Conditions: Epilepsy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a phase 2, crossover study of Ataluren for the treatment of nonsense mutation Dravet syndrome or cyclin-dependent kinase-like 5 (CDKL5) deficiency, resulting in drug-resistant epilepsy. Patients will receive 12 weeks of ataluren or placebo during each treatment period. Treatment Period 1 will be followed by a 4-week Washout Period. Based on ataluren PK and pharmacodynamic data, the 4-week washout period is deemed an appropriate length of time to eliminate any ataluren drug effects. Following the Washout Period, patients will crossover to receive the opposite treatment during Treatment Period 2 as follows: Patients receiving ataluren during Treatment Period 1 will receive placebo during Treatment Period 2. Patients receiving placebo during Treatment Period 1 will receive ataluren during Treatment Period 2.

Detailed description:
Investigators will try to characterize the safety profile of ataluren in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation and evaluate changes in convulsive and/or drop seizure frequency from Baseline following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation. Investigators will measure changes in minor seizure types (absence, myoclonic, complex partial/focal dyscognitive) following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation and changes from Baseline in cognitive, motor, and behavioral function as well as QOL following ataluren treatment in patients with CDKL5 or Dravet syndrome resulting from a nonsense mutation.

Arms:
arm 1: Cross Over Design: Treatment Period 1 with Ataluren (Week 0/Day 1 to Week 12), Washout Period (Week 12 to Week 16), crossover to Placebo Treatment Period 2 (Week 16 to Week 28), and Follow-up (Week 28 to Week 32). arm 2: Treatment Period 1 with Placebo (Week 0/Day 1 to Week 12), Washout Period (Week 12 to Week 16), crossover to Treatment Period 2 with Ataluren(Week 16 to Week 28).

Interventions: intervention 1: ataluren intervention 2: Placebo
Intervention descriptions: intervention 1: Powder formulation intervention 2: Powder formulation

Protocol document:
Prot_SAP_000.pdf: 
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A Phase 2 Randomized, Double-Masked Placebo-Controlled Crossover Safety and Tolerability 
Study of Ataluren for Drug-Resistant Epilepsy in Patients with Nonsense Mutation CDKL5 or 
Dravet Syndrome 
 
 
 
Regulatory Sponsor: 
New York University Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
Principal Investigator: 
Orrin Devinsky, MD 
New York University Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 US 
 
Funding Collaborator: 
PTC Therapeutics, Inc. 
100 Corporate Court 
South Plainfield, NJ 07080 US 
Study Product: 
Ataluren 
Protocol Number: 
s15-00426 
 
Other Study ID Number: 
PTC124-GD-035-EP 
IND Number: 
127715 
NCT Number:                           NCT02758626 
 
 
Initial version: 
18 December 2015 
Follow up version: 
N/A, Version 2.0 
Amended: 
03 October 2016, Version 3.0 
27 April 2017, Version 4.0 
25 January 2018, Version 5.0 
27 February 2018, Version 6.0 
21 June 2018, Version 7.0 
13 November 2018, Version 8.0 
01 Aug 2019, Version 9.0 
22 Oct 2019, Version 10.0


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................... 2 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF FIGURES ........................................................................................................................ 6 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE ...................................... 8 
LIST OF ABBREVIATIONS ........................................................................................................ 9 
CLINICAL PROTOCOL SYNOPSIS ........................................................................................ 11 
1 
INTRODUCTION ............................................................................................................ 13 
1.1 Background .................................................................................................................... 13 
1.1.1 CDKL5 ..................................................................................................................... 13 
1.1.2 Dravet Syndrome ...................................................................................................... 14 
1.2 Study Drug History ....................................................................................................... 14 
1.2.1 Ataluren .................................................................................................................... 15 
1.2.2 Placebo ..................................................................................................................... 16 
1.3 Preclinical Data ............................................................................................................. 16 
1.4 Clinical Data to Date ..................................................................................................... 18 
1.5 Study Design .................................................................................................................. 19 
1.5.1 Drug Administration Plan ........................................................................................ 20 
1.5.2 Research Risks & Benefits ....................................................................................... 20 
1.5.2.1 Risk of Study Drug .............................................................................................. 20 
1.5.2.2 
Potential Benefits ................................................................................................. 21 
1.5.3 Justification for Inclusion of Minors ........................................................................ 22 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 23 
2.1 Objectives ....................................................................................................................... 23 
2.2 Endpoints ....................................................................................................................... 23 
2.2.1 Primary Endpoint ..................................................................................................... 23 
2.2.2 Secondary Endpoints ................................................................................................ 23 
2.2.3 Exploratory Endpoints .............................................................................................. 24 
3 
SUBJECT SELECTION AND WITHDRAWAL.......................................................... 25 
3.1 Inclusion Criteria .......................................................................................................... 25 


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3.2 Exclusion Criteria ......................................................................................................... 25 
3.3 Subject Recruitment and Screening .............................................................................. 26 
3.4 Randomization ................................................................................................................. 26 
3.5 Masking ............................................................................................................................ 27 
3.6 Early Withdrawal of Subjects ........................................................................................ 27 
3.6.1 When and How to Withdraw Subjects ....................................................................... 27 
3.6.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................... 28 
4 
STUDY DRUG .................................................................................................................. 29 
4.1 Description ....................................................................................................................... 29 
4.1.1 Ataluren ...................................................................................................................... 29 
4.1.2 Placebo ....................................................................................................................... 29 
4.1.3 Drug Kits .................................................................................................................... 29 
4.2 Treatment Regimen ........................................................................................................ 29 
4.2.1 Instructions for Delays in Dosing............................................................................... 30 
4.2.2 Study Drug Preparation and Storage ........................................................................ 30 
4.3 Method for Assigning Subjects to Treatment Groups ................................................ 30 
4.4 Subject Compliance Monitoring .................................................................................... 31 
4.5 Prior and Concomitant Therapy ................................................................................... 31 
4.6 Receiving, Storage, Dispensing, and Return................................................................. 31 
4.6.1 Receipt of Drug Supplies ........................................................................................... 31 
4.6.2 Storage ........................................................................................................................ 32 
4.6.3 Dispensing of Study Drug .......................................................................................... 32 
4.6.4 
Study Drug Accountability, Return and Destruction of Study Drug ......................... 32 
4.6.5 Overdose Precautions ................................................................................................. 33 
4.6.6 Inadvertent Exposure and Spill Precautions............................................................... 33 
5 
SAFETY MONITORING AND STUDY DRUG TREATMENT MODIFICATION 
...........................................................................................................................................34 
5.1 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and Potential 
Drug Interruption/Modification ............................................................................................... 34 
5.1.1 
Evaluation of Adverse Events or Laboratory Abnormalities ..................................... 34 
5.1.2 
Instructions for Resuming Study Drug Administration after an Interruption  for 
Safety Concerns ....................................................................................................................... 35 


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5.2 
Instructions for Discontinuation of Study Drug Administration for Safety Concerns 
35 
6 
SCHEDULE OF EVENTS AND STUDY PARAMETERS ......................................... 36 
6.1 
Schedule of Events .......................................................................................................... 36 
6.1.1 Screening, Treatment, and Follow-up Periods ........................................................... 40 
6.1.1.1 
Visit 1 (Screening, 4 Weeks Prior to Baseline Visit 2) ....................................... 40 
6.1.1.2 
Visit 2 (Baseline, Week 0)................................................................................... 41 
6.1.1.3 
Visit 3 (Week 6) .................................................................................................. 41 
6.1.1.4 Visit 4 (Week 12 [Beginning of 4-Week Washout]) ........................................... 42 
6.1.1.5 
Treatment Period 2 - Visit 5 (Week 16 [Crossover Visit]) ................................. 42 
6.1.1.6 
Visit 6 (Week 22) ................................................................................................ 43 
6.1.1.7 
Visit 7 (Week 28 – EOS Visit [or Early Termination Visit])/Start of Open-Label 
Extension Study .................................................................................................................... 44 
6.1.2 Open-Label Extension Study ..................................................................................... 45 
6.1.2.1 
Visit 8 (Week 52) ................................................................................................ 45 
6.1.2.2 
Visit 9 (Week 76) ................................................................................................ 45 
6.1.2.3 
Visit 10 (Week 100) ............................................................................................ 46 
6.1.2.4 
Visit 11 (Week 124) ............................................................................................ 46 
6.1.2.5 
Visit 12 (Week 128 [Follow-up Visit]) ............................................................... 47 
6.2 
PK for AED and Ataluren .............................................................................................. 47 
6.3 
Blood Collection Summary ............................................................................................ 47 
6.4 
Blood for Analysis of Pharmacokinetics ....................................................................... 48 
6.4.1 Ataluren Plasma Concentration .................................................................................. 48 
7 
STATISTICS ..................................................................................................................... 49 
7.1 
Sample Size Determination ............................................................................................ 49 
7.2 
Randomization................................................................................................................. 49 
7.3 Populations for Analyses .............................................................................................. 49 
7.4 
Efficacy Endpoint Definitions ........................................................................................ 49 
7.4.1 Seizures ...................................................................................................................... 49 
7.4.2 
Clinical and Adaptive Measures of Personality and Behavior................................... 50 
7.4.2.1 
Adaptive Level of Behavioral Function .............................................................. 50 
7.4.2.2 
Quality of Life ..................................................................................................... 50 


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7.5 Statistical Analyses .......................................................................................................... 50 
7.5.1 Study Conduct .......................................................................................................... 50 
7.5.2 Study Population ........................................................................................................ 50 
7.5.2.1 Subject Disposition .............................................................................................. 50 
7.5.2.2 Demographics and Baseline Characteristics........................................................ 50 
7.5.2.3 Medical History and Prior Medication ................................................................ 51 
7.5.3 Extent of Exposure ..................................................................................................... 51 
7.5.3.1 Discontinuation of Study Therapy ....................................................................... 51 
7.5.3.2 Treatment Compliance......................................................................................... 51 
7.6 Safety Analyses ................................................................................................................ 51 
7.6.1 Adverse Events ........................................................................................................... 51 
7.6.2 Laboratory Parameters ............................................................................................... 52 
7.6.3 Other Parameters ........................................................................................................ 52 
7.7 Efficacy Analyses ............................................................................................................. 52 
8 
SAFETY AND ADVERSE EVENTS ............................................................................. 54 
8.1 Definitions ........................................................................................................................ 54 
8.1.1 
Unanticipated Problems Involving Risk to Subjects or Others .................................. 54 
8.1.2 Adverse Event ............................................................................................................ 54 
8.1.3 Serious Adverse Event ............................................................................................... 55 
8.2 Adverse Event Reporting Period ................................................................................... 56 
8.2.1 Preexisting Condition ................................................................................................. 56 
8.2.1.1 General Physical Examination Findings.............................................................. 56 
8.2.2 Post-study Adverse Event .......................................................................................... 56 
8.2.3 Abnormal Laboratory Values ..................................................................................... 56 
8.3 
Hospitalization, Prolonged Hospitalization or Surgery .............................................. 56 
8.4 Recording of Adverse Events ......................................................................................... 57 
8.5 
Reporting of Serious Adverse Events and Unanticipated Problems .......................... 57 
8.5.1 Narrative Reports of Safety Events ............................................................................ 58 
8.5.2 
Investigator Reporting: Notifying the Supplier of the Study Drug  (PTC 
Therapeutics) ........................................................................................................................... 58 
8.5.2.1 Initial Report: Within 24 Hours ........................................................................... 58 
8.5.2.2 Follow-up Report: Within 48 Hours .................................................................... 58 


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8.5.2.3 
Other Reportable Events ...................................................................................... 58 
8.5.3 Investigator Reporting: Notifying the IRB ................................................................. 59 
8.5.4 Report Promptly, but No Later Than 5 Working Days: ............................................. 59 
8.5.4.1 
Other Reportable Events: ..................................................................................... 59 
8.5.4.2 
Reporting Process ................................................................................................ 60 
8.5.5 Sponsor Reporting: Notifying the FDA ..................................................................... 60 
8.6 Unmasking Procedures ................................................................................................... 61 
8.7 Medical Monitoring ........................................................................................................ 61 
9 
DATA HANDLING AND RECORD KEEPING .......................................................... 62 
9.1 Confidentiality ................................................................................................................. 62 
9.2 Confidentiality and HIPAA ............................................................................................ 62 
9.3 Source Documents ........................................................................................................... 62 
9.4 Case Report Forms ......................................................................................................... 63 
9.5 Records Retention ........................................................................................................... 63 
10 
Data Safety Monitoring Plan ........................................................................................... 64 
10.1 Study Monitoring Plan ................................................................................................. 64 
10.2 Auditing and Inspecting ............................................................................................... 64 
11 
ETHICAL CONSIDERATIONS .................................................................................... 65 
12 
STUDY FINANCES ......................................................................................................... 66 
12.1 Funding Source ............................................................................................................. 66 
12.2 Costs to Subjects ............................................................................................................ 66 
12.3 Payments to Subjects .................................................................................................... 66 
12.4 Conflict of Interest ........................................................................................................ 67 
13 
PUBLICATION PLAN .................................................................................................... 68 
14 
REFERENCES ................................................................................................................. 69 
15 
APPENDICES ................................................................................................................... 72 
Appendix A .................................................................................................................................... 72 
LIST OF TABLES 
Table 1 
Schedule of Events ......................................................................................................... 37 


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LIST OF FIGURES 
Figure 1 
Ataluren Chemical Structure ...................................................................................... 15 
Figure 2 
Study Design .............................................................................................................. 20 


