Clinical trial NCT02721069
Conditions: Acute Repetitive Seizures Breakthrough Seizures
Keywords: Seizures Epilepsy
Sponsor: Neurelis, Inc.
Start date: 2016-04-11; Completion date: 2020-07-23
Enrollment: 175 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a 12 month safety study to evaluate the safety of repeated doses of NRL-1

Detailed description:
This is a Phase 3, repeat dose, open-label, safety study in Epilepsy subjects who have frequent breakthrough seizures or Acute Repetitive Seizures (ARS). NRL-1 will be administered as needed to treat bouts of those seizures over a 12-month period of time. Doses will be defined as 5 mg, 10 mg, 15 mg, or 20 mg based on the subject's body weight. A diary will be used to record the seizure and NRL-1 administration.

Arms: arm 1: Intranasal dose of NRL-1 will be administered at either 5 mg, 10 mg, 15 mg, or 20 mg based on the subject's body weight.
Interventions: intervention 1: NRL-1
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Neurelis, Inc. 
VALTOCO® (diazepam nasal spray) 
Protocol DIAZ.001.05 
Confidential/Proprietary Information 
STUDY TITLE: 
A 12-Month Open-Label, Repeat-Dose Safety Study of NRL-1 in 
Epilepsy Subjects 
STUDY PHASE: 
Phase 3  
PROTOCOL NUMBER: 
DIAZ.001.05 
NCT Number:  NCT02721069 
Protocol Version 4.0 - 28 September 2017  


 
NEURELIS, INC. 
 
INVESTIGATIONAL NEW DRUG PROTOCOL 
 
NRL-1 (INTRANASAL DIAZEPAM) 
 
PROTOCOL NUMBER DIAZ.001.05 
VERSION 4 
28 SEPTEMBER 2017 
 
 
A 12-MONTH, OPEN-LABEL, REPEAT-DOSE SAFETY STUDY OF NRL-1 IN 
EPILEPSY SUBJECTS 
 
SPONSOR: 
 
NEURELIS INC. 
11682 EL CAMINO REAL, SUITE 255 
SAN DIEGO, CA 92130 
 
 
CONFIDENTIAL 
 
 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
28 September 2017 
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CONFIDENTIAL 
KEY CONTACTS FOR THE STUDY 
SPONSOR’S  
REPRESENTATIVES: 
 
Sponsor Contact 
Richard E. Lowenthal, MSc, MBA 
Program Manager 
Neurelis, Inc. 
Cell: 1-858-335-1300 
Tel: 1-858-227-3008 
E-mail: richard@pacificlinkconsulting.com 
 
Study Manager 
Robert Hasson 
Project Manager 
Neurelis, Inc. 
Cell:  1-619-540-6253 
Tel: 1-858-368-9925 
E-mail: rhasson@pacificlinkconsulting.com 
 
Study Medical Monitor 
Sarina Tanimoto, MD, PhD 
Chief Medical Officer, PLC 
Neurelis, Inc. 
Cell: 1-858-774-8716  
Tel: 1-858-227-3008  
E-mail: sarina@pacificlinkconsulting.com 
 
Serious Adverse Event Reporting 
Fax: 1-858-436-1401 
Email: NeurelisSafety@pacificlinkconsulting.com 
 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
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TABLE OF CONTENTS 
KEY CONTACTS FOR THE STUDY .......................................................................................... 2 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF FIGURES ........................................................................................................................ 6 
LIST OF APPENDICES ................................................................................................................. 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
INVESTIGATOR STATEMENT ................................................................................................ 10 
PROTOCOL SYNOPSIS ............................................................................................................. 12 
1.0 
INTRODUCTION ............................................................................................................ 16 
1.1 
Nonclinical Assessments ................................................................................................... 17 
1.1.1 Pharmacology ................................................................................................................... 18 
1.1.2 Toxicology of NRL-1 and Diazepam ............................................................................... 18 
1.1.2.1 Single Dose Toxicity Studies ............................................................................................ 18 
1.1.2.2 Repeated-Dose Toxicology Studies .................................................................................. 19 
1.1.2.3 Genotoxicity and Carcinogenicity Studies........................................................................ 19 
1.1.2.4 Reproductive and Developmental Studies ........................................................................ 20 
1.1.3 Pharmacology and Toxicology of Intravail A3 ................................................................ 20 
1.2 
Clinical Experience (Diazepam and NRL-1) ..................................................................... 21 
1.2.1 Clinical Trials with NRL-1 ............................................................................................... 22 
1.2.2 Pharmacokinetics and Product Metabolism in Humans ................................................... 24 
1.3 
Study Rationale .................................................................................................................. 26 
2.0 
PURPOSE AND STUDY OBJECTIVES ........................................................................ 27 
2.1 
Purpose .............................................................................................................................. 27 
2.2 
Study Objectives ............................................................................................................... 27 
2.2.1 Primary Objective ............................................................................................................. 27 
2.2.2 Secondary Objectives........................................................................................................ 27 
2.3 
Description of Study Design ............................................................................................. 27 
2.4 
Study Endpoints ................................................................................................................ 28 
2.4.1 Primary Endpoint .............................................................................................................. 28 
2.4.2 Secondary Endpoints ........................................................................................................ 28 
2.4.3 Randomization/Assignment to Study Drug ...................................................................... 28 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
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2.5 
Study Drugs ...................................................................................................................... 29 
2.5.1 Test Product ...................................................................................................................... 29 
2.5.2 Dose and Dose Justification .............................................................................................. 29 
2.5.3 Bioanalytical Method ........................................................................................................ 30 
2.6 
Concomitant Medications ................................................................................................. 30 
2.6.1 Prior and Concomitant Medications ................................................................................. 30 
2.7 
Procedures for Monitoring Subject Compliance............................................................... 30 
3.0 
STUDY POPULATION ................................................................................................... 31 
3.1 
Inclusion Criteria .............................................................................................................. 31 
3.2 
Exclusion Criteria ............................................................................................................. 32 
4.0 
SAFETY ASSESSMENTS ............................................................................................... 32 
4.1 
Collection of Adverse Events Data ................................................................................... 32 
4.2 
Clinical Laboratory Evaluations ....................................................................................... 33 
4.2.1 Hematology ....................................................................................................................... 33 
4.2.2 Serum Chemistry .............................................................................................................. 33 
4.2.3 Urinalysis .......................................................................................................................... 33 
4.2.4 Urine Drug, Alcohol, and Tobacco Screen ....................................................................... 34 
4.2.5 Other Blood Tests ............................................................................................................. 34 
4.3 
Physical Examinations and Medical History .................................................................... 34 
4.3.1 Physical and Neurological Examination ........................................................................... 34 
4.3.2 Medical History ................................................................................................................ 34 
4.4 
C-SSRS ............................................................................................................................. 34 
4.5 
ECG................................................................................................................................... 34 
4.6 
Height and Weight ............................................................................................................ 35 
4.7 
Vital Signs ......................................................................................................................... 35 
4.8 
Smell Test ......................................................................................................................... 35 
4.9 
Nasal Irritation Assessments ............................................................................................. 35 
4.9.1 Assessment of Nasal Irritation: ......................................................................................... 35 
4.9.2 Assessment of Mucosal Erythema: ................................................................................... 36 
4.9.3 Assessment of Mucosal Edema: ....................................................................................... 36 
4.9.4 Assessment of Nasal Discharge: ....................................................................................... 36 
4.9.5 Assessment of Mucosal Crusting: ..................................................................................... 36 


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4.9.6 Assessment of Mucosal Epistaxis: .................................................................................... 37 
4.10 
Quality of Life questionnaire ............................................................................................ 37 
4.11 
Pregnancy Test .................................................................................................................. 37 
5.0 
PHARMACOKINETICS .................................................................................................. 37 
6.0 
PHARMACODYNAMICS............................................................................................... 37 
7.0 
EFFICACY ....................................................................................................................... 38 
8.0 
STUDY VISITS ................................................................................................................ 38 
8.1 
Screening........................................................................................................................... 38 
8.2 
Screening Evaluations (Days -21 to -1) ............................................................................ 38 
8.3 
Baseline Evaluations (Day -3 to 0, pre-dose) ................................................................... 39 
8.4 
Drug Administration ......................................................................................................... 40 
8.5 
Day 30 to 330 (± 7 days) ................................................................................................... 40 
8.6 
Day 365 (± 7 days) ............................................................................................................ 40 
8.7 
Treatment beyond Day 365 ............................................................................................... 41 
8.8 
Follow Up telephone contact ............................................................................................ 41 
8.9 
Termination Procedures .................................................................................................... 41 
9.0 
PREMATURE DISCONTINUATION FROM STUDY .................................................. 41 
10.0 
PRODUCT SPECIFICATIONS ....................................................................................... 42 
10.1 
Description ........................................................................................................................ 42 
10.2 
Formulation, Packaging, and Labeling ............................................................................. 43 
10.3 
Receipt, Storage and Stability of NRL-1 .......................................................................... 43 
10.4 
Preparation of Study Drug ................................................................................................ 43 
10.5 
Administration of Study Drug .......................................................................................... 43 
10.6 
Ordering and Distribution of Study Drug ......................................................................... 44 
10.7 
Accountability of Study Drugs ......................................................................................... 44 
11.0 
SAFETY MONITORING AND ADVERSE EVENTS ................................................... 45 
11.1 
Adverse Events ................................................................................................................. 45 
11.2 
Serious Adverse Events .................................................................................................... 47 
11.2.1 Reporting Requirements for Serious Adverse Events ...................................................... 47 
11.2.2 Recording of Serious Adverse Events .............................................................................. 48 
12.0 
STATISTICAL CONSIDERATIONS.............................................................................. 48 
12.1 
Sample Size Determination............................................................................................... 48 


Neurelis, Inc. 
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12.2 
Safety ................................................................................................................................ 48 
13.0 
DATACOLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ............ 49 
13.1 
Data Collection and Reporting .......................................................................................... 49 
13.2 
Study Monitoring .............................................................................................................. 50 
13.3 
Data Disclosure and Subject Confidentiality .................................................................... 50 
14.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 51 
14.1 
Basic Principles ................................................................................................................. 51 
14.2 
Institutional Review Board/Ethics Committee ................................................................. 51 
15.0 
REFERENCE LIST .......................................................................................................... 52 
 
LIST OF TABLES 
Table 1:  Intravail A3 Safety Margins Based on Current NRL-1 Formulation ............................ 21 
Table 2:  Summary of Pharmacokinetic Data from the DIAZ.001.01 Study ............................... 23 
Table 3:  Severity Assessment Terminology for Reporting Adverse Events (CTCAE v 4.03) .... 46 
Table 4:  Contact Information for SAE Reporting ........................................................................ 48 
 
LIST OF FIGURES 
Figure 1:  Diazepam ...................................................................................................................... 16 
 
LIST OF APPENDICES 
APPENDIX A: 
SCHEDULE OF STUDY PROCEDURES ..................................................... 54 
APPENDIX B: 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ................ 57 
APPENDIX C: 
NIH TOOLBOX ODOR IDENTIFICATION TEST ...................................... 77 
APPENDIX D: 
QUALITY OF LIFE IN EPILEPSY (QOLIE) ................................................ 78 
APPENDIX E: 
DIRECTIONS FOR USE ................................................................................ 96 
 
 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
AEDs 
antiepileptic drugs 
ARS 
acute repetitive seizures 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-t 
area under the plasma concentration-time curve from 0 to t hours  
AUC∞ 
area under the plasma concentration-time curve to infinity 
ß-hCG 
serum pregnancy test 
BUN 
blood urea nitrogen 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CFSAN 
Center for Food Safety and Nutrition  
cGMP 
current Good Manufacturing Practices 
Cmax 
Maximum plasma concentration 
CNS 
central nervous system 
CO2 
bicarbonate/carbon dioxide 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFU 
Directions for Use 
E.coli 
Escherichia coli 
ECG 
Electrocardiogram 
EPA 
Environmental Protection Agency 
FDA 
US Food and Drug Administration 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
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ABBREVIATION 
DEFINITION 
GRAS 
generally recognized as safe 
HbSAg 
Hepatitis B surface antigen 
HEENT 
head, ears, eyes, nose, and throat 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IM 
Intramuscular 
IP 
investigational product 
IRB/EC 
Institutional Review Board/Ethics Committee 
IUD 
intrauterine device 
IV 
intravenous 
kg 
kilogram(s) 
LD50 
lethal dose 50% or median lethal dose 
LDH 
lactate dehydrogenase 
MRHD 
maximum recommended human dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter 
NOEL 
no observable effect level 
NRL-1.A 
100 mg/mL diazepam nasal spray suspension manufactured for Neurelis, Inc. 
NRL-1.B 
100 mg/mL diazepam nasal spray solution manufactured for Neurelis, Inc. 
OECD 
Organisation for Economic Co-operation and Development 
PBMC 
blood peripheral mononuclear cells 
PI 
principal investigator 
PK 
pharmacokinetics 
QOLIE 
Quality of Life in Epilepsy 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
Standard Deviation 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
28 September 2017 
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ABBREVIATION 
DEFINITION 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
t1/2 
mean elimination half-life 
tmax 
time to maximum plasma concentration 
µL 
microliter 
UDS 
unit dose sprayer 
US/USA 
United States of America 
WBC 
white blood cell 
WHODD 
World Health Organization Drug Dictionary 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
28 September 2017 
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CONFIDENTIAL 
INVESTIGATOR STATEMENT 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Conference on Harmonisation Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will maintain accurate source documents from which data are transcribed onto case report 
forms and accurate drug accountability records that show the receipt and disposition of all study 
drugs. 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in 
the conduct of the study.  
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form prior to enrollment of subjects in the study. I understand that any 
modifications to the protocol made during the course of the study must first be approved by the 
IRB/EC prior to implementation except when such modification is made to remove an immediate 
hazard to the subject. 
I will ensure that a fully executed IRB-approved Informed Consent Form is obtained from each 
subject prior to initiation of any study procedures.  
I will report (within 24 hours) any serious adverse event, regardless of relationship to study drug, 
or pregnancy that occurs during the course of the study, in accordance with the procedures 
described in Section 11.0 of the protocol. I will notify the Sponsor if I become aware that a 
partner of a study subject becomes pregnant while the subject was receiving this study drug. 
I will submit all protocol inclusion/exclusion violations to the Medical Monitor for approval 
prior to enrollment of the subject in the study. 
I will allow the Sponsor, Neurelis, Inc. (Neurelis) and its agents, as well as the United States 
(U.S.) Food and Drug Administration (FDA) and other regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than one week). 
This protocol contains information that is proprietary to Neurelis.  The information contained 
herein is provided for the purpose of conducting a clinical trial for Neurelis. 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version: 4 
 
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CONFIDENTIAL 
The contents of this protocol may be disclosed to study personnel under your supervision and to 
your IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Neurelis. 
 
 
 
__________________________________________ 
_______________________ 
Investigator’s Signature 
Date 
 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
Version:4 
 
28 September 2017 
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CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Study Title 
A 12-Month Open-Label, Repeat-Dose Safety Study of NRL-1 in Epilepsy Subjects 
(DIAZ.001.05) 
Phase 
Phase 3 
Study Drug 
NRL-1 (Intranasal Diazepam) 
Objectives 
Primary objective:  
• 
The primary objective of this study is to assess the safety of diazepam after repeat 
intranasal doses of NRL-1 administered to Epilepsy subjects who experience frequent 
breakthrough seizures or Acute Repetitive Seizures (ARS), over a 12-month period.  
Secondary objective: 
• 
To assess the tolerability of diazepam after repeat intranasal administration of NRL-1; 
• 
To assess the ability of caregivers to administer NRL-1 based on the Directions for Use 
(DFU) (see APPENDIX E.); 
To assess an improvement in the Quality of Life with NRL-1 use as compared to Diastat. 
Study Design 
This is a Phase 3, repeat dose, open-label, safety study in Epilepsy subjects who have frequent 
breakthrough seizures or ARS.  NRL-1 will be administered as needed to treat bouts of those 
seizures over a 12-month period of time.  Doses will be defined as 5 milligrams (mg), 10 mg, 
15 mg, or 20 mg based on the subject’s body weight.  The dosage may be increased or 
decreased for efficacy or safety reasons, if determined by the Principal Investigator that a 
different dose is necessary and there is no safety concern.  A diary will be used to record the 
seizure and NRL-1 administration. 
The study consists of a screening phase, a baseline, a 12-month treatment period and a follow-
up telephone contact 28-days after the last dose of NRL-1 or at study termination.  The 
primary purpose of this study is to assess the safety of repeat doses of NRL-1 as intermittent 
chronic therapy to treat frequent break through seizures or ARS. Subjects will return to the site 
per the Schedule of Events with all study visits having a ±7 day window around visits. 
Safety assessments include physical and neurological examination including head, ears, eyes, 
nose, and throat (HEENT), vital signs, laboratories (hematology, serum chemistry, and 
urinalysis), 12-lead ECGs, and AE assessment.  Concomitant medications will be recorded.  
Columbia-Suicide Severity Rating Scale (C-SSRS for adults or pediatric), Nasal Examination 
and Irritation Assessment (The following will be assessed on separate scales: nasal irritation, 
nasal discharge, mucosal erythema, mucosal edema, mucosal crusting and mucosal epistaxis), 
Sedation Score Assessment, and Smell Test (NIH Toolbox Odor Identification Test, (1, 2) will 
be conducted at each visit.  A targeted physical examination may be used to evaluate any 
potentially related side effects. 
Subjects and caregivers will be trained on the proper use of the NRL-1 nasal sprayer at 
screening period and as needed during treatment period.  The ability of caregivers to 
administer NRL-1 based on the Directions for Use (DFU) will be assessed (see APPENDIX 
E). 
The Quality of Life in Epilepsy (QOLIE) questionnaire will be administered to assess the 
quality of life while on NRL-1 compared to baseline therapy at time of enrollment. 
Naïve subjects may be entered into this study as well as those subjects completing the protocol 
DIAZ.001.04 are eligible for the long-term safety study (DIAZ.01.05) and may receive 
treatment with NRL-1 under DIAZ.01.05 protocol. 
Sample Size 
Up to 100 subjects, at least 30 age 6 to 11 years and up to 70 over 12 years of age, are to be 
enrolled. 
Study 
Population 
Subjects with a clinical diagnosis of frequent break through seizures or ARS with bouts of 
uncontrolled seizures, who, in the opinion of the Investigator, may need a benzodiazepine for 
seizure control. 


