedule of drug administration is derived directly from Phase 1 PK modeling and from 
Phase 2 exposure information.  The intent of administering 2 smaller doses at 6-hour 
intervals during the day and a larger dose at a 12-hour interval overnight (e.g., at 7:00 AM, 
1:00 PM, and 7:00 PM) is to optimally sustain target plasma concentrations while 
minimizing total exposures.  This schedule is likely to fit well with daily patterns of living 
for subjects, thus enhancing compliance.  As confirmation of that premise, compliance with 
ataluren dosing in Phase 2 and Phase 3 testing has been excellent. 


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In clinical studies of ataluren in other nonsense mutation genetic disorders, particularly 
nmDMD and nmCF, ataluren has been studied most extensively at the 10, 10, 20 mg/kg dose 
level.  In the Phase 2b, randomized, double-masked, placebo-controlled study of ataluren in 
nmDMD (Study 007), a total of 57 subjects received ataluren 10, 10, 20 mg/kg for 48 weeks.  
In addition, all subjects in the ongoing open-label safety studies of ataluren in nmDMD 
(Studies 016 and 019) are receiving the 10, 10, 20 mg/kg dose level.  As of 31 January 2015, 
the estimated median duration of exposure was 196.6 weeks for Study 016 (N=108) and 
102.4 weeks for Study 019 (N=93).  Across the Phase 3, randomized, double-masked, 
placebo-controlled study of ataluren in nmCF (Study 009) and its open-label extension 
(009e), a total of 170 nmCF subjects have received ataluren 10, 10, 20 mg/kg for ≥48 weeks, 
including 132 subjects who have received ataluren 10, 10, 20 mg/kg for ≥96 weeks.  The 
controlled studies in nmDMD (Study 007) and nmCF (Study 009) have documented a 
favorable risk-benefit at the 10, 10, 20 mg/kg dose level in these indications (Bushby 2014, 
Kerem 2014).  In nmDMD, ataluren has been conditionally approved at a dose of 10, 10, 
20 mg/kg for the treatment of nmDMD.  Based on the collective clinical experience with 
ataluren 10, 10, 20 mg/kg in other indications, this dose level will be evaluated in subjects 
with nonsense mutation aniridia. 
13.2.2 
Duration of Therapy 
The primary objective of this Phase 2 study is to evaluate the effect of ataluren on Maximum 
Reading Speed as measured using the MNREAD Acuity Charts in subjects with nonsense 
mutation aniridia. Secondarily, this study also aims to evaluate other efficacy outcome 
measures in this patient population. Given that there have been very few clinical trials in 
aniridia, it is important to gather information regarding long-term changes and variability of 
outcome measures.  
This study also aims to determine whether ataluren can be safely administered as a chronic 
treatment for subjects with nonsense mutation aniridia.  In subjects with other nonsense 
mutation genetic disorders, ataluren has been generally well tolerated when administered 
chronically for >4 years.  Therefore, exposure to ataluren for up to 240 weeks in this study is 
not expected to pose undue safety risk. 
13.2.3 
Selection of Outcome Measures 
The proposed efficacy, safety, and exposure evaluations are chosen based on relevance to the 
pathophysiology and clinical manifestations of the disease and past experience that these 
assessments can be performed with acceptable accuracy. 
13.2.3.1 
Slit-Lamp Examination and Macro Photography 
Slit-lamp examination and macro photography are standard ophthalmological techniques to 
inspect the anterior segment of the eye.  In the diagnosis of aniridia, slit-lamp examination 
and macro photography are critical to identify and document iris and pupillary abnormalities 
(Hingorani 2012).  Corneal opacification and vascularization and cataract or glaucoma can 
also be detected, if present.  The procedure is non-invasive and can be performed in children 
and adults.  Images will be analyzed by an independent central reader masked to subject 
identity. 


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13.2.3.2 
Fundus Photography 
Fundus examination including posterior segment photography will be used to assess for 
abnormalities in the retina, macula, and choroid as well as the optic disc.  Abnormalities of 
posterior ocular structures, namely foveal and optic nerve hypoplasia, often occur in patients 
with aniridia and cause or contribute to visual impairment (McCulley 2005).  Images will be 
analyzed by an independent central reader masked to subject identity. 
13.2.3.3 
MNREAD 
An MNREAD Acuity Chart curve of reading speed vs print size is characterized by 
3 summary values. At large print sizes, reading speed remains constant, forming a plateau 
that represents the Maximum Reading Speed. As the print size decreases, a Critical Print Size 
is reached at which reading speed begins to decline rapidly. Finally, the smallest print size 
that can be read is defined as the Reading Acuity. These 3 parameters of the MNREAD 
Acuity Chart curve are used to summarize visual reading function. 
Maximum Reading Speed is a person’s reading speed when reading is not limited by print 
size. Maximum Reading Speed is known to be reduced when foveal vision is degraded, such 
as is seen in patients with aniridia. Reading speed, in words per minute, has been widely used 
in psychophysical studies because it can be measured objectively, is reproducible, and is 
sensitive to variations in visual parameters (Legge 1985). Maximum Reading Speed is a 
measure that reflects the dynamic nature of reading. 
The Reading Accessibility Index is defined as an individual’s mean reading speed measured 
across the 10 largest print sizes on the MNREAD Acuity Chart (0.4–1.3 logarithm of the 
minimum angle of resolution at 40 cm), normalized by 200 words per minute (the mean 
value for a group of 365 normally sighted young adults). The Reading Accessibility Index is 
a single-value measure that captures an individual’s range of accessible print sizes and 
reading fluency within this range (Calabrese 2016). These charts were developed at the 
Minnesota Laboratory for Low-Vision Research, University of Minnesota, Minneapolis, 
Minnesota, USA. 
The reading level of the MNREAD Acuity Charts is approximately 2nd to 3rd grade level. It 
is estimated that subjects around the age of 8 years or older will be able to complete this 
assessment. Any subject less than the age of 8 years old will not be required to have this 
study assessment administered. 
13.2.3.4 
Optical Coherence Tomography 
High-resolution OCT enables the measurement and visualization of microscopic structures of 
the anterior and posterior segments.  Anterior segment OCT imaging will be performed to 
detect potential changes in the anterior angle structures.  Posterior segment OCT will be 
attempted to detect potential changes in foveal and optic disc structures, although corneal 
opacities may preclude clear imaging in some patients (Gregory-Evans 2011). Images will be 
analyzed by an independent central reader masked to subject identity. 


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13.2.3.5 
Best Corrected Visual Acuity (BCVA) and Refraction 
Poor visual acuity resulting from iris hypoplasia and foveal hypoplasia is a hallmark 
symptom of aniridia (Netland 2011, Hingorani 2012).  BCVA and refraction will be 
evaluated using the well-established ETDRS method.  If needed, an age-appropriate 
alternative visual acuity chart (e.g., LEA symbols) may be used; however, the same chart 
should be used throughout the duration of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.2.3.9 
Body Mass Index 
Systemic abnormalities associated with aniridia include increased body mass index (BMI) 
and obesity (Netland 2011).  Accordingly, BMI will be calculated. 
 