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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: Orrin Devinsky, MD 
Institution: New York University Comprehensive Epilepsy Center 
Address: 223 East 34th Street 
City: New York 
State/Province and Zip Code: NY 10016 
Country: US 
Phone: 646-558-0803 
Date 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AED 
antiepileptic drug 
BCRP 
breast cancer resistance protein 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDKL5 
cyclin-dependent kinase-like 5 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CMP 
comprehensive metabolic panel 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ILAE 
International League Against Epilepsy 
IRB 
institutional review board 
ITT 
Intent-to-Treat 
LFT 
liver function test 
MECP2 
methyl CpG binding protein-2 
MMA 
methylmelonic acidemia 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NORD 
National Organization for Rare Disorders 
nm 
nonsense mutation 
nmCF 
nonsense mutation cystic fibrosis 
nmDMD 
nonsense mutation Duchenne muscular dystrophy 
NYU CEC 
New York University Comprehensive Epilepsy Center 
NYULMC 
New York University Langone Medical Center 
OAT 
organic anion transporter 
PHI 
protected health information 


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Abbreviation 
Definition 
PK 
pharmacokinetic(s) 
PTC124 
ataluren 
QOL 
quality of life 
QOLCE 
Quality of Life in Childhood Epilepsy 
SAE 
serious adverse event 
SCN1A 
sodium channel, voltage-gated type 1 alpha 
SUDEP 
sudden unexpected death in epilepsy 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
TID 
three (3) times per day 
UGT 
uridine 5’-diphospho-glucuronosyltransferase 
US 
United States 
VABS-II 
Vineland Adaptive Behavior Scales, Second Edition 
VNS 
vagus nerve stimulator 


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CLINICAL PROTOCOL SYNOPSIS 
 
Title: 
A Phase 2 Randomized, Double-Masked Placebo-Controlled Crossover 
Safety and Tolerability Study of Ataluren for Drug-Resistant Epilepsy 
in Patients with Nonsense Mutation CDKL5 or Dravet Syndrome 
Short Title: 
Ataluren for nonsense mutation CDKL5 or Dravet syndrome 
Protocol Number: 
s15-00426 
Other Study ID 
Number: 
PTC124-GD-035-EP 
Phase: 
Phase 2 
Methodology: 
Interventional study 
Study Duration: 
32 weeks with extension available 
Study Center(s): 
Single-center at New York University Comprehensive Epilepsy Center 
Objectives: 
The primary objective of this study is to: 
● 
Evaluate changes in convulsive and/or drop seizure frequency 
from Baseline following ataluren treatment in subjects with 
CDKL5 or Dravet syndrome resulting from a nonsense 
mutation 
The secondary objectives of this study are to: 
● 
To determine changes in minor seizure types following ataluren 
treatment in subjects with CDKL5 or Dravet syndrome 
resulting from a nonsense mutation. (Seizure types as defined 
by the International League Against Epilepsy criteria.) 
● 
Characterize the safety profile of ataluren in subjects with 
CDKL5 or Dravet syndrome resulting from a nonsense 
mutation 
The exploratory objectives of this study are to: 
● 
Evaluate changes from Baseline in cognitive, motor, and 
behavioral function as well as quality of life following ataluren 
treatment in subjects with CDKL5 or Dravet syndrome 
resulting from a nonsense mutation. 
Number of 
Subjects: 
18 evaluable (10 nonsense mutation CDKL5, 8 nonsense mutation 
Dravet syndrome) 


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Diagnosis and Main 
Inclusion Criteria: 
● 
Age ≥ 2 years old and ≤ 12 years old, male or female, at Week 
0 (at time informed consent/assent is signed) 
● 
Documentation of a diagnosis of nonsense mutation in 1 allele 
for Dravet syndrome or CDKL5 deficiency as evidenced by 
medical records, genetic testing, and the following clinical 
feature: 
o Failure to control seizures despite appropriate trial of 2 
or more antiepileptic drug (AEDs) at therapeutic doses 
● 
Current regimen of 1 to 3 baseline AEDs at stable doses for a 
minimum of 4 weeks prior to enrollment (i.e., Screening 
Visit). (Vagus nerve stimulator, ketogenic diet, and modified 
Atkins diet do not count towards this limit but must be 
unchanged for 3 months prior to enrollment [Screening].) 
● 
Minimum of 6 convulsive or drop seizures with duration 
> 3 seconds over the 4 weeks of diary screening prior to 
randomization and ≥ 6 convulsive or drop seizures with 
duration > 3 seconds during the 4 weeks from Screening to 
Baseline. 
Study Product, 
Dose, Route, 
Regimen: 
Ataluren (powder for oral suspension) 
Dose: 3 times per day (TID; 10 mg/kg, 10 mg/kg, and 20 mg/kg 
morning, midday, and evening, respectively) 
Titration: None 
Maximum dose: TID (10 mg/kg, 10 mg/kg, 20 mg/kg morning, 
midday, and evening respectively) 
Duration of 
Administration: 
Each subject will receive a total of 12 weeks of active drug (ataluren) 
and 12 weeks of placebo, in a masked fashion 
Reference 
Therapy: 
None 


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1 INTRODUCTION 
This document is a clinical research protocol for a human research study. This study will be 
conducted in accordance with the protocol, United States (US) government research regulations, 
applicable international standards of Good Clinical Practice (GCP), and institutional research 
policies and procedures. 
 
1.1 
Background 
Drug-resistant epilepsy is a serious condition that negatively impacts patients’ quality of life 
(QOL). Those with drug-resistant epilepsy are at a higher risk for sudden unexpected death in 
epilepsy (SUDEP). The risk factors associated with SUDEP, including frequent generalized 
tonic-clonic seizures, antiepileptic drug (AED) polytherapy, and common nocturnal seizures, are 
also factors present in those with drug-resistant epilepsy (Pack 2012). The risk of SUDEP in 
those with drug-resistant epilepsy can exceed 5% per decade (Devinsky 2011). Most patients 
with drug-resistant epilepsy, despite trials of multiple combinations of AEDs, have no US Food 
and Drug Administration (FDA)-approved treatment options left. CDKL5 and Dravet syndrome 
are rare epilepsies commonly associated with drug-resistant epilepsy. 
 
1.1.1 CDKL5 
Cyclin-dependent kinase-like 5 (CDKL5) is a gene that produces the CDKL5 protein, which is 
primarily expressed in the brain, thymus, and testes. The gene is composed of 24 exons; exons 2– 
11 code for the catalytic domain whereas exons 12–18 code for the carboxy-terminus. In mice, 
the gene expression profile suggests that the CDKL5 protein is involved in neuronal maturation 
(Rusconi 2008). CDKL5 phosphorylates the protein product of the methyl CpG binding protein-  
2 (MECP2) gene in the nucleus MECP2 regulates genes associated with synapse function and 
maintenance. Loss of CDKL5 function drives phenotype and likely accounts for the similarity 
between Rett syndrome and CDKL5 (Mari 2005). CDKL5 also phosphorylates DNA 
methyltransferase 1 and amphiphysin, and interacts with Rac1 to influence actin remodeling and 
neuronal morphogenesis. 
CDKL5 is an X-linked genetic epileptic encephalopathy most often present in females. Males, 
however, are more severely affected than females (Melani 2011). The incidence of CDKL5 is 
~1 in 45,000 live births. Patients with CDKL5 exhibit early signs of poor developmental skills 
(eg, poor sucking, poor eye contact) in the first several months of life. Later, impairment of hand 
motor skills, lack of speech acquisition, and severe and global developmental delays become 
apparent (Fehr 2013, Melani 2011). Eye contact and social interactions are often reduced. Many 
patients are never able to walk independently. However, CDKL5 is not associated with cortical 
atrophy or degeneration. 
CDKL5 causes an epileptic encephalopathy in which epileptiform abnormalities contribute to 
progressive functional impairment. Epilepsy often presents with infantile spasms within the first 
four months of age (Mei 2010). The average age of seizure onset is 6 weeks, with more than 
90% of patients experiencing seizures in the first 3 months of life. Later, tonic–clonic seizures, 
consisting of a vibratory tonic phase followed by a clonic phase, occur and often last 2 to 
4 minutes (Melani 2011). After age 3 years, seizures remit in many children while others 
continue to have drug-resistant epilepsy, with tonic spasms and myoclonic seizures (Mei 2010). 


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The electroencephalogram findings often include slowing of the background with interictal 
generalized, focal, or multifocal discharges. A burst-suppression pattern may be seen in younger 
children (Melani 2011). 
 
1.1.2 Dravet Syndrome 
Sodium channel, voltage-gated type 1 alpha (SCN1A or Nav1.1) is the sodium channel α1 
subunit gene and is expressed almost exclusively in the brain. Mutations in SCN1A can cause a 
variety of epilepsies that range from benign febrile seizures to severe epileptic encephalopathy 
and Dravet syndrome (Severe Myoclonic Epilepsy of Infancy; Mulley 2005, Catterall 2010). 
The major mechanism underlying epilepsy appears to be impairment of gamma-aminobutyric 
acid interneuron inhibitory function (Catterall 2005, Yu 2006). 
Dravet syndrome was initially described in 1978 as Severe Myoclonic Epilepsy of Infancy by 
Charlotte Dravet (Dravet 2011). The incidence of Dravet syndrome is ~1 in 15,700 live births, 
comprising approximately 6% of epilepsies starting before the age of 3 years (Hurst 1990, 
Yakoub 1992, Wu 2015). It causes febrile and afebrile, generalized and unilateral, clonic or 
tonic-clonic seizures; it can also cause absence, absence-myoclonic, and complex partial 
seizures. Seizures typically begin in the first year of life in an otherwise normal infant. Initial 
seizures are often febrile status epilepticus (Dravet 2005). Later, myoclonic, atypical absence, 
and partial seizures often develop. Seizures are usually drug-resistant but the severity of the 
epilepsy tends to diminish around puberty. Developmental delays in the second year of life and 
intellectual disability are present in more than 95% of patients (Chieffo 2011). Autism spectrum 
disorder is diagnosed in approximately 25% of patients (Genton 2011). Most patients develop 
cerebellar dysfunction in later childhood, manifesting as an ataxic gait disorder, dysarthria, and 
intention tremor (Genton 2011). The mortality rate is high; approximately 15% of patients die 
by adolescence and 20% die by early adulthood (Genton 2011). SUDEP and status epilepticus 
are the most common causes of death. 
 
1.2 
Study Drug History 
PTC Therapeutics 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. Nonsense mutations are single-point alterations in the DNA that, when transcribed, 
result in conversion of a messenger ribonucleic acid (mRNA) triplet (eg, CAG) that codes for an 
amino acid to a triplet (eg, UAG) that is interpreted as a stop codon. The presence of the 
premature stop codon within the mRNA leads to a premature cessation of translation, with a 
protein truncation and consequent disease due to loss of enzymatic function or a structural deficit. 
Nonsense mutations are the basis for approximately 13% to 40% of the individual cases of most 
inherited disease, including CDKL5 and Dravet syndrome amongst many others 
(Frame 2013). 
PTC Therapeutics conducted a high-throughput screening program that 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 the identification of ataluren as an orally bioavailable small 
molecule with potential clinical utility in treating genetic disorders through induction of 


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read-through of nonsense mutations and production of full-length, functional proteins 
(Welch 2007, Du 2008). In the subset of patients whose disease is mediated by a nonsense 
mutation, ataluren may offer an effective therapy by restoring critical protein production for 
CDKL5, Dravet syndrome, and other disabling and life-threatening genetic disorders. 
Phase 1 clinical testing in 62 healthy volunteers (ages 18–30 years) who were administered 
ataluren at relevant doses through 14 days of dosing has documented that oral ataluren can 
achieve target plasma concentrations associated with activity in preclinical testing. Phase 2a 
studies in 77 patients (ages 6–57 years) with nonsense mutation cystic fibrosis (nmCF) receiving 
oral ataluren for periods of 14 days to 12 weeks demonstrated that oral ataluren is generally well- 
tolerated and can generate production of apically localized epithelial cystic fibrosis 
transmembrane conductance regulator protein. Phase 2a studies in 38 patients (ages 5–17 years) 
with nonsense mutation Duchenne muscular dystrophy (nmDMD) administered oral ataluren 
through 28 days confirmed 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 authorized ataluren for the treatment of nmDMD. 
This study will specifically enroll patients with nonsense mutation CDKL5 and Dravet 
syndrome, which are both major forms of drug-resistant epilepsy. 
 
1.2.1 Ataluren 
Ataluren (PTC124) is a novel 1,2,4-oxadiazole linked to 2 ring structures: fluorobenzene and 
benzoic acid. The molecule has no chiral centers. Its chemical name is 3-[5-(2-fluorophenyl)- 
1,2,4 oxadiazol-3-yl]-benzoic acid and its chemical formula is C15H9FN2O3. The compound has 
no structural similarity to other currently used drugs. The drug substance is a white to off-white, 
crystalline powder. The ataluren chemical structure is shown in Figure 1. 
 
Figure 1 
Ataluren Chemical Structure 
F 
N O 
N 
 
 
CO2H 
Ataluren to be used in this study will be in the form of a white to off-white granules for 
suspension packaged in child-resistant aluminum foil packets. Each packet contains 125, 250, or 
1000 mg of drug substance, which is 25% of the total formulation weight. 
Ataluren is practically insoluble in water and has high permeability across layers of Caco-2 
gastrointestinal epithelial cells. Ataluren, as well as its primary metabolite, an acyl glucuronide, 


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are excreted by both hepatic and renal routes. The plasma level peaks 1 to 2 hours after oral 
administration. The half-life (t½) in healthy volunteers ranges from 2 to 6 hours. The side effects 
of ataluren that have been indicated in trials include vomiting, nausea, abdominal pain, headache, 
pyrexia, rhinitis, and sinusitis (PTC Therapeutics; ataluren Investigator’s Brochure [IB]). 
 