Neurelis, Inc. 
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NRL-1 (Diazepam Intranasal) 
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Main Inclusion 
Criteria 
Subjects must meet All of the following inclusion criteria to be enrolled in this study: 
1. Male and female subjects between the ages of 6 and 65 years, inclusive. 
2. Written informed consent to participate in the study. 
3. Subject has a clinical diagnosis of Epilepsy and while on a stable regimen of anti-epileptic 
medication, still experiences bouts of seizures (e.g. frequent break through seizures or 
ARS), and who, in the opinion of the Investigator, may need benzodiazepine intervention 
for seizure control 1 time every other month on average (i.e. average 6 times a year). 
4. Subject has a qualified caregiver or medical professional available that can administer 
study medication in the event of a seizure. 
5. Subjects having either partial or generalized Epilepsy with motor seizures or seizures with 
clear alteration of awareness. 
6. Female subjects of childbearing potential, defined as having a menstrual cycle and who 
are not surgically sterile or less than two (2) years postmenopausal, must complete a 
pregnancy screen and agree to utilize one of the following forms of contraception during 
the trial and for 21 days after the last dose of study drug:  abstinence, hormonal (oral, 
transdermal, implant, or injection), barrier (condom, diaphragm with spermicide), 
intrauterine device (IUD), or vasectomized partner (six months minimum).  Subjects must 
have used the same method for at least one (1) month prior to starting the study. 
7. No clinically significant abnormal findings in the medical history, on the physical 
examination or electrocardiogram (QTcF<450 msec for males and QTcF<470 msec for 
females). 
Subjects and caregivers must agree to return to the study site for all study visits and must be 
willing to comply with all required study procedures. 
Main 
Exclusion 
Criteria  
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. A history of clinically significant gastrointestinal, renal, hepatic, hematologic, endocrine, 
oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other 
condition which, in the opinion of the Investigator, would jeopardize the safety of the 
subject. 
2. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days 
prior to study screening. 
3. Subjects with active major depression or a past suicide attempt, or any Suicidal Ideation 
of 3, 4, or 5 or any Suicidal Behavior in Lifetime using Columbia-Suicide Severity Rating 
Scale (C-SSRS). The pediatric C-SSRS should be used for subjects age 6 to 11.  The adult 
C-SSRS should be used for subjects 12 and greater years of age. 
4. A history of allergic or adverse responses to diazepam or any comparable or similar 
product. 
5. Participation in a clinical trial other than protocol DIAZ.001.04 within 30 days prior to 
Day 0.  Participation in an observational (non-interventional) study is not excluded as 
long as there are no scheduling conflicts with this study. 
6. Positive serum pregnancy test (ß-hCG) at screening for subjects age 12 or greater. 
Positive blood screen for Human immunodeficiency virus (HIV), Hepatitis B surface antigen 
(HbSAg), or Hepatitis C, or a positive urine screen for alcohol, or drugs of abuse, except 
marijuana use for medical reasons.  When marijuana was used for medical reasons in the 
opinion of the investigator, it is not considered as drug abuse and the patient can be enrolled 
even if the marijuana metabolites in the urine revealed as positive. 


Neurelis, Inc. 
Protocol DIAZ.001.05 
NRL-1 (Diazepam Intranasal) 
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Dosage and 
Administration 
of Study Drug 
The initial dose of 5 mg, 10 mg, 15 mg, or 20 mg of NRL-1 will be selected according to the 
subject’s weight (rounded to the nearest kg) based on the following: 
For Children Age 6-11 Years: 
• 
10 kg to 18 kg body weight will receive a 5 mg dose (50 mg/milliliter [mL], 100 
microliters [µL]) administered as one spray in the left nostril. 
• 
19 kg to 37 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one 
spray in the left nostril. 
• 
38 kg to 55 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two 
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed 
by the right nostril). 
• 
56 kg to 74 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 
administered as two 10 mg sprays with one in each nostril (the left nostril will be 
sprayed first followed by the right nostril). 
For Age 12 Years or greater: 
• 
14 kg to 27 kg body weight will receive a 5 mg dose (50 mg/mL, 100 µL) 
administered as one spray in the left nostril. 
• 
28 kg to 50 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one 
spray in the left nostril. 
• 
51 kg to 75 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two 
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed 
by the right nostril). 
• 
Greater than 76 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 
administered as two 10 mg sprays with one in each nostril (the left nostril will be 
sprayed first followed by the right nostril). 
A second dose may be administered if needed 4-12 hours after the initial dose of NRL-1.  
Additionally, the dosage may be increased or decreased for efficacy or safety reasons, if 
determined by the Principal Investigator that a different dose is necessary and there is no 
safety concern. 
Safety Analysis 
AEs will be collected and reviewed to evaluate the safety and tolerability of diazepam nasal 
solution.  Other safety measures will include physical examination, neurological examination, 
vital sign measurement, and clinical laboratory tests, nasal irritation and examination, and C-
SSRS.  
AE collection will begin on Day 0 after baseline assessments are complete prior to the initial 
treatment with NRL-1 and continue for 28-days after study termination. AE may be either 
spontaneously reported or elicited during questioning and examination of a subject. AE 
information will be elicited at appropriate intervals by indirect questioning using a non-leading 
question. AEs that occur after dosing in a home setting will be recorded in a diary and reported 
at the next study visit.  Subjects will receive follow-up telephone contact approximately 28 
days (± 3 days) after study termination to determine if any AE has occurred and to follow-up 
on any TEAEs ongoing since last communication with the subject. 
Nasal irritation will be assessed at baseline and each study visit as well as based on reports of 
any nasal mucosal AEs between visits to the clinical site.  Smell tests will be conducted at 
baseline and at each study visit.  The NIH Toolbox Odor Identification Test will be used as 
smell test in this study (1, 2).  
The C-SSRS for adults and pediatrics, a measure of suicidal ideation and behavior, will be 
used to document suicidality in order to classify suicidal events.  Suicidality will be assessed 
at screening for eligibility (see APPENDIX B). 
The incidence and severity of TEAEs reported during the study and their relationship to study 
drug will be tabulated.  TEAEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be presented by body system. 


Neurelis, Inc. 
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The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by therapeutic class and preferred term.  Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication within each therapeutic class by dose cohort. 
Study 
Duration 
It is planned that each subject will participate in the primary safety portion of the study for up 
to 414-days, which comprises a 21-day screening period, baseline, a treatment period of up to 
365-days, and follow-up period up to 28 days.  Subjects may be continued on treatment 
beyond Day 365 at the discretion of the investigator and approval of the sponsor. For 
treatment beyond Day 365, it is recommended that subjects are contacted by the Investigator at 
least each 3 months to obtain information on any adverse events.  Study visits after Day 365 
for safety assessment will be recorded in the EDC (CRF) as Unscheduled visits. 
Study Centers 
Up to twenty (20) centers will enroll patients. 
 
 
 
 
 


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1.0 
INTRODUCTION 
Epilepsy is a significant health problem affecting 50 million people worldwide, including 
2.7 million Americans. Epilepsy negatively impacts quality of life and increases morbidity and 
mortality. In the US, 25-50,000 deaths each year are attributed to seizures and related causes. 
Seizure emergencies include acute repetitive seizures (ARS), which are defined as intermittent 
increases of seizure activity while on stable regimens of antiepileptic drugs (AEDs).  The 
intravenous (IV) formulation of diazepam has been used for over 30 years in the treatment of 
seizure emergencies, including status epilepticus, but the current standard of care for ARS is a 
rectal gel formulation of diazepam, Diastat®(3). 
Diastat rectal gel was approved for marketing by the United States (US) Food and Drug 
Administration (FDA) in 1997 and is the only diazepam formulation in the US that is approved 
for ARS.  Although Diastat has an excellent post-approval safety profile and is highly effective 
in the management of ARS, the product is considered inconvenient and cumbersome, particularly 
for adult patients, because use of the product requires rectal administration by the caregiver.  Due 
to this route of administration, the use of Diastat has been limited primarily to the pediatric 
population, ages 2-12 years. 
Diazepam, illustrated in Figure 1 below, is a benzodiazepine anticonvulsant with the chemical 
name; 7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one.  It is a colorless to 
light yellow crystalline compound, insoluble in water. The empirical formula is C16H13ClN2O 
and the molecular weight is 284.75. 
Figure 1:  Diazepam 
Neurelis is investigating NRL-1 for the treatment of ARS as an alternative, more convenient to 
use product than the current standard of care, Diastat rectal gel, which is administered rectally at 
the time of occurrence of an acute seizure.  Two different formulations of NRL-1 were evaluated 
in an absolute bioavailability study to assess the best absorption profile between a suspension 


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formulation (NRL-1.A) and a solution formulation (NRL-1.B).  This initial pharmacokinetics 
(PK) study demonstrated that the solution formulation of NRL-1 gave the best pharmacokinetic 
characteristics with over 97% absolute bioavailability versus the IV diazepam, and was most 
comparable to the Diastat rectal gel PK profile reported in the label.  As a result of this PK study, 
Neurelis will pursue additional studies with NRL-1 to evaluate the safety and pharmacokinetic 
characteristics of a final commercial product. 
NRL-1 is a novel formulation that includes a proprietary functional excipient called Intravail® 
A3, supplied by Aegis Therapeutics.  Intravail A3 is a GRAS (Generally Recognized As Safe) 
excipient that is being evaluated in low concentrations (less than 1%) to improve the 
bioavailability of drugs administered by the intranasal route. The absorption enhancing 
properties of alkylglycoside surfactants, such as Intravail A3, are believed to occur via loosening 
of the tight junctions (paracellular) coupled with the fluidization and penetration of cell 
membranes (transcellular) causing increased drug movement into the cell (4). The NRL-1 
formulation was found to have an optimal bioavailability with the addition of 0.25% 
Intravail A3. 
A Phase 1 study with NRL-1 was completed in healthy volunteers to evaluate the absorption and 
PK of two different formulations.  The primary objective of this study was to assess the 
bioavailability and PK of diazepam after intranasal administration of suspension and solution 
formulations compared to IV administration to healthy volunteers under fasted conditions. The 
secondary objective of this study was to assess the safety and tolerability of two formulations of 
diazepam nasal spray after a single intranasal administration of each formulation.  
Based on the pilot PK work completed, it is anticipated that NRL-1 will provide comparable 
exposures of diazepam by the intranasal route of administration to that observed with Diastat 
rectal gel.  Intranasal delivery is anticipated to be a more convenient and more acceptable route 
of administration for patients and their caregivers. 
1.1 
Nonclinical Assessments 
Given the clinical history of diazepam, the pharmacology, toxicology, and general safety are well 
understood.  Since it was first approved for marketing more than 40 years ago, a large amount of 
the relevant data on the safety and efficacy of diazepam is derived from clinical use.  The 
following section provides a brief overview of the literature and public information on the 
nonclinical safety of diazepam for the benefit of the investigator. 
Neurelis has conducted animal PK studies to assess the bioavailability and tolerability of the 
NRL-1 formulations intended for use in clinical studies.  These studies were conducted in rats, 
rabbits, and dogs.  No unexpected or adverse clinical observations were noted in these studies. 


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1.1.1 Pharmacology 
Diazepam has anticonvulsant properties unique to some benzodiazepines and is the only product 
that is specifically approved for the treatment of ARS.  Benzodiazepines act via micromolar 
benzodiazepine binding sites and significantly inhibit depolarization-sensitive calcium uptake in 
rat nerve cell preparations (5).  Diazepam inhibits acetylcholine release in mouse hippocampal 
synaptosomes.  This has been found by measuring sodium-dependent high affinity choline 
uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo.  This 
may play a role in explaining diazepam's anticonvulsant properties (6).  Diazepam binds with 
high affinity to glial cells in animal cell cultures (7).  Diazepam at high doses has been found to 
decrease histamine turnover in mouse brain via direct action at the benzodiazepine-gamma-
aminobutyric acid (GABA) receptor complex (8).  Diazepam also decreases prolactin release in 
rats (9).  Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase 
activity, but has a slight effect on GABA transaminase activity (10). 
Metabolism studies in animals and man have indicated that oral diazepam is rapidly absorbed 
from the gastrointestinal tract.  Peak blood levels are reached within 1-2 hours after 
administration.  The acute half-life is 6-8 hours with a slower decline thereafter, possibly due to 
tissue storage. 
Limited data are available on nonclinical evaluations of diazepam in safety pharmacology studies 
for central nervous system (CNS) effects.  However, diazepam has been extensively studied in 
humans and its effects on the CNS are well established clinically.  Diazepam is a benzodiazepine 
with CNS depressant properties and a somewhat flatter dose-response slope than other sedative-
hypnotic drugs.  In laboratory animals, diazepam produces, in varying doses, taming, 
disinhibitory, sedative, anticonvulsant, muscle relaxant, ataxic, and hypnotic effects. 
Diazepam is relatively devoid of autonomic effects and does not significantly reduce locomotor 
activity at low doses, nor depress amphetamine-induced excitation.  In high doses, it activates the 
drug metabolizing enzymes in the liver.  Diazepam also possesses dependence liability and may 
produce withdrawal symptoms, but has a wide margin of safety against poisoning. 
Diazepam has a slight depressive effect on cardiovascular function, but is widely considered to 
have less cardiovascular liability than any other benzodiazepines. 
1.1.2 Toxicology of NRL-1 and Diazepam 
1.1.2.1 Single Dose Toxicity Studies 
The acute toxicity of diazepam is considered to be very low relative to other benzodiazepine 
compounds or other psychotropic drugs.  Generally, after very large acute doses (more than 
450 times the typical human dose), respiratory depression and failure are the primary causes of 
death in animals.  Acute toxicology studies have been reported in the rat, dog, and mouse (11).  


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Based on these studies a median lethal dose (LD50) for diazepam has been established or each 
species. 
LD50 (oral) rat: 
1200 milligrams (mg)/kilogram (kg) 
 
LD50 (oral) dog: 
1000 mg/kg 
 
LD50 (oral) mouse: 
700 mg/kg 
1.1.2.2 Repeated-Dose Toxicology Studies 
The toxicology of diazepam is well understood in the literature and based on literature for 
approved marketed products. 
During animal PK studies, a total of 12 formulations of diazepam with Intravail A3 
concentrations up to 0.50% were evaluated in rabbits.  These studies also included evaluation of 
clinical signs and symptoms of toxicology, as well as nasal irritation.  During these studies with 
intranasal doses up to 10 mg/animal, no unexpected clinical signs of toxicity were observed, with 
the only notable effect of sedation being the expected pharmacological effect of diazepam.  
Gross pathology and histopathology evaluations of nasal mucosa from animals after sacrifice did 
not reveal signs of nasal irritation or other findings that were abnormal as compared to controls.  
Thus no significant toxicity or nasal irritation (of selected formulations within the two studies) 
was observed with any of the NRL-1 formulations tested in the rabbit. 
Intranasal doses of NRL-1 non-aqueous solution were well tolerated in rats up to 1 mg/day (a 
10 microliters [µL] dose volume of 100 mg diazepam per milliliter [mL]) and dogs dosed with 
20 mg/day (a 200 µL dose volume of 100 mg diazepam per mL).  After intranasal administration 
of NRL-1 formulations to rabbits in single dose PK and tolerability studies, and to rats and dogs 
in non-Good Laboratory Practices (GLP) intranasal toxicity studies for 28 days, there were no 
significant signs of clinical effects to indicate acute irritation and after sacrifice there were no 
dose-limiting clinical observations or toxicologically important events.  All dose levels were well 
tolerated with only minimal histopathological changes.  A full summary of the repeat-dose 
toxicology studies is provided in the NRL-1 Investigator's Brochure. 
The anticipated safety of the NRL-1 formulations is expected to be similar to diazepam dosed by 
rectal gel administration.  Based on animal studies there does not appear to be any significant 
acute or chronic irritation of the nasal mucosa. 
1.1.2.3 Genotoxicity and Carcinogenicity Studies 
Diazepam has been reported to have mutagenic activity in the Salmonella typhimurium tester 
strain TA100 in the Ames test (12).  Little or no effect was seen in an assay for chromosomal 
aberrations, performed in Chinese hamster cells in vitro(13). 
Studies by De la Iglesia et al.(14) have demonstrated no increase in tumors frequency after 
feeding diazepam, 75 mg/kg/day, to rats and mice for 104 and 80 weeks, respectively. 


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1.1.2.4 Reproductive and Developmental Studies 
Diazepam has been shown to be teratogenic in mice and hamsters when given orally at single 
doses of 100 mg/kg or greater (approximately eight times the maximum recommended human 
dose [MRHD=1 mg/kg/day] or greater on a mg/m basis).  Cleft palate and exencephaly are the 
most common and consistently reported malformations produced in these species by 
administration of high, maternally-toxic doses of diazepam during organogenesis.  Rodent 
studies have indicated that prenatal exposure to diazepam doses similar to those used clinically 
can produce long term changes in cellular immune responses, brain neurochemistry, and 
behavior (15). 
1.1.3 Pharmacology and Toxicology of Intravail A3 
The toxicokinetics and metabolism of alkylglycosides, such as Intravail A3 (dodecylmaltoside), 
have been studied in detail under the Organisation for Economic Co-operation and Development 
(OECD) Guidelines for Testing of Chemicals.  Orally and nasally administered alkylglycosides 
are hydrolyzed to glucose and the corresponding long chain alcohol.  No toxic metabolites are 
formed at any stage in the metabolic process.  Dodecyl maltoside is a component (up to 
approximately 25%) of a mixture of alkylglycosides that are the subject of an application for 
GRAS status designation by the US FDA Center for Food Safety and Nutrition (CFSAN) and the 
US Environmental Protection Agency (EPA) based on their use as detergents or surfactants as a 
component of compounds in food industry and agricultural usages.  With their use in these 
contexts, there is no established limitation on the oral or topical exposure allowed for humans. 
Twenty (20) GLP nonclinical studies of the pharmacology and toxicology of Intravail A3 have 
been conducted by a number of investigators, as a single agent and in combination with 
pharmacologically active ingredients in in vitro studies and in rats, Guinea pigs, rabbits, dogs, 
and monkeys.  Conclusions from the rat and rabbit studies include findings of a regenerative 
response typically seen following local irritation of nasal mucosa which may be attributed to the 
use of pipettes for dosing (most likely the result of whole droplet instillation), according to 
Charles Rivers pathologists.  In contrast, nasal spray actuators were used for dosing in the dog 
and monkey toxicology studies (for delivery as a mist or fine plume representative of human 
administration), and these same findings were not observed.  The pathologist concludes the 
effects were mild and reversible, and should be considered of minimal risk for clinical trial. 
Spack et al.(16)evaluated Intravail A3 for its potential to cause genotoxicity in preclinical studies 
for use as a mucosal surface permeation enhancer of AG284, a protein peptide complex for the 
treatment of multiple sclerosis.  Intravail A3 was tested in the bacterial reverse mutation assay 
using S.typhimurium and Escherichia coli (E.coli) tester strains.  The maximum dose tested was 
25 mg/plate.  No positive response was observed and hence deemed not mutagenic at 0.5 mg/mL 
Intravail A3 was also tested in the chromosomal aberration assay using in vitro mammalian 
cytogenetic tests with human blood peripheral mononuclear cells (PBMCs).  A dose range was 
established first and then its clastogenic potential was tested.  The maximum concentration tested 


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was 50 mg/mL.  No statistically significant increases were observed in either the non-activated 
or S9 activated test systems relative to the control group.  Therefore, based on these findings, 
Intravail A3 was not considered a mutagen or genotoxic agent. 
The dosage of NRL-1 that will be used in the current studies is based on patient weight ranges 
from the Diastat label.  The NRL-1 doses administered in these clinical studies will be 5 mg dose 
for patients with a body weight < 20 kg, 10 mg dose for patients with a weight of 20 kg to 
≤ 50 kg, a 15 mg dose for patients with a weight of > 50 – 75 kg, and a 20 mg dose for patients 
with a weight ≥ 75 kg.  The doses used in the clinical studies are supported by clinical 
experience and approved dosing given that the bioavailability of NRL-1 is 97%. 
The NRL-1 formulation contains 0.25% Intravail A3 (0.025 mg/100 µL).  Table 1 provides the 
calculated safety margins based on a rat no oberservable effect level (NOEL) of 80 µg/day and a 
dog NOEL of 330 µg/day for Intravail A3. 
Table 1:  Intravail A3 Safety Margins Based on Current NRL-1 Formulation 
Species 
NOEL 
Human Equivalent 
Dose (HED) 
Intravail A3  
Safety Margins 
Rat 
0.32 mg/kg (80 µg/day) 
0.05 mg/kg 
74 - 144 fold 
Dog 
0.036 mg/kg (330 µg/day) 
0.02 mg/kg 
55 - 28 fold 
Human 
 
0.00036 - 0.0007 mg/kg 
(0.025 mg/spray) 
 
*based on weights for rat, dog, and humans as 0.25 kg, 9.1 kg, and 60 kg, respectively. 
1.2 
Clinical Experience (Diazepam and NRL-1) 
Diazepam has been in clinical trials and human use for over 40 years by multiple routes of 
administration including intranasal and IV dosage forms.  In general, the product has a good 
safety profile and has not been associated with any chronic or serious side effects in humans.  
Diazepam has been extensively studied and its PK and metabolism in humans is well understood.  
When administered orally, intravenously, or rectally, most of diazepam is extensively and 
rapidly absorbed, with bioavailability varying from 80 to 100 % and time to maximum plasma 
(tmax) concentration ranging from minutes (IV) to several hours (oral). 
The safety of diazepam by the intranasal route of administration is also supported by the IV 
formulation as the IV route of administration gave the most rapid tmax and highest maximum 
plasma concentration (Cmax) of any other route of administration.  Doses of diazepam by IV 
administration are safe up to 30 mg administered as a 20 to 30 minute infusion time in adults, 
according to the FDA product labeling.  Given the bioavailability demonstrated for NRL-1 
(97%) in the absolute bioavailability study in comparison to IV diazepam, it is considered that a 
dose of up to 20 mg of diazepam given by intranasal administration would not cause a safety 
concern even if completely and rapidly absorbed. 