 
 
 
 
 


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13.2.3.11 Safety 
In defining therapeutic activity in a particular clinical setting, it is imperative that the drug’s 
safety profile be fully characterized.  As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug.  In this study, particular focus 
will be placed on monitoring for ocular adverse findings.  For consistency of interpretation, 
adverse events will be coded using the standard MedDRA, and the severity of these events 
will be graded using the well-defined CTCAE Version 4.0.  Standard definitions for 
seriousness will be applied.  Particular attention will be paid to any adverse events causing 
discontinuation of ataluren and to SAEs requiring rapid regulatory reporting. 
Ocular safety will be monitored via slit lamp, ophthalmoscopy, and visual field assessments. 
14 
BENEFITS AND RISKS 
14.1 
Benefits and Risks: Non-Clinical 
In addition to the non-clinical studies of PAX6Sey+/– mice described in Section 2.2.1.2 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 
lowest-observed-adverse-effect levels, no-observed-adverse-effect levels, and no-effect 
levels in the toxicology program was greater than the exposure observed in humans 
administered the clinical dose of 10, 10 and 20 mg/kg 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-gp.  Enzyme inhibition 
studies with human liver microsomes showed that ataluren has a weak potential for direct 
inhibition of CYP2C8 and CYP2C9.  As an added measure of safety, investigators should 
pay specific attention to use of drugs that are known substrates of these enzymes, particularly 


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when such drugs may have a narrow therapeutic index.  Enzyme induction evaluations in 
human hepatocytes showed that ataluren did not induce the activities of CYP450 enzymes.  
Induction of metabolism by ataluren is not expected since slight increases in CYP2B6 and 
CYP2C9 activity are observed only at an ataluren concentration that is 3- to 5-fold higher 
than the average peak concentration after a 20 mg/kg dose. 
Based on in vitro studies, ataluren is a substrate of UGT1A9 and BCRP.  Coadministration 
with rifampin, a strong inducer of metabolic enzymes, including UGT1A9 and CYP3A4, did 
not affect exposure of ataluren in healthy subjects.  No dose adjustment is required when 
ataluren is co-administered with UGT1A9-inducing medications. Caution should be 
exercised when ataluren is co-administered with drugs that are inhibitors of BCRP (e.g., 
cyclosporine, eltrombopag, gefitinib), as these drugs may affect ataluren plasma 
concentrations. 
Note: Topical cyclosporine therapy is permitted. 
In vitro data indicate that ataluren is an inhibitor of OAT1, OAT3 and OATP1B3.  Caution 
should be exercised when ataluren is co-administered with drugs that are substrates of OAT1, 
OAT3, or OATP1B3 (e.g., oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, 
bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) because of the risk 
of increased plasma concentration of these drugs. 
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, i.e., observed in one toxicology 
species only.  These findings included kidney findings in mice (nephrosis, predominantly in 
the distal nephron, reversible following cessation of dosing) and adrenal gland cortical 
findings in dogs (lymphohistiocytic infiltrates with focal parenchymal cell degeneration in 
regions responsible for synthesis of glucocorticoids).  Chronic studies were conducted in 
weanling rats and dogs to support dosing in children as young as 2 years of age.  Ataluren 
was not genotoxic and was not teratogenic in rats and rabbits.  In rats and rabbits, fetal 
toxicity was observed only at materno-toxic doses.  Ataluren had no effect on the fertility of 
male and female rats.  In rats, postnatal developmental effects were observed only at 
materno-toxic doses.  Maternal administration of 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/or 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, 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 subjects as young as 2 years of age. 


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The nonclinical evaluation of ataluren presented in this summary support its use for the 
treatment of nonsense mutation aniridia. 
14.2 
Benefits and Risks: Clinical 
The ability of ataluren to enable readthrough of nonsense mutations has been clinically 
demonstrated in other indications of nonsense mutation-mediated disease (Kerem 2008, 
Sermet-Gaudelus 2010, Wilschanski 2011, Finkel 2013).  Ataluren’s effect in treatment of 
nmDMD has been demonstrated (Bushby 2014), and in July 2014 ataluren was approved by 
the EMA for treatment of nmDMD.  In addition, in a Phase 3 study of nmCF subjects, 
ataluren-treated subjects had less lung function decline and fewer pulmonary exacerbations 
than placebo-dosed subjects (Kerem 2014). 
Totaling all ataluren clinical studies, including healthy volunteers as well as subjects with 
several nonsense mutation genetic disorders, >750 subjects have been exposed to ataluren in 
Phase 1 (Hirawat 2007), Phase 2 (Kerem 2008, Sermet-Gaudelus 2010, Wilschanski 2011, 
Finkel 2013) and Phase 3 (Bushby 2014, Kerem 2014) clinical studies.  Ataluren has shown a 
favorable safety profile in clinical studies. 
Approximately 40% of patients with aniridia have a nonsense mutation in one allele of the 
PAX6 gene (Tzoulaki 2005).  Because ataluren-induced readthrough of nonsense mutations 
has been demonstrated in Phase 2 and Phase 3 clinical studies of other nonsense mutation 
genetic diseases, while showing a favorable clinical safety profile, it can be expected that 
ataluren treatment of nonsense mutation aniridia will exhibit acceptable benefit vs risk. 
14.2.1 
Justification for Inclusion of Minors 
In standard toxicology studies, dosing is initiated in young adult rats (6 to 8 weeks old) and 
in 4-to 6-month old dogs.  However, the chronic toxicology studies conducted with ataluren 
initiated dosing in weanling animals (approximately 4- to 5-week-old rats, and dogs 
<3 months of age) to support dosing of pediatric subjects as young as two years of age.  A 
detailed summary of methods and results of these chronic toxicity studies is provided in 
Section 7 of the ataluren investigator’s brochure. 
In the clinic, ataluren has already been administered to subjects as young as three years old.  
A Phase 2 study of ataluren in subjects with methylmelonic acidemia (MMA) enrolled 
11 subjects, including two subjects who were three years old and one subject who was 
4 years old.  All three of these subjects completed the study as planned, receiving ataluren 
5, 5, 10 mg/kg for 28 days in Cycle 1 and ataluren 10, 10, 20 mg/kg for 28 days in Cycle 2; 
there was a washout period of 21 days between the cycles. 
Ataluren was well tolerated by the three subjects <6 years old in the MMA study.  
Treatment-emergent adverse events in these subjects were vomiting, pyrexia, 
nasopharyngitis, cough, flatulence, and rash.  All treatment-emergent adverse events were 
mild or moderate in severity, and none were serious or led to discontinuation of treatment.  
Overall, the ataluren safety profile was similar in <6 years old and ≥6 years old. 