1.2.2 Placebo 
The placebo for placebo-controlled clinical studies will be provided as a white to off-white 
powder for suspension.  The placebo powder will be supplied in packets matching the fill 
weights of the active drug product that contain 125, 250, or 1000 mg of the drug substance. The 
placebo is similar to the active product except that ataluren is replaced by the addition of a filler 
(microcrystalline cellulose) and an increased amount of mannitol, which together comprise 
approximately 50% of the powder. 
 
1.3 
Preclinical Data 
In cellular assays and animal models of genetic disease, ataluren has demonstrated the ability to 
specifically and selectively enable read-through of mRNA containing a premature stop codon, 
resulting in production of full-length protein that localizes to the appropriate cellular location and 
is functionally active (Welch 2007, Du 2008). Ataluren is selective for premature stop codons 
and does not promote read-through of normal stop codons, consistent with evidence that normal 
translation termination and premature translation termination appear to have significant 
mechanistic differences (Amrani 2004, Amrani 2006, Ghosh 2010).  Studies demonstrated that 
the ataluren dose-response relationship is bell-shaped (ie, the response initially increases with 
increasing drug concentrations, but at higher concentrations the response is reduced despite 
increasing drug concentrations). 
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 
read-through of premature stop codons due to frameshift mutations (insertions or deletions) or of 
mRNAs harboring multiple sequential premature 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/day at 
morning, midday, and evening, respectively. Ataluren is highly bound (> 97%) to plasma 
proteins in all species, including humans. Ataluren is neither a substrate for nor an inhibitor of P-
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Preclinical studies have suggested that the target ataluren plasma concentrations are similar 
across multiple diseases. Concentration response studies were performed in various systems 
including an in vitro translation system. In cell model systems, an ataluren concentration of 
10 µg/mL is the most active concentration in a range of cell culture models, including: (1) human 
and mouse myotube cultures that were used to measure dystrophin protein production and (2) 
mouse embryonic fibroblasts from the Idua-W392X mouse model of nmHurler syndrome that 
were used to measure changes in glycosaminoglycan levels. These data show that different cell 
types demonstrate similar sensitivity to ataluren. In addition, efficacy pharmacology data 
following oral administration of ataluren in animal models of nmDMD (mdx mouse), nmCF 
(Cftr-/-FABP-hCFTR-G542X mouse), and nmHurler syndrome (Idua-W392X mouse) support the 
in vitro data demonstrating that achieving ataluren concentrations that range from ~1 to 
20 µg/mL were associated with pharmacodynamic activity. Therefore, across different mouse 
models and assessing different tissues (brain, intestine, muscle, lung, liver, spleen), activity was 
seen within the target dose range. Concentrations outside the target range of 1 to 20 µg/mL 
result in reduced activity (bell-shaped concentration response). 
Enzyme inhibition studies with human liver microsomes showed that ataluren has a weak 
potential for direct inhibition of cytochrome P450 (CYP) 2C8 and CYP2C9. As an added 
measure of safety, investigators should pay specific attention to the use of drugs that are known 
substrates of these enzymes, particularly 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 uridine 5’-diphospho-glucuronosyltransferase 
(UGT) 1A9 and breast cancer resistance protein (BCRP). Caution should be exercised when 
ataluren is co-administered with drugs that are inducers of UGT1A9, or inhibitors of BCRP (eg, 
systemic cyclosporine, eltrombopag, gefitinib). Note: Topical cyclosporine therapy is permitted. 
In vitro data indicate that ataluren is an inhibitor of UGT1A9, organic anion transporter 
(OAT)-1, OAT3, and OATP1B3. Caution should be exercised when ataluren is co-administered 
with drugs that are substrates of UGT1A9 (eg, propofol, mycophenolate mofetil), OAT1, OAT3, 
or OATP1B3 (eg, oseltamivir, acyclovir, ciprofloxacin, captopril, furosemide, bumetanide, 
valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) because of the risk of increased 
concentration of these drugs. The investigator is encouraged to consult the PTC Therapeutics 
medical monitor or designee with questions relating to specific drugs and their potential for 
interactions with ataluren. 
Ataluren was evaluated in safety pharmacology studies and was found to have no effects on the 
cardiovascular system, respiratory system, or central nervous system. In the toxicology program, 
the major findings observed were species-specific (ie, observed only in one species). 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 


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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/day, respectively. Ataluren is a small 
molecular weight compound, and therefore, is not expected to produce anti-drug antibodies. 
Ataluren had no effect on the immune system in the toxicology program and in clinical trials; 
therefore, immunotoxicity studies were not performed with ataluren. 
Nonclinical safety pharmacology and toxicology studies indicate that ataluren has an acceptable 
safety profile. The findings seen pose a low human safety risk and the program supports chronic 
administration of ataluren in patients as young as 2 years of age. 
The nonclinical evaluation of ataluren presented in this summary support its use for the treatment 
of nonsense mutation aniridia. 
Refer to the IB for a detailed presentation of efficacy pharmacology, safety pharmacology, 
toxicology, and pharmacokinetic (PK) data from ataluren nonclinical studies. 
 
1.4 
Clinical Data to Date 
Ataluren has shown a favorable safety profile in clinical studies. In total, more than 750 
subjects, including healthy volunteers as well as patients with several nonsense mutation genetic 
disorders, have been exposed to ataluren in Phase 1 (Hirawat 2007), Phase 2 (Kerem 2008, 
Sermet-Gaudelus 2010, Wilschanski 2011, Finkel 2013), and Phase 3 (Bushby2014, 
Kerem 2014) clinical studies. The effect of ataluren in the treatment of nmDMD has been 
demonstrated (Bushby 2014), and in July 2014 ataluren was conditionally approved by the EMA 
for treatment of nmDMD. In addition, in a Phase 3 study of nmCF patients, ataluren-treated 
patients had fewer pulmonary exacerbations than placebo-dosed patients (Kerem 2014). 
In clinical studies of ataluren in other nonsense mutation genetic disorders, particularly nmDMD 
and nmCF, dose-ranging studies were performed to identify the active dose of ataluren. Three 
dose levels were evaluated in patients with nmDMD, a disease that predominantly affects 
skeletal muscle due to mutations in the structural protein dystrophin, and 2 doses were evaluated 
in patients with nmCF, a channelopathy that primarily affects lung tissue due to mutations in a 
chloride channel. In both studies, 10, 10, 20 mg/kg was identified as the active dose of ataluren. 
The first dosing regimen studied in both disease settings was 4, 4, 8 mg/kg, the second dose 
studied was the 10, 10, 20 mg/kg dose, and, in DMD, a third dose was studied, 20, 20, 40 mg/kg. 
In both nmDMD and nmCF patients, the 10, 10, 20 mg/kg dose-maintained plasma levels in the 
predicted efficacious range based on preclinical work in a cell and animal models of disease. 
Confirmatory studies in both nmCF and nmDMD evaluating the 10, 10, 20 mg/kg dose are either 
ongoing (CF Study 021) or recently completed (DMD Study 020). Open-label extension studies 
are ongoing at the 10, 10, 20 mg/kg dose for each of these trials. 


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Approximately 20% of people suffering from CDKL5 and 20% of people suffering from Dravet 
syndrome have a nonsense mutation. Because ataluren-induced read-through 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 Dravet syndrome/CDKL5 will exhibit acceptable benefit versus risk. 
Refer to the IB for a detailed presentation of safety, efficacy, and PK data from these clinical 
studies.) 
 
1.5 
Study Design 
Crossover designs are usually statistically efficient and thus require fewer subjects.  
Additionally, the influence of confounding covariates is reduced because each crossover subject 
serves as his or her own control. A 12-week treatment period with ataluren provides sufficient 
time to assess changes in the subject’s seizure activity and QOL while still allowing appropriate 
monitoring of the subject. Due to the lack of effective alternative treatment, subjects and their 
parents/legal guardians will be motivated to participate in this study. Therefore, we expect a 
low dropout rate. 
The study to be conducted is a Phase 2 interventional study which includes the following: 
Screening (Week -4 to Week 0/Day 1), Treatment Period 1 (Week 0/Day 1 to Week 12), 
Washout Period (Week 12 to Week 16), crossover to Treatment Period 2 (Week 16 to Week 28), 
and a Follow-up visit after 4 weeks. Subjects who complete this study may be eligible to enroll 
in a 96-week open-label extension study (Week 28 to Week 124).  A Follow-up visit is to occur 
4 weeks after the last dose of study drug for all subjects, regardless of whether a subject 
discontinues prematurely or completes the End-of-Study (EOS) visit and/or the open-label 
extension. For subjects who enroll in the extension study, Follow-up is scheduled to occur at 
Week 128. The opportunity to enroll in the extension study will be explained to subjects during 
the initial study informed consent by the site investigator; subjects enrolling in the extension 
study do not need to re-consent. 
The treatment period in this study ends at Week 124 (Visit 11). However, for subjects that want 
to continue on study medication beyond Week 124, PTC Therapeutics will continue to supply 
drug. All subsequent visits will be standard of care and any blood work will be at the discretion 
of the investigator. A follow up visit for subjects who do not want to continue will be scheduled 
4 weeks following the last dose. Access to study drug will continue until commercial   
availability of ataluren for this indication or until a positive risk-benefit assessment in this 
indication is not demonstrated whichever is first. 
The study design is shown in Figure 2. The Schedule of Events is provided in Table1. 
 
Figure 2: Study Design 


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Note: Subjects have the option to continue receiving open-label drug upon completion of the 96-week open-label 
extension. The Follow-up visit is to occur 4 weeks after the last dose of study drug, regardless of whether the subject 
discontinues prematurely or completes the EOS visit and/or the open-label extension. 
Abbreviations: EOS = end of study; F/U = follow-up; IC = informed consent; Wk = week 
 
1.5.1 Drug Administration Plan 
Subjects will receive 12 weeks of ataluren or placebo during each treatment period. Treatment 
Period 1 will be followed by a 4-week Washout Period. Based on ataluren PK and 
pharmacodynamic data, the 4-week washout period is deemed an appropriate length of time to 
eliminate any ataluren drug effects. Following the Washout Period, subjects will crossover to 
receive the opposite treatment during Treatment Period 2 as follows: 
● 
Subjects receiving ataluren during Treatment Period 1 will receive placebo during 
Treatment Period 2. 
● 
Subjects receiving placebo during Treatment Period 1 will receive ataluren during 
Treatment Period 2. 
Study drug will be administered 3 times per day (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. 
Dosing will be based on the subject’s body weight at Baseline. Weight will be assessed at every 
clinic visit. If the subject’s body weight changes by ≥ 10% from Baseline, the actual dose may 
be re-calculated. 
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 Treatment Period, the last dose of study drug 
will be taken on the evening before the clinic visit (ie, the night before the Visit 4/Week 12 [end 
of Treatment Period 1] and the night before Visit 7/Week 28 [end of Treatment Period 2]). 


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1.5.2 Research Risks & Benefits 
 
1.5.2.1 Risk of Study Drug 
Ataluren has been studied in previously completed as well as ongoing clinical trials for other 
diseases.  The side effects of ataluren indicated in trials include vomiting, nausea, abdominal 
pain, headache, pyrexia, rhinitis, and sinusitis. All subjects will be closely monitored for adverse 
events (AEs) throughout the study. 
CYP Inhibition 
Ataluren is a weak inhibitor of CYP2C9 and CYP2C8. Clinical drug interaction studies between 
ataluren and CYP2C8 and CYP2C9 substrates have not been conducted. Ataluren has the 
potential to increase the plasma concentration of drugs that are primarily metabolized by 
CYP2C8 or CYP2C9, which includes drugs with a narrow therapeutic index that are substrates of 
CYP2C8 or CYP2C9. The effects of other concomitant AEDs and other drug levels metabolized 
by these enzyme systems are not known, but it may increase their levels leading to potential 
toxicities. Therefore, AED plasma levels will be measured at Baseline (pre-dose of AED) and 6 
weeks following the first ataluren dose in each Treatment Period (ie, Visit 3/Week 6 and Visit 
6/Week 22), Visit 5/Week 16, , Visit 7/Week 28 [EOS], and Visit 8/Week 52, and Visit 11/Week 
124 [EOT]. Antiepileptic drugs may be adjusted as needed based on signs and symptoms of 
toxicity and/or changes in drug levels. 
 
1.5.2.2 Potential Benefits 
Both the CDKL5 and the Dravet syndromes are conditions that lead to devastating 
neurological, developmental, and physical conditions that significantly impair the QOL of the 
affected patients. Current therapeutic approaches to treat these conditions are limited in 
efficacy. There is a high unmet medical need for an effective treatment for CDKL5 and Dravet 
syndromes. 
Evaluation of ataluren as a treatment for nonsense mutation CDKL5 or Dravet syndromes has 
sound scientific rationale founded on activity data from nonclinical disease models and clinical 
data from patients with other nonsense mutation 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. 
The potential benefits of this study include the possibility of reduced seizure frequency due to 
the addition of ataluren to the patient’s current AED regimen. We hope that knowledge gained 
about the efficacy and tolerability of ataluren during this study will benefit all study participants’ 
QOL by reducing their seizure frequency. 
Given the seriousness of these conditions and the limitations of available therapies, the aggregate 
potential benefits relative to the potential risks support further development of ataluren for these 
diseases. 