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For IV diazepam, the US product labeling states that the usual recommended dose in older 
children and adults ranges from 2 to 20 mg by IM or IV administration, depending on the 
indication and its severity.  In some conditions, e.g., tetanus, larger doses may be required.  For 
seizure emergencies, such as status epilepticus and severe recurrent convulsive seizures, IV 
doses of up to 30 mg diazepam administered over a 20 to 30 minute time period is approved for 
adults according to US FDA labeling.  Thus, an intranasal dose of 20 mg of diazepam as NRL-1 
should not present a significant safety risk to subjects. 
1.2.1 Clinical Trials with NRL-1 
An absolute bioavailability study of two formulations of NRL-1 has been completed.  Study 
DIAZ.001.01 was an open-label, randomized, three-treatment, three-period, six-sequence 
crossover study to evaluate the PK of diazepam after administration of an intranasal suspension 
(NRL-1.A), 10 mg, or an intranasal solution (NRL-1.B), 10 mg, compared to 5 mg administered 
by IV. Each diazepam dose was separated by a minimum 14-day washout period.  
Subjects were randomized into 6 sequence groups with 4 subjects per sequence group. The 
sequence of the treatments was randomly assigned, and all subjects received each of the 
following diazepam treatments:  
• Diazepam nasal spray, suspension (NRL-1.A), single 10-mg intranasal dose  
• Diazepam nasal spray, solution (NRL-1.B), single 10-mg intranasal dose  
• Diazepam IV, 5 mg/mL, administered over 1 minute  
Diazepam was absorbed after intranasal administration of both proprietary formulations to 
humans, with higher exposure after administration as a solution (NRL-1.B) (absolute 
bioavailability 97%) than as a suspension (NRL-1.A) (absolute bioavailability 67%). With the 
exception of two subjects who had longer tmax for the intranasal solution, tmax was randomly 
distributed between the two intranasal treatments with comparable medians and ranges. The 
difference in exposure between the intranasal solution and intranasal suspension is therefore due 
to the extent rather than to the rate of absorption. 
The mean elimination half-life (t1/2) of diazepam was comparable for the two intranasal 
formulations of diazepam and the IV treatment indicating that there does not appear to be a 
prolonged absorption of diazepam after intranasal administration. 
Differences between the solution and suspension with respect to the metabolite, 
desmethyldiazepam, were consistent with those for the parent compound. The mean (SD) 
metabolite-to-parent ratios of area under the plasma concentration-time curve to infinity (AUC∞), 
uncorrected for molecular weight, were 1.47 (0.28) for the intranasal solution and 1.49 (0.38) for 
the intranasal suspension, consistent with the ratio of 1.54 (0.43) for the IV. This suggests little 
or no contribution to the extent of formation of desmethyldiazepam by first-pass metabolism and 
thus a low likelihood that any of the intranasal-administered diazepam was absorbed from the 


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gastrointestinal tract after swallowing any “run off” from the back of the nose. 
Table 2:  Summary of Pharmacokinetic Data from the DIAZ.001.01 Study 
 
Diazepam Nasal Spray (10 mg/100μL) 
Diazepam Injection 
NRL-1.A Suspension 
NRL-1.B Solution 
5 mg/mL IV 
Parameter a 
 n 
Mean (SD) b 
 n 
Mean (SD) b 
 n 
Mean (SD) b 
Cmax (ng/mL) 
24 
221 (78.6) 
24 
272 (100) 
24 
555 (316) 
tmax (h) 
24 
1.00 (0.6, 2.0) 
24 
1.50 (0.8, 4.0) 
24 0.03 (0.03, 0.50) 
AUC0-t (h*ng/mL) 
24 
5229 (1463) 
24 
7340 (1882) 
24 
3832 (1150) 
AUC0-∞ (h*ng/mL) 
20 
5381 (1409) 
20 
7338 (2072) 
24 
4104 (1318) 
λz (h-1) 
20 
0.0142 (0.0053) 
20 
0.0155 (0.0046) 
24 
0.0142 (0.0055) 
t½ (h) 
20 
56.2 (23.0) 
20 
49.2 (16.9) 
24 
56.2 (21.0) 
a: Mean values are presented as arithmetic means. 
b: Median (min, max) reported for tmax 
The safety results show that administration of intranasal diazepam suspension (NRL-1.A), 
solution (NRL-1.B), and IV diazepam were well-tolerated. While most (71%) subjects 
experienced at least one treatment-emergent adverse event (TEAE) during the study, the 
frequency of adverse event (AE) occurrence did not appear to be dependent on diazepam 
formulation, and the AE profile provided no clear evidence of treatment differences. All TEAEs 
were considered by the Investigator to be of mild or moderate intensity. 
Overall, the most frequently reported TEAEs were epistaxis (7 subjects) and somnolence 
(6 subjects). While AEs of somnolence were more commonly associated with IV diazepam 
(4 subjects) than with either of the intranasal diazepam formulations (1 subject each), sedation 
scores were similar across treatment groups at most post-dose time points.  
For epistaxis, it is noteworthy that intranasal delivery of diazepam did not appear to be a 
predictor of epistaxis (or nasal irritation). The number of AEs of epistaxis was greater following 
IV diazepam (5 events) than after administration of NRL-1.A (1 event) or NRL-1.B (3 events). 
In addition, previous exposure to intranasal diazepam did not appear to influence the onset of 
nasal bleeding/irritation in the presence of IV diazepam exposure. In this study, nasal bleeding 
was identified after IV diazepam administration when subjects had no prior exposure to 
intranasal diazepam and when subjects’ prior exposure to intranasal diazepam did not produce 
bleeding/irritation. 
In addition to events of epistaxis and somnolence, other AEs reported for more than one subject 
overall included; headache (5 subjects), nasal discomfort (4 subjects) and nasal inflammation 
(3 subjects).  No other AE was reported for more than one subject, either within a treatment 
group or overall. 


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There were no AE reports of nasal pain by any subject in any treatment period. 
Of the 24 subjects who received study drug, 13 experienced at least one AE considered by the 
Investigator to be related to treatment. The most commonly experienced treatment-related AEs 
were somnolence (6 events total), nasal discomfort (4 events total), headache (4 events total), 
and epistaxis (3 events total). 
No subject was withdrawn from the study in response to an adverse event. No serious adverse 
events (SAEs) were reported, and no deaths occurred during the study. There were no clinically 
important findings noted in the vital sign data, electrocardiogram (ECG) findings, or in the 
individual clinical laboratory data. One subject had a clinically significant finding in the physical 
examination at the end of study assessment; this event, mouth ulceration (an AE), was 
considered by the Investigator to be both mild in severity and unrelated to study drug. 
Conclusion 
Overall, the results of past clinical studies and the long history of diazepam use in patients, 
support the proposed Phase 3 clinical trial for NRL-1 and the safety of the proposed intranasal 
doses of diazepam intended for this trial. 
1.2.2 Pharmacokinetics and Product Metabolism in Humans 
Oral Administration: 
After oral administration, greater than 90% of diazepam is absorbed and the average time to 
achieve peak plasma concentrations is 1–1.5 hours with a range of 0.25 to 2.5 hours. Absorption 
is delayed and decreased when administered with a moderate fat meal. In the presence of food 
mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There 
is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the 
presence of food as compared with 1.25 hours when fasting. This results in an average decrease 
in Cmax of 20% in addition to a 27% decrease in area under the curve (AUC) (range 15% to 50%) 
when administered with food. 
In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The decline 
in the plasma concentration-time profile after oral administration is biphasic. The initial 
distribution phase has a half-life of approximately one hour, although it may range up to 3 
hours (3). 
Intravenous Administration: 
IV administration of diazepam results in a tmax at the end of the infusion time and Cmax dependent 
on the rate of infusion.  Doses of 10 mg given over a 20 to 30 minute infusion time are common 
in clinical trials and practice.  Doses of up to 30 mg in a 30 minute infusion time are allowed in 
the product labeling for IV diazepam. 


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Rectal Administration: 
Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma 
concentrations in 1.5 hours. The absolute bioavailability of diazepam rectal gel relative to 
diazepam injectable according to the product labeling of Diastat is 90%. The volume of 
distribution of diazepam rectal gel is calculated to be approximately 1 L/kg. The mean t1/2 of 
diazepam and desmethyldiazepam following administration of a 15 mg dose of diazepam rectal 
gel was found to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively (17). 
Intranasal Administration: 
Several clinical studies with intranasal formulations of diazepam have been reported in the 
literature.  Generally, absolute bioavailability of these formulations was low (approximately 
50%) and have been conducted in both healthy volunteers and patients with similar outcomes.  
Gizurarson et al. administered a 2 mg dose of a 20 mg⁄mL diazepam solution dissolved in 
5%glycofurol in polyethylene glycol 200.  The mean bioavailability was 50.4 ± 23.3% with a 
time to peak concentration of 18 ± 11 minutes(18). 
Lindhardt et al. evaluated an intranasal formulation of diazepam with doses of 4 and 7 mg in 
polyethylene glycol 300 in seven healthy volunteers as compared to a 5 mg IV dose.  The 
intranasal formulation had a relative bioavailability of 45% and 42%, a Cmax of 99 and 
179 ng⁄mL and a tmax of 18 and 42 minutes for the 4 and 7 mg doses, respectively (19). 
Ivaturi et al. conducted a study of the bioavailability and tolerability of intranasal diazepam in 
healthy volunteers.  They compared 5 and 10 mg intranasal diazepam doses of their 
investigational formulation with a 5 mg dose of diazepam solution intravenously.  Following the 
5 and 10 mg doses, the median tmax were 20 and 30 minutes respectively and the mean Cmax were 
134.3 ± 62 and 247.6 ± 61 ng/mL.  Estimated bioavailability was 75% for both doses.  In the 
same study, a group of subjects was evaluated to compare 5 mg of diazepam and 5 mg of 
midazolam with intranasal and IV routes of administration.  Intranasal diazepam was rapidly 
absorbed, with a tmax of 28.8 ± 20.96 minutes. Cmax was 179.2 ± 8.85(ng⁄mL) and half-life was 
22.4 ± 3.45 hours (20). 
Results of the DIAZ.001.01 study with NRL-1 are provided above in Section 1.2.1. 
Intranasal Use of Intravail in Human Subjects: 
Intravail A3 is being evaluated in human clinical trials. As of September 2014, Intravail A3 has 
been used in: (i) eight intranasal human programs with a total of 13 human studies; and (ii) three 
human oral programs with a total of five human studies.  These human studies have been 
conducted in the United States and India and have included more than 280 subjects with over 
3,500 aggregate doses.  Each study has been a single dose study with the exception of one 7 day 


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study with 24 subjects and one six-week study with 75 subjects.  No clinically relevant AEs have 
been observed to date that were attributable to Intravail A3. 
In three (3) completed and one ongoing clinical studies conducted outside the United States with 
an undisclosed active pharmaceutical ingredient, 84 normal subjects have been exposed to 1 to 
3 single 100 µL intranasal doses of Intravail A3 at concentrations of 0.1-0.2%.  Two hundred 
thirty-eight (238) AEs have been reported with 237 being mild and of a nature expected with the 
active drug.  One SAE (pancreatitis) was reported during the study, but the subject had not 
received the reference product containing Intravail A3. 
The current toxicology and clinical studies with Intravail A3 show no evidence of any 
concerning or non-reversible findings at the dose levels anticipated to be used in humans. 
In 2007 alkylpolyglycosides, the class of compounds, which includes Intravail A3, were the 
subject of a GRAS Exemption Claim submitted to the FDA (21).  The subject of this claim was 
the use of alkylpolyglycosides as “surfactants for use in the cleaning of food products, the 
cleaning of equipment used to process food, the manufacture of products that come in contact 
with food, fruits and vegetables including meat and poultry carcasses, the cleaning of materials 
that subsequently come in contact with food, paper, cardboard, plastic or stainless steel lines 
and/or production vessels, and the cleaning and sanitizing of surfaces in food preparation areas.” 
In the FDA’s response to the GRAS Exemption Claim(21), the FDA (Office of Food Additive 
Safety, Center for Food Safety and Applied Nutrition) had no questions with respect to the 
conclusion reached by the Applicant, stating that: “Based on the information provided by 
Cognis, as well as other information available to the FDA, the agency has no questions at this 
time regarding Cognis' conclusion that alkylpolyglycosides are GRAS under the intended 
conditions of use.” The Agency noted that it has not, however, made its own determination 
regarding the GRAS status of the subject use of alkylpolyglycosides.  Nonetheless, 
alkylpolyglycosides and Intravail A3 are commonly regarded as GRAS(22). 
In September 2005, the US EPA determined that there is a reasonable certainty of no harm from 
aggregate exposure to residues of C10-C16-alkyl glycosides and that establishing an exemption 
from the requirement of a tolerance for C10-C16-alkyl glycosides will be safe for the general 
population including infants and children(23). 
Overall the introduction of Intravail into the NRL-1 formulation is anticipated to provide an 
absolute bioavailability comparable to Diastat rectal gel with reduced variability and a more 
convenient, less invasive delivery system. 
1.3 
Study Rationale 
Diazepam rectal gel (Diastat) is the only formulation of diazepam indicated for the management 
of selected, refractory patients with epilepsy on stable regimens of AEDs who require 
intermittent use of diazepam to control bouts of increased seizure activity, i.e., ARS. 


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A diazepam nasal spray is being developed for patients who experience ARS to provide an 
alternative more convenient and acceptable route of diazepam administration. 
The purpose of this study is to assess the long-term safety of NRL-1. 
2.0 
PURPOSE AND STUDY OBJECTIVES 
2.1 
Purpose 
The purpose of this study is to assess the safety of repeat intranasal doses of NRL-1administered 
to Epilepsy subjects. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
The primary objective of this study is to assess the safety of diazepam after repeat intranasal 
doses of NRL-1 administered to Epilepsy subjects who experience frequent breakthrough 
seizures or Acute Repetitive Seizures, over a 12-month period. 
2.2.2 
Secondary Objectives 
The secondary objectives of this study include: 
• To assess the tolerability of diazepam after repeat intranasal administration of NRL-1; 
• To assess the ability of caregivers to administer NRL-1 based on the Directions for Use 
(DFU) (see APPENDIX E); 
• To assess an improvement in the Quality of Life with NRL-1 use as compared to Diastat. 
2.3 
Description of Study Design 
This is a Phase 3, repeat dose, open-label, safety study in Epilepsy subjects who have frequent 
breakthrough seizures or ARS.  NRL-1 will be administered as needed to treat bouts of those 
seizures over a 12-month period of time.  Doses will be defined as 5 mg, 10 mg, 15 mg, or 20 mg 
based on the subject’s body weight.  The dosage may be increased or decreased for efficacy or 
safety reasons, if determined by the Principal Investigator that a different dose is necessary and 
there is no safety concern.  A diary will be used to record the seizure and NRL-1 administration. 
The study consists of a screening phase, a baseline, a 12-month treatment period and a follow-up 
telephone contact 28-days after the last dose of NRL-1 or study termination.  The primary 
purpose of this study is to assess the safety of repeat doses of NRL-1 as intermittent chronic 
therapy to treat frequent break through seizures or ARS.  Subjects will return to the site per the 
Schedule of Events with all study visits having a ± 7-day window around visits. 


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Safety assessments include physical and neurological examination including head, ears, eyes, 
nose, and throat (HEENT), vital signs, laboratories (hematology, serum chemistry, and 
urinalysis), 12-lead ECGs, and AE assessment.  Concomitant medications will be recorded.  
Columbia-Suicide Severity Rating Scale (C-SSRS for adults or pediatric), Nasal Examination 
and Irritation Assessment (The following will be assessed on separate scales: nasal irritation, 
nasal discharge, mucosal erythema, mucosal edema, mucosal crusting and mucosal epistaxis),  
Sedation Score Assessment, and Smell Test (NIH Toolbox Odor Identification Test, (1, 2) will 
be conducted at each visit.  A targeted physical examination may be used to evaluate any 
potentially related side effects.   
Subjects and caregivers will be trained on the proper use of the NRL-1 nasal sprayer at screening 
period and as needed during treatment period.  The ability of caregivers to administer NRL-1 
based on the DFU will be assessed (see APPENDIX E). 
The Quality of Life in Epilepsy (QOLIE) questionnaire will be administered to assess the quality 
of life while on NRL-1 compared to baseline therapy at time of enrollment.  If under the age of 
11, no Quality of Life questionnaire will be administered. 
Naïve subjects may be entered into this study as well as those subjects completing the protocol 
DIAZ.001.04 are eligible for the long-term safety study (DIAZ.01.05) and may receive treatment 
with NRL-1 under DIAZ.01.05 protocol. 
2.4 
Study Endpoints 
2.4.1 
Primary Endpoint 
The primary endpoint of this study is safety of NRL-1.  There are no efficacy measures evaluated 
in this study. 
2.4.2 
Secondary Endpoints 
The secondary endpoints in this study include: 
• Assessment of the tolerability of diazepam after repeat intranasal administration of 
NRL-1 
• Assessment of the ability of caregivers to administer NRL-1 based on the DFU 
• Assessment of improvement in the Quality of Life with NRL-1 use as compared to 
Diastat 
2.4.3 
Randomization/Assignment to Study Drug 
There are no randomization/assignments to study drug as this is an open-label study. 