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Twenty-four-hour blood sampling for ataluren PK assessments was performed on Day 28 of 
each cycle; the data from Cycle 2, in which a dose of 10, 10, 20 mg/kg was administered, are 
of particular relevance to the proposed study in nonsense mutation aniridia.  Ataluren plasma 
concentrations in the 3 subjects <6 years old were comparable to ataluren plasma 
concentrations in the 8 subjects ≥6 years old who participated in this study.  Mean area under 
the curve (AUC)0-24h was 279.3 h•µg/mL and 358.4 h•µg/mL for subjects <6 and ≥6 years 
old, respectively, on Day 28 of Cycle 2.  Mean maximum concentration (Cmax) was 
28.2 µg/mL and 29.9 µg/mL for subjects <6 and ≥6 years old, respectively, on Day 28 of 
Cycle 2 (10, 10, 20 mg/kg).  These data suggest similar ataluren PK profiles in subjects 
<6 and ≥6 years old. 
Based on the above considerations, inclusion of young children in this protocol is 
appropriate.  Furthermore, there has been careful consideration of the study design, wherein 
measures have been taken to minimize the number of subject visits and blood draws while 
maximizing the amount and quality of data required to effectively achieve the study 
objectives. 
Study of young children is important given the onset of disease in early childhood, the 
importance of intervention when the disorder is still in its early phases, the limited treatment 
options that are currently available for this condition, and ataluren’s favorable benefit/risk 
profile. 
14.3 
Benefit/Risk Conclusions 
Aniridia is a devastating disease wherein patients have multiple ocular pathologies and 
become progressively visually handicapped.  Current therapeutic approaches to treat aniridia 
are limited in efficacy, such as surgical management of cataracts and glaucoma treatments to 
relieve intraocular pressure.  These treatments do not correct the anatomical defects 
associated with aniridia nor halt the progressive decline in visual acuity.  There is a high 
unmet medical need for an effective treatment for aniridia. 
Evaluation of ataluren as a treatment for nonsense mutation aniridia has sound scientific 
rationale founded on activity data from nonclinical disease models and clinical data from 
subjects with other genetic diseases, including efficacy and safety data from Phase 2b/3, 
placebo-controlled trials in nmDMD and nmCF.  The safety profile of ataluren is supported 
by safety pharmacology and toxicology studies of appropriate type and duration, and by 
Phase 1, Phase 2, and Phase 3 safety data obtained in children and adults; the development 
program has identified potential clinical safety risks and appropriate monitoring strategies are 
included in the clinical studies. 
Given the seriousness of aniridia and the limitations of available therapies, the aggregate 
potential benefits relative to the potential risks support further development of ataluren in this 
disease. 
 
 


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of patient-reported outcome measures in registered clinical trials: Evidence from 
ClinicalTrials.gov (2007-2013). Contemporary clinical trials 2015;43:1-9. 
Wang, X and Gregory-Evans, CY. Nonsense suppression therapies in ocular genetic diseases. 
Cell Mol Life Sci 2015;72(10):1931-1938. 
Welch, EM, Barton, ER, Zhuo, J, Tomizawa, Y, Friesen, WJ, Trifillis, P, et al. PTC124 
targets genetic disorders caused by nonsense mutations. Nature 2007;447(7140):87-91. 
Welch, EM, Wang, W and Peltz, SW. Translation termination: it's not the end of the story. 
COLD SPRING HARBOR MONOGRAPH SERIES 2000;39:467-486. 
Wen, JH, Chen, YY, Song, SJ, Ding, J, Gao, Y, Hu, QK, et al. Paired box 6 (PAX6) 
regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 
1/3 (PC1/3). Diabetologia 2009;52(3):504-513. 
Wilschanski, M, Miller, L, Shoseyov, D, Blau, H, Rivlin, J, Aviram, M, et al. Chronic 
ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. European Respiratory 
Journal 2011;38(1):59-69. 
Wilschanski, M, Yahav, Y, Yaacov, Y, Blau, H, Bentur, L, Rivlin, J, et al. Gentamicin-
induced correction of CFTR function in patients with cystic fibrosis and CFTR stop 
mutations. N Engl J Med 2003;349(15):1433-1441. 
Yasuda, T, Kajimoto, Y, Fujitani, Y, Watada, H, Yamamoto, S, Watarai, T, et al. PAX6 
mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes 
2002;51(1):224-230. 
 


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16 
APPENDICES 
16.1 
Protocol Amendment History 
Changes in Version 6.0 (08 Nov 2018) to Version 7.0 (17 DEC 2019) 
Justification for the amendment: Due to the continuing unavailability of any treatment 
options targeting the underlying cause of nonsense mutation aniridia, a very small disease 
population, and the enrollment challenges that were encountered during the study,  PTC 
Therapeutics amended the protocol, changing the primary endpoint from safety to efficacy in 
order to investigate the clinical utility of intervention with ataluren in the current study. The 
revised primary endpoint is the change from baseline (Visit 2/Day 1) to Week 48 in 
Maximum Reading Speed of OU as measured using the MNREAD Acuity Charts, 
 
 Maximum Reading Speed is a person’s reading speed 
when reading is not limited by print size and is a measure that reflects the dynamic nature of 
reading. Maximum Reading Speed is known to be reduced when foveal vision is degraded, 
such as is seen in patients with aniridia. The primary objective was amended accordingly to 
reflect this change in primary endpoint. Additionally, the characterization of the systemic and 
ocular safety profile of ataluren in subjects with nonsense mutation aniridia was moved from 
being the primary objective to one of the secondary objectives. A corresponding secondary 
safety endpoint was added to reflect this change.  
Summary of Protocol Changes 
Item 
No. 
Protocol 
Section(s) 
Update 
Rationale 
1 
Protocol 
Text modified 
Document date and protocol version number were 
updated where they occurred; visual acuity was 
specified to be best corrected visual acuity (BCVA) 
where applicable; abbreviations and references were 
updated as needed; minor editorial revisions were 
incorporated throughout to provide clarity. 
2 
Synopsis 
Text added 
A protocol synopsis was included in this version (7.0) 
of the protocol. 
3 
Section 1.1 
Introduction and 
Section 2.2.1 
Therapeutic 
Rationale 
Text modified 
The number of times ataluren was renewed by the 
EMA was updated. 
4 
Section 3.1.1 
Primary Objective 
Text modified 
Text was modified to reflect the change in primary 
objective from “to characterize the systemic and 
ocular safety profile of ataluren when administered 
chronically in subjects with nonsense mutation 
aniridia” to “to evaluate the effect of ataluren on 
Maximum Reading Speed as measured using the 
Minnesota Low Vision Reading Test (MNREAD) 
Acuity Charts in subjects with nonsense mutation 
aniridia”. 
5 
Section 3.1.2 
Secondary 
Objectives 
Text added 
Text added to reflect the modification of the 
secondary objectives to include the effect of ataluren 
on the Reading Accessibility Index, Critical Print Size 
and Reading Acuity and the systemic and ocular 
safety profile of ataluren in subjects with nonsense 
mutation aniridia. 


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Summary of Protocol Changes 
Item 
No. 
Protocol 
Section(s) 
Update 
Rationale 
6 
Section 3.1.3 
 
 
Text deleted 
Text deleted to reflect the removal of MNREAD as 
one of the 
. 
7 
Section 3.2.1 
Primary Endpoint 
Text modified 
Text modified  to reflect the change in primary 
endpoint to “change from baseline (Visit 2/Day 1) to 
Week 48 in Maximum Reading Speed of OU as 
measured using the MNREAD Acuity Charts”.  
8 
Section 3.2.2 
Secondary 
Endpoints 
Text 
added/moved 
Text added/moved to reflect the addition of key 
secondary endpoints: “change from baseline (Visit 
2/Day 1) to Week 48 in Reading Accessibility Index of 
OU” and “change from baseline (Visit 2/Day 1) to 
Week 48 in BCVA”. 
Text added to reflect the addition of secondary 
efficacy endpoints related to Reading Accessibility 
Index, Maximum Reading Speed, Critical Print Size 
and Reading Acuity associated with the change in 
primary endpoint. 
Text added to reflect the addition of a secondary 
safety endpoint of assessments related to the 
systemic and ocular safety profile of ataluren in 
subjects with nonsense mutation aniridia. 
9 
Section 3.2.3 
 
 
Text 
added/deleted 
 
 
 
 
 
 
 
 
10 
Section 8.3.15 
MNREAD 
Text added 
Text added to further elaborate on the endpoints 
Maximum Reading Speed and Reading Accessibility 
Index. 
11 
Section 11.7 
Efficacy 
Text modified 
Text modified to reflect change in primary endpoint 
and secondary efficacy endpoints and associated 
analysis shown in Sections 3.2.1 and 3.2.2.  
12 
Sections 11.7 
Efficacy, 11.8 
Safety and 11.9 
 
 
 
Text moved 
Sections were re-arranged to reflect changes to the 
primary endpoint from being a safety endpoint to an 
efficacy endpoint. 
13 
Section 11.13 
Multiplicity 
Text added 
Text added describing multiplicity. 
14 
Section 13.2.2 
Duration of 
Therapy 
Text modified 
Text modified to reflect changes to the primary and 
secondary objectives. 
15 
Section 13.2.3.3 
MNREAD 
Text modified 
Text modified to include more detail about the new 
primary endpoint “change from baseline (Visit 2/Day 
1) to Week 48 in Maximum Reading Speed of OU as 
measured using the MNREAD Acuity Charts”. 
 