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1.5.3 Justification for Inclusion of Minors 
In the clinic, ataluren has already been administered to patients as young as 3 years old.   A 
Phase 2 study of ataluren in patients with methylmelonic acidemia (MMA) enrolled 11 patients, 
including 2 patients who were 3 years old and 1 patient who was 4 years old. All 3 of these 
patients completed the study as planned, receiving ataluren 5, 5, 10 mg/kg for 28 days in Cycle 1 
and ataluren 10, 10, 20 mg/kg for 28 days in Cycle 2; there was a washout period of 21 days 
between the cycles. 
In the MMA study, 24-hour blood sampling for ataluren PK assessments was performed on 
Day 28 of each cycle (ie, the data from Cycle 2, in which a dose of 10, 10, 20 mg/kg was 
administered). Ataluren plasma concentrations in the 3 patients < 6 years old were comparable 
to ataluren plasma concentrations in the 8 patients ≥ 6 years old who participated in this study. 
Mean area under the curve from 0 to 24 hours was 279.3 h•µg/mL and 358.4 h•µg/mL for 
patients < 6 and ≥ 6 years old, respectively, on Day 28 of Cycle 2. Mean maximum plasma 
concentration was 28.2 µg/mL and 29.9 µg/mL for patients < 6 and ≥ 6 years old, respectively, 
on Day 28 of Cycle 2 (10, 10, 20 mg/kg). These data suggest similar ataluren PK profiles in 
patients < 6 and ≥ 6 years old. 
Ataluren was well-tolerated by the 3 patients < 6 years old in the MMA study. 
Treatment-emergent adverse events (TEAEs) in these patients were vomiting, pyrexia, 
nasopharyngitis, cough, flatulence, and rash. All TEAEs were mild or moderate in severity, and 
none were serious or led to discontinuation of treatment. Overall, the ataluren safety profile was 
similar in those < 6 years old and those ≥ 6 years of age. 
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 patient visits and blood draws while maximizing the 
amount and quality of data required to effectively achieve the study objectives. 
Study of children including the age group from > 2 to 6 years 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 the 
favorable benefit/risk profile of ataluren. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of this study is to: 
● 
Evaluate changes in convulsive and/or drop seizure frequency from Baseline following 
ataluren treatment in subjects with CDKL5 or Dravet syndrome resulting from a 
nonsense mutation. 
The secondary objectives of this study are to: 
● 
To determine changes in minor seizure types (absence, myoclonic, complex partial/focal 
dyscognitive) following ataluren treatment in subjects with CDKL5 or Dravet syndrome 
resulting from a nonsense mutation. (Seizure types as defined by the International 
League Against Epilepsy [ILAE] criteria [Appendix A].) 
● 
Characterize the safety profile of ataluren in subjects with 
CDKL5 or Dravet syndrome resulting from a nonsense 
mutation 
The exploratory objectives of this study are to: 
● 
Evaluate changes from Baseline in cognitive, motor, and behavioral function as well as 
QOL following ataluren treatment in subjects with CDKL5 or Dravet syndrome resulting 
from a nonsense mutation. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
The primary study endpoints of this study include: 
● 
Change in convulsive and/or drop seizure frequency from baseline. Convulsive/Motor 
seizures to be counted are tonic-clonic seizures, hemiconvulsive seizures, atonic/drop 
attacks, tonic seizures, and focal motor seizures. 
● 
The effect on myoclonic seizures (ie, persistence or disappearance) will also be 
evaluated. 
● 
Data will be collected at Baseline and at each 6-week post-Baseline visit to identify 
changes in: 
o Number of episodes of status epilepticus, defined as a convulsion lasting 
> 10 minutes 
o Number of uses of rescue medications 
o Number of emergency room visits/hospitalizations 
 
2.2.2 Secondary Endpoints 
The secondary endpoints of this study are as follows: 


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● 
Changes in minor seizure types: 
o Number of myoclonic seizures 
o Number of staring (absence or complex partial) seizures 
o Number of other seizure types (atypical; absence, pure sensory seizure, etc) 
2.2.3 Exploratory Endpoints 
Exploratory endpoints will include the severity of epilepsy, cognitive and motor scales, QOL, 
and safety and tolerability will be assessed using the following instruments: 
● 
Clinical and adaptive measures of personality and behavior using the Behavior 
Assessment System for Children: Third Edition (Sabaz 2003) 
● 
Adaptive level of behavioral function as measured by the Vineland Adaptive Behavior 
Scales, Second Edition (VABS-II) (Sparrow 2005) 
● 
QOL as assessed by the Quality of Life in Childhood Epilepsy (QOLCE) (Sabaz 2003) 


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3 SUBJECT SELECTION AND WITHDRAWAL 
All subjects and/or their parent/legal guardian must sign the appropriate informed consent prior 
to beginning any study-related activities, including Screening procedures. Additionally, an 
assent form should be signed by subjects age 7 to 12 years old, unless lacking capacity. 
 
3.1 
Inclusion Criteria 
Subjects who will be selected for this study must meet the following criteria: 
1. Age ≥ 2 years old and ≤ 12 years old, male or female, at Week 0 (at time informed 
consent/assent is signed) 
2. Documentation of a diagnosis of Dravet syndrome or CDKL5 deficiency resulting from a 
nonsense mutation in 1 allele, as evidenced by medical records, genetic testing, and the 
following clinical feature: 
a. Failure to control seizures despite appropriate trial of 2 or more AEDs at therapeutic 
doses 
3. Between 1 to 3 baseline AEDs at stable doses for a minimum of 4 weeks prior to 
enrollment (ie, Screening visit) 
a. Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet do not 
count towards this limit but must be unchanged for 3 months prior to enrollment 
(Screening). 
4. VNS must be on stable settings for a minimum of 3 months prior to the Baseline visit 
5. If on ketogenic or modified Atkins diet, must be on stable ratio for a minimum of 
3 months prior to the Baseline visit 
6. Written consent obtained from the subject or subject’s legal representative must be 
obtained prior to performing any study procedures 
7. Minimum of 6 convulsive or drop seizures with duration > 3 seconds over the 4 weeks of 
diary screening prior to randomization and ≥ 6 convulsive or drop seizures with duration 
> 3 seconds during the 4 weeks from Screening to Baseline. 
 
3.2 
Exclusion Criteria 
Subjects cannot be included in the study if any of the following exclusion criteria are met: 
1. Subject is < 2 years old or >12 years old 
2. Epilepsies associated with genetic disorders other than Dravet syndrome or CDKL5 
deficiency 
3. Subject has Dravet or CDKL5 genetic mutations that are NOT nonsense mutations 
4. Felbamate has been initiated within the past 12 months prior to the Screening Visit 
5. Subjects who are currently or have participated in clinical trials in the 30 days prior to 
enrollment (Screening Visit) 


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6. Prior or ongoing medical condition (eg, concomitant illness, 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 thecourse 
of study drug administration or follow-up would be completed, or could impair the 
assessment of study results 
7. Ongoing intravenous administration of aminoglycosides or vancomycin. 
 
3.3 
Subject Recruitment and Screening 
Approximately eight nonsense mutation Dravet syndrome subjects and 10 nonsense mutation 
CDKL5 subjects will be recruited for the study from the Principal Investigator or sub- 
investigator’s clinical practice at New York University Comprehensive Epilepsy Center (NYU 
CEC). All subjects will have had diagnoses confirmed by a geneticist. If this has not been done, 
then they will be referred to a neurogeneticist at New York University Langone Medical Center 
(NYULMC). During a routine visit, subjects who meet criteria for the study (or their 
parents/legal guardians) will be asked if they would like to participate in the study. Male and 
female subjects of any ethnicity between ages of 2 and 12 (inclusive) will be assessed for 
inclusion. During the routine visit, the investigator will inform each prospective 
subject/parent/legal guardian of the nature of the study, and explain the potential risks and 
study-related procedures. If the subject/parent/legal guardian agrees, they will be given the 
informed consent documents to read and sign prior to starting any study procedures. Only the 
Principal Investigator, sub-investigators, and other research personnel listed on the study will 
have access to subject information. Once the study subject/parent/legal guardian has signed the 
informed consent, the investigator will explain the study during the routine visit and inform the 
subject and surrogate that a capacity assessment will be performed to determine whether the 
subject is capable of providing an informed decision to participate in the study. At this time, a 
capacity assessment will be conducted if the subject does not refuse the assessment. Capacity 
will be assessed through neurological examinations and neuropsychology reports conducted by 
the physician as well as learning and/or development delays that have been documented. If there 
is already documentation of lack of capacity, no assessment will be needed. If it has been 
determined by the investigator that the subject has capacity, they will be given the assent formto 
review. The investigator will go over the study as described in the assent form including study 
visits and procedures. The subject will be allowed time to ask questions. If the subject is 
comfortable, then they can sign the assent. All documentation will be placed in the study binder 
and documented in the study visit note. A copy of the informed assent and consent documents 
will be given to the subject and the subject’s parent/legal guardian. Screening procedures may 
begin. The Screening Period is 4 weeks, during which study candidates must complete a diary 
documenting the frequency and duration of convulsive or drop seizures. 
Refer to Section 6 for the Schedule of Events and specific requirements for each study visit. 
 
3.4 
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. 


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Eighteen subjects (8 with CDKL5 syndrome and 10 with Dravet syndrome) will be enrolled. 
Within each disorder group, subjects will be randomized in a 1:1 ratio to 1 of 2 possible 
treatment assignments during Treatment Period 1: 
● 
Placebo 
● 
Ataluren (10, 10, 20 mg/kg/day) 
 
3.5 
Masking 
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 before study completion will only occur in the case of subject emergencies. Except 
for emergency unmasking, individual subjects and their parents/legal guardians 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 the investigator. 
 
3.6 
Early Withdrawal of Subjects 
 
3.6.1 When and How to Withdraw Subjects 
A subject may be discontinued from study drug at any time if the subject, subject’s legal 
guardian, or the investigator feels that it is not in the subject’s best interest to continue (see also 
Section 7). The following is a list of possible reasons for study drug discontinuation: 
1. Parental/legal guardian withdrawal of consent. 
2. Subject is not compliant with study procedures. 
3. Protocol violation requiring discontinuation of study drug. 
4. Severe adverse events, including significant toxicity such as severe cognitive or 
behavioral toxicity, impaired liver and renal function, or impaired hematopoiesis. 
5. Seizure exacerbation not attributable to other known provocative factors. 
6. Interaction with concomitant AED regimen that leads to unacceptable toxicity. 
Medication adjustments will be avoided, if possible, and may require the subject to exit 
the study, at the discretion of the Investigator. 
Specific drug-related toxicities will be assessed and managed by the Principal Investigator. 
Depending on the nature of the signs (eg, changes in serum chemistries, liver function tests) or 
symptoms (eg, rash), the subject will be assessed to determine the severity and likelihood of 
relation to study medication. Based on this assessment, the medication may be discontinued, the 
dose may be reduced, or the drug may be continued with ongoing assessment.   If the study drug 
is discontinued due to a suspected toxicity, it will only be restarted if there is strong evidence that 
the toxicity was likely not related to the study medication (eg, liver tests were elevated due to a 
cytomegalovirus infection). 
If a subject must discontinue study drug, the method for discontinuation from study drug will be 
determined based on the type of reaction and/or reason for withdrawal. For example, if the 
subject experiences a rapidly progressive rash, it would lead to abrupt cessation of study drug, 


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but if subject experiences excess tiredness, study drug may be tapered off. A discussion of the 
method of cessation will occur between the subject and/or subject’s parent/legal guardian and the 
physician. 
 
3.6.2 Data Collection and Follow-up for Withdrawn Subjects 
For all subjects who withdraw from the study, there will be 1 final visit 4 weeks after the last 
dose of study drug (Follow-up Visit). If the subject/parent/legal guardian cannot be contacted 
after 4 phone calls to subject/parent/legal guardian, a certified letter will be sent to the 
subject/parent/legal guardian. 
Refer to Section 6 for the Schedule of Events and specific requirements for each study visit. 


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4 STUDY DRUG 
4.1 
Description 
 
4.1.1 Ataluren 
Ataluren will be provided as a white to off-white granules for oral suspension. The drug 
substance and drug product are manufactured under current Good Manufacturing Practices 
(cGMP) conditions. The formulation includes matrix and suspending agents, surfactants, and 
various excipients that aid in the manufacturing process. The powder for oral suspension is 
packaged in aluminum foil, child-resistant sachets (packets) and supplied in dose strengths 
containing 125, 250, or 1000 mg of the active drug substance. All of the excipients have been 
tested to pharmaceutical or food grade and are generally recognized as safe.  (See  also 
Section 1.2.1 for additional details.) 
 
4.1.2 Placebo 
A white to off-white powder placebo formulation will be provided for oral suspension. The 
placebo formulation has been manufactured under cGMP conditions. The dry powder 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 (packets) matching each of the 
125-, 250-, and 1000-mg dose strengths of active drug sachets. 
 
4.1.3 Drug Kits 
Drug kits will be provided, each of which contains 90 sachets of 1 of the dose strengths 
(125, 250, or 1000 mg or matching placebo). 
 
4.2 
Treatment Regimen 
Subjects will receive 90 days (12 weeks + 6 days) of masked ataluren or placebo during each 
treatment period. Each subject will start at a dose based on their weight in kilograms. The study 
drug is to be administered in a TID fashion of 10 mg/kg, 10 mg/kg and 20 mg/kg (morning, 
midday, and evening, respectively). The dose will be administered from 125, 250, and 1000 mg 
foil packets. 
Dosing will be based on the subject’s body weight at Baseline. Weight will be assessed at every 
clinic visit. If the subject’s body weight changes by ≥10% from Baseline, the actual dose maybe 
re-calculated. 
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 Treatment Period, the last dose of study drug 
will be taken on the evening before the clinic visit (ie, the night before the Visit 4/Week 12 [end 
of Treatment Period 1] and the night before Visit 7/Week 28 [end of Treatment Period 2). 
Intervals for dosing should be ~6 hours (D1 hour) between morning and mid-day doses, ~6 hours 
(D1 hour) between mid-day and evening doses, and ~12 hours (D1 hour) between evening doses 
and the morning dose on the next day. 