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2.5 
Study Drugs 
2.5.1 
Test Product 
NRL-1 is a solution formulation of diazepam intended for nasal administration.  NRL-1 contains 
diazepam, Intravail A3, vitamin E, benzyl alcohol and ethanol.  To provide the range of desired 
doses, NRL-1 will be available with three different concentrations of diazepam: 
•
50 mg/mL
•
75 mg/mL
•
100 mg/mL
To obtain a 15 mg dose, two sprayers containing the 75 mg/mL formulation will be used with 
one 100 μL spray in each of nostril. To obtain a 20 mg dose, two sprayers containing the 100 
mg/mL formulation will be used with one 100 μL spray in each of nostril. 
NRL-1 is packaged in a disposable molded polymer commercially-available device marketed by 
Aptar Pharma as the UDS (unit dose sprayer).  This single actuation device contains a small 
glass vial with a rubber stopper.  The Aptar UDS will deliver an exact dose of 100 µL of NRL-1 
solution.  
2.5.2 
Dose and Dose Justification 
An initial dose of 5 mg, 10 mg, 15 mg, or 20 mg of NRL-1 will be selected according to the 
subject’s weight (rounded to the nearest kg) based on the following: 
For Children Age 6-11 Years: 
•
10 kg to 18 kg body weight will receive a 5 mg dose (50 mg/mL, 100 µL) administered
as one spray in the left nostril.
•
19 kg to 37 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one spray
in the left nostril.
•
38 kg to 55 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed by
the right nostril).
•
56 kg to 74 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 administered as
two 10 mg sprays with one in each nostril (the left nostril will be sprayed first followed
by the right nostril).


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For Age 12 Years or greater: 
• 14 kg to 27 kg body weight will receive a 5 mg dose (50 mg/mL, 100 µL) administered 
as one spray in the left nostril. 
• 28 kg to 50 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one spray 
in the left nostril. 
• 51 kg to 75 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two 
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed by 
the right nostril). 
• Greater than 76 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 
administered as two 10 mg sprays with one in each nostril (the left nostril will be sprayed 
first followed by the right nostril). 
A second dose may be administered if needed 4-12 hours after the initial dose of NRL-1.  
Additionally, the dosage may be increased or decreased for efficacy or safety reasons, if 
determined by the Principal Investigator that a different dose is necessary and there is no safety 
concern. 
2.5.3 
Bioanalytical Method 
Bioanalytical methods will not be used in this study. 
2.6 
Concomitant Medications 
2.6.1 
Prior and Concomitant Medications 
Prior medications are defined as medications that were taken within 30 days prior to initial 
dosing with study drug.  
Concomitant medications are defined as medications taken any time after the start of dosing until 
the final follow-up telephone contact.  
2.7 
Procedures for Monitoring Subject Compliance 
NRL-1 will be administered as needed to treat bouts of those seizures over a 12-month period of 
time. A diary will be used to record the seizure and NRL-1 administration.  At each visit, the 
seizure and dosing information from the diary including the time when the seizure occurs, when 
it ended, the dose, and date and time of dosing will be recorded to case report form (CRF).  


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3.0 
STUDY POPULATION 
The study population will be subjects with a clinical diagnosis of frequent break through seizures 
or ARS with bouts of uncontrolled seizures, who, in the opinion of the Investigator, may need a 
benzodiazepine for seizure control. 
3.1 
Inclusion Criteria 
Subjects must meet All of the following inclusion criteria to be enrolled in this study: 
1. Male and female subjects between the ages of 6 and 65 years, inclusive. 
2. Written informed consent to participate in the study. 
3. Subject has a clinical diagnosis of Epilepsy and while on a stable regimen of anti-epileptic 
medication, still experiences bouts of seizures (e.g. frequent break through seizures or ARS), 
and who, in the opinion of the Investigator, may need benzodiazepine intervention for seizure 
control 1 time every other month on average (i.e. average 6 times a year). 
4. Subject has a qualified caregiver or medical professional available that can administer study 
medication in the event of a seizure. 
5. Subjects having either partial or generalized Epilepsy with motor seizures or seizures with 
clear alteration of awareness. 
6. Female subjects of childbearing potential, defined as having a menstrual cycle and who are 
not surgically sterile or less than two (2) years postmenopausal, must complete a pregnancy 
screen and agree to utilize one of the following forms of contraception during the study and 
for 21 days after the last dose of study drug:  abstinence, hormonal (oral, transdermal, 
implant, or injection), barrier (condom, diaphragm with spermicide), intrauterine device 
(IUD), or vasectomized partner (six months minimum).  Subjects must have used the same 
method for at least one (1) month prior to starting the study. 
7. No clinically significant abnormal findings in the medical history, on the physical 
examination or electrocardiogram (QTcF < 450 msec for males and QTcF < 470 msec for 
females). 
8. Subjects and caregivers must agree to return to the study site for all study visits and must be 
willing to comply with all required study procedures. 


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3.2 
Exclusion Criteria 
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. A history of clinically significant gastrointestinal, renal, hepatic, hematologic, endocrine, 
oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other 
condition which, in the opinion of the Investigator, would jeopardize the safety of the 
subject. 
2. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days 
prior to study screening. 
3. Subjects with active major depression or a past suicide attempt, or any Suicidal Ideation of 3, 
4, or 5 or any Suicidal Behavior in Lifetime using C-SSRS. The pediatric C-SSRS should be 
used for subjects ages 6 to 11.  The adult C-SSRS should be used for subjects 12 and greater 
years of age. 
4. A history of allergic or adverse responses to diazepam or any comparable or similar product. 
5. Participation in a clinical trial other than protocol DIAZ.001.04 within 30 days prior to Day 
0.  Participation in an observational (non-interventional) study is not excluded as long as 
there are no scheduling conflicts with this study. 
6. Positive serum pregnancy test (ß-hCG) at screening for subjects age 12 years or greater. 
7. Positive blood screen for Human immunodeficiency virus (HIV), Hepatitis B surface antigen 
(HbSAg), or Hepatitis C, or a positive urine screen for alcohol, or drugs of abuse except 
marijuana use for medical reasons.  When marijuana was used for medical reasons in the 
opinion of the investigator, it is not considered as drug abuse and the patient can be enrolled 
even if the marijuana metabolites in the urine revealed as positive. 
4.0 
SAFETY ASSESSMENTS 
4.1 
Collection of Adverse Events Data 
Data regarding TEAEs will be collected in this study.  TEAEs are events that are not present at 
baseline, or if present at baseline, have worsened in severity. AEs will be assessed and followed 
up during the treatment period and until follow-up telephone contacts.  
Any AE reported by the subject or noted by the Investigator or his/her designee will be recorded 
on the CRF regardless of the Investigator opinion of causality.  Events that occur after dosing in 
a home setting will be recorded in a diary and reported at the next study visit. The following 
information will be recorded for each AE: description of the event, date and time of onset, date 


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and time of resolution, severity, causal relationship to study drug, outcome, action taken with the 
study drug and any treatment given. 
All clinically significant abnormal changes from baseline in physical examination findings, vital 
signs, and laboratory evaluations will be collected, graded with regards to severity or clinical 
significance, assessed for causal relationship and recorded on the CRF. 
4.2 
Clinical Laboratory Evaluations 
Screening blood samples and urine specimens for laboratory evaluation may be collected up to 
21 days prior to initial dose of study drug.  
Subjects with clinically significant abnormal laboratory values during the study will be 
monitored until the value is no longer considered clinically significant or no further change is 
anticipated.  All abnormal changes from screening in laboratory values will be collected, graded 
with regards to severity, assessed with regards to causality and recorded in the CRF to be 
reported as abnormal laboratory findings.  Only clinically significant abnormal laboratory 
findings associated with clinical sequelae or that require therapeutic intervention are considered 
AEs. All clinical laboratory analyses will be performed at the clinical site and the results will be 
recorded on the appropriate CRF.  Clinical laboratory reports must be reviewed, signed, and 
dated by the Investigator.  The Investigator will assess each abnormal test result for clinical 
significance and the result of the evaluation will be recorded on the CRF. 
4.2.1 
Hematology 
Complete blood cell count (CBC) will include red blood cell (RBC), RBC morphology, 
reticulocyte count, hemoglobin, hematocrit, white blood cell (WBC) with differential, and 
platelet count. 
4.2.2 Serum Chemistry 
Comprehensive metabolic panel will include serum alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), glucose, calcium, phosphorus, 
chloride, sodium, potassium, blood urea nitrogen (BUN), creatinine, total bilirubin, albumin, 
total protein, amylase, bicarbonate/carbon dioxide (CO2), uric acid, and lactate dehydrogenase 
(LDH).  
4.2.3 
Urinalysis 
Urinalysis will include appearance, color, pH, specific gravity, glucose, protein, ketones, blood, 
creatinine clearance, and a detailed microscopic analysis.  Microscopic analysis will be 
performed regardless of macroscopic results and will include the following: WBC, RBC, 
cast/type, crystal/type, and bacteria.  Standard urinalysis will be conducted on the same day as 
blood chemistry.  


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4.2.4 
Urine Drug, Alcohol, and Tobacco Screen 
Urine samples will be collected at screening for amphetamines, barbiturates, cocaine metabolites, 
methadone, opiate metabolites, phencyclidine, marijuana metabolites, and alcohol.  When 
marijuana was used for medical reasons in the opinion of the investigator, it is not considered as 
drug abuse and the patient can be enrolled even if the marijuana metabolites in the urine revealed 
as positive. In this case, information about marijuana use for medical reasons should be entered 
in the CRF page for concomitant medication. 
4.2.5 
Other Blood Tests 
The presence of human immunodeficiency virus (HIV) antibody, Hepatitis B surface antigen 
(HbSAg), and Hepatitis C antibody will be assessed at screening. 
4.3 
Physical Examinations and Medical History 
4.3.1 
Physical and Neurological Examination 
The Investigator or designee will perform a physical and neurological examination at screening 
and Day 365. Targeted physical examination may be used during the treatment period to assess 
potentially related adverse events. Results will be recorded on the appropriate page of the CRF. 
4.3.2 
Medical History 
A medical history including seizure history will be obtained at screening and baseline. Medical 
history will include demographic data (age, sex, race/ethnicity, etc.).   C-SSRS will be used to 
document suicidality at Screening in order to classify suicidal events. 
4.4 
C-SSRS 
The C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality at 
Screening in order to classify suicidal events and on Days 150 and 365 using the C-SSRS.  For 
adults, screening assessments will use the Baseline/Screening version of the C-SSRS.  The 
Since Last Visit version of the C-SSRS will be used for post-dosing assessments.  For children 
age 6 to 11 years old, screening assessments will use Children’s Baseline/Screening version and 
Children’s Since Last Visit version will be used for post-dosing assessments. 
4.5 
ECG 
A standard supine (after resting for at least 5 minutes) 12-lead ECG will be performed in 
triplicate by a trained technician at screening and baseline visits. 
All ECGs are obtained in triplicate. Three consecutive ECGs (each approximately 1-2 minutes 
apart) are performed. 


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ECGs will be assessed by the Investigator or a cardiologist, and a comparison to baseline ECGs 
will be performed. The ECG report must be reviewed, signed, and dated by the Investigator or 
cardiologist. The original ECG results will be kept on file at the site as source documentation. 
4.6 
Height and Weight 
Height will be measured in centimeters.  Body weight will be measured in kg. Assessments of 
height and weight will be recorded on the CRF. 
4.7 
Vital Signs 
Vital signs (temperature, pulse, respiratory rate, and blood pressure) are to be obtained at 
screening, baseline, and at each visit during the treatment period.  Vital signs will be recorded on 
the CRF. 
4.8 
Smell Test  
Smell tests will be conducted at baseline and at each study visit.  The NIH Toolbox for Odor 
Identification Test will be used for smell tests (1, 2). 
4.9 
Nasal Irritation Assessments 
Nasal irritation will be assessed at baseline and each study visit based on the following scales 
outlined in Section 4.9.1 through 4.9.6 below. 
4.9.1 
Assessment of Nasal Irritation: 
Objective evaluations of nasal irritation will be assessed at baseline and each study visit based on 
the following assessment scale: 
 
Grade 0: 
No sign of nasal irritation or mucosal erosion 
 
Grade 1A: 
Focal nasal mucosal irritation or Inflammation 
 
Grade 1B: 
Superficial mucosal erosion 
 
Grade 2: 
Moderate mucosal erosion 
 
Grade 3: 
Ulceration 
 
Grade 4: 
Septal perforation 
The subjects will also be required to report any incident of bleeding or inflammation in-between 
the actual evaluation time points. 


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4.9.2 
Assessment of Mucosal Erythema: 
Objective evaluations of mucosal erythema will be assessed at baseline and at each study visit 
using the following scale. 
 
Score 0: 
No sign of mucosal erythema 
 
Score 1: 
Mild mucosal erythema (slight redness) 
 
Score 2: 
Moderate mucosal erythema (redness) 
 
Score 3: 
Severe mucosal erythema (marked redness) 
4.9.3 
Assessment of Mucosal Edema: 
Objective evaluations of mucosal edema will be assessed at baseline and at each study visit 
based on the following assessment scale 
 
Score 0: 
No sign of mucosal edema 
 
Score 1: 
Mild mucosal edema 
 
Score 2: 
Moderate mucosal edema  
 
Score 3: 
Severe mucosal edema 
4.9.4 
Assessment of Nasal Discharge: 
Objective evaluations of nasal discharge will be assessed at baseline and at each study visit based 
on the following assessment scale 
 
Score 0: 
No sign of nasal discharge 
 
Score 1: 
Mild nasal discharge 
 
Score 2: 
Moderate nasal discharge 
 
Score 3: 
Severe nasal discharge 
4.9.5 
Assessment of Mucosal Crusting: 
Objective evaluations of mucosal crusting will be assessed at baseline and at each study visit 
based on the following assessment scale 
 
Score 0: 
No sign of mucosal crusting 
 
Score 1: 
Mild mucosal crusting  
 
Score 2: 
Moderate mucosal crusting  
 
Score 3: 
Severe mucosal crusting  


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4.9.6 
Assessment of Mucosal Epistaxis: 
Objective evaluations of mucosal epistaxis will be assessed at baseline and at each study visit 
based on the following assessment scale 
 
Score 0: 
No sign of mucosal epistaxis 
 
Score 1: 
Mild mucosal epistaxis  
 
Score 2: 
Moderate mucosal epistaxis  
 
Score 3: 
Severe mucosal epistaxis  
4.10 
Quality of Life questionnaire 
The QOLIE questionnaire will be administered to assess the quality of life while on NRL-1 
compared to baseline therapy at time of enrollment (see APPENDIX D).  QOLIE-AD-48 will be 
used for subjects age 11-18 years of with epilepsy.  Subjects age 18 years or older should 
complete the QOLIE-31-P (APPENDIX D).  If under the age of 11, no Quality of Life 
questionnaire will be administered. 
4.11 
Pregnancy Test 
A serum ß-hCG will be administered to females of childbearing potential at screening.  Urine 
pregnancy test is only required for female subjects of child bearing potential. A urine pregnancy 
test will be conducted at baseline and at each visit during the treatment period. Please note that 
subjects age 6 to 11 are not required to take a pregnancy test.  If a serum pregnancy test is done 
on Day -1, urine pregnancy test does not have to be repeated if done within 72 hours of study 
initiation (baseline). 
If a pregnancy occurs in the subject or in the partner of a subject during the course of the study, 
the Investigator must report it to the Sponsor within 24 hours using the pregnancy notification 
form provided by the sponsor.  For females who experience pregnancy during the trial, the study 
medication will be discontinued immediately and the patient will be monitored for any adverse 
problems with the pregnancy. 
5.0 
PHARMACOKINETICS 
No pharmacokinetic measures will be assessed during this trial. 
6.0 
PHARMACODYNAMICS 
No pharmacodynamic measures will be assessed during this trial. 


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7.0 
EFFICACY 
No efficacy measures will be assessed during this study. 
8.0 
STUDY VISITS 
Refer to APPENDIX A for the Schedule of Study Procedures.  Subjects will return to the site per 
the Schedule of Events with all study visits having a ± 7-day window around visits. 
Within a period of 21 days before dosing, all screening tests establishing subject eligibility will 
be performed. 
In addition to signing the Informed Consent Form (ICF) and meeting the protocol-specific 
entrance criteria, eligible subjects must agree to return to the study site for all study visits, 
including the confinement period during each treatment.  The study schedule will be provided in 
writing for the subject’s review and signature acknowledging agreement. 
8.1 
Screening 
The Investigator or his/her approved designee must explain the nature of the study protocol and 
associated risks to the potential study participant. The potential participant must be allowed to 
review the study information and to ask questions before being asked to sign the ICF. Written 
informed consent must be provided by the potential study participant prior to initiation of any 
screening evaluations or other study-related procedures. The signature date and the name of the 
individual at the site who obtained the informed consent will be recorded in the subject’s medical 
record.  
After written informed consent is obtained, the subject will be assigned a screening number and 
will undergo the designated screening procedures listed in APPENDIX A within 21 days prior to 
study drug administration. The Investigator will assess the results of these screening evaluations 
to determine eligibility for entry into the study according to the inclusion/exclusion criteria listed 
in Section 3.0. 
8.2 
Screening Evaluations (Days -21 to -1) 
After subjects have signed an Institutional Review Board/Ethics Committee (IRB/EC) approved 
ICF for the purpose of this study, they will begin the screening process.  Screening evaluations 
may be performed up to 21 days prior to Day 0. Screening evaluations performed within 24 
hours (Day -1 to Day 0) of dosing do not need to be repeated. 
The following study evaluations and procedures are required to determine eligibility: 
• Medical history including seizure history, demographics, prior medications, and 
concomitant medications. 