 


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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
STAR: A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-
MASKED, PLACEBO CONTROLLED STUDY OF THE SAFETY AND 
EFFICACY OF ATALUREN (PTC124) FOR THE TREATMENT OF 
NONSENSE MUTATION ANIRIDIA 
PTC124-GD-028‑ANI 
05 FEBRUARY 2020 
VERSION 4.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where 
required by applicable law) and should not be used for unauthorized purposes. In the event of an actual or 
suspected breach of this obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #NCT02647359


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


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AUTHOR SIGNATURES 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 


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TABLE OF CONTENTS 
APPROVAL SIGNATURES ..................................................................................................2 
AUTHOR SIGNATURES .......................................................................................................3 
TABLE OF CONTENTS ........................................................................................................4 
LIST OF TABLES ...................................................................................................................5 
LIST OF FIGURES .................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................6 
1 
INTRODUCTION .........................................................................................7 
2 
OBJECTIVES ................................................................................................7 
2.1 
Primary ...............................................................................................7 
2.2 
Secondary ...........................................................................................7 
2.3 
 ........................................................................................7 
2.4 
Study Design .......................................................................................8 
2.5 
Sample Size .........................................................................................9 
3 
STUDY ENDPOINTS ...................................................................................9 
3.1 
Primary Endpoint ..............................................................................9 
3.2 
Secondary Endpoints .........................................................................9 
3.3 
 ....................................................................10 
4 
HYPOTHESES ............................................................................................11 
5 
DEFINITIONS .............................................................................................12 
6 
ANALYSIS POPULATIONS .....................................................................14 
6.1 
Safety Analysis Population .............................................................14 
6.2 
Intent-to-Treat Analysis Population ..............................................14 
6.3 
Efficacy Analysis Populations ........................................................14 
7 
STATISTICAL METHODS OF ANALYSIS ...........................................14 
7.1 
Sample Size .......................................................................................14 
7.2 
General Principles ...........................................................................14 
7.3 
Study Population .............................................................................15 
7.3.1 
Subject Disposition.................................................................15 
7.3.2 
Demographic and Baseline Characteristics .........................15 
7.3.3 
Medical History and Prior Medication ................................16 
7.4 
Extent of Exposure ..........................................................................16 
7.4.1 
Defining Rules ........................................................................16 
7.4.2 
Study Drug Compliance ........................................................16 
7.5 
Safety Analyses ................................................................................17 
7.5.1 
Adverse Events .......................................................................17 
7.5.2 
Concomitant Medications .....................................................17 
7.5.3 
Clinical Laboratory Tests......................................................18 
7.5.4 
Vital Signs ...............................................................................18 
7.5.5 
Physical Examinations and Other Parameters ...................18 
7.6 
...................................18 


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7.7 
Efficacy Analysis ..............................................................................18 
7.8 
Multiplicity Adjustment ..................................................................19 
7.9 
 ....................................................................19 
7.10 
Subgroup Analyses ..........................................................................19 
7.11 
Post Hoc/Exploratory Analyses ......................................................19 
8 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES .................19 
9 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS ................20 
10 
MISSING DATA HANDLING ..................................................................20 
10.1 
Handling Missing Efficacy Data .....................................................20 
10.2 
Handling Partial Dates or Missing Dates ......................................21 
10.2.1 
Missing Date Information for Adverse Events ....................21 
10.2.2 
Missing Date Information for Prior or Concomitant 
Medications .............................................................................21 
11 
REFERENCES ............................................................................................24 
 
LIST OF TABLES 
Table 1. 
Schedule of Events (Stage 1) ..............................................................................25 
Table 2. 
Schedule of Events (Stage 2) ..............................................................................27 
Table 3. 
Schedule of Events (Open-label Sub-study) .....................................................28 
 
LIST OF FIGURES 
Figure 1. STAR Aniridia Study Schematic .........................................................................9 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Definition 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best corrected visual acuity 
β-HCG 
Beta-human chorionic gonadotropin 
CI 
Confidence interval 
CSR 
Clinical Study Report  
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EOS/EOT 
End of study/end of treatment 
 
 
ITT 
Intent to treat 
Lea 
LEA Symbols Visual Acuity Test System 
LOCF 
Last observation carried forward 
MCMC 
Markov Chain Monte Carlo 
MNREAD 
Minnesota Low Vision Reading Test (MNREAD) Acuity Charts 
MRS 
MNREAD Maximum Reading Speed 
OCT 
Optical coherence tomography 
OD 
Right eye 
OS 
Left eye 
OU 
Both eyes 
PAX6 
Paired box 6 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Software from SAS Institute 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) outlines the proposed statistical methods to be 
implemented in the analysis of data collected within the scope of PTC Therapeutics, Inc. 
Protocol PTC124-GD-028-ANI, “STAR: A Phase 2, Multicenter, Randomized, 
Double-Masked, Placebo Controlled Study of the Safety and Efficacy of Ataluren (PTC124) 
for the Treatment of Nonsense Mutation Aniridia,” protocol, Version 7, dated 17 December, 
2019. 
It is not intended that each and every table, listing, or graph will be included in the clinical 
study report (CSR). It is also possible that additional analyses will be conducted after review 
of the data. Any analyses or summaries not specified in the SAP, but performed after review 
of the data, will be identified in the CSR as post hoc. 
2 
OBJECTIVES 
2.1 
Primary  
The primary objective of this study is to evaluate the effect of ataluren on Maximum Reading 
Speed as measured using the Minnesota Low Vision Reading Test (MNREAD) Acuity 
Charts in subjects with nonsense mutation aniridia. 
2.2 
Secondary 
The secondary objectives of this study are to: 
● 
Evaluate the effect of ataluren on the following: 
○ 
Reading Accessibility Index 
○ 
Best-corrected visual acuity (BCVA) 
○ 
Critical Print Size 
○ 
Reading Acuity 
○ 
Severity of corneal keratopathy 
○ 
Iris area 
● 
Characterize the systemic and ocular safety profile of ataluren in subjects with 
nonsense mutation aniridia. 
2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.4 
Study Design 
This is a Phase 2, multicenter, stratified, randomized, double-masked, placebo-controlled 
study with a 4-week screening period, a 144-week treatment period, an optional 96-week 
open label sub-study, and a 4-week post-treatment follow-up period (either study completion 
or early termination). A minimum of 36 subjects with nonsense mutation aniridia who are 
≥2 years of age are planned for enrollment into this study at investigator sites in US and 
Canada. 
During the 4-week screening period, subjects will be assessed for eligibility. 
Eligible subjects will enter the 144-week treatment period consisting of two stages: 
● 
Stage 1 (Weeks 1 to 48) during which subjects will receive either ataluren or 
placebo in a masked fashion; 
● 
Stage 2 (Weeks 49 to 144) during which subjects will receive open-label ataluren. 
Eligible subjects will be randomized in a masked 2:1 fashion to either ataluren or placebo. 
Randomization will be stratified by age: ≤10 years versus >10 years. Masked study drug will 
be dosed three times a day: 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in 
the evening for 48 weeks. Subjects (or parent/legal guardian) will record each dose on a diary 
card provided by PTC Therapeutics. 
After completion of the Stage 1 (Week 48), subjects will be eligible for an additional 
96 weeks of open-label ataluren treatment. Subjects who received ataluren during Stage 1 
will continue to receive ataluren; subjects who had been randomized to placebo will receive 
ataluren during Stage 2 
There will be an optional sub-study at the end of the Stage 2 Open-Label Extension. Subjects 
will be able to consent to receive an additional 96 weeks of ataluren treatment, returning to 
the clinic every 24 weeks. The assessments to be conducted are outlined in the schedule of 
events. Subjects who choose not to participate in the sub-study will be required to complete 
the Post-treatment follow-up visit at the end of the Stage 2 Open-Label Extension. 
The start of the sub-study will require prior approval of a protocol amendment from 
applicable Institutional Review Boards and will continue for 96 week or until commercial 
availability of ataluren for this indication, whichever is first, or until a positive risk-benefit 
assessment in this indication is not demonstrated. 
After the subject’s last dose of ataluren, there will be a 4-week post-treatment follow-up 
period. A primary analyses of the double-masked phase will be conducted after the last 
subject has completed Week 96. 