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4.2.1 Instructions for Delays in Dosing 
Dosing delays in study drug (masked ataluren or placebo) administration should adhere to the 
following guidelines: 
● 
If dosing of study drug is delayed by ≤ 1 hour, the planned dose should be taken with no 
changes to the subsequent dose schedules; 
● 
If study drug 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 study drug dosing is delayed by D 4 hours, the dose should not be taken. Study drug 
administration may continue but the missed dose should not be taken and the planned 
timing of subsequent study drug dosing should not be altered. 
 
4.2.2 Study Drug Preparation and Storage 
Study drug sachets should be stored at room temperature, away from the reach of children until 
time of reconstitution and should only be opened at the time of dose preparation. The full 
contents of each sachet should be mixed with at least 30 mL (1 ounce) of liquid (water, milk, 
fruit punch), or 3 tablespoons of semi-solid food (yogurt or applesauce). The prepared dose 
should be mixed well before administration. The amount of the liquid or semi-solid food can be 
increased based on subject preference. 
Each prepared dose is best administered immediately after preparation. The prepared dose 
should be discarded if not consumed within 24 hours of preparation if kept refrigerated (2°C– 
8°C), or within 3 hours at room temperature (15°C–30°C). 
The clinic staff will instruct each subject or 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 caregiver when drug supplies are dispensed. 
 
4.3 
Method for Assigning Subjects to Treatment Groups 
This interventional study contains a placebo portion where subjects will not receive active drug 
therapy beyond the existing background AED regimen. The allocation of ataluren and placebo to 
treatment number will be completed according to a masked randomization schedule. 
Randomization is an accepted means to reduce bias and allows for the highest standard of 
evidence in documenting a treatment effect.  The permuted block randomization technique will be 
used.  Such a method allows the treatment groups to be balanced with respect to the predefined 
stratification factors as well as for the number of subjects in each arm. The process will be 
established and performed by experienced clinical research organizations to maximize the 
integrity and security of the randomization and ensure appropriate access and convenience-of- use 
by the investigational sites. The method should be sufficient to preclude site personnel from 
making inferences regarding treatment assignments based on known block sizes. A 1:1 
randomization of ataluren to placebo is planned in order to avoid the loss of statistical power 
associated with an unbalanced randomization. 


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To minimize the potential compromise of study drug masking and to reduce the chance of 
inadvertent dosing errors or intentional attempts to mix active drug and placebo within families, 
if the case occurs, the randomization system will allocate subsequently enrolled family members 
(eg, siblings) to the same treatment group as the first family member enrolled. There is past 
precedence for this approach. 
When a subject is randomized in the study and is ready to begin study drug, the Principal 
Investigator or qualified designee will dispense the appropriate quantity of masked study 
medication and distribute it to the subject and/or subject’s caregiver. Extensive instructions on 
the correct dosage administration and schedule will be discussed and fully understood prior to 
leaving the appointment. 
 
4.4 
Subject Compliance Monitoring 
The study team will assess and track subject compliance with the study drug regimen via clinical 
evaluations and follow-up email or phone calls. The subjects will be seen for clinical evaluations 
every month for up to the next 10 months on study drug regimen. 
Any subject who is significantly non-compliant with the study drug regimen (< 80% or > 120%) 
will be withdrawn from the study as per the Principal Investigator. 
 
4.5 
Prior and Concomitant Therapy 
Throughout the study, including during the Treatment Periods with study drug administration, 
subjects will continue their current AED regimen consisting of 1 to 3 drugs at stable doses for at 
least 4 weeks prior to the Screening Visit. Concomitant AED concentrations will be collected at 
the Baseline Visit and during the study to assess for the potential interactions.  If the subject has 
a VNS, the settings must be on stable settings for a minimum of 3 months prior to the Screening 
Visit. In addition, if the subject is on a ketogenic diet, a stable ratio must be present for at least3 
months prior to the Screening Visit. All concomitant AEDs are permitted during the randomized 
portion of the study; felbamate is allowed if the subject has been on a stable dose for ≥ 12 
months prior to the Screening Visit. Epidiolex will be allowed as a concomitant AED as it has 
received FDA approval. Medication adjustments will be avoided, if possible, and may require 
the subject to exit the study at the discretion of the investigator. Medication adjustments and 
changes will be allowed in the open label portion of the study. 
 
4.6 
Receiving, Storage, Dispensing, and Return 
 
4.6.1 Receipt of Drug Supplies 
Study drug (ie, masked ataluren and masked placebo) will be shipped to the site of the Principal 
Investigator at NYU from PTC Therapeutics, via FedEx. 
Upon receipt of the study drug supplies, an inventory will be performed and a drug receipt log 
filled out and signed by the person accepting the shipment. The designated study staff will count 
and verify that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be 
documented in the study files. The investigator will notify PTC Therapeutics of any damaged or 
unusable study drugs that were supplied to the investigator’s site. 


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4.6.2 Storage 
Sachets containing study drug will be stored at controlled room temperature (15°C–30 °C) in a 
locked room accessible only to study personnel. 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. 
 
4.6.3 Dispensing of Study Drug 
Dosing of ataluren will be based on mg/kg of subject body weight and will be adjusted to allow 
for dosing with up to 3 of the available sachet dose strengths (125 mg, 250 mg, and/or 1000 mg). 
The entire contents of the sachet will be constituted with the constitution medium and will be 
administered. Supply of study drug will be calculated based on subject weight and will be 
provided by the Principal Investigator or qualified designee. Quantity of study drug sachets 
distributed to each study subject will be noted in a study log upon dispensation. Regular study 
drug reconciliation will be performed to document drug assigned and drug remaining. This 
reconciliation will be logged on the drug reconciliation form, and signed and dated by the study 
team. 
 
4.6.4 Study Drug Accountability, Return and Destruction of Study Drug 
Study personnel must ensure that all study drug supplies are kept in a temperature-monitored, 
secure, locked area with access limited to authorized personnel. Study product must not be used 
outside the context of this protocol. Under no circumstances should the investigator or site 
personnel supply study product to other investigators or clinics, or allow the supplies to be used 
other than as directed by this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by PTC Therapeutics or its designee, including, but not limited 
to, the date received, lot number, amount received, and the disposition of all study drug. Current 
dispensing records will be maintained that include the date and amount of drug dispensed, 
relevant kit and sachet numbers, and subject’s assigned study number. 
Subjects and/or caregivers should return all remaining study drug (all unused sachets) to the 
study site at each onsite study visit. A Subject Study Drug Accountability Log will serve as the 
source document for drug supply to the subjects and will document the return of any unused drug 
for compliance assessments. 
A final reconciliation of drug shipped, drug consumed, and drug remaining will be completed at 
the completion of the study. Any discrepancies noted will be investigated, resolved, and/or 
documented prior to destruction of unused study drug. 
Unused clinical supplies will be destroyed or returned to PTC Therapeutics or its designee, as per 
investigator/PTC Therapeutics agreement. Records documenting the date of study drug 
destruction or shipping, relevant sachet numbers, and amount shipped (or destroyed) should be 
kept in the investigator site study file. 


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4.6.5 Overdose Precautions 
For any subject experiencing an overdose (administration of an ataluren dose > 4 times the 
intended total daily dose level for this protocol [ie, > 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 Principal 
Investigator must be contacted if an overdose occurs and the overdose must be reported as an AE 
according to Section 8.5 (or as an SAE if the overdose meets the applicable criteria for an SAE). 
The Principal Investigator is responsible for reporting the information to PTC Therapeutics. 
 
4.6.6 Inadvertent Exposure and Spill Precautions 
Reference can be made to the IB for current information on inadvertent exposures and spill 
precautions. 


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5 
SAFETY MONITORING AND STUDY DRUG TREATMENT 
MODIFICATION 
5.1 
Laboratory Abnormalities and Adverse Events Requiring Evaluation and Potential 
Drug Interruption/Modification 
Subjects must be monitored closely for AEs or laboratory abnormalities during the course of the 
study. 
For AEs or laboratory abnormalities, the investigator will use judgment in determining whether 
the event or abnormality is clinically significant, whether diagnostic evaluation is warranted, and 
whether potential interruption of study drug treatment is appropriate. In general, life-threatening 
(Grade 4) or severe (Grade 3) AEs or laboratory abnormalities should be considered clinically 
significant, although recurrent or persistent moderate events (Grade 2) may also be considered 
clinically significant in certain circumstances. Reference should be made to the Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.1 (see 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) for 
grading the severity of AEs and laboratory abnormalities. 
 
5.1.1 Evaluation of Adverse Events or Laboratory Abnormalities 
The Principal Investigator (Dr. Devinsky) or designee should be notified of any AE or laboratory 
abnormality that leads to dose interruption and should be apprised of ancillary laboratory or other 
diagnostic findings and the evolving data from any work-up of the initial abnormality. 
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, aspartate aminotransferase, 
and alanine aminotransferase values), and all concomitant medications should be 
reviewed. Depending upon changes observed, the recommended diagnostic workup may 
include more frequent monitoring or further evaluations for viral hepatitis and immune 
disorders; tests for cholelithiasis; or abdominal ultrasound, computed tomography (CT), 
magnetic resonance imaging (MRI), or other imaging methods. 
● 
Renal: The medical history, all clinical blood and urine renal values, serum electrolytes, 
medications, and potential pre- or post-renal conditions should be reviewed. Depending 
upon the changes observed, recommended diagnostic workup may include further 
evaluations of blood or urine; tests of glomerular filtration rate, concentrating ability, or 
other renal functions; CT, MRI, or other imaging methods; and/or renal biopsy. 
● 
Elevation of aspartate aminotransferase or alanine aminotransferase to > 3× baseline will 
lead to repeat laboratory studies and if these remain elevated, to a reduction in study 
medication and repeat laboratory studies. No other significant toxicities have been 
reported with ataluren, and elevated liver function studies are rare. 


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5.1.2 Instructions for Resuming Study Drug Administration after an Interruption for 
Safety Concerns 
In deciding whether to re-institute study drug after a dose interruption due to any clinically 
significant safety concern, the investigator should consider factors such as the following (and 
may confer with the appropriate personnel at PTC Therapeutics if needed): 
● 
Type and severity of the AE or laboratory abnormality 
● 
The potential causal relationship of study drug 
● 
The subject’s status in terms of epileptic seizures (frequency and types) and other health 
conditions 
● 
The ability to monitor for recurrence of the event 
If further evaluation reveals that the AE 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 AE or laboratory abnormality, 
the investigator will interrupt study drug and may confer with the appropriate personnel at 
PTC Therapeutics if needed regarding the potential need to discontinue study drug permanently. 
 
5.2 
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 drug, 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 will be 
completed (see Section 8.5). In addition, details regarding the reasons for discontinuation and 
the AEs leading to the discontinuation should be recorded in the source documents and in the 
appropriate case report form (CRF). The EOS Visit CRF should be completed and appropriate 
follow-up (at ~4 weeks as per protocol or until recovery from or stabilization of the AE, 
whichever comes last) should be instituted. 
Study drug may be permanently discontinued as a result of an SAE. If study drug is 
discontinued for lack of efficacy or other side effects, it will be reduced by 50% for 5 days and 
then discontinued. 


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6 SCHEDULE OF EVENTS AND STUDY PARAMETERS 
6.1 
Schedule of Events 
The types and timing of data to be recorded are summarized in Table 1. 


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Table 1 
Schedule of Events 
 
Protocol 
Activities 
Screeninga 
Treatment Period 1 
4-Week 
Washout/ 
Crossover 
Treatment 
Period 2b 
EOS Visitc 
or Begin 
Open- 
Label 
Open- 
Label 
Extensiond 
End of 
Treatment 
Follow 
Upe 
Week (±6 
days) 
-4 (Wk -4 to 
Wk 0; 
Day -28 
to 
Day 1) 
0 
6 
12 
16 
22 
28 
52 
76 
100 
124 
128 
Visit 
1 
2f 
3 
4 
5 
6 
7 
8g 
9 
10 
11 
12 
Informed 
consent/assent 
X 
Medical history 
X 
Serum viral 
screen 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure data 
diary provided 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure data 
diary collected 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensed 
Xh 
X 
Xh 
X 
Xh 
Xh 
Xh 
Xh 
Study drug 
administration 
Xi 
Xi 
Xi 
Study drug 
compliance and 
return 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol 
Activities 
Screeninga 
Treatment Period 1 
4-Week 
Washout/ 
Crossover 
Treatment 
Period 2b 
EOS Visitc 
or Begin 
Open- 
Label 
Open- 
Label 
Extensiond 
End of 
Treatment 
Follow 
Upe 
Week (±6 
days) 
-4 (Wk -4 to 
Wk 0; 
Day -28 
to 
Day 1) 
0 
6 
12 
16 
22 
28 
52 
76 
100 
124 
128 
Visit 
1 
2f 
3 
4 
5 
6 
7 
8g 
9 
10 
11 
12 
Blood for CBC, 
CMP, LFTs, 
BUN, creatinine 
levels, serum 
HCGj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for 
plasma PK for 
atalurenk 
X 
X 
X 
Blood for 
plasma PK for 
AED 
assessmentl 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavior 
Assessment 
System for 
Children 
X 
X 
X 
X 
X 
Vineland 
Adaptive 
Behavior Scales 
X 
X 
X 
X 
X 
Quality of Life 
in Childhood 
Epilepsy 
X 
X 
X 
X 
X 
Abbreviations: AED = antiepileptic drug; BUN = blood urea nitrogen; CBC = complete blood count; CMP = comprehensive metabolic panel; EOS = end of study; EOT = End of 
treatment; F/U = follow-up; HCG= human chorionic gonadotropin; LFTs = liver function tests; PK = pharmacokinetics; wk = week 
a. Screening will occur from Week -4 to Week 0 (ie, 28 days). The ±6 day visit window is not applicable to the Screening Period. 
b. During Treatment Period 2, subjects will crossover and begin receiving masked study drug opposite of what they received during Treatment Period 1 (ie, subjects previously 
receiving masked ataluren will now receive placebo and subjects previously receiving placebo will now receive ataluren). 