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• The C-SSRS, a measure of suicidal ideation and behavior, will be used to document 
suicidality at screening. The screening assessment will use the Baseline/Screening 
version of the C-SSRS. If the subject reports a history of major depression or a past 
suicide attempt, she/he is not eligible for the study.  The pediatric C-SSRS should be used 
for subjects age 6 to 11.  The adult C-SSRS should be used for subjects 12 and greater 
years of age. 
• Physical and neurological examination, including height and weight measurements. 
• Vital signs consisting of temperature, blood pressure, respiratory rate, and pulse. 
• Blood and serum samples for the following laboratory evaluations: 
o Hematology 
o Serum chemistry 
o Serum ß-hCG (all females) 
o HIV antibody 
o Hepatitis screening 
• Urinalysis 
• Urine drug and alcohol test 
• 12-lead ECG (in triplicate) 
• Subject/caregiver training 
8.3 
Baseline Evaluations (Day -3 to 0, pre-dose) 
Baseline assessments include the followings: 
• Review of the inclusion/exclusion criteria and medical history (including seizure history) 
• Any restricted concomitant medications 
• Weight 
• Vital signs consisting of temperature, respiratory rate, blood pressure, and pulse 
• Urine sample for pregnancy test.  If a serum pregnancy test is done on Day -1, urine 
pregnancy test does not have to be repeated if done within 72 hours of study initiation 
(baseline) 
• 12-lead ECGs 
• Assessment of the ability of caregivers to administer NRL-1 
• Quality of Life questionnaire.  If under the age of 11, no Quality of Life questionnaire 
will be administered. 
• Smell Test (1, 2)  


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• Nasal examination and irritation assessments (The following will be assessed on separate 
scales: nasal irritation, nasal discharge, mucosal erythema, mucosal edema, mucosal 
crusting and mucosal epistaxis) 
• Diary to record seizure and NRL-1 administration 
• AE assessment 
8.4 
Drug Administration 
The calendar date and 24-hour clock time of all doses will be recorded on the CRF.  A second 
dose may be administered if needed 4-12 hours after the initial dose of NRL-1. 
8.5 
Day 30 to 330 (± 7 days) 
Post-dose assessments include the followings (Refer Appendix A1 for the timing of each 
assessment): 
• Vital signs consisting of temperature, blood pressure, respiratory rate, and pulse 
• C-SSRS.  The pediatric C-SSRS should be used for subjects age 6 to 11.  The adult C-
SSRS should be used for subjects 12 and greater years of age. 
• Hematology, Serum Chemistry and Urinalysis 
• Urine pregnancy test 
• Smell Test (1, 2) 
• Nasal examination and irritation assessments (The following will be assessed on separate 
scales: nasal irritation, nasal discharge, mucosal erythema, mucosal edema, mucosal 
crusting and mucosal epistaxis) 
• Concomitant medications  
• AEs 
• Assessment of the ability of caregivers to administer NRL-1 
• Quality of Life questionnaire.  If under the age of 11, no Quality of Life questionnaire 
will be administered. 
• Diary to record seizure and NRL-1 administration 
8.6 
Day 365 (± 7 days) 
Assessments on Day 365 include the followings: 
• Physical and neurological examination including height and weight 
• Vital signs consisting of temperature, blood pressure, respiratory rate, and pulse 


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• C-SSRS.  The pediatric C-SSRS should be used for subjects age 6 to 11.  The adult C-
SSRS should be used for subjects 12 and greater years of age. 
• Hematology, Serum Chemistry and Urinalysis 
• Urine pregnancy test 
• Smell Test (1, 2) 
• Nasal examination and irritation assessments (The following will be assessed on separate 
scales: nasal irritation, nasal discharge, mucosal erythema, mucosal edema, mucosal 
crusting and epistaxis) 
• Concomitant medications  
• AEs 
• Assessment of the ability of caregivers to administer NRL-1 
• Quality of Life questionnaire.  If under the age of 11, no Quality of Life questionnaire 
will be administered. 
• Diary to record seizure and NRL-1 administration 
8.7 
Treatment beyond Day 365 
Subjects may continue treatment on NRL-1 after the primary study period on Day 365 at the 
discretion of the investigator, and until discontinuation of the DIAZ.001.05 study by the 
Sponsor.  For treatment beyond Day 365, it is recommended that subjects are contacted by the 
Investigator at least each 3 months to obtain information on any adverse events.  Study visits 
after Day 365 for safety assessment will be recorded in the EDC (CRF) as Unscheduled visits. 
8.8 
Follow Up telephone contact 
Follow-up phone calls 28 days (± 3 days) after the last dose of NRL-1 dosing to determine if any 
AE has occurred and to follow-up on any TEAE(s) ongoing since last communication with the 
subject and concomitant medications.   
8.9 
Termination Procedures 
At early termination, all subjects will be contacted by phone calls approximately 7 days (± 2 
days) after the subject withdrew the study or after the final dose of NRL-1.  Subject will be 
followed up for AEs and concomitant medications. 
9.0 
PREMATURE DISCONTINUATION FROM STUDY 
A premature discontinuation from study will occur when a subject who signed informed consent 
ceases participation in this study, regardless of circumstances, prior to completion of the 


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protocol. Subjects can be prematurely discontinued from the study for one of the following 
reasons:  
• Failure to meet inclusion/exclusion criteria before receiving first dose of study drug has 
been administered 
• Female subjects who experience pregnancy 
• Potential suicide attempt assessed by C-SSRS and/or Investigator’s assessment  
• Death 
• Significant safety event that in the opinion of the Investigator warrants discontinuation 
• Lost to follow-up after every attempt has been made to contact the subject, including 
sending a registered letter 
• Subject withdraws consent 
The principal investigator (PI) and the IRB/EC reserve the right to prematurely terminate the 
study in the interest of subject safety and welfare. The Sponsor reserves the right to prematurely 
terminate the study at any time for administrative reasons. 
Subjects will be followed for one-week after the administration of the last dose of study drug for 
early termination (Termination Procedures). 
10.0 
PRODUCT SPECIFICATIONS 
10.1 
Description 
Diazepam, illustrated in Figure 1, is a benzodiazepine anticonvulsant with the chemical name; 
7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one.  It is a colorless to light 
yellow crystalline compound, insoluble in water. The empirical formula is C16H13ClN2O and the 
molecular weight is 284.75. 
NRL-1 is a solution formulation of diazepam intended for nasal administration.  NRL-1 contains 
diazepam, Intravail A3, vitamin E, benzyl alcohol and ethanol.  To provide the range of desired 
doses, NRL-1 will be available with four different concentrations of diazepam; 
• 50 mg/mL (5 mg) 
• 100 mg/mL (10 mg) 
• 75 mg/mL (15 mg administered as two 7.5 mg sprays) 
• 100 mg/mL (20 mg administered as two 10 mg sprays with one in each nostril) 
The drug product is manufactured under current Good Manufacturing Practices (cGMP) at a 
contract manufacturing facility. 


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10.2 
Formulation, Packaging, and Labeling 
NRL-1 will be supplied for this study as either the 50 mg/mL, 75 mg/mL, or 100 mg/mL 
formulation planned for commercial distribution. 
NRL-1 is packaged in a disposable molded polymer commercially-available device marketed by 
Aptar Pharma as the UDS.  This single actuation device contains a small glass vial with a rubber 
stopper.  The Aptar UDS will deliver an exact dose of 100 µL of NRL-1 solution.  
Each vial of NRL-1 study drug packaging will be affixed with a single label panel containing the 
following information: 
NRL-1 (Intranasal Diazepam) 
50, 75 or 100 mg/mL (w/v) each vial to deliver 100 µL 
Lot: XXXXX 
10.3 
Receipt, Storage and Stability of NRL-1 
NRL-1 will be packaged in a glass vial with the commercially available UDS and placed in 
boxes.  Excursions are permitted to 15- 30 °C (59˚F to 86 ˚F), and after receipt should be stored 
at 15 - 25 °C (59 ˚F-77˚F) [see USP Controlled Room Temperature] until use. 
10.4 
Preparation of Study Drug 
NRL-1 is supplied as a solution for intranasal administration.  Dosing is based on the cohort 
assignment.  There is no manipulation or preparation of study drug required.  NRL-1 will be 
dispensing to study staff responsible for administration to study subjects and reconciliation will 
occur after dosing. 
10.5 
Administration of Study Drug 
Dosing will be according to the following procedure: 
The dose of 5 mg, 10 mg, 15 mg, or 20 mg of NRL-1 will be selected according to the subject’s 
weight (rounded to the nearest kg) based on the following: 
For Children Age 6-11 Years: 
• 10 kg to 18 kg body weight will receive a 5 mg dose (50 mg/mL, 100 µL) administered 
as one spray in the left nostril. 
• 19 kg to 37 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one spray 
in the left nostril. 
• 38 kg to 55 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two 
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed by 
the right nostril). 


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• 56 kg to 74 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 administered as 
two 10 mg sprays with one in each nostril (the left nostril will be sprayed first followed 
by the right nostril). 
For Age 12 Years or greater: 
• 14 kg to 27 kg body weight will receive a 5 mg dose (50 mg/mL, 100 µL) administered 
as one spray in the left nostril. 
• 28 kg to 50 kg will receive a 10 mg dose (100 mg/mL, 100 µL) administered as one spray 
in the left nostril. 
• 51 kg to 75 kg will receive a 15 mg dose (75 mg/mL, 100 µL) administered as two 
7.5 mg sprays with one in each nostril (the left nostril will be sprayed first followed by 
the right nostril). 
• Greater than 76 kg will receive a 20 mg dose (100 mg/mL, 100 µL) of NRL-1 
administered as two 10 mg sprays with one in each nostril (the left nostril will be sprayed 
first followed by the right nostril). 
A second dose may be administered if needed 4-12 hours after the initial dose of NRL-1.  
Additionally, the dosage may be increased or decreased for efficacy or safety reasons, if 
determined by the Principal Investigator that a different dose is necessary and there is no safety 
concern.  
10.6 
Ordering and Distribution of Study Drug 
Please contact your Clinical Research Associate or Study Project Manager to order clinical 
supplies. 
10.7 
Accountability of Study Drugs 
All study drugs received, dispensed, and returned must be accounted for in the study drug 
Dispensing Log, including: 
• Subject number and initials 
• Date study drug was dispensed 
• Quantity of study drug dispensed 
• Quantity of study drug returned 
All study drug received and dispensed by the Investigator will be inventoried and accounted for 
throughout the study. The study drug must be stored in a restricted area with limited access. 
Contents of the study drug containers must not be combined. 
The Investigator must maintain an accurate, up to date Dispensing Log for all study drugs 
supplied by the Sponsor. Study drug dispensed for all subjects must be recorded on the Drug 


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Accountability Form. The study drug Dispensing Log and remaining drug inventory will be 
reviewed at each monitoring visit by the Sponsor-designated clinical monitor. 
The study drug supplied for this study is for use only in subjects properly consented and enrolled 
into this protocol. Study drugs must be kept in a secure location physically separated from 
standard clinic or office drug supplies. 
11.0 
SAFETY MONITORING AND ADVERSE EVENTS 
11.1 
Adverse Events 
Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at 
baseline, or if present at baseline, have worsened in severity. 
Definition of Adverse Events and Adverse Drug Reactions: 
AEs in the CRF will be classified according to the most recent FDA definitions and in a manner 
consistent with International Conference on Harmonization (ICH) guidelines.  As such, the 
following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational (medicinal) product (IP) or other protocol-imposed intervention, 
regardless of attribution.  An AE may include intercurrent illnesses or injuries that represent an 
exacerbation (increase in frequency, severity, or specificity) of pre-existing conditions (e.g., 
worsening of asthma).  A laboratory abnormality will be reported on the “Adverse Event” case 
report form only if it is associated with clinical sequelae or requires therapeutic intervention.  
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis.  AEs will be coded according to Medical Dictionary for 
Regulatory Activities (MedDRA) and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.03. 
The reporting period for AEs starts on Day 0 after the baseline assessment is completed and ends 
28-days (± 3-days) after study termination by telephone contact. 
If an AE remains unresolved at final follow-up telephone contact, the subject may be followed, 
at the Investigator’s discretion, until resolution of the event.  SAEs must be followed until 
resolution by the PI, even if this extends beyond the study-reporting period.  Resolution is 
defined as the return to baseline status or stabilization of the condition with the expectation that it 
will remain chronic. 
The Investigator will assess AEs for severity, for relationship to IP, and as to whether the event 
meets one or more of the definitions of an SAE.  The assessments will be recorded on the source 
documents and AE CRF, using the categories defined below. 


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Causality 
Category 
Description 
Unlikely 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. For the purpose of 
this protocol, the term unlikely will be considered not related to study 
medication and an “Adverse Event”. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal maybe lacking or unclear. 
For the purpose of this protocol, an event that has possible relationship 
to study medication will be defined as a “Suspected Adverse Drug 
Reaction”.   
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal. For the 
purpose of this protocol, an event that has probable relationship to 
study medication will be defined as an “Adverse Drug Reaction”.  
 
In order to classify adverse events and diseases, preferred terms will be assigned by the sponsor 
or its designee to the original terms entered on the CRF, using MedDRA.  
For those AEs that are not described on the CTCAE v 4.0, such AEs will be graded on a 5-point 
scale (mild, moderate, severe) and reported as indicated on the CRF. Intensity of such an AE is 
defined as follows: 
Table 3:  Severity Assessment Terminology for Reporting Adverse Events (CTCAE v 4.03) 
CTCAE 
Grade 
Common 
Term 
Description 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL. 


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CTCAE 
Grade 
Common 
Term 
Description 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care 
ADL. 
4 
Life-
Threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Death 
Death related to AE  
 
11.2 
Serious Adverse Events 
According to the ICH Guidelines for Good Clinical Practice (GCP) (E6), an SAE is any 
untoward medical occurrence during the course of a clinical investigation that is characterized by 
one or more of the following: 
• Results in death 
• Is life-threatening 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical events 
Although not an SAE, exposure to study drug during pregnancy, even if no AE is reported in the 
mother, should be reported within 24 hours. 
11.2.1 
Reporting Requirements for Serious Adverse Events 
All SAEs must be reported to the Sponsor by the Investigator, study coordinator, other 
designated study personnel, or clinical research associate within 24 hours of notification of the 
SAE. To report such events, an SAE form must be completed by the Investigator and sent within 
24 hours by email or fax with relevant information. 
Within the 48 hours following the initial report, the Investigator must provide further information 
on the SAE. This should include a copy of the completed SAE form, and any other information 
that will assist the understanding of the event. Significant new information on ongoing SAEs 
should be provided promptly as a follow-up. 
The Investigator also must report all SAEs promptly to the appropriate IRB/EC as required by 
the institution. 
 


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Report SAEs by fax or email to: 
Fax: +1-858-769-0288 
Email: NeurelisSafety@pacificlinkconsulting.com 
 
Table 4:  Contact Information for SAE Reporting 
Primary Contact 
Sponsor Contact 
Medical Monitor  
Clinical Manager: 
Sarina Tanimoto, MD, PhD 
Robert Hasson 
Mobile: 
1-858-774-8716 
Mobile: 
1-619-540-6253 
Office: 
1-858-227-3008  
Office: 
1-858-368-9925 
Fax: 
1-858-436-1401 
Fax: 
1-858-436-1401 
Email: 
sarina@pacificlinkconsulting.co
m 
Email: 
rhasson@pacificlinkconsulting.co
m 
 
11.2.2 
Recording of Serious Adverse Events 
All SAE information must be recorded on the SAE form provided by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) must be obtained to 
supplement the SAE report form. A copy of all initial and follow-up reports must be filed with 
the subject’s CRF. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Sample Size Determination 
Up to 100 subjects, at least 30 age 6 to 11 years and up to 70 over 12 years of age, are to be 
enrolled. 
12.2 
Safety 
Safety data will be summarized by dose group and based on their initial dose level or treatment 
group (i.e., if a dose reduction occurs they will be considered in their initial group). Descriptive 
statistics will be provided for actual values and change from baseline values for vital signs and 
change from screening for clinical laboratory tests (serum chemistry, hematology, and 
urinalysis). 
Nasal examination and irritation assessments will be conducted to evaluate any effects of the 
NRL-1 formulation on the nasal mucosa.  The following will be assessed on separate scales: 
nasal irritation, nasal discharge, mucosal erythema, mucosal edema, mucosal crusting and 


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mucosal epistaxis.  Nasal irritation will be assessed at baseline and each study visit as well as 
based on reports of any nasal mucosal adverse events between visits to the clinical site 
AE collection will begin on Day 0 after baseline assessments are complete prior to the initial 
treatment with NRL-1 and continue for 28-days after Day 365.  AEs may be either spontaneously 
reported or elicited during questioning and examination of a subject.  AE information will be 
elicited at appropriate intervals by indirect questioning using a non-leading question.  AEs that 
occur after dosing in a home setting will be recorded in a diary and reported at the next study 
visit.  Subjects will receive follow-up telephone contact approximately 28 days (± 3 days) after 
Day 365 to determine if any AE has occurred and to follow-up on any TEAEs ongoing since last 
communication with the subject. 
The incidence and severity of TEAEs reported during the study and their relationship to study 
drug will be tabulated. TEAEs will be coded using the MedDRA and will be presented by body 
system. 
Smell tests will be conducted at baseline and at each study visit.  The NIH Toolbox for Odor 
Identification Test will be used as smell tests (1, 2). 
The C-SSRS for adults and pediatrics, a measure of suicidal ideation and behavior, will be used 
to document suicidality in order to classify suicidal events.  Suicidality will be assessed at 
screening for eligibility. The pediatric C-SSRS should be used for subjects age 6 to 11.  The 
adult C-SSRS should be used for subjects 12 and greater years of age. 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by therapeutic class and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication within each therapeutic class by dose cohort. 
13.0 
DATACOLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
13.1 
Data Collection and Reporting 
A CRF will be completed for each subject who receives at least one dose of study drug. All 
entries on the CRF must be supported by original source documentation (e.g., laboratory reports, 
medical records) maintained at the investigational site.  
The Investigator will make all safety assessments (AEs, clinical laboratory tests, ECGs, vital 
signs, and results from physical examinations) on an ongoing basis. The Investigator is required 
to review all entries on the CRF and sign at appropriate time intervals. 


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13.2 
Study Monitoring 
All aspects of the study will be monitored carefully by the Sponsor’s designees with respect to 
cGMP and standard operating procedure (SOP) for compliance with applicable government 
regulations. It is the responsibility of the Investigator to provide all study records, including 
CRFs, source documents, etc., for review and inspection by the clinical monitor. 
All CRFs will be 100% source verified against corresponding source documentation (e.g., office 
and clinical laboratory records) for each subject. Clinical monitors will evaluate periodically the 
progress of the study, including the verification of appropriate consent form procedures, review 
of drug accountability and preparation procedures, adherence to dosing procedures, and the 
verification of the accuracy and completeness of CRFs. Clinical monitors will also ensure that all 
protocol requirements, applicable FDA regulations, other requirements, and Investigator’s 
obligations are being fulfilled. 
13.3 
Data Disclosure and Subject Confidentiality 
Subject medical information obtained as a result of this study is considered confidential. 
Disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection on 
request by FDA or other government regulatory agency auditors, the Sponsor clinical monitor (or 
designee), and the IRB/EC. 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by a coded number to maintain subject confidentiality. All records will be kept in a 
locked file cabinet. All computer entry and networking programs will be identifiable only by 
coded numbers. Clinical information will not be released without written permission from the 
subject, except as necessary for monitoring by the IRB/EC, the FDA, or the study Sponsor.  
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole property of 
the Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
The results of this study will be published under the direction of the Sponsor. Results will not be 
published without prior review and approval by the Sponsor. 