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Subjects who complete the parent study will be eligible to participate in the sub-study. The 
principal investigator or sub-investigator will discuss the possibility of participation directly 
with study subjects and/or parent/legal guardian in the clinic. 
A schematic of the study design is provided in Figure 1. 
Figure 1. 
STAR Aniridia Study Schematic 
 
2.5 
Sample Size  
The study was planned to enroll a minimum of 36 subjects with nonsense mutation aniridia 
who are ≥2 years of age. This number of subjects has been reduced to 24 and should provide 
adequate information for an initial evaluation the efficacy safety of ataluren in this 
population.  
3 
STUDY ENDPOINTS  
3.1 
Primary Endpoint  
The primary endpoint of this study is the percent change from baseline (Visit 2/Day 1) to 
Week 48 in Maximum Reading Speed of OU as measured using the MNREAD Acuity 
Charts. 
3.2 
Secondary Endpoints  
The key secondary efficacy endpoints of this study are: 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OU 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in BCVA 


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Other secondary efficacy endpoints of this study are as follows: 
● 
Percent change from baseline (Visit 2/Day 1) to Week 48 in Maximum Reading 
Speed of OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Accessibility Index 
of OD and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Critical Print Size of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in Reading Acuity of OU, OD 
and OS 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in severity of corneal 
keratopathy 
● 
Change from baseline (Visit 2/Day 1) to Week 48 in iris area 
● 
Change from baseline (Visit 2/Day 1, Stage 1) to Week 240 (Sub-study End of 
Treatment Visit) in BCVA. Note: This endpoint will be assessed only for the 
cohort of subjects who enroll into the sub-study. 
The secondary safety endpoint of this study is the overall systemic and ocular safety profile 
of ataluren as determined by: 
● 
Incidences of treatment-emergent adverse events (TEAEs) 
● 
Abnormal findings on laboratory assessments 
● 
Vital signs 
● 
Physical examinations 
● 
Ophthalmoscopy 
● 
Slit-lamp examination 
● 
Visual field testing 
3.3 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
HYPOTHESES 
1) Percent change from baseline (Visit 2/Day 1) to Week 48 in Maximum Reading 
Speed (MRS) of OU as measured using the MNREAD Acuity Charts: 
Null Hypothesis: 
 
μA = μP 
Alternate Hypothesis:  
μA ≠ μP 
Where μA = mean percent change in MRS in ataluren arm; μP = mean percent change 
in MRS in placebo arm.  


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5 
DEFINITIONS 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug 
(investigational medicinal product) in humans, whether or not it is considered related to the 
drug. An 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 
study drug in this study. A specific list of occurrences that should be reported as AEs is 
provided in section 9.1.1 of the study protocol. Subjects must be followed for adverse events 
for at least 28 days after the last dose of ataluren administration, or until any drug-related 
adverse events and/or ongoing serious adverse events (SAEs) have resolved or become 
stable, whichever is later. Any event that starts within 35 days (to account for visit window) 
after last dose of ataluren will be summarized. 
Adverse events will be graded for severity using Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4 grading, where 1=Mild, 2=Moderate, 3=Severe, 
4=Life-threatening, and 5=Fatal. 
Relationship to study treatment will be coded using the following categories: Unrelated, 
Unlikely related, Possibly related, and Probably related. In summaries where relatedness is 
dichotomized to related or not, Unrelated and Unlikely related will be classified as not 
related and Possibly related and Probably related will be classified as related. 
Serious Adverse Event: 
A serious adverse event is defined as an adverse event that 
● 
Results in death 
● 
Is life-threatening (patient is at immediate risk of death from the event as it 
occurred) 
● 
Requires in-patient hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
● 
Results in persistent or significant disability/incapacity 
● 
Results in a congenital anomaly/birth defect 
Treatment-Emergent AE: 
A TEAE is any AE that begins or increases in severity after the initial dose of study drug and 
within 5 weeks of the last dose of study drug. 
Age 
Subject’s age is defined as from date of birth to randomization date. The formula used is 
(randomization date – date of birth+1) / 365.25. 
Ataluren Exposure 
The duration of exposure to ataluren treatment is defined as the last dose date minus the first 
dose date + 1 day. 


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Baseline 
For any variable, unless otherwise defined, baseline is the last assessment taken prior to the 
first study drug administration.  
Change from Baseline 
The arithmetic difference between a post-baseline value and the baseline value:  
Change from Baseline = (Post-baseline Value – Baseline Value) 
Percentage Change from Baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
End of Double-masked study period 
End of double-masked study period is at Week 48 (day 337 ± 28 days), unless terminated 
early. 
End of Study 
End of study is at Week 144 (day 1008 ± 7 days), unless terminated early. 
Early termination from study 
Early termination would be assigned to the visit whose visit window included the termination 
date. In the event that an early termination visit does not fall within a nominal visit window, 
then the termination visit will be assigned to the visit closest to that date. If duplicate data 
result from the assignment of a termination visit, then the values measured last will be 
selected for analysis. 
Enrollment date 
Enrollment date will be assigned after confirmation of eligibility has been received from 
PTC Therapeutics, but not after the first day of study drug administration. 
Study drug 
Study drug in this study is ataluren (PTC124) or placebo. 
Randomization date 
Randomization date is the day the subject is assigned a randomization number on study 
Day 1. 
Study Day 1 
Day 1 is defined as the first day that study drug is administered to the subject. 
Study Day 
Day on study = Starting from Day 1 