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c. The EOS visit (Week 28) will be completed for all subjects who complete or discontinue early from Treatment Period 1 and 2. Subjects who complete the EOS visit may 
continue in the open-label portion of the study at Week 28, otherwise a follow-up visit should be scheduled after 4 weeks. 
d. All subjects enrolling in the open-label extension study will receive ataluren 10, 10, 20 mg/kg 3 times per day for 96 weeks. 
e. The Follow-up visit is to occur 4 weeks after the last dose of study drug, regardless of whether the subject discontinues prematurely or completes the EOS visit and/or the 
open-label extension. 
f. Visit 2 is considered the Baseline Visit. Visit 2 must occur no sooner than 28 days and up to 42 days after Visit 1. All study and laboratory assessments must be completed 
prior to the first dose of study drug administration. 
g. If the subject begins but does not complete the open-label extension, complete EOT (Week 124). 
h. The first dose of study drug should be given in the clinic at Visit 2 (Baseline), Visit 5 (Week 16), and, if applicable, in the open-label extension at Visit 7 (Week 28). 
i. The last dose of study drug prior to Visit 4/Week 12 (Treatment Period 1) and Visit 7/Week 28 (EOS Visit) should be taken the night before, at home. No morning dose should 
be taken prior to the clinic visit. 
j. Serum HCG samples taken only for female subjects of childbearing potential 
k. Ataluren plasma PK will be assessed at 0 hr (pre-dose) at Visit 5/Week 16 and at 0 hr (pre-dose) and 2 hr post-dose at Visit 3/Week 6 and Visit 6/Week 22. 
l. AED plasma PK will be assessed at 0 hr (pre-dose of AED, including but not limited to valproate, clonazepam, lamotrigine, topiramate, and levetiracetam). 


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6.1.1 Screening, Treatment, and Follow-up Periods 
The investigator/study staff member must inform each study candidate 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 parent(s)/legal guardian (as required by local regulations) prior 
to performing any study-related Screening procedures. Screening evaluations for the study will 
be performed at the clinical research facility. Study participants will report to the clinic on the 
morning of each scheduled on-site visit and will remain in the clinic until released by the 
investigator after all study-related procedures have been completed and the subject has been 
instructed regarding drug storage, reconstitution, and administration. 
Adverse events will be assessed beginning at the time of informed consent through the end of the 
follow-up period. 
Subjects must return to the clinic for a follow-up assessment at 4 weeks after the last dose. If 
subjects enroll in the open-label extension, follow-up assessment will occur 4 weeks after the last 
dose of the extension period. 
 
6.1.1.1 Visit 1 (Screening, 4 Weeks Prior to Baseline Visit 2) 
The Screening Visit (Visit 1) will occur 4 weeks prior to the Baseline Visit during a routine visit 
at NYU CEC. Screening procedures will proceed as follows: 
● 
Obtain written informed consent/assent. 
● 
Determine if the subject meets the preliminary eligibility criteria: 
o Collect demographic information 
o Collect current and relevant medical history 
o Identify concomitant medications used 
o Identify and confirm stable use AED medications 
If the subject meets the preliminary eligibility criteria, the following assessments will be 
performed: 
● 
Vital signs (including systolic and diastolic blood pressure, radial pulse rate, and body 
temperature): perform in sitting position 
● 
Physical examination 
● 
Height and weight 
● 
Blood draw for clinical laboratory evaluations: 
o Blood urea nitrogen (BUN), complete blood count (CBC), comprehensive 
metabolic panel (CMP), liver function tests (LFTs) and creatinine levels 
o Serum human chorionic gonadotropin (HCG), as applicable (sample taken only 
for female subjects of childbearing potential) 
o Serum viral screen 
● 
Urinalysis 
● 
Record any AEs occurring since signing the ICF and any that occur during this visit 


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● 
Instruct subject or subject’s caregiver to keep a seizure diary for the next 4 weeks, 
including the following information: 
o Seizure type, duration, intensity 
o Presence or absence of cyanosis 
o Use of rescue medications 
6.1.1.2 Visit 2 (Baseline, Week 0) 
After the 4-week Screening period, the diary card provided at the Screening Visit will be 
reviewed and all inclusion/exclusion criteria will be confirmed. Eligible subjects complete the 
Baseline Visit (Visit 2/Week 0) as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
o Plasma PK for AED level assessment (0 hr, pre-dose) 
● 
Urinalysis 
● 
Dispense new seizure diary and review instructions for completion 
● 
Dispense masked study drug and review administration instructions 
o TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
o The first dose of study drug should be administered in the clinic after completion 
of all other assessments and procedures required at this visit. 
● 
Instruct subject to return in 6 weeks for Visit 3 
 
6.1.1.3 Visit 3 (Week 6) 
The subject will return to the site for Visit 3. Procedures at Visit 3 will proceed as follows: 
● 
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 


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● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for plasma PK of ataluren (0 hr, pre-dose, and 2 hr post-dose) 
● 
Blood draw for plasma PK AED level assessment (0 hr, pre-dose) 
● 
Dispense new seizure diary and review instructions for completion 
● 
Review returned study drug and compliance 
● 
Dispense masked study drug and review administration instructions 
o TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Instruct subject to return in 6 weeks for Visit 4 
 
6.1.1.4 Visit 4 (Week 12 [Beginning of 4-Week Washout]) 
The subject will return to the site for Visit 4. Visit 4 will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
Review returned study drug and compliance 
● 
Dispense new seizure diary and review instructions for completion 
● 
No study drug will be dispensed at this visit 
● 
Instruct subject to return in 4 weeks for Visit 5. 
 
6.1.1.5 Treatment Period 2 - Visit 5 (Week 16 [Crossover Visit]) 
The subject will return to the site for Visit 5. Subjects will crossover and begin receiving 
masked study drug opposite of what they received during Treatment Period 1 (ie, subjects 


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previously receiving masked ataluren will now receive placebo and subjects previously receiving 
placebo will now receive ataluren). Visit 5 will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for plasma PK of ataluren (0 hr, pre-dose) 
● 
Blood draw for plasma PK AED level assessment (0 hr, pre-dose) 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
Dispense new seizure diary and review instructions for completion 
● 
Dispense masked study drug and review administration instructions 
o TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
o The first dose of study drug should be administered in the clinic after completion 
of all other assessments and procedures required at this visit. 
● 
Instruct subject to return in 6 weeks for Visit 6 
 
6.1.1.6 Visit 6 (Week 22) 
The subject will return to the site for Visit 6. Visit 6 will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for plasma PK of ataluren (0 hr, pre-dose and 2 hr post-dose) 
● 
Blood draw for plasma PK AED level assessment (0 hr, pre-dose) 


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● 
Dispense new seizure diary and review instructions for completion 
● 
Review returned study drug and compliance 
● 
Dispense masked study drug and review administration instructions 
o TID dosing 10 mg/kg, 10 mg/kg, 20 mg/kg (morning, midday, evening) 
● 
Instruct subject to return in 6 weeks for Visit 7 
 
6.1.1.7 Visit 7 (Week 28 – EOS Visit [or Early Termination Visit])/Start ofOpen-Label 
Extension Study 
The subject will return to the site for Visit 7. This visit will be considered the EOS visit and 
should be completed for all subjects. Subjects should have taken their final dose of study drug 
the night before the clinic visit. 
Additionally, any subject who discontinues early from the study should complete this visit. 
Visit 7 will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw plasma PK for AED level assessment (0 hr, pre-dose) 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Review returned study drug and compliance 
● 
If subject is enrolling in the open-label extension study, dispense new seizure diary and 
review instructions for completion 
● 
No study drug will be dispensed at this visit if the subject is not enrolling in the 
open-label extension study. 
● 
If the subject is enrolling in the open-label extension study, open-label study drug willbe 
dispensed to the subject. 


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6.1.2 Open-Label Extension Study 
 
6.1.2.1 Visit 8 (Week 52) 
The subject will return to the site for Visit 8 (Week 52), of the open-label extension study. 
Visit 8 (Week 52) will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Review returned study drug and compliance 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw plasma PK for AED level assessment 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
Open-label study drug will be dispensed at this visit. 
● 
Dispense new seizure diary and review instructions for completion. 
 
6.1.2.2 Visit 9 (Week 76) 
The subject will return to the site for Visit 9 (Week 76). 
Visit 9 (Week 76) will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Review returned study drug and compliance 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for clinical laboratory evaluations 


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o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Open-label study drug will be dispensed at this visit. 
● 
Dispense new seizure diary and review instructions for completion. 
 
6.1.2.3 Visit 10 (Week 100) 
The subject will return to the site for Visit 10 (Week 100). 
Visit 10 (Week 100) will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Review returned study drug and compliance 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 
● 
Urinalysis 
● 
Open-label study drug will be dispensed at this visit. 
● 
Dispense new seizure diary and review instructions for completion. 
 
6.1.2.4 Visit 11 (Week 124) 
The subject will return to the site for Visit 11 (Week 124) 
Visit 11 (Week 124) will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Review returned study drug and compliance 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications 
● 
Blood draw plasma PK for AED level assessment 
● 
Blood draw for clinical laboratory evaluations 
o CBC, CMP, LFTs, BUN, creatinine, serum HCG 


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● 
Urinalysis 
● 
Complete the following QOL assessments: 
o Behavior Assessment System for Children 
o VABS-II 
o QOLCE 
● 
For subjects that want to continue on study medication, open-label study drug will be 
dispensed at this visit. 
● 
For subjects that do not want to continue, study drug will not be dispensed at this visit 
and subjects will return in 4 weeks for the final follow up. 
● 
Dispense new seizure diary if subject continues to visit 12 and review instructions for 
completion. 
 
6.1.2.5 Visit 12 (Week 128 [Follow-up Visit]) 
The Follow-up visit is to occur 4 weeks after the last dose of study drug, regardless of whether 
the subject discontinues prematurely or completes the EOS visit and/or the open-label extension. 
Visit 12 will proceed as follows: 
● 
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 
● 
Collect seizure diary and review entries 
● 
Record any AEs occurring since last visit and any that occur during this visit 
● 
Record any changes in concomitant medications. 
 
6.2 
PK for AED and Ataluren 
Antiepileptic drug plasma PK will be assessed at 0 hr (pre-dose of AED). The AED levels will 
be done prior to the subject taking the medication (trough level). Antiepileptic drug levels will be 
analyzed by NYU outpatient labs and/or MedTox laboratories. 
Ataluren plasma PK will be assessed at 0 hr (pre-dose) at Week 16 and at 0 hr (pre-dose) and 2 
hr post-dose at Weeks 6 and 22. Ataluren plasma samples will be shipped to InVentiv 
Bioanalytical Facility, 301D College Road East, Princeton, NJ 08540, for analysis and levels. 
 
6.3 
Blood Collection Summary 
Assuming a subject completes the study, the maximum amount of blood to be drawn at a visit is 
approximately 8 to 20 mL (depending on the number of AEDs the subject is taking and blood 
withdrawn for the ataluren PK assessment).  The total amount of blood to be drawn over the 
entire study period (including the Screening Visit, Treatment Period 1, Treatment Period 2, and 
EOS) is approximately 70 mL (depending on the number of AEDs the subject is taking as well as 
blood samples collected for the ataluren PK assessment). 


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6.4 
Blood for Analysis of Pharmacokinetics 
 
6.4.1 Ataluren Plasma Concentration 
Blood for trough ataluren concentrations will be collected at 0 hr (pre-dose) at Visit 5/Week 16 
and at 0 hr (pre-dose) and 2 hr post-dose at Visit 3/Week 6 and Visit 6/Week 22. Reference the 
Instruction Manual for handling ataluren in human PK samples for collection, processing, and 
shipping details. Samples will be stored at the bioanalytical laboratory for analysis of ataluren 
parent drug using a validated high-performance liquid chromatography with tandem mass 
spectrometry method. Thereafter, samples may be retained for potential follow-up analyses of 
ataluren metabolites. 


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7 STATISTICS 
7.1 
Sample Size Determination 
The original study was  not powered for statistical testing since the primary objective is to 
characterize the safety profile of ataluren in subjects with CDKL5 or Dravet syndrome resulting 
from a nonsense mutation. Eighteen subjects (10 with CDKL5 syndrome and 8 with Dravet 
syndrome) was planned to be included in this study. At the time of protocol amendment, 7 
subjects Dravet syndrome have been randomized and 8 subjects with Dravet syndrome have 
been randomized. Enrolment has been stopped. The number of subjects randomized will provide 
an initial assessment on the efficacy for subjects with CDKL5 syndrome and with Dravet 
syndrome. 
The number of subjects enrolled in the open-label extension study will be determined by the 
number of subjects who complete the initial study and remain eligible to participate in the 
extension study. 
 
7.2 
Randomization 
Eighteen subjects (10 with CDKL5 syndrome and 8 with Dravet syndrome) will be enrolled. 
Within each disorder group, subjects will be randomized in a 1:1 ratio to 1 of 2 possible 
treatment assignments during Treatment Period 1: 
● 
Placebo 
● 
Ataluren (10, 10, 20 mg/kg/day) 
After the completion of Treatment Period 1 and a 4-week Washout Period, subjects will 
crossover and begin receiving masked study drug opposite of what they received during 
Treatment Period 1 (ie, subjects previously receiving masked ataluren will now receive placebo 
and subjects previously receiving placebo will now receive ataluren). 
 
7.3 
Populations for Analyses 
Intent-to-Treat (ITT) Population - The ITT Population will contain all randomized subjects. 
 