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14.0 
PROTECTION OF HUMAN SUBJECTS 
14.1 
Basic Principles 
This research will be carried out in accordance with the clinical research guidelines established 
by the Basic Principles defined in the U.S. 21 Code of Federal Regulations (CFR) Parts 11, 50, 
56, and 312, the principles enunciated in the Declaration of Helsinki concerning medical 
research in humans (“Ethical Principles for Medical Research Involving Human Subjects,” 
Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996), and 
the GCP guidelines of the ICH of the Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH E6 (May 1996). 
14.2 
Institutional Review Board/Ethics Committee 
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the ICF. The study will not be initiated until the Investigator obtains written approval of the 
research plan and the ICF from the appropriate IRB/EC and copies of these documents are 
received by the Sponsor. Appropriate reports on the progress of this study will be made by the 
Investigator to the IRB/EC and Sponsor in accordance with applicable government regulations 
and in agreement with the policies established by the Sponsor. The Sponsor ensures that the 
IRB/EC complies with the requirements set forth in 21 CFR Part 56. 


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15.0 
REFERENCE LIST 
1. 
NIH. NIH Toolbox Odor Identification Test NIH [Available from: 
http://www.nihtoolbox.org/WhatAndWhy/Sensation/Olfaction/Pages/NIH-Toolbox-Odor-
Identification-Test.aspx. 
2. 
Dalton P, Doty RL, Murphy C, Frank R, Hoffman HJ, Maute C, et al. Olfactory 
assessment using the NIH Toolbox. Neurology. 2013;80(11 Suppl 3):S32-6. 
3. 
Valium. Prescribing Information. Valeant Pharmaceuticals. 2007. 
4. 
Arnold JJ, Ahsan F, Meezan E, Pillion DJ. Correlation of tetradecylmaltoside induced 
increases in nasal peptide drug delivery with morphological changes in nasal epithelial cells. 
Journal of pharmaceutical sciences. 2004;93(9):2205-13. 
5. 
Taft WC, DeLorenzo RJ. Micromolar-affinity benzodiazepine receptors regulate voltage-
sensitive calcium channels in nerve terminal preparations. Proceedings of the National Academy 
of Sciences of the United States of America. 1984;81(10):3118-22. 
6. 
Miller JA, Richter JA. Effects of anticonvulsants in vivo on high affinity choline uptake 
in vitro in mouse hippocampal synaptosomes. British journal of pharmacology. 1985;84(1):19-
25. 
7. 
Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J. [3H]Diazepam binding in 
mammalian central nervous system: a pharmacological characterization. The Journal of 
neuroscience : the official journal of the Society for Neuroscience. 1981;1(2):218-25. 
8. 
Oishi R, Nishibori M, Itoh Y, Saeki K. Diazepam-induced decrease in histamine turnover 
in mouse brain. European journal of pharmacology. 1986;124(3):337-42. 
9. 
Grandison L. Suppression of prolactin secretion by benzodiazepines in vivo. 
Neuroendocrinology. 1982;34(5):369-73. 
10. 
Battistin L, Varotto M, Berlese G, Roman G. Effects of some anticonvulsant drugs on 
brain GABA level and GAD and GABA-T activities. Neurochemical research. 1984;9(2):225-
31. 
11. 
Clark G. Clarke's Isolation and Identification of Drugs. 1st ed: Pharmaceutical Press; 
1978. 


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12. 
Batzinger RP, Ou SY, Bueding E. Antimutagenic effects of 2(3)-tert-butyl-4-
hydroxyanisole and of antimicrobial agents. Cancer research. 1978;38(12):4478-85. 
13. 
Matsuoka A, Hayashi M, Ishidate M, Jr. Chromosomal aberration tests on 29 chemicals 
combined with S9 mix in vitro. Mutation research. 1979;66(3):277-90. 
14. 
de la Iglesia FA, Barsoum N, Gough A, Mitchell L, Martin RA, Di Fonzo C, et al. 
Carcinogenesis bioassay of prazepam (Verstran) in rats and mice. Toxicology and applied 
pharmacology. 1981;57(1):39-54. 
15. 
Diastat Prescribing Information. FDA: Valeant Pharmaceuticals Int'l.; 2014. 
16. 
Spack EG, Wehner NG, Winkelhake JL. Preclinical and Pharmacological Studies of 
AG284, a Soluble HLA-DR2:Myelin Basic Protein Peptide Complex for the Treatment of 
Multiple Sclerosis. CNS Drug Reviews. 1998;4(3):225.46. 
17. 
Diastat. Valium Prescribing Information. 2010. 
18. 
Gizurarson S, Bechgaard E. Intranasal administration of insulin to humans. Diabetes 
research and clinical practice. 1991;12(2):71-84. 
19. 
Lindhardt K, Gizurarson S, Stefansson SB, Olafsson DR, Bechgaard E. 
Electroencephalographic effects and serum concentrations after intranasal and intravenous 
administration of diazepam to healthy volunteers. British journal of clinical pharmacology. 
2001;52(5):521-7. 
20. 
Ivaturi VD, Riss JR, Kriel RL, Cloyd JC. Pharmacokinetics and tolerability of intranasal 
diazepam and midazolam in healthy adult volunteers. Acta neurologica Scandinavica. 
2009;120(5):353-7. 
21. 
Center for Food Safety and Nutrition/Office of Food Additive Safety FaDA. Agency 
Response Letter GRAS Notice No. GRN 000237. 14 October 2008. 
22. 
Dandiker Y. Handbook of Pharmaceutical Excipients2000. 
23. 
Environmental. 40 CFR Part 180. 
 


 
 
APPENDIX A: 
SCHEDULE OF STUDY PROCEDURES 
 


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Appendix A1:  Schedule of Study Procedure 
a. 
Screening evaluations must be performed within 21 days prior to dosing on Day 0.  Screening evaluations performed within 24 hours (Day -1 to Day 0) of dosing do not need to be repeated.  
b. 
Baseline evaluations will be performed within 72 hours prior to study initiation on Day 0.  Baseline assessment may be conducted at clinic. 
c. 
Subjects will receive follow-up telephone contact approximately 28 days (± 3 days) after study termination. 
d. 
Study window at visits from Days 30 to 365 is ± 7 days. 
e. 
Subjects that continue on therapy after Day 365 should be contacted to solicit information on potential adverse events at least each 3 months.  Any site visits for standard of care evaluations should 
be recorded in the EDC (CRF) as Unscheduled visits. 
f. 
C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality in order to classify suicidal events. The pediatric C-SSRS should be used for subjects age 6 to 11.  The 
adult C-SSRS should be used for subjects 12 and greater years of age (see APPENDIX B). 
g. 
Targeted physical examinations may be used during the treatment period to evaluate potentially related adverse events. 
h. 
Vital signs (temperature, pulse, respiratory rate, and blood pressure) are to be obtained. 
i. 
Weight only. 
Study Procedure 
Screeninga 
Baselineb 
Treatment period and Visit Days 
Follow Up 
telephone 
contactc 
Study Day 
Day -21 to  
Day -1 
Day -3 to Day 
0 
Day 
30d 
Day 
90d 
Day 
150d 
Day 
210d 
Day 
270d 
Day 
330d 
Day 
365d 
Day 
>365e 
28 Days after 
Termination 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history including seizure history 
X 
X 
 
 
 
 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale (C-
SSRS)f 
X 
 
 
 
X 
 
 
 
X 
 
 
Physical and Neurologicalexam (including 
HEENT)g 
X 
 
 
 
 
 
 
 
X 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height and Weight 
X 
Xi 
 
 
 
 
 
 
X 
 
 
Hematology, Serum Chemistry and Urinalysis 
X 
 
 
 
X 
 
X 
 
X 
 
 
Serum or urine ß-hCG (Pregnancy)j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
HIV Antibody and Hepatitis Testk 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug and AlcoholScreenl 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medication assessment 
X 
X 
X-------------------------------------------------------------------------- 
 
X 
Adverse event assessmentm 
 
X 
X-------------------------------------------------------------------------------------- 
X 
ECG (12-Lead in triplicate)n 
X 
X 
 
 
 
 
 
 
 
 
 
Smell Testo 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessment of the ability of caregivers to 
administer NRL-1p 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Nasal Examination and Irritation Assessmentq 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Quality of Life in Epilepsy questionnaire 
(QOLIE)r 
 
X 
X 
 
X 
 
X 
 
X 
 
 
NRL-1 Dispenseds 
 
X 
X--------------------------------------------------------------------------------------- 
 
Diary to record seizure and NRL-1 administration 
 
X 
X--------------------------------------------------------------------------------------- 
 
Subject/caregiver trainingt 
X 
 
X--------------------------------------------------------------------------------------- 
 


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j. 
A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at screening. Pregnancy test will be done with urine at baseline and at the visits during the treatment 
period. If a serum pregnancy test is done on Day -1, urine pregnancy test does not have to be repeated if done within 72 hours of study initiation (baseline).  
k. 
Hepatitis B surface antigen (HbSAg), or Hepatitis C  
l. 
When marijuana is used for medical reasons in the opinion of the investigator, it is not considered as drug abuse and the patient can be enrolled even if the marijuana metabolites in the urine 
revealed as positive. In this case, information about marijuana use should be entered in the CRF page for concomitant medication. 
m. 
Adverse event assessment is continuous from Day 0 after baseline assessments are complete.  Events that occur after dosing in a home setting will be recorded in a diary and reported at the next 
study visit. 
n. 
ECG is to be performed in triplicate. Three consecutive ECGs (each approximately 1-2 minutes apart) are performed. 
o. 
Smell tests will be conducted at baseline and at each visit. The NIH Toolbox Odor Identification Test will be used as smell tests. 
p. 
Ability of caregivers to administer NRL-1 will be assessed. 
q. 
Nasal examination and scoring for nasal irritation, mucosal erythema, mucosal edema, nasal discharge, mucosal crusting and mucosal epistaxis will be performed at baseline and at each site visit. 
r. 
QOLIE questionnaire will be administered to assess the quality of life while on NRL-1 compared to baseline therapy at time of enrollment (see APPENDIX D ).  If under the age of 11, no Quality 
of Life questionnaire will be administered. 
s. 
NRL-1 may be dispensed to treat bouts of uncontrolled seizures (frequent break through seizures or ARS) after baseline procedures completed.   The amount of drug dispensed is dependent on the 
investigators judgment and anticipated need of the subjects to cover the period between study visits, but should not exceed the amount needed to treat 5 seizure episodes a month. 
t. 
Subjects and caregivers will be trained based on the Direction for Use (DFU) for the proper use of the NRL-1 nasal sprayer.  Training may be given as needed during the treatment period.  Primary 
caregivers who are trained may train other secondary caregivers. 


 
 
APPENDIX B: 
COLUMBIA SUICIDE SEVERITY 
RATING SCALE (C-SSRS) 
 


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APPENDIX B:  Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS), a measure of suicidal ideation and behavior, 
will be used to document. For adults, screening assessments will use the Baseline/Screening version 
of the C-SSRS.  The Since Last Visit version of the C-SSRS will be used for post-dosing 
assessments.  For children age 6 to 11, screening assessments will use Children’s 
Baseline/Screening version and Children’s Since Last Visit will be used for post-dosing 
assessments.  
 


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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is 
“yes”, complete “Intensity of Ideation” section below. 
Lifetime: 
Time 
He/She 
Felt Most 
Suicidal 
Past 6 
Months 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes      No 
□    □ 
 
Yes    No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes   No 
   □   □ 
 
Yes    No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g., thought of method to kill self but not a 
specific plan).  Includes person who would say, “I thought about taking an overdose but I never made a specific plan as 
to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
Yes     No 
 □    □ 
 
Yes    No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to 
“I have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
   Yes      
No 
□    □ 
 
Yes    No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
Yes      No 
 □    □ 
 
Yes    No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, 
with 1 being the least severe and 5 being the most severe).  Ask about time he/she was feeling the most 
suicidal.  
 
Lifetime -           Most Severe Ideation:  _______                  
________________________________________ 
                         Type # (1-5)                                                 Description of  Ideation 
 
Past 6 Months - Most Severe Ideation:  _______                   
________________________________________ 
                        Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times 
each day 
 
 
____ 
 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
____ 


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Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
 
____ 
____ 
INTENSITY OF IDEATION 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this 
pain or how you were feeling) or was it to get attention, revenge or a reaction from others? Or 
both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you 
couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were 
feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you 
couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were 
feeling) 
                                                                                                                 (0)  Does not apply 
____ 
 
____ 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can 
be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or 
harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred 
(e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that 
what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, 
feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act(if not for that, 
actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather 
than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow 
prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is 
poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang 
- is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something 
stopped you before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in 
any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, 
instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or 
thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide 
(e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as 
collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 


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Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal    
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required 
(e.g., comatose with reflexes intact; third-degree burns less than 20% of body; extensive 
blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose 
without reflexes; third-degree burns over 20% of body; extensive blood loss with unstable 
vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter 
Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no 
actual medical damage, had potential for very serious lethality: put gun in mouth and pulled the 
trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but 
pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter 
Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 


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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit Version 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Since 
Last 
Visit 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than 
a specific plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  
Includes person who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or 
how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 
1 being the least severe and 5 being the most severe).  
 
Most Severe Ideation:             _____                      
_________________________________________________ 
 
Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each 
day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 


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Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
 
 
 
____ 
INTENSITY OF IDEATION 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end 
the pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or how 
you were feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go 
on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t 
go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since 
Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as 
method to kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can 
be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or 
harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. 
For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to 
head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did 
could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself?
 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, 
feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act(if not for that, actual 
attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather 
than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow 
prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is 
poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - 
is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something 
stopped you before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in 
any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead 
of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped 
yourself before you actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, 
such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving 
things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as 
collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
 
 
 
 
   Yes    
No 
□   □ 


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Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter 
Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter 
Code 
 
 
 
______ 
 
References 
 
K Posner; MA Oquendo; M Gould; B Stanley; M Davies. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s Pediatric Suicidal 
Risk Analysis of Antidepressants, Am J Psychiatry, 2007; 164:1035-1043.  
Center for Drug Evaluation and Research (CDER), Guidance for Industry Suicidality: Prospective 
Assessment of Occurrence in Clinical Trials. September 2010. 
K Posner; GK Brown; B Stanley; DA Brent; KV Yershova; MA Oquendo; GW Currier; GA Melvin; 
L Greenhill; S Shen; JJ Mann. The Columbia–Suicide Severity Rating Scale: Initial Validity and 
Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. Am J 
Psychiatry 2011;168:1266-1277. 
 
 


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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Children’s Baseline/Screening 
Version 6/23/10 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 


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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Children’s Since Last Visit Version 
Version 6/23/10 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk 
factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


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APPENDIX C: 
NIH TOOLBOX ODOR 
IDENTIFICATION TEST 
 
This test assesses a person’s ability to identify various odors.  Participants use scratch ’n’ sniff 
cards and after scratching them one at a time, are asked to identify which of four pictures on the 
computer screen matches the odor they have just smelled.  
Participants ages 10-85 are administered nine odor cards, while those ages 3-9 are administered 
five odor cards. Child participants (ages 3 -9 years) are first asked to identify the eight pictures 
that are used as answer choices, to ensure they can complete the task.  Having identified the 
pictures, they are asked if they have tasted or smelled the objects or foods depicted.  
This test takes approximately 4 to 5 minutes to administer and is recommended for ages 3-85.   
 
http://www.nihtoolbox.org/WhatAndWhy/Sensation/Olfaction/Pages/NIH-Toolbox-Odor-
Identification-Test.aspx 
 
 


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APPENDIX D: 
QUALITY OF LIFE IN EPILEPSY 
(QOLIE)  
Quality of Life in Epilepsy will be administered to assess the quality of life while on NRL-1 
compared to baseline therapy at time of enrollment.  QOLIE-AD-48 will be used for subjects age 
11-18 years with epilepsy.  Subjects age 18 years or older should complete the QOLIE-31-P. If 
under the age of 11, no Quality of Life questionnaire will be administered. 
 
 
 


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APPENDIX E: 
DIRECTIONS FOR USE 


NRL-1 INSTRUCTION GUIDE 
FOR INVESTIGATIONAL USE ONLY.  KEEP OUT OF REACH OF CHILDREN. 
IMPORTANT: FOR USE IN THE NOSE ONLY. 
DO NOT REMOVE OR TEST THE NRL-1 NASAL SPRAYER UNTIL READY TO USE. 
 
Neurelis, Inc. 
Version Date: 07 JUNE 2016 
 
Identify 
Seizure 
Occurrence 
 
 
Safely Secure the Person 
During a Seizure: 
• 
Stay Calm 
• 
If the person appears 
to be having a seizure 
and is standing, 
prevent them from 
falling by holding in a 
hug, or try to help them 
gently to the floor and 
lay the person on their 
side 
• 
If the person having a 
seizure is on the 
ground when you 
arrive, try to position 
them on their side so 
that any saliva or vomit 
may leak out of their 
mouth 
• 
Move furniture or 
other objects away to 
prevent injury to the 
person during the 
seizure 
 
Give 
NRL-1 
Nasal 
Spray 
HOLD
• The person can be in 
any position to receive a 
dose of NRL-1 nasal 
spray 
 the NRL-1 nasal 
spray with your thumb on 
the bottom of the nasal 
spray and your first and 
middle fingers on either 
side of the nozzle. 
 
• Insert the tip of the 
nozzle into one nostril, 
until your fingers on 
either side of the nozzle 
are against the bottom 
of the patient’s nose 
Gently insert the tip of 
the nozzle into either 
nostril. 
Press the bottom of the 
nasal spray firmly
• 
Remove the NRL-1 
nasal spray from the 
nose 
 to give 
the dose of NRL-1 nasal 
spray. 
 
For 15mg or 20mg dose, 
repeat with second 
sprayer in other nostril 
After the 
Seizure: 
Evaluate 
and 
Support 
Check the person for 
injuries.  
Move the person on their 
side (recovery position) 
if you could not turn the 
person onto their side 
during the seizure. 
Loosen tight clothing and 
provide a safe area where 
the person can rest 
Keep the person on their 
side
Your doctor may 
prescribe an 
 and note the time 
NRL-1 was given and 
observe 
additional 
dose of NRL-1 spray 
which may be given 
4 hours after the first 
dose.  Repeat Step 2 to 
give another dose of NRL-1 
nasal spray. 
3
2
1
Not more than 2 doses per seizure episode.  Call 
911 if seizure does not subside after second dose 
of NRL-1.  Allow 5 days before repeating dose. 