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6 
ANALYSIS POPULATIONS 
6.1 
Safety Analysis Population 
The safety population will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects will be analyzed as treated. 
6.2 
Intent-to-Treat Analysis Population 
The intent-to-treat (ITT) population will include all randomized subjects who receive at least 
1 dose of study drug. Subjects will be analyzed as randomized. The ITT population will be 
the primary efficacy population. 
6.3 
Efficacy Analysis Populations 
The efficacy analysis population will include subjects for the ITT analysis population who 
have a baseline value and at least 1 post-baseline value. Subjects will be analyzed as treated. 
Analyses based on the efficacy analysis population will be supportive of those performed on 
the ITT population. 
7 
STATISTICAL METHODS OF ANALYSIS 
All statistical analyses will be programmed using Statistical Software from SAS Institute 
(SAS®) software version 9.4 or later. Standard macros will be used in programming when 
possible. Testing and validation plans for all programs will be developed in accordance with 
Promedica International Inc. guidelines and will include independent programming of tables 
and analyses. 
7.1 
Sample Size 
The study is planned to enroll a minimum of 36 subjects with nonsense mutation aniridia 
who are ≥2 years of age. This number of subjects should provide adequate information to 
evaluate the safety of ataluren in this population. For a statistical hypothesis test for any 
efficacy endpoint, the study will have 60% power to detect an effect size (i.e., standardized 
mean difference) of 0.85, or 80% power to detect an effect size of 1.06, at the 0.05 
significance level (2-sided). 
7.2 
General Principles 
By-subject listings will be created for each eCRF module. Summary tables for continuous 
variables will contain the following statistics: N, mean, median, standard deviation, standard 
error, minimum, maximum, and 95% confidence interval (CI) as appropriate. Summary 
tables for categorical variables will include N, percentage, and 95% CIs on the percentage, as 
appropriate. Confidence intervals for proportions, when provided, will be calculated using 
the Clopper-Pearson exact method (Clopper 1934). Graphical techniques will be used when 
such methods are appropriate and informative. For safety summaries, CIs will not be 
presented, unless specified otherwise. Tables will separate data by treatment arm. 
Transformations of the data may be explored if warranted by the distribution of the data. 
Analyses resulting from transformations applied after the data are unmasked will be 
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The primary efficacy analyses are based on percent changes in the MNREAD Maximum 
Reading Speed endpoint at Week 48, the period where the double-masked randomized phase 
of the study will end. Hypotheses are stated to test for differences in this clinical outcome 
relative to baseline between ataluren-treated and placebo-treated subjects at this time. At 
Week 48, subjects will proceed to the open-open label Stage 2 of the study until week 96, 
where subjects originally on placebo will receive ataluren. Subsequent to Week 96, subjects 
will have the option of continuing study drug (ataluren) through Week 144. Descriptive 
statistics will be provided for all visits till Week 144 for all efficacy endpoints by placebo 
and ataluren treatment groups. In addition, all descriptive statistics for combined ataluren 
treatment will also be provided till Week 144. For the latter analysis the baseline for placebo 
group will be Week 48 value. 
Differences in non-visit specific safety data, for example, AE and concomitant medication, 
will be compared directly between ataluren-treated and placebo-treated subjects during the 
first stage of the study, through Week 48. Ataluren experience during the whole study will 
also be displayed. For visit specific data, for example, lab data, similar analysis will be 
performed as for efficacy data except no hypothesis testing will be performed.  
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance. 
All analyses will be performed using SAS® Software (Version 9.4, or later) (SAS Institute 
Inc. 1990). 
7.3 
Study Population 
7.3.1 
Subject Disposition 
The number of subjects who are screened, randomized, receive study drug, and complete 
each study stage will be summarized. The number of subjects included in the safety/ITT, and 
efficacy analysis populations will be included in the table. Attendance at each visit, including 
missed visits, discontinuations, lost to follow-up, and percentage accountability will be 
summarized. Accountability is determined by dividing the number of subjects attending a 
visit by the sum of those who attended the visit, who missed the visit, or who were lost to 
follow-up at the visit). Subjects discontinued or who have not yet reached the visit of interest, 
are not counted in the denominator. The formula would read: 
   % Accountability = 100* (number attending visit /  
(number attending visit + number missing visit + number lost to follow-up) 
A list of subjects who withdraw early will be provided. This listing will include the reason 
and timing of the withdrawal. Similarly, the reason any subject is excluded from an analysis 
set will also be provided. In addition, significant known protocol deviations will be noted for 
individual subjects; a summary table may also be provided for these deviations. 
7.3.2 
Demographic and Baseline Characteristics 
Age, race, ethnicity, sex, height, weight, body mass index, and medical history will be 
summarized by treatment arm for ITT subjects receiving study drug, using descriptive 
statistics.  


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7.3.3 
Medical History and Prior Medication 
Medical history and prior medication information will be summarized. 
7.4 
Extent of Exposure 
7.4.1 
Defining Rules 
The extent of exposure to ataluren treatment is defined as the last dose date minus the first 
dose date + 1 day. The frequency will be presented according to the duration ranges as 
follows: 
The extent of exposure to ataluren treatment is defined as the last dose date minus the first 
dose date + 1 day. The frequency will be presented according to the duration ranges in each 
Stage (i.e., Stage 1 [double-masked dosing] or Stage 2 [open-label dosing]): <24 weeks, 
>24 to <48 weeks, >48 to <72 weeks, >72 to <96 weeks, >96 to <120 weeks, >120 to 
<144 weeks, and ≥144 to <168 weeks, ≥168 to <192 weeks, ≥192 to <216 weeks, and 
≥216 to ≥240 weeks. Descriptive statistics (mean, standard deviation, median, min, max) will 
be presented for Stage 1, Stage 2, Week 144 – end of the study, and the whole study. 
7.4.2 
Study Drug Compliance 
Study drug compliance will be assessed by analysis of unused study drug reported. 
Compliance will be summarized by treatment arm in terms of the percentage of drug actually 
taken, as reported by the subject, relative to the amount that should have been taken during 
the study, per the protocol. 
Based on the mg total from number of color-coded sachets prescribed (125 mg in yellow, 
250 mg in pink, and 1000 mg in blue), the protocol-specified dose will be calculated for each 
subject at each administration. The amount in mg reported taken by the subject will be 
recorded. The sum of the reported mg taken, divided by the mg prescribed, will be the basis 
upon which percentage compliance is calculated. 
The numerator and denominator are based on these calculations 
The amount taken (numerator) is the sum of  
(Number of tablets distributed – number of tablets remained in 125 mg sachets)*125, 
(Number of tablets distributed – number of tablets remained in 250 mg sachets)*250, and 
(Number of tablets distributed – number of tablets remained in 1000 mg sachets)*1000. 
Protocol specified sum to be taken (denominator) is calculated using the rules below.  
The amount supposed to be taken between Visit i and Visit i+1 is  
mi = (weight at Visit i)*40*(number of days between Visit i and Visit i+1) 
The amount supposed to be taken in a period (for example, stage 1) is the sum of mi for the 
visits in the period.  
Compliance will be assessed in Stage 1, Stage 2 and the entire study.  