7.4 
Efficacy Endpoint Definitions 
 
7.4.1 Seizures 
Based on observational studies of subjects with CDKL5 and Dravet syndrome in other drug 
studies, mean seizure frequency of 70 with a standard deviation of 65 has been estimated. From 
the epilepsy literature (Cramer 1999), a clinically meaningful difference will be a ≥ 20% 
reduction in seizure frequency over placebo. 
Seizure activity will be assessed based on ILAE criteria for the following: 
● 
Motor seizure including tonic-clonic seizures, hemiconvulsive seizures, drop attacks, 
tonic seizures, focal motor seizures. 
● 
Staring seizure is an absence seizure or a complex partial seizure. 
● 
Myoclonic seizure is the persistence or disappearance seizure. 
● 
Episode of status epilepticus: a convulsive state lasting longer than 10 minutes. 


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Baseline total number of seizures/emergency room visits/hospitalizations is defined as the total 
number of seizures/emergency room visits/hospitalizations during the 4-week Screening Period 
(Week -4 to Week 0 [Day 1]). 


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7.4.2 Clinical and Adaptive Measures of Personality and Behavior 
Assessment of clinical and adaptive measures of personality and behavior will be made using the 
Behavior Assessment System for Children (Third Edition). This is a screening system for 
measuring behavioral and emotional strengths and weaknesses. It will be conducted by the 
Principal Investigator or Clinical Research Nurse/Coordinator. 
 
7.4.2.1 Adaptive Level of Behavioral Function 
Adaptive level of behavioral function will be measured by the VABS-II (Sparrow 2005). The 
assessment is used to evaluate the child’s ability to adapt to practical, everyday skills that are 
required to function and meet environmental demands. The assessment will be conducted by the 
Principal Investigator or Clinical Research Nurse/Coordinator. 
 
7.4.2.2 Quality of Life 
Quality of life will be assessed by the QOLCE (Sabaz 2003). This questionnaire is used to 
evaluate the QOL of these children living with epilepsy. It will be distributed to the caregivers to 
complete. 
 
7.5 
Statistical Analyses 
The confidence interval (CI) for the proportion, if presented, will be computed using normal 
approximation, if the number of the events is at least 5. Otherwise, CI using an exact method 
will be provided. For safety summaries, CI will not be presented, unless specified otherwise. 
Summary statistics will be analyzed within each disorder group. 
All analyses will be performed using Statistical Analysis System (SAS®), Version 9.0 or higher. 
 
7.5.1 Study Conduct 
All protocol deviations will be listed and summarized. 
 
7.5.2 Study Population 
Frequency distributions or summary statistics of data pertaining to subject disposition, 
demographics, baseline characteristics, and medical history will be tabulated. 
 
7.5.2.1 Subject Disposition 
The disposition of subjects, including the number of subjects screened, the number of subjects 
randomized, the number of randomized subjects who received at least 1 dose of study drug, and 
the number of subjects who prematurely discontinue study drug will be tabulated. The number 
of subjects enrolled in the open-label extension study will also be tabulated. 
 
7.5.2.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics of subjects will be summarized descriptively by means 
and standard deviations for continuous variables, and frequency distribution for categorical 
variables. Summaries will be performed based on all randomized subjects (ie, ITT Population). 


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7.5.2.3 Medical History and Prior Medication 
Medical history and prior medication information will be summarized. 
 
7.5.3 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 days): ≤ 28 
(≤ 4 weeks), 29 to 42 (4–6 weeks), 43 to 84 (6–12 weeks), 85 to 112 (12–16 weeks), 113 to 154 
(16–22 weeks), 155 to 196 (22–28 weeks), 197 to 364 (28-52 weeks), 365 to 532 (52-76 weeks), 
533 to 700 (76-100 weeks), 701 to 868 (100-124 weeks), and 869 to 896 (124-128 weeks). The 
number of subjects in each category as well as the mean duration will also be displayed. 
 
7.5.3.1 Discontinuation of Study Therapy 
The ITT Population will be used to summarize discontinuation from study drug as indicated in 
Section 7 as well as the reason for the premature termination of study drug. The proportion of 
subjects who discontinue study drug will be summarized using point estimates and 95% CI. 
 
7.5.3.2 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 disorder group and treatment 
group. 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. 
 
7.6 
Safety Analyses 
All safety presentations will be based on the ITT Population and will be based only on data 
included in the analysis period of interest. Listings of all AEs will also be based on all available 
data at the scheduled analysis time point. Adverse event and SAE summaries will also be 
presented for the following periods: 
● 
Up to the end of Visit 4 (Week 12) 
● 
Up to the end of Visit 7 (Week 28, EOS Visit) 
● 
Between the start of Week 17 and the end of Week 28. 
● 
Up to the end of the open-label extension (Week 124, if applicable) 
● 
Between the start of Week 29 and the end of Week 124 (if applicable). 
Additional frequency tables summarizing the occurrence of AEs and SAEs after the end of the 
analysis period of interest will also be provided. All AEs and SAEs will be summarized by 
treatment group. Marked laboratory abnormalities will also be descriptively summarized. No 
statistical tests will be performed for AEs or laboratory marked abnormalities. 
 
7.6.1 Adverse Events 
Summary information (the number and percent of subjects by treatment) will be tabulated for: 
● 
TEAEs, including clinical and laboratory AEs 


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● 
Treatment-related AEs 
● 
TEAEs by severity 
● 
Treatment-related AEs by severity 
● 
SAEs 
● 
AEs leading to discontinuation 
Summaries will be presented by treatment groups and categorized by System Organ Class and 
Preferred Term. The frequencies of AEs displayed will be the crude rates that represent the 
number of subjects experiencing AEs divided by the total number of subjects. 
It should be noted that all laboratory data sent to and analyzed by the NYU laboratory will be 
reported to the investigator. However, only those laboratory abnormalities meeting the 
protocol-defined criteria of an AE (ie, those that require clinical intervention or further 
investigation beyond ordering a repeat [confirmatory] test) should be reported as AEs in the 
appropriate CRF, whether they were analyzed by the NYU laboratory or another laboratory. 
 
7.6.2 Laboratory Parameters 
Changes in clinical laboratory tests from Baseline (last measurement prior to randomization) and 
laboratory marked abnormalities (laboratory AEs) using pre-defined abnormality criteria will be 
descriptively 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. 
 
7.6.3 Other Parameters 
Height, weight, vital signs, and physical examination data will be descriptively summarized. 
Concomitant medications will be summarized. 
 
7.7 
Efficacy Analyses 
All efficacy endpoints will be summarized within each disorder group (Dravet syndrome or 
CDKL5) and by treatment group. 
Summary statistics for the total numbers of the following measurements per 28 days along 
with percent changes from Baseline per 28 days will be tabulated for the following: 
● 
Convulsive/motor seizures 
o Tonic-Clonic Seizures 
o Hemiconvulsive Seizures 
o Drop Attacks  
o Tonic Seizures  
o Focal Motor Seizures 
o Staring seizures 
o Myoclonic seizures 
● 
Use of rescue medications 


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● 
Emergency room visits/hospitalizations 
For the primary endpoint, the percent change from baseline in 28 day convulsive seizure frequency 
in each treatment period, the method from Mary E. Putt and Vernon M. Chinchilli[1] will be used. In 
short, differences dij between two treatment periods in percent change in total seizure frequency per 
28 days will be calculated for each patient, where i is the sequence and j is the patient. Wilcoxon 
rank sum test and Hodges–Lehmann confidence interval will be applied to the two sequences 
dij, as in [1].  
As a supportive analysis rank mixed models will also be used. The rank of percent change from 
baseline in 28 day total seizure frequency in each treatment period are used as dependent variables, 
with the rank of baseline 28 day total seizure frequency, treatment group, treatment sequence and 
treatment period as fixed factors, subjects within treatment sequence as random factors. The rank 
mixed model will be applied in each disorder group separately.  
Summary statistics at each measurement time point, along with changes from Baseline will be 
tabulated for: 
● 
Behavior Assessment System for Children 
● 
VABS-II 
● 
QOLCE 
The same methods described above to assess efficacy outcome measures will be continued for 
subjects that enroll in the extension study up to Week 124 or final dose, if prematurely 
discontinued. 


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8 SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
 
8.1.1 Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
● 
Unexpected in nature, severity, or frequency (ie, not described in study-related 
documents such as the Institutional Review Board (IRB)-approved protocol or consent 
form, the IB, etc) 
● 
Related or possibly related to participation in the research (ie, possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
● 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
8.1.2 Adverse Event 
An AE is any symptom, sign, illness, or experience that develops or worsens in severity during 
the course of the study. Intercurrent illnesses or injuries should be regarded as AEs. Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality: 
● 
results in study withdrawal 
● 
is associated with an SAE 
● 
is associated with clinical signs or symptoms 
● 
leads to additional treatment or to further diagnostic tests 
● 
is considered by the investigator to be of clinical significance 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
● 
All AEs that are suspected or are not suspected to be due to study drug. 
● 
Overdose (administration of a study drug dose > 4 times the highest intended total daily 
dose level for this protocol [> 160 mg/kg/day]) of study drug. 
● 
All reactions from medication misuse, abuse, withdrawal, sensitivity, or toxicity. 
● 
All reactions that result from medication errors or uses of the study drug outside what is 
described in the protocol. 
● 
Apparently unrelated illnesses, including the worsening of a preexisting illness. 
● 
Injury or accidents. Note that if a medical condition is known to have caused the injury 
or accident (a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate AEs. The outcome of the accident 
(hip fracture secondary to the fall) should be recorded in source documents. 


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● 
Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
● 
A pre-existing condition (eg, allergic rhinitis) must be noted on the appropriate CRF for 
Visit 1, but should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period. Diagnostic and therapeutic 
non-invasive and invasive procedures, such as surgery, should not be reported as AEs. 
However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded in the source documents. If a surgical procedure was 
planned prior to entry into the study, and the surgery is not performed because of a 
worsening of a baseline condition, this should not be reported as an AE. Note that, as 
described in the SAE paragraph below, any inpatient hospitalization occurring as the 
consequence of an AE during the study period should be reported as an SAE. 
Each AE is to be classified as serious or non-serious by the investigator using medical and 
scientific judgment. 
 
8.1.3 Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that 
is: 
● 
fatal 
● 
life-threatening 
● 
requires or prolongs hospital stay 
● 
results in persistent or significant disability or incapacity 
● 
a congenital anomaly or birth defect 
● 
an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, study drug or other drug 
overdose or abuse, a seizure that did not result in inpatient hospitalization, or intensive treatment 
of bronchospasm in an emergency department would typically be considered serious. 
Overdose of study drug is considered to be administration of a study drug dose > 4 times the 
intended total daily dose level for this protocol (> 160 mg/kg/day). 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
Note that any SAEs occurring within 4 weeks of the date of last dose should be reported to the 
investigator who will notify PTC Therapeutics. 


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8.2 
Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from the initiation 
of any study procedures (ie, after informed consent is given) to the end of the study drug follow- 
up. For this study, the study drug follow-up is defined as 4 weeks following the final 
administration of study drug. 
 
8.2.1 Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an AE if the frequency, intensity, or the character of the condition worsens 
during the study period. 
 
8.2.1.1 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the EOS Visit, any new clinically significant findings/abnormalities that meet the 
definition of an AE will also be recorded and documented as an AE. 
 
8.2.2 Post-study Adverse Event 
All unresolved AEs will be followed by the Investigator until the events are resolved, the patient 
is lost to follow-up, or the AE is otherwise explained. At the last scheduled visit, the investigator 
will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study. The 
investigator will notify PTC Therapeutics of any death or AE occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this 
study. The investigator will notify PTC Therapeutics if he becomes aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
 
8.2.3 Abnormal Laboratory Values 
A clinical laboratory abnormality will be documented as an AE if any one of the following 
conditions is met: 
● 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality. 
● 
The abnormality suggests a disease and/or organ toxicity. 
● 
The abnormality is of a degree that requires active management: change of dose, study 
drug discontinuation, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
8.3 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization will be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol. Any condition 


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responsible for surgery will be documented as an AE if the condition meets the criteria for an 
AE. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances: 
● 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome of 
an AE if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
● 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
● 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as judged 
by the clinical investigator. 
 
8.4 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on AEs by specific 
questioning and, as appropriate, by examination. Information on all AEs will be recorded 
immediately in the source document, and also in the appropriate AE module of the CRF. All 
clearly related signs, symptoms, and abnormal diagnostic procedures results will be recorded in 
the source document, but should be grouped under one diagnosis whenever possible. 
All AEs occurring during the study period will be recorded. The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that the study drug 
or participation is not the cause. Serious adverse events that are still ongoing at the end of the 
study period will be followed up to determine the final outcome. Any SAE that occurs after the 
study period and is considered to be possibly related to the study drug or study participation will 
be recorded and reported immediately. 
 
8.5 
Reporting of Serious Adverse Events and Unanticipated Problems 
The investigator will conform to the AE reporting timelines, formats, and requirements of the 
various entities to which they are responsible, but at a minimum those events that will be 
reported are those that meet any of the following criteria (see also Section 8.1): 
● 
Related to study participation 
● 
Unexpected 
● 
Serious or involve risks to subjects or others (see Section 8.1). 


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8.5.1 Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes the following: 
● 
Study identifier 
● 
Study Center 
● 
Subject number 
● 
A description of the event 
● 
Date of onset 
● 
Current status 
● 
Whether study drug was discontinued 
● 
The reason why the event is classified as serious 
● 
Investigator assessment of the association 
between the event and study drug 
 
8.5.2 Investigator Reporting: Notifying the Supplier of the Study Drug (PTC 
Therapeutics) 
This study is a physician-sponsored intermediate-sized study. 
The following describes events that will be reported to the supplier of the study drug in an 
expedited fashion. 
 
8.5.2.1 Initial Report: Within 24 Hours 
The following events will be reported to PTC Therapeutics within 24 hours of awareness of the 
event: 
● 
Unanticipated problems related to study participation 
● 
Serious adverse events, regardless of whether they are unexpected. 
Additionally, an SAE report form will be completed and emailed to the following mailbox within 
24 hours. The investigator will maintain a copy of the form on file at the study site. 
 