SAP_001.pdf: 
Neurelis, Inc. 
VALTOCO® (diazepam nasal spray) 
Protocol DIAZ.001.05 
Confidential/Proprietary Information 
STUDY TITLE: 
A 12-Month Open-Label, Repeat-Dose Safety Study of NRL-1 in 
Epilepsy Subjects 
STUDY PHASE: 
Phase 3  
PROTOCOL NUMBER: 
DIAZ.001.05 
NCT Number:  NCT02721069 
Protocol Version 4.0 - 28 September 2017 
Statistical Analysis Plan Version 1.1 – 8 July 2020 


Page 1 of 61 
NEURELIS, INC. 
STATISTICAL ANALYSIS PLAN 
Section 14 and 16 
Protocol No.: DIAZ.001.05 
A 12-Month Open-Label, Repeat-Dose Safety Study of NRL-1 in Epilepsy Subjects 
(DIAZ.001.05) 
CONFIDENTIAL 
Version:  1.1 
Date: July 8, 2020 


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SIGNATURE PAGE 
Prepared By: 
Name 
Jaekwan Kim 
Signature 
Manager, Statistics, GSG 
Date 
(yyyy/mm/dd) 
Reviewed By: 
Name 
Chaeyong Chang 
Signature 
President, GSG 
Date 
(yyyy/mm/dd) 
Name 
Richard E. Lowenthal, 
MSc, MBA 
Signature 
Program Manager, Neurelis, Inc 
Date 
(yyyy/mm/dd) 
Approved By: 
Name 
Enrique Carrazana 
Signature 
Chief Medical Officer, Neurelis 
Date 
(yyyy/mm/dd) 
7/08/2020
08Jul2020
08Jul2020
08Jul2020


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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................ 2 
1.
INTRODUCTION ...................................................................................................... 7
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 7 
2.1. 
Study Objectives ........................................................................................... 7 
Primary objective .......................................................................................... 7 
Secondary objective ..................................................................................... 7 
2.2. 
Study Endpoints............................................................................................ 7 
2.2.1. 
Efficacy Endpoints ......................................................................... 7 
2.2.2. 
Safety Endpoints ............................................................................ 7 
3.
STUDY DESIGN ...................................................................................................... 8 
4.
PLANNED ANALYSES .......................................................................................... 12 
4.1. 
Interim Analysis .......................................................................................... 12 
4.2. 
Final Analysis ............................................................................................. 12 
5.
SAMPLE SIZE CONSIDERATIONS ....................................................................... 12 
5.1. 
Sample Size Determination ........................................................................ 12 
5.2. 
Sample Size Re-estimation ......................................................................... 12 
6.
ANALYSIS POPULATIONS ................................................................................... 12 
7.
GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 12 
7.1. 
Multicenter Studies ..................................................................................... 13 
7.2. 
Other Strata and Covariates ....................................................................... 13 
7.3. 
Examination of Subgroups .......................................................................... 13 
7.4. 
Multiple Comparisons and Multiplicity ......................................................... 13 
8.
DATA HANDLING CONVENTIONS ....................................................................... 13 
8.1. 
Premature Withdrawal and Missing Data .................................................... 13 
8.2. 
Derived and Transformed Data ................................................................... 13 
8.2.1. 
ECG ............................................................................................. 13 
8.2.2. 
QOLIE ......................................................................................... 14 
8.3. 
Values of Clinical Concern .......................................................................... 15 
9.
STUDY POPULATION ........................................................................................... 15 
9.1. 
Disposition of Subjects ................................................................................ 15 
9.2. 
Protocol Deviations ..................................................................................... 15 
9.3. 
Demographic and Baseline Characteristics ................................................. 15 
10. EFFICACY ANALYSES .......................................................................................... 15 
11. SAFETY ANALYSES ............................................................................................. 15 
11.1. 
Extent of Exposure ..................................................................................... 15 
11.2. 
Adverse Events ........................................................................................... 17 
11.2.1. 
Additional Adverse Events Tables ............................................... 17 
11.3. 
Deaths and Serious Adverse Events ........................................................... 17 


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11.4. 
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events........................................................................................... 18 
11.5. 
Pregnancies (as applicable) ........................................................................ 18 
11.6. 
Clinical Laboratory Evaluations ................................................................... 18 
11.7. 
Other Safety Measures ............................................................................... 18 
11.7.1. 
Concomitant Medication .............................................................. 18 
11.7.2. 
Vital Signs .................................................................................... 18 
11.7.3. 
Electrocardiograms ...................................................................... 19 
11.7.4. 
Physical examination ................................................................... 19 
11.7.5. 
C-SSRS assessments (children and adult) .................................. 19 
11.7.6. 
QOLIE (children and adult) .......................................................... 19 
11.7.7. 
Nasal Irritation, Mucosal Erythema, Mucosal Edema, 
Nasal Discharge, Mucosal Crusting and Mucosal Epistaxis ......... 19 
11.7.8. 
NIH Toolbox Odor Identification Test ........................................... 20 
11.7.9. 
Sedation Score Assessment ........................................................ 20 
11.8. 
Exploratory Analysis ................................................................................... 20 
12. TABLES, LISTINGS, GRAPHS .............................................................................. 22 
12.1.1. 
Tables .......................................................................................... 22 
12.1.2. 
Listings ........................................................................................ 58 
12.1.3. 
Graphs ......................................................................................... 59 
13. REFERENCES ....................................................................................................... 61 
 
 
 
 
 
 
 
 
 
 
 
 


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Document History 
Verision 
Date of Issue 
Summary of Change 
1.0 
May 26, 2018 
Original 
1.1 
July 8, 2020 
Additional analysis has been added 
(Safety/Tolerability & Effectiveness) 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
AUC(0-6) 
area under the plasma concentration time-curve to 6 hours post dose 
BLQ 
below the limit of quantization  
C-SSRS 
Columbia Suicide Severity Rating Scale 
Cmax 
Maximum plasma concentration 
ECG 
Electrocardiogram 
EMU 
Epilepsy Monitoring Unit 
FDA 
US Food and Drug Administration 
HEENT 
head, ears, eyes, nose, and throat 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter 
NIH 
National Institutes of Health 
NRL-1 
Diazepam nasal spray 
PK 
pharmacokinetics 
QOLIE 
Quality Of Life In Epilepsy  
QTcF 
Corrected QT interval, Fridericia’s formula 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
VAS 
Visual Analog Scale 
WHODD 
World Health Organization Drug Dictionary 
 
 
 


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Neurelis, Inc. Protocol DIAZ.001.05 
1. 
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures to be 
used for analyzing and reporting results for study DIAZ.001.05. 
This SAP is based on the final protocol version 3 (23-May-2016). 
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1. 
Study Objectives
The purpose of this study is to assess the safety of repeat intranasal doses of NRL-1 
administered to Epilepsy subjects. 
Primary objective 
The primary objective of this study is to assess the safety of diazepam after repeat 
intranasal doses of NRL-1 administered to Epilepsy subjects who experience frequent 
breakthrough seizures or Acute Repetitive Seizures, over a 12-month period.  FDA has 
requested that analyses be presented by Overall and age group of 6-11 and 12+ dosing in 
the Diastat labeling.  
Secondary objective 
•
To assess the tolerability of diazepam after repeat intranasal administration of
NRL-1.
•
To assess the ability of caregivers to administer NRL-1 based on the Directions
for Use (DFU).
•
To assess an improvement in the Quality of Life with NRL-1 use as compared to
Diastat.
2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
There are no efficacy endpoints for this study. 
2.2.2. 
Safety Endpoints 
Safety data will be summarized by dose group and based on their initial dose level or 
treatment group (i.e., if a dose reduction occurs they will be considered in their initial 
group).  Overall and age group of 6-11 and 12+ descriptive statistics will be provided for 
actual values and change from baseline values for vital signs and change from screening 
for clinical laboratory tests (serum chemistry, hematology, and urinalysis). 


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A nasal examination and irritation assessments will be conducted to evaluate any effects 
of the NRL-1 formulation on the nasal mucosa.  The following will be assessed on 
separate scales: nasal Irritation, erythema, edema, nasal discharge, mucosal erythema, 
mucosal edema, nasal discharge, mucosal crusting and epistaxis.   Overall and age group 
of 6-11 and 12+ descriptive statistics will be provided. 
Smell tests and examination of the nasal mucosa will be conducted at screening and at 
each study visit.  The NIH Toolbox for Odor Identification Test will be used as smell 
tests. 
The Columbia-Suicide-Severity Rating Scale (C-SSRS), a measure of suicidal ideation 
and behavior, will be used to document suicidality in order to classify suicidal events.  
Suicidality will be assessed at screening for eligibility, day 150 and day 365. The 
pediatric C-SSRS should be used for subject age 6 to 11.  The adult C-SSRS should be 
used for subjects 12 and greater years of age. 
The Quality of Life in Epilepsy will be administered to assess the quality of life while on 
NRL-1 compared to baseline therapy at time of enrollment, day 30, day 150, day 270 and 
day 365.  QOLIE-AD-48 will be used for subject age 11-18 years with epilepsy.  Subjects 
age 18 years or older should complete the QOLIE-31-P.  
Adverse event (AE) collection will begin on Day 0 after baseline assessments are 
complete prior to the initial treatment with NRL-1 and continue for 28-days after Day 
365.  AE may be either spontaneously reported or elicited during questioning and 
examination of a subject.  Adverse event information will be elicited at appropriate 
intervals by indirect questioning using a non-leading question.  Adverse events that occur 
after dosing in a home setting will be recorded in a diary and reported at the next study 
visit.  Subjects will receive follow-up telephone contact approximately 28 days (± 3 days) 
after Day 365 to determine if any AE has occurred and to follow-up on any treatment-
emergent AEs (TEAE[s]) ongoing since last communication with the subject. 
The incidence and severity of TEAEs reported during the study and their relationship to 
study drug will be tabulated. TEAEs will be coded using the MedDRA and will be 
presented by body system. 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior 
and concomitant medications by therapeutic class and preferred term. Prior and 
concomitant medication usage will be summarized by the number and percentage of 
subjects receiving each medication within each therapeutic class by dose cohort. 
 
3. 
STUDY DESIGN 
This is a Phase 3, repeat dose, open-label, safety study in Epilepsy subjects who have 
frequent breakthrough seizures or Acute Repetitive Seizures (ARS).  NRL-1 will be 
administered as needed to treat bouts of those seizures over a 12-month period of time.  
Doses will be defined as 5 mg, 10 mg, 15 mg, or 20 mg based on the subject’s body 
weight.  A diary will be used to record the seizure and NRL-1 administration. 


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Neurelis, Inc. Protocol DIAZ.001.05 
The study consists of a screening phase, a baseline, a 12-month treatment period and a 
follow-up telephone contact 28-days after the last dose of NRL-1 or study termination.  
The primary purpose of this study is to assess the safety of repeat doses of NRL-1 as 
intermittent chronic therapy to treat frequent break through seizures or ARS. 
Safety assessments include physical and neurological examination including head, ears, 
eyes, nose, and throat (HEENT), vital signs, laboratories (hematology, serum chemistry, 
and urinalysis), 12-lead electrocardiograms (ECGs), and adverse event assessment.  
Concomitant medications will be recorded.  Columbia-Suicide Severity Rating Scale (C-
SSRS for adults or pediatric), Nasal Irritation Assessment, Sedation Score Assessment, 
and Smell Test (NIH Toolbox Odor Identification Test) and examination of nasal mucosa 
will be conducted at each visit.  A targeted physical examination may be used to evaluate 
any potentially related side effects.   
Subjects and caregivers will be trained on the proper use of the NRL-1 nasal sprayer at 
screening period and as needed during treatment period.  The ability of caregivers to 
administer NRL-1 based on the Directions for Use (DFU) will be assessed. 
The Quality of Life in Epilepsy (QOLIE) questionnaire will be administered to assess the 
quality of life while on NRL-1 compared to baseline therapy at time of enrollment.  
Naïve subjects may be entered into this study as well as those subjects completing the 
protocol DIAZ.001.04 are eligible for the long-term safety study (DIAZ.01.05) and may 
receive treatment with NRL-1 under DIAZ.01.05 protocol. 


Neurelis, Inc. Protocol DIAZ.001.05 
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a. 
Screening evaluations must be performed within 21 days prior to dosing on Day 0.  Screening evaluations performed within 24 hours (Day -1 to Day 0) of dosing do not need to be repeated.  
b. 
Baseline evaluations will be performed within 72 hours prior to study initiation on Day 0.  Baseline assessment may be conducted at clinic. 
c. 
Subjects will receive follow-up telephone contact approximately 28 days (± 3 days) after Day 365 
d. 
Study window at visits from Days 30 to 365 is ± 7 days. 
e. 
C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality in order to classify suicidal events. The pediatric C-SSRS should be used for subjects age 6 to 11.  The adult 
C-SSRS should be used for subjects 12 and greater years of age (see APPENDIX B). 
f. 
Targeted physical examinations may be used during the treatment period to evaluate potentially related adverse events. 
g. 
Vital signs (temperature, pulse, and blood pressure) are to be obtained. 
h. 
Weight only. 
i. 
A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at screening. Pregnancy test will be done with urine at baseline and at the visits during the treatment period. If a 
serum pregnancy test is done on Day -1, urine pregnancy test does not have to be repeated if done within 72 hours of study initiation (baseline).  
j. 
Hepatitis B surface antigen (HbSAg), or Hepatitis C  
Study Procedure 
Screeninga 
Baselineb 
Treatment period and Visit Days 
Follow Up 
telephone 
contactc 
Study Day 
Day -21 to Day -1 
Day -3 to Day 0 
Day 
30d 
Day 
90d 
Day 
150d 
Day 
210d 
Day 
270d 
Day 
330d 
Day 
365d 
Day 393 or 
termination 
visit 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history including seizure history 
X 
X 
 
 
 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale (C-SSRS)e 
X 
 
 
 
X 
 
 
 
X 
 
Physical and Neurological exam (including 
HEENT)f 
X 
 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height and Weight 
X 
Xh 
 
 
 
 
 
 
X 
 
Hematology, Serum Chemistry and Urinalysis 
X 
 
 
 
X 
 
X 
 
X 
 
Serum or urine ß-hCG (Pregnancy)i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV Antibody and Hepatitis Testj 
X 
 
 
 
 
 
 
 
 
 
Urine Drug, Alcohol and Cotinine Screenk 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medication assessment 
X 
X 
X-------------------------------------------------------------------- 
X 
Adverse event assessmentl 
 
X 
X-------------------------------------------------------------------- 
X 
ECG (12-Lead in triplicate)m 
X 
X 
 
 
 
 
 
 
 
 
Smell Testn 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of the ability of caregivers to administer 
NRL-1o 
 
X 
X 
 
X 
 
X 
 
X 
 
Nasal Examination and Irritation Assessmentp 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Quality of Life in Epilepsy questionnaire (QOLIE)q 
 
X 
X 
 
X 
 
X 
 
X 
 
NRL-1 administrationr 
 
X 
X---------------------------------------------------- 
 
 
Diary to record seizure and NRL-1 administration 
 
X 
X-------------------------------------------------------------------- 
 
Subject/caregiver trainings 
X 
 
X---------------------------------------------------- 
 
 


Neurelis, Inc. Protocol DIAZ.001.05 
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k. 
When marijuana was prescribed for medical reason by a licensed practitioner, it is not considered as drug abuse and the patient can be enrolled even if the marijuana metabolites in the urine revealed as 
positive. In this case, information about marijuana prescription should be entered in the CRF page for concomitant medication. 
l. 
Adverse event assessment is continuous from Day 0 after baseline assessments are complete.  Events that occur after dosing in a home setting will be recorded in a diary and reported at the next study 
visit. 
m. 
ECG is to be performed in triplicate. Three consecutive ECGs (each approximately 1-2 minutes apart) are performed. 
n. 
Smell tests will be conducted at baseline and at each visit. The NIH Toolbox Odor Identification Test will be used as smell tests. 
o. 
Ability of caregivers to administer NRL-1 will be assessed. 
p. 
Nasal examination and scoring for nasal irritation, mucosal erythema, mucosal edema, nasal discharge, mucosal crusting and mucosal epistaxis will be performed at baseline and at each site visit. 
q. 
QOLIE questionnaire will be administered to assess the quality of life while on NRL-1 compared to baseline therapy at time of enrollment (see APPENDIX D ). 
r. 
NRL-1 administration will be as needed to treat bouts of uncontrolled seizures (frequent break through seizures or ARS) after baseline procedures completed.  
s. 
Subjects and caregivers will be trained based on the Direction for Use (DFU) for the proper use of the NRL-1 nasal sprayer.  Training may be given as needed during the treatment period. 


Neurelis, Inc. Protocol DIAZ.001.05 
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4. 
PLANNED ANALYSES 
4.1. 
Interim Analysis 
One interim analysis will be performed done using soft lock data (cut off date :  
April 30, 2018 ) for regulatory approval. 
 
4.2. 
Final Analysis 
Final analyses will be completed following database lock in the study. Any changes from 
the planned analyses described in this section will be stated in the final study report. 
 
5. 
SAMPLE SIZE CONSIDERATIONS 
5.1. 
Sample Size Determination 
Up to 100 subjects, at least 30 age 6 to 11 years and up to 70 over 12 years of age, are to 
be enrolled. 
5.2. 
Sample Size Re-estimation 
A re-estimation of sample size will not be performed on this study. 
 
6. 
ANALYSIS POPULATIONS 
Safety Population 
Subjects who have taken at least one dose of NRL-1will be included in the safety 
analyses. 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
In general, the sort order for listings will be dose level (ascending dose levels of NRL-1), 
subject and assessment time, while summaries will be presented by dose level (ascending 
dose levels of NRL-1) and assessment time.  A separate but identical analysis will be 
performed by age groups (6-11 and 12+). 