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7.5 
Safety Analyses 
The safety profile will be based on adverse events, concomitant medications, vital signs, 
physical examinations, and clinical laboratory measurements. All treated subjects will be 
included in the safety analyses. 
Adverse event and SAE summaries will also be presented for the following periods: 
● 
Through Week 48 (double-masked phase)  
● 
Through End of Treatment (entire study, including the sub-study)  
7.5.1 
Adverse Events 
Adverse events will be grouped by system organ class and by preferred term within system 
organ class according to the latest version of the Medical Dictionary for Regulatory 
Activities coding dictionary. The number of subjects reporting at least 1 adverse event will 
be summarized by treatment group. Tables and/or narratives of any on-study death, serious or 
significant adverse events, including early withdrawals because of adverse events, will be 
provided should they occur. 
Summary information (the number and percent of subjects by treatment) will be tabulated 
for: 
● 
Treatment-emergent adverse events, including clinical and laboratory adverse 
events 
● 
Treatment-related adverse events 
● 
Treatment-emergent adverse events by severity 
● 
Treatment-related adverse events by severity 
● 
SAEs 
● 
Adverse events leading to discontinuation 
● 
Ocular adverse events 
Adverse events will be summarized separately through Week 48 (Study Phase 1), from Week 
48 through Week 148, through Week 148, and through end of treatment, including sub-study. 
Adverse events will be assigned to a study phase based on the start date of the adverse event. 
In study Stage 1 and entire study, AEs will be summarized by treatment. In addition, AEs 
while subjects are on ataluren will be presented for the entire study.  
7.5.2 
Concomitant Medications 
The number and percentage of patients receiving concomitant medications or treatments 
prior to and during each study stage and over both study stages will be tabulated and 
presented overall and by treatment group for the Safety analysis population. Concomitant 
medications and treatments will be summarized using descriptive statistics and will be 
presented by type of drug (WHO DRUG classification preferred term and Anatomical 
Therapeutic Chemical Classification [ATC] level 1) by treatment group. 


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7.5.3 
Clinical Laboratory Tests  
Summary of observed values and changes from baseline (last measurement prior to entering 
the study) will be summarized at each visit. In addition, for laboratory adverse events, 
severity will be graded by CTCAE, when such grading is available. The frequency of 
subjects with values below, within, and above the normal reference range will be also be 
summarized in shift tables at each visit. Worst CTCAE grade will be presented for Stage 1, 
Stage 2, Week 144 – end of the study, and over the entire study. A subject having the same 
abnormality more than once within a time interval will be counted only once based on the 
worst severity grade observed. 
7.5.4 
Vital Signs 
Vital signs will be listed for each subject. These will include temperature, respiration, pulse, 
and blood pressure. Summaries over time and changes from baseline will be provided at each 
visit. 
7.5.5 
Physical Examinations and Other Parameters 
Height, weight, physical examination, ophthalmoscopy, slit-lamp examination, and visual 
fields will be summarized by visit using descriptive statistics over the course of the study. 
Medications taken prior to entering the study and started while on study (i.e., concomitant) 
will be summarized to Week 48, from Week 48 to Week 148, and through end of treatment, 
including sub-study. 
7.6 
 
 
7.7 
Efficacy Analysis 
All efficacy analyses will be conducted in both ITT population as the primary analysis. 
Visual acuity, corneal keratopathy, and iris area will also be analyzed using the efficacy 
analysis population as a supportive analysis. 
The primary efficacy analysis will be by analysis of covariance (ANCOVA) where baseline 
Maximum Reading Speed (OU) and age will be included as covariates, with treatment as a 
fixed effect. LS means for the two treatment arms will be provided along with 95% 
confidence intervals. 
To assess treatment effect on the change from baseline in secondary endpoints, general linear 
models/ANCOVA models, with baseline adjustment and treatment as factors will be used. 
For the analysis of MNREAD endpoints, age will be included as a continuous covariate; all 
other secondary endpoints will include age stratum as a factor in the model.  


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To adjust for other potential effects, some other appropriate statistical models, e.g., 
ANCOVA models, and/or mixed effect models, may be explored. The p-value of testing 
treatment difference will be provided. The trend of assessments overtime may be assessed. A 
summary of the efficacy endpoints listed above will also be provided by visit to assess the 
trend. Tests of trend, if performed, would include repeated measures over visits with an 
appropriate covariance structure fitted (first order autoregressive). The effect of linear time 
would be fit along with its product with treatment to test for differences in trend over time 
between the two treatment arms. If missing Week 48 assessments for the primary efficacy 
endpoint exist, sensitivity analyses will be conducted. The reasons of missing will be 
reported. Analysis results for data with and without imputations (using methods defined in 
Section 10.1) will be compared. 
7.8 
Multiplicity Adjustment 
The key secondary endpoints will be tested sequentially in the order of Reading Accessibility 
Index and then BCVA at the two-sided significance level 0.05. For example, if the 
hypothesis for the primary endpoint, Maximum Reading Speed, is rejected at 0.05 level, then 
Reading Accessibility Index will be tested at 0.05 level. Further, if the hypothesis for 
Reading Accessibility Index is rejected at 0.05 level, then BCVA will be tested at 0.05 level. 
If the hypothesis for the primary endpoint is not rejected at 0.05 level, then no hypothesis 
testing will be performed for the key secondary endpoints. 
All other analyses are exploratory and will not be corrected for multiplicity. 
7.9 
  
 
 
 
 
 
7.10 
Subgroup Analyses  
Data may be summarized within subject subgroups of interest based on potentially relevant 
demographic, and clinical factors, such as age, nonsense mutation stop codon type (UGA, 
UAG, UAA), and/or baseline efficacy parameters, baseline VA, baseline iris area, and 
corneal keratopathy. 
7.11 
Post Hoc/Exploratory Analyses 
Correlations between subject characteristics and outcome measures, and correlations among 
outcomes measures may be explored using regression models or other appropriate 
techniques. 
8 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
Modifications to the planned statistical analyses should be minimized. Nonetheless, the data 
obtained from the study may indicate that the planned analyses are inappropriate or that 
additional analyses need to be performed. The study report will document any deviations 
from the planned analyses. 


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9 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
Tables are categorized and numbered in accordance with ICH E3 guidelines. Each table, 
figure and listing are presented by treatment arm. Efficacy tables will be provided both for 
ITT and Efficacy Evaluable populations. Accountability tables will also include an overall 
column. Listings will be sorted by treatment, subject identification, and by visit, if multiple 
visits exist. 
10 
MISSING DATA HANDLING 
10.1 
Handling Missing Efficacy Data 
Missing data for the primary efficacy endpoint will be imputed through Week 48 using last 
observation carried forward (LOCF) as the primary method of imputation for the efficacy 
and ITT analysis populations. 
As a sensitivity analysis to the use of LOCF, multiple imputation (using SAS PROC MI and 
SAS PROC MIANALYZE) will also be used to impute missing endpoint data. Missing data 
at week 48 will be imputed for the primary endpoint for the ITT population only. Missing 
data predictors will be baseline MRS, MNREAD baseline parameters of reading acuity 
index, critical print size, reading acuity, and subject age. Twenty iterations will be generated 
with a prespecified seed number of 20191015 using the Markov Chain Monte Carlo 
(MCMC) method. 
A second sensitivity analysis will be performed using a tipping point approach. The best and 
worst MRS change will be selected over the entire sample. These values will be rounded to 
one decimal places. All ataluren-treated subjects with missing endpoint data will be imputed 
with the worst value and all placebo treated subjects with missing endpoint data will be 
imputed with the best value and a p-value derived. Next, all ataluren-treated missing values 
will be replaced by the next worst value all placebo-treated missing data will be replaced by 
the next best value and a p-value derived. This process will be continued until all ataluren-
treated missing data are replaced with the best value and all placebo-treated missing data are 
replaced by the worst value. The point at which the p-value “tips” from non-significance to 
significance will be noted relative to its order and number of analyses performed. In the event 
that all permutations are statistically significant, then it can be concluded that imputation 
does not result in a false positive. 
Efficacy data will not be imputed for the open-label study period.  
If any needed/permitted surgical treatment is performed during the study, and as a 
consequence, any assessment outcomes are affected significantly due to the surgical 
procedure, these assessment outcomes on and after the surgery will be set as missing and the 
last assessment prior to the surgery will be used for later assessment time points. 