E-mail: Pharmacovigilance@ptcbio.com 
 
 
8.5.2.2 Follow-up Report: Within 48 Hours 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the 
investigator will provide further information, as applicable, on the unanticipated adverse event or 
the unanticipated problem in the form of a written narrative. This will include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing unanticipated adverse 
effects will be provided promptly to the supplier of the study drug. 
 
8.5.2.3 Other Reportable Events 
Deviations from the protocol will receive the investigator’s IRB approval before they are 
initiated. Any protocol deviations initiated without the investigator’s IRB approval that may 
affect the scientific soundness of the study, or affect the rights, safety, or welfare of study 


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subjects, will be reported to the investigator’s IRB as soon as a possible, but no later than 5 
working days of the protocol deviation. 
 
8.5.3 Investigator Reporting: Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated 
problems posing risks to subjects or others. The following describes the NYULMC IRB 
reporting requirements, though investigators at participating sites are responsible for meeting the 
specific requirements of their IRB of record. 
 
8.5.4 Report Promptly, but No Later Than 5 Working Days: 
Researchers are required to submit reports of the following problems promptly but no later than 
5 working days from the time the investigator becomes aware of the event: 
● 
Unanticipated problems including AEs that are unexpected and related 
o Unexpected: An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable IB, and the current IRB-approved informed 
consent document and other relevant sources of information, such as product 
labeling and package inserts. 
o Related to the research procedures: An event is related to the research procedures 
if in the opinion of the Principal Investigator, the event was more likely than not 
to be caused by the research procedures. 
● 
Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
8.5.4.1 Other Reportable Events: 
The following events also require prompt reporting to the IRB, though no later than 5 working 
days: 
● 
Complaint of a research subject when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
● 
Protocol deviations or violations (includes intentional and accidental/unintentional 
deviations from the IRB approved protocol) for any of the following situations: 
o One or more participants were placed at increased risk of harm 
o The event has the potential to occur again 
o The deviation was necessary to protect a subject from immediate harm 
● 
Breach of confidentiality 
● 
Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study. 
● 
New information indicating a change to the risks or potential benefits of the research, 
in terms of severity or frequency (eg, analysis indicates lower-than-expected response 


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rate or a more severe or frequent side effect; other research finds arm of study has no 
therapeutic value; FDA labeling change or withdrawal from market). 
 
8.5.4.2 Reporting Process 
The reportable events noted above will be reported to the IRB using the form “Reportable Event 
Form” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution, and need for revision to 
consent form and/or other study documentation). 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
clinical investigator’s study file. 
 
8.5.5 Sponsor Reporting: Notifying the FDA 
The Principal Investigator at NYU, in collaboration with PTC Therapeutics, is required to report 
certain study events in an expedited fashion to the FDA. These written notifications of AEs are 
referred to as IND safety reports. In order for the study sponsor to notify the FDA within the 
required timelines, after notification that an event meeting serious criteria has occurred, the 
following information will be obtained within the timelines noted: 
● 
Within 4 calendar days (via telephone or facsimile report) 
Any study event that is: 
o Associated with the use of the study drug 
o Unexpected 
o Fatal or life-threatening 
● 
Within 10 calendar days (via written report) 
Any study event that is: 
o Associated with the use of the study drug, 
o Unexpected 
o Serious, but not fatal or life-threatening 
-or- 
o A previous AE that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that: 
o Suggests a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
Additional reporting requirements 
The Principal Investigator at NYU, in collaboration with PTC Therapeutics, is also required to 
identify in IND safety reports all previous reports concerning similar AEs and to analyze the 
significance of the current event in light of the previous reports. 


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Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form) or in a narrative 
format. If supplied as in a narrative format, the minimum information to be supplied is noted in 
Section 8.5. The contact information for submitting IND safety reports is noted below: 
Jack Dan, RPh 
Regulatory Project Manager 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Neurology Products 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
Office:(240)-402‐6940 
Fax:(301)796‐9842 
Email: Jack.Dan@fda.hhs.gov 
8.6 
Unmasking Procedures 
All subjects will receive a pack (depending on the visit) of study drug according to the 
randomization code. The identity of study drug (placebo vs ataluren) assigned to subjects will be 
contained in individually sealed randomization code-break mailers, held by the investigator. The 
Principal Investigator is responsible for ensuring that information on how to access the treatment 
allocation for an individual subject is available to the relevant staff in case of an emergency and 
unmasking is required. A subject’s treatment assignment should only be unmasked when 
knowledge of the treatment is essential to make a decision on the medical management of the 
subject.  Unmasking for any other reason will be considered a protocol deviation.  Subjects 
whose treatment is unmasked will be withdrawn from the study (Section 7). 
 
8.7 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of AEs as 
noted above, as well as the construction and implementation of a site data and safety-monitoring 
plan (see Section 10 Data Safety Monitoring Plan). Medical monitoring will include a regular 
assessment of the number and type of SAEs. 


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9 DATA HANDLING AND RECORD KEEPING 
9.1 
Confidentiality 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. Research records such as laboratory test results, study notes, questionnaires, 
and CRFs will be collected at the time of the visit from the study subjects. This information will 
be stored in subject study binders that will be located at the Epilepsy Center in a locked room. 
Only the research team will have access to the key and the information.  The names and 
identities of all research subjects will be kept in strict confidence and will not appear on the 
CRFs or other records provided to or retained by the investigator or 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 the investigator or PTC Therapeutics. The informed consent form 
must include appropriate statements explaining these requirements. 
 
9.2 
Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following: 
● 
What protected health information (PHI) will be collected from subjects in this study 
● 
Who will have access to that information and why 
● 
Who will use or disclose that information 
● 
The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject/parent/legal guardian revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of subject authorization. For subjects that have revoked authorization to collect or 
use PHI, attempts should be made to obtain permission to collect at least vital status (ie, that the 
subject is alive) at the end of their scheduled study period. 
 
9.3 
Source Documents 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subject diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 


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9.4 
Case Report Forms 
The study CRF is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”. All entries should be printed legibly in black 
ink. If any entry error has been made, to correct such an error, draw a single straight line through 
the incorrect entry and enter the correct data above it. All such changes must be initialed and 
dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
 
9.5 
Records Retention 
It is the investigator’s responsibility to retain essential study documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. 


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10 Data Safety Monitoring Plan 
A Safety Project Plan will be provided by PTC Therapeutics Pharmacovigilance outlining safety 
activities, processes, and study responsibilities. The PTC Therapeutics Pharmacovigilance 
Safety Lead-Pharmacist and Pharmacovigilance Safety Physician will be responsible for 
monitoring all SAEs, requesting follow-up information, and performing reconciliation. 
The overall safety and conduct of the study will be monitored by the Principal Investigator, Orrin 
Devinsky, MD, the PTC Pharmacovigilance Safety Lead, and the PTC Pharmacovigilance Safety 
Physician. Under the safety monitoring plan, all SAEs will be reviewed.  Data monitoring 
reviews will take place quarterly. Summary reports of the data monitoring review will also be 
taken quarterly. 
 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities. The investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the above noted study-related documents and study-related facilities (e.g., pharmacy, 
diagnostic laboratory), and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, 
PTC Therapeutics, government regulatory bodies, and New York University compliance and 
quality assurance groups of all study-related documents (e.g., source documents, regulatory 
documents, data collection instruments, study data). The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g., pharmacy, diagnostic laboratory). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable New York University compliance and quality 
assurance offices. 


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11 ETHICAL CONSIDERATIONS 
This study is to be conducted accordance with applicable US government regulations and 
international standards of GCP, and applicable institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted IRB in agreement 
with local legal prescriptions, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be filed in the investigator study file before commencement of this study. The 
investigator should also file a list of IRB members and their affiliate. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. See Attachment for a copy of the Subject Informed Consent Form.  This consent form 
will be submitted with the protocol for review and approval by the IRB for the study. The 
formal consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject undergoes any study procedure. The consent form must be signed by the subject or a 
legally acceptable surrogate, and the investigator-designated research professional obtaining the 
consent. 
In addition, describe who will obtain consent and how the process of informed consent will be 
structured to be conducive to rational and thoughtful decision making by the subject/subject’s 
parent/guardian. If children will be subjects, include a specific plan to assess comprehension 
during assent or the subject’s agreement Individuals who are authorized to obtain consent must 
be listed on the protocol (or FDA form 1572) and consent form document. If necessary to use 
‘Auditor/Witness’ and/or translator, these roles would be described in this section. 
The investigator will explain the study during the routine visit and inform the subject and 
surrogate that a capacity assessment will be performed to determine whether the subject is 
capable of providing an informed decision to participate in the study. At this time, capacity 
assessment will be conducted if the subject does not refuse the assessment. If there is already 
documentation of lack of capacity, no assessment will be needed. 
Capacity will be assessed through neurological examinations and neuropsychology reports 
conducted by the physician as well as learning and/or development delays that have been 
documented. Capacity will be monitored through the documentation in the subject’s diary, the 
questionnaires administered, study visits and AEs. We do not expect the capacity of subject to 
change throughout the study. However, if at any time, the subject appears to have a change in 
their capacity (capacity is lost or gained), the independent assessor will perform a capacity 
assessment again. If capacity is lost, a parent/legal guardian must be consented in order for the 
subject to continue in the study. If capacity is gained, the subject must sign a consent form 
him/herself in order to continue participation in the study. 
Once capacity has been determined, the subject will review and sign an assent form. 
Subjects and/or their parent/legal guardian/or surrogate who does not wish to participate in the 
capacity assessment (adults) or decline consent (and assent for minors) will not participate in this 
study. Any individuals who appear to be distressed during participation will be withdrawn based 
on a decision by the physician. 


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12 STUDY FINANCES 
12.1 Funding Source 
This study is financed through a grant from the Epilepsy and Dravet Foundation as well as PTC 
Therapeutics. 
 
12.2 Costs to Subjects 
PTC Therapeutics will provide the study medicine free of charge to participating research 
subjects for the duration of this study. The subjects will be receiving medical care as a part of 
this research study. Subjects or their insurance company will not be charged or held responsible 
for the costs of that care. 
All costs related to procedures and assessments associated with participating in this study will be 
free of charge. 
Procedures that are part of routine care or to assess the subject’s health but are not mandatory for 
the study will not be covered. The subject’s individual insurance or government health insurance 
program may not cover certain services, items, or procedures. This may be discussed with the 
subject’s insurance carrier in advance. The subject/parent/legal guardian will be responsible for 
any co-payments and/or deductibles for services rendered. 
The subject and/or the subject’s health insurance may be billed for the costs of medical care 
during this study if these expenses would have happened even if the subject was not in the study, 
or if the subject’s insurance agrees in advance to pay.  If the subject has health insurance, the 
cost of these services will be billed to the subject’s insurance company.  If the subject’s 
insurance does not cover these costs or the subject does not have insurance, these costs will be 
the subject’s responsibility. 
 
12.3 Payments to Subjects 
Reasonable reimbursement will be made for travel expenses required for subjects in this study. 
Subjects will receive compensation at each visit for their participation as follows: 
Screening Visit - $75 
All Other Visits up to Week 128 - $50 for each 
If compensation is greater than the minimum reporting requirements as set by the Internal 
Revenue Service (>$600), the sponsor must report this income to the IRS and will issue subjects 
a 1099 form as compensation will be considered taxable income. The sponsor will ask that 
subjects provide social security number for this purpose. Subjects will be responsible for 
reporting this compensation when they file tax returns. If subjects withdraw from the study prior 
to its completion, subjects will be compensated for the time actually spent in proportion to the 
fraction of the study completed. 
The National Organization for Rare Disorders (NORD) can provide assistance with travel and 
lodging arrangements for subjects who go to study research centers in the United States. If 
subjects participate in this optional program, they will need to provide personal information such 


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as name, address, and telephone numbers to a member of NORD. The research center will 
provide a separate brochure from NORD, which explains the details and rules of the program. 
 
12.4 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by NYU prior to participation in 
this study. All NYULMC investigators will follow the applicable New York University conflict 
of interest policies. 


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13 PUBLICATION PLAN 
The publication plan will be to publish the entire series of subjects, inclusive of efficacy and 
tolerability findings. Depending on what other groups are involved in similar studies, we may 
elect to publish in collaboration with other groups. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by PTC Therapeutics for the purposes of performing the study, 
will be published or passed on to any third party without the consent of PTC Therapeutics. Any 
investigator involved with this study is obligated to provide PTC Therapeutics with complete test 
results and all data derived from the study. 


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14 REFERENCES 
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promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature. 
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patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50(4):477-487. 
Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. 
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Ghosh S, Ganesan R, Amrani N, Jacobson A. Translational competence of ribosomes released 
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Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, et al. Ataluren 
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15 APPENDICES 
 
Appendix A 
Seizure definition 
Absence: A generalized seizure with abrupt onset and offset of altered awareness, which can 
vary in severity. Memory for events during the seizures is usually impaired although there may 
be some retained awareness, particularly for adolescents. Clonic movements of eyelids, head, 
eyebrows, chin, perioral, or other facial parts may occur, most typically at 3 Hz (International 
League Against Epilepsy). 
Myoclonic: A single or series of jerks (brief muscle contractions). Each jerk is typically 
milliseconds in duration (International League Against Epilepsy). 
Complex partial/focal dyscognitive: Focal seizures are conceptualized as originating within 
networks limited to one hemisphere. They may be discretely localized or more widely 
distributed. Focal seizures may originate in subcortical structures. Dyscognitive refers to altered 
awareness or responsiveness. Degree of loss of awareness or responsiveness may vary 
(International League Against Epilepsy).