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10.2 
Handling Partial Dates or Missing Dates  
10.2.1 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date is incomplete (i.e., 
partially missing). 
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. 
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. 
10.2.2 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete  
(i.e., 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. 
10.2.2.1 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. 


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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. 
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. 
10.2.2.2 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. 


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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 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. 
● 
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. 
 
 


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11 
REFERENCES 
Clopper, CJ and Pearson, ES. The Use of Confidence or Fiducial Limits in the Case of the 
Binomial. Biometrika 1934;26(4):404-413. 
SAS Institute Inc. (1990). SAS Language: version 8 first edition, SAS Institute, Inc., Cary, 
NC, USA. 


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Appendix A 
Schedule of Events 
The types and timing of data to be recorded are summarized in Table 1 (Stage 1, double-masked period), Table 2 (Stage 2, open-label 
period), and Table 3 (open-label sub-study). 
Table 1. 
Schedule of Events (Stage 1) 
Protocol Activities 
Screening 
Double-Masked Treatment 
Day±Window 
Week 
-28 
-4 
1a 
1 
169±28 
24 
337±28 
48/ 
End of Stage 1b 
Visit 
1 
2 
3 
4 
Informed consent 
X 
 
 
 
Medical and ophthalmic historyc 
X 
 
 
 
Serum viral screen 
X 
 
 
 
Physical exam 
X 
X 
 
X 
Height and weight 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
Hematology, biochemistry, urinalysis 
X 
 
X 
X 
Serum β-HCGd 
X 
X 
X 
X 
Study drug and diary dispensing 
 
X 
X 
X 
Study drug administration 
 
X 
X 
X 
Study drug compliance and return 
 
 
X 
X 
Collect diary  
 
 
X 
X 
Adverse events 
 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
MNREAD 
 
X 
 
X 
 
 
X 
X 
X 
Slit-lamp examinatione  
 
X 
X 
X 
Slit-lamp photography 
 
X 
X 
X 
OCT  
 
X 
X 
X 
Fundus photography 
 
X 
X 
X 
Humphrey visual fields 
 
X 
 
X 
BCVA (visual acuity and refraction)f 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
X 
 blood 
sample for plasma PKg 
 
If feasible  
(i.e., during surgery for glaucoma, cataracts, etc.) 


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Abbreviations: β-HCG, beta-human chorionic gonadotropin; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; 
; LEA, LEA Symbols Visual Acuity Test System; MNREAD, Minnesota Low Vision Reading (MNREAD) Acuity Charts; OCT, optical 
coherence tomography; PK, pharmacokinetic(s) 
a All study and laboratory assessments on the first day of treatment must be done prior to in-clinic administration of the first dose.  
b Open-label study drug administration will start at the end of Stage 1 (Visit 4/Week 48). 
c Should include capture of available historical values for ocular assessments included in this study, such as visual acuity, 
, etc. 
d Sample taken only for female subjects of childbearing potential. 
e Slit-lamp examination should precede 
 measurement.  
f Visual acuity and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an age-appropriate alternative (e.g., LEA). 


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Table 2. 
Schedule of Events (Stage 2) 
Protocol Activities 
Open-Label Treatment 
End of Study)/ Early 
Terminationa 
Follow-Upb 
Day±Window 
Week 
505±28 
72 
673±28 
96 
841±28 
120 
1009±28 
144 
28 Days Post 
EOS/ET±7 
148 
Visit 
5 
6 
7 
8 
9 
Physical exam 
 
X 
 
X 
X 
Height and weight 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
X 
Hematology, biochemistry, urinalysis 
X 
X 
X 
X 
X 
β-HCGc 
X 
X 
X 
X 
 
Study drug and diary dispensing 
X 
X 
X 
 
 
Study drug administration 
X 
X 
X 
 
 
Study drug compliance and return 
X 
X 
X 
X 
 
Collect diary  
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
MNREAD 
 
X 
 
X 
 
Slit-lamp examination d 
X 
X 
X 
X 
 
Slit-lamp photography 
X 
X 
X 
X 
 
OCT 
X 
X 
X 
X 
 
Fundus photography 
X 
X 
X 
X 
 
Humphrey visual field 
 
X 
 
X 
 
BCVA (visual acuity and refraction)e 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
blood sample for plasma PKf 
If feasible (e.g., during surgery for glaucoma, cataracts, etc.) 
Abbreviations: β-HCG, beta-human chorionic gonadotropin; BCVA, best corrected visual acuity; EOS/EOT, end of study/end of treatment; ETDRS, Early 
Treatment Diabetic Retinopathy Study; 
; LEA, LEA Symbols Visual Acuity Test System; MNREAD, Minnesota Low Vision Reading 
(MNREAD) Acuity Charts; OCT, optical coherence tomography; PK, pharmacokinetic(s) 
a Refer to Table 3 for the schedule of events for subjects participating in the sub-study for Visits 8-13. 
b This visit is only required for subjects not participating in the sub-study. 
c Sample taken only for female subjects of childbearing potential. 
d Slit-lamp examination should precede 
 measurement. 
e Visual acuity and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an age-appropriate alternative (e.g., LEA). 
f 
 


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Table 3. 
Schedule of Events (Open-label Sub-study) 
Protocol Activities 
Open-Label Treatment 
End of Study)/ 
Early Termination 
Follow-Up 
Week 
144 ±28 days 
168±28 days 
192±28 days 
216±28 days 
240 ±28 days 
28 Days (4 weeks) 
Post EOS/ET (Week 
244±7days) 
Visit 
8 
9 
10 
11 
12 
13 
Informed consent 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
X 
Height and weight 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Ophthalmoscopy 
X 
X 
X 
X 
X 
X 
Hematology, biochemistry, urinalysis 
X 
X 
X 
X 
X 
X 
β-HCGa 
X 
X 
X 
X 
X 
 
Study drug and diary dispensing 
X 
X 
X 
X 
 
 
Study drug administration 
X 
X 
X 
X 
 
 
Study drug compliance and return 
X 
X 
X 
X 
X 
 
Collect diary  
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
MNREAD 
X 
X 
X 
X 
X 
 
Slit-lamp examination b 
X 
 
 
 
 
 
Slit-lamp photography 
X 
 
 
 
 
 
OCT 
X 
 
 
 
 
 
Fundus photography 
X 
 
 
 
 
 
Humphrey visual field 
X 
 
 
 
X 
 
BCVA (visual acuity and Refraction)c 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
  
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Schedule next visit 
X 
X 
X 
X 
X 
 
Abbreviations: β-HCG, beta-human chorionic gonadotropin; BCVA, best corrected visual acuity; EOS/EOT, end of study/end of treatment; ETDRS, Early 
Treatment Diabetic Retinopathy Study; 
; LEA, LEA Symbols Visual Acuity Test System; MNREAD; Minnesota Low Vision Reading 
(MNREAD) Acuity Charts; OCT, optical coherence tomography 
a Sample taken only for female subjects of childbearing potential. 
b Slit-lamp examination should precede 
 measurement. 
c Visual acuity and refraction will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) or an age-appropriate alternative (e.g., LEA).