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Unless stated otherwise, descriptive summaries will include n(Number of subjects), 
mean, standard deviation, median, range for continuous variables and n(Number of 
subjects) and percent for categorical variables. For planned ECG parameter assessments 
that are done in triplicate, the mean value will be used in the calculation of all descriptive 
statistics. If there are repeated assessments at a scheduled time point, the assessment 
closest to the scheduled time will be used in the calculation of all descriptive statistics. 
Any unscheduled or unplanned readings will be presented within the subject listings, but 
only the scheduled readings will be used in any summaries. Version 9.4 of the SAS™ 
system (SAS is a registered trademark of the SAS Institute, Inc., Cary, NC, USA) will be 
used to analyze the data as well as to generate tables, figures, and listings. 
7.1. 
Multicenter Studies 
Multi center will participate in the study. 
7.2. 
Other Strata and Covariates 
There are no other strata and covariates. 
7.3. 
Examination of Subgroups 
There is subgroup analysis of safety data by age group of 6-11 and 12+ will be provided. 
7.4. 
Multiple Comparisons and Multiplicity 
No adjustments for multiple comparisons are planned. 
8. 
DATA HANDLING CONVENTIONS 
8.1. 
Premature Withdrawal and Missing Data 
All subjects who withdraw from the study prematurely will be documented and the 
reason for their withdrawal will be reported in the final study report. Subjects who 
discontinue participation in the study prior to receiving study drug for a given dose level 
will be replaced, if possible. Missing data will not be imputed. 
8.2. 
Derived and Transformed Data 
8.2.1. 
ECG 
QTc intervals will be calculated by Fridericia’s (QTcF) formulas.  
Fridericia’s formula is: 


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QTcF interval (msec) = QT interval (msec)/ (RR interval (sec))1/3 
where RR interval (sec) = 1/(heart rate (bpm)/60) 
8.2.2. 
QOLIE 
Following component summary will be populated following each scoring manuals. 
 QOLIE31: Quality of Life In Epilepsy QOLIE-31 (Version 1.0) Scoring manual 
will be used to calculate sub-scale parameters for version 1 of QOLIE-31. 
e. 
Energy 
f. 
Mood 
g. Daily Activities 
h. Cognition 
i. 
Medication effects 
j. 
Seizure Worry 
k. Overall Quality of Life 
l. 
Final QOLIE-31-P Score 
 
 QOLIE-31-P : Patient-Weighted Quality of Life in Epilepsy (v.2) will be used to 
calculate sub-scale parameters for version 2 of QOLIE-31-P.  
a. 
Seizure worry 
b. Overall quality of life 
c. 
Emotional well-being 
d. Energy/fatigue 
e. 
Cognitive functioning 
f. 
Medication effects 
g. Social functioning 
h. Overall scores 
 
 QOLIE-AD-48.  Quality of Life in Epilepsy for Adolescents (version 1.0) will be 
used to calculate sub-scale parameters and Total (Summary) Score. 
a. Epilepsy Impact 
b. Memory/Concentration 
c. Physical Functioning 
d. Stigma 
e. Social Support 
f. School Behavior 
g. Attitudes Toward Epilepsy 
h. Health Perceptions 
i. Total (Summary) Score 
 


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8.3. 
Values of Clinical Concern 
Values that exceed the lower/upper limits of clinical lab values, all abnormal or “not 
clinically significant” and all changes in vital signs will be reviewed for clinical 
relevance by the Medical Monitor (PLC). 
9. 
STUDY POPULATION 
Subjects with a clinical diagnosis of frequent break through seizures or ARS with bouts 
of uncontrolled seizures, who, in the opinion of the Investigator, may need a 
benzodiazepine for seizure control. 
9.1. 
Disposition of Subjects 
All data from enrolled subjects will be summarized to provide the number of subjects 
who complete the study within each treatment and the number of subjects withdrawn and 
the reasons for withdrawal will be summarized. Also, subject listing will be provided. 
9.2. 
Protocol Deviations 
Protocol deviations will be reported to Neurelis, Inc and will be documented in the 
clinical study report.  Any changes from the analyses described within this statistical 
analysis plan will be stated in the final study report. 
9.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics for the subject population will be listed and 
summarized using the safety population. Descriptive summaries (n(Number of subjects), 
mean, standard deviation, minimum, median, and maximum and n(Number of subjects) 
and percent for categorical variables) will be provided by treatment group. 
10. 
EFFICACY ANALYSES 
No efficacy measures will be assessed during this study. 
11. 
SAFETY ANALYSES 
No formal statistical comparisons of the safety data will be conducted. 
 
11.1. 
Extent of Exposure 
The exposure data will be a by-subject listing, including the treatment administered with 
the dates and times of treatment administration. 


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11.2 Analysis of Seizure Events 
A seizure event is defined as the initial event of a 24-hour period.   For example, consider 
the following hypothetical data from a subject with 5 records: 
Record  
Date/time of seizure record 
1 
 
2019-07-08T13:00 
2 
 
2019-07-09T14:00 
3 
 
2019-07-10T01:00 
4 
 
2019-07-10T02:00 
5 
 
2019-07-19T05:00 
 
This subject has three seizure events (records 1, 2, and 5).   Because records 3 and 4 
occur within 24 hours of record 2, these are retreatment records. 
The number and percentage of seizure events for which retreatment was required will be 
summarized for all events and by dose level for the following time intervals of 
retreatment: 
• 0-10 minutes 
• 10-30 minutes 
• 30 minutes-1 hour 
• 1-2 hours 
• 2-3 hours 
• 3-4 hours 
 
• 0-4 hours 
• 0-6 hours 
• 0-8 hours 
• 0-12 hours 
• 0-16 hours 
• 0-20 hours 
• 0-24 hours 
In addition to the overall summary, results will be provided for the following subgroups: 
• 6-11 year olds 
• 12-17 year olds 
• 18 years of age and older 
• Subjects with seasonal allergies/rhinitis 
• Subjects without seasonal allergies/rhinitis 


Neurelis, Inc. Protocol DIAZ.001.05 
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•
Subjects with concomitant use of other benzodiazepines
•
Subjects without concomitant use of other benzodiazepines
11.2. 
Adverse Events 
All adverse events (AEs) will be coded and classified according to System Organ Class 
(SOC) and Preferred Term (PT) using MedDRA(Version 16.1or more). TEAE(treatment 
emergent Adverse Event) will be populated. All AEs (non-serious and serious) will be 
listed. A summary, by treatment group, of the number and percent of subjects reporting 
each event at least once will be generated for all AEs and also for drug-related AEs. 
Adverse events by System Organ Class, Preferred Term, and Severity will be 
summarized by Treatment group.  A listing of the relationship with study drug by System 
Organ Class and Preferred Term will also be produced. 
11.2.1. 
Additional Adverse Events Tables 
Summary AE table, Incidence of TEAE by MedDRA system Organ Class, PT term, by 
strongest relationship, maximum severity, Seriousness will be produced.  Similar tables 
will be produced by following subgroups.     
a.
By age group (12-17 years, >= 18 years)what about 6-11?
b. By gender (Female, Male)
c.
By subjects whose mean dose is <1 dose/month, 1-2 doses/month, 3-5
doses/month, > 5 doses/month
d. By Subjects whose second dose of NRL-1 was used prior to 4 hours,  second
doses given 4-24 hours after first dose
e.
By subject's the NRL-1 treatment was sooner than the 5 days in-between events
f.
By subject who have used more than 5 doses within a 30 days period, don’t
have used more than 5 doses within a 30 days period
g. By subjects who used  benzodiazepines as Concomitant medication
h. By subjects who has seasonal allergies/rhinitis history vs. don’t have seasonal
allergies/rhinitis
i.
By subjects whose AE onset month is Winter : Jan-Mar, Spring : Apr-Jun,
Summer : Jul-Sep, Winter : Oct-Dec
j.
By subjects who has AE PT are Cardiorespiratory/, Nasal/nasopharyngeal
k. By subjects who had AE Requires/Prolongs Hospitalization
l.
By subjects who had Status Epilepticus, Recurrent Seizures – which led to
ER/Hospitalization and within the 48 hours after first NRL-1 dose
m. By subjects who were SELF-ADMINISTRATORS from the survey
11.3. 
Deaths and Serious Adverse Events 
Any deaths and other serious adverse events will be summarized and listed as appropriate 
to the data. 


Neurelis, Inc. Protocol DIAZ.001.05 
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11.4. 
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events 
If any subject withdraws due to an AE, then a listing and a summary will be provided for 
these subject(s). 
11.5. 
Pregnancies (as applicable) 
If any female subject becomes pregnant during the course of the study, this information 
will be tabulated and listed. 
11.6. 
Clinical Laboratory Evaluations 
All laboratory data will be listed for each subject. Summary statistics (n(Number of 
subjects), mean, standard deviation, median, range for continuous variables and 
n(Number of subjects) and percent for categorical variables) will be displayed for 
laboratory parameters. Clinically significant abnormalities, if they occur, will also be 
listed. To assess changes in laboratory parameters occurring during treatment, a shift 
summary of change from baseline to time-point (visit) and summary of change from 
baseline will be produced. Urine analysis for categorical variables will be categorized by 
treatment, class variable (e.g., negative or positive) and visit. 
11.7. 
Other Safety Measures 
11.7.1. 
Concomitant Medication 
Prior and concomitant medication will be coded and classified to according Preferred 
Term (PT) and modified drug name using The World Health Organization Drug Dictionary 
(WHODRL). Prior and concomitant medication by Preferred Term and modified drug 
name will be summarized by Treatment group. 
 
11.7.2. 
Vital Signs 
All vital sign data will be listed for each subject. Summary statistics (n(Number of 
subjects), mean, standard deviation, minimum, median, and maximum)for vital 
parameter(temperature, breathing rate, radial pulse, systolic blood pressure, diastolic 
blood pressure, height and weight) will be presented by treatments and visit. And also 
summary of the change from baseline will be summarized. 


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11.7.3. 
Electrocardiograms 
In order to assess the effect of treatment on cardiac intervals, triplicate 12-lead digital 
ECGs will be collected. ECG sign data will be listed for each subject. A descriptive 
summary (n(Number of subjects), mean, standard deviation, minimum, median, and 
maximum and n(Number of subjects) and percent for categorical variables)for ECG 
parameter will be presented by treatments. 
11.7.4. 
Physical examination 
All physical examination data will be listed for each subject. Frequency and percent by 
treatment group will be displayed for physical examination parameters. A shift summary 
of change from screening to time-point (visit) will be produced. 
 
11.7.5. 
C-SSRS assessments (children and adult) 
C-SSRS assessments (children and adult) data will be listed for each treatment and 
subject by visit.  
11.7.6. 
QOLIE (children and adult) 
QOLIE assessments data will be listed for each treatment and subject by visit. 
The descriptive statistics (mean, SD, maximum value, minimum value, median, two sided 
95% CI) for the populated QOLIE scores and changed from baseline value per visit will 
be summarized per visit (baseline, day30, day150, day270, day365) by treatment groups.  
For Adult (Age 18 Years old), QOLIE-31 and QOLIE-31-P have been used in this trial.  
For the descriptive statistics table, formula in the QOLIE-31 (version 1.0) scoring manual 
will be used for both QOLIE-31 & QOLIE-31-P results to calculate sub-scale parameter 
and overall score, due to lack of distress item score obtained in QOLIE-31-P 
questionnaires but not in QOLIE-31 questionnaires.    
 
11.7.7. 
Nasal Irritation, Mucosal Erythema, Mucosal Edema, Nasal 
Discharge, Mucosal Crusting and Mucosal Epistaxis 
Nasal examination and irritation assessments (Nasal Irritation, Mucosal Erythema, 
Mucosal edema, Nasal discharge, Mucosal crusting and Mucosal epistaxis) data will be 
listed for each subject. Frequency and percent by treatment group will be displayed for 
Nasal examination and irritation assessments. 


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Assessment will be dichomized for each assessment (Nasal Irritation, Mucosal Erythema, 
Mucosal edema, Nasal discharge, Mucosal crusting and Mucosal epistaxis).  One 
category will be Grade 0 or Score 0 and other category will be combination of any Non 
Grade 0 or Non Score 0 assessments.  A shift summary of change from screening to time-
point (visit) will be produced.  A figure showing each assessment (Nasal Irritation, 
Mucosal Erythema, Mucosal edema, Nasal discharge, Mucosal crusting and Mucosal 
epistaxis) mean and standard deviation by visit will be provided.  Same tables and figures 
by age group of 6-11 and 12+ will be provided. 
11.7.8. 
NIH Toolbox Odor Identification Test 
NIH Toolbox Odor Identification Test will be listed for each subject. Summary statistics 
(n(Number of subjects), mean, standard deviation, minimum, median, and maximum)for 
NIH Toolbox Odor Identification Test will be presented by treatments and visit.  A figure 
showing mean and standard deviation by visit will be provided.  Same tables and figures 
by age group of 6-11 and 12+ will be provided. 
11.7.9. 
Sedation Score Assessment 
Sedation Score Assessment will be summarized for each subject. Summary statistics 
(n(Number of subjects), mean, standard deviation, minimum, median, and maximum)for 
Sedation Score Assessment will be presented by treatments and visit. 
11.8. 
Exploratory Analysis 
Table for Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure that 
occurred time will be presented by age group (6-11, 12-17, 18 < years old), by gender 
(female, male), by super users vs. infrequent user and by subject with concomitant use of 
other benzodiazepines. 
Table for Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a second dose 
will be presented by age group (6-11, 12-17, 18 < years old), by gender (female, male) by 
super users vs. infrequent user and by subject with concomitant use of other 
benzodiazepines. 
Tables for Mean doses use per patient per month by treatment will be presented by age 
group (6-11, 12-17, 18 < years old) and by gender (female, male). 
Table for Pattern of use for Single -> Second Dose by TIME-POINT (0-10 minutes, 10-
30 minutes, 30 minutes-1 hour, 1-2 hours, 2-3 hours,3-4 hours, 0-4 hours, 0-6 hours, 0-8 
hours, 0-12 hours, 0-16 hours, 0-20 hours, 0-24 hours) by Treatment will be present by 
Subject with concomitant use of other benzodiazepines and by Subject who have Status 
Epilepticus or seizures as AE that leading to hospitalization. 


Neurelis, Inc. Protocol DIAZ.001.05 
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Kaplan-Meier plot for following subgroups will be presented in figures. 
a.
KM plot of time to second dosed subject (first vs. second in each seizure cluster)
by treatment
b. KM plot of time to dosed subject (first vs. second in each seizure cluster) by age
c.
KM plot of time to dosed subject (first vs. second in each seizure cluster) by use
pattern (< 1 dose/month, 1-2 doses/month, >2 doses/month), > 5 doses/month)
d. KM plot of time to dosed subject (first vs. second in each seizure cluster) by
usage time (6,1 2 and > 12 months)
e.
KM plot of time to dosed subject (first vs. second in each seizure cluster) by
gender
f.
KM plot of time to last dosed subject (first vs. last in each seizure cluster) by
treatment
g. KM plot of time to last dosed subject (first vs. last in each seizure cluster) by age
h. KM plot of time to last dosed subject (first vs. last in each seizure cluster) by use
pattern (< 1 dose/month, 1-2 doses/month, >2 doses/month), > 5 doses/month)
i.
KM plot of time to last dosed subject (first vs. last in each seizure cluster) by
usage time (6,1 2 and > 12 months)
j.
KM plot of time to last dosed subject (first vs. last in each seizure cluster) by
gender


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12.
TABLES, LISTINGS, GRAPHS
12.1.1. 
Tables 
Table No 
Title 
Table 14.1.1.1 
Subject Disposition (6-11 years old subject) -  All Population 
Table 14.1.1.2 
Subject Disposition (>= 12 years old subject) -  All Population 
Table 14.1.1.3 
Subject Disposition (All subject) -  All Population 
Table 14.1.1.4 
Subject Disposition (SELF-ADMINISTRATORS) -  All Population 
Table 14.1.2.1 
Analysis Populations -  All Population 
Table 14.1.2.2.1 
Demographics (6-11 years old subject) -  Safety Population 
Table 14.1.2.2.2 
Demographics (>= 12 years old subject) -  Safety Population 
Table 14.1.2.2.3 
Demographics (All subject) -  Safety Population 
Table 14.1.2.2.4 
Demographics (SELF-ADMINISTRATORS) -  Safety Population 
Table 14.1.2.3 
Seizure -  Safety Population 
Table 14.1.2.4 
Number of Dose Per Subject by Month -  Safety Population 
Table 14.1.2.5 
Dose Summary -  Safety Population 
Table 14.1.2.6 
Dose (6-11 years old subject) -  Safety Population 
Table 14.1.2.7 
Dose (>= 12 years old subject) -  Safety Population 
Table 14.1.2.8 
Dose (All subject) -  Safety Population 
Table 14.1.2.9 
Dose (SELF-ADMINISTRATORS) -  Safety Population 
Table 14.1.2.10 
Dosing Error by Treatment -  Safety Population 
Table 14.1.2.11 
Dosing Error Subject -  Safety Population 
Table 14.1.3 
Inclusion/Exclusion Criteria Fulfilled  -  Safety Population 
Table 14.1.4 
Medical History by Body System  -  Safety Population 
Table 14.1.5 
Urine Drug Screening -  Safety Population 
Table 14.1.6 
Serology at Screening -  Safety Population 
Table 14.1.7 
Pregnancy Test  -  Safety Population 
Table 14.1.8.1 
Incidence of Treatment-Period Concomitant Medications  -  Safety 
Population 
Table 14.1.8.2 
Incidence of Prior Medications -  Safety Population 
Table 14.2.1.1 
Nasal Irritation Assessments by Treatment and Visit (6-11 years old 
subject) -  Safety Population 
Table 14.2.1.2 
Nasal Irritation Assessments by Treatment and Visit (>= 12 years old 
subject) -  Safety Population 
Table 14.2.1.3 
Nasal Irritation Assessments by Treatment and Visit  (All subject) -  
Safety Population 
Table 14.2.1.4 
Nasal Irritation Assessments - Shift Tables by Treatment and Visit (6-
11 years old subject) -  Safety Population 
Table 14.2.1.5 
Nasal Irritation Assessments - Shift Tables by Treatment and Visit (>= 
12 years old subject) -  Safety Population 
Table 14.2.1.6 
Nasal Irritation Assessments - Shift Tables by Treatment and Visit  
(All subject) -  Safety Population 
Table 14.2.2.1 
Mucosal Erythema by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Table 14.2.2.2 
Mucosal Erythema by Treatment and Visit (>= 12 years old subject) -  
Safety Population 


Neurelis, Inc. Protocol DIAZ.001.05 
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Table 14.2.2.3 
Mucosal Erythema by Treatment and Visit  (All subject) -  Safety 
Population 
Table 14.2.2.4 
Mucosal Erythema - Shift Tables by Treatment and Visit (6-11 years 
old subject) -  Safety Population 
Table 14.2.2.5 
Mucosal Erythema - Shift Tables by Treatment and Visit (>= 12 years 
old subject) -  Safety Population 
Table 14.2.2.6 
Mucosal Erythema - Shift Tables by Treatment and Visit  (All subject) 
- Safety Population
Table 14.2.3.1 
Mucosal Edema by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Table 14.2.3.2 
Mucosal Edema by Treatment and Visit (>= 12 years old subject) -  
Safety Population 
Table 14.2.3.3 
Mucosal Edema by Treatment and Visit  (All subject) -  Safety 
Population 
Table 14.2.3.4 
Mucosal Edema - Shift Tables by Treatment and Visit (6-11 years old 
subject) -  Safety Population 
Table 14.2.3.5 
Mucosal Edema - Shift Tables by Treatment and Visit (>= 12 years 
old subject) -  Safety Population 
Table 14.2.3.6 
Mucosal Edema - Shift Tables by Treatment and Visit  (All subject) -  
Safety Population 
Table 14.2.4.1 
Nasal Discharge by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Table 14.2.4.2 
Nasal Discharge by Treatment and Visit (>= 12 years old subject) -  
Safety Population 
Table 14.2.4.3 
Nasal Discharge by Treatment and Visit  (All subject) -  Safety 
Population 
Table 14.2.4.4 
Nasal Discharge - Shift Tables by Treatment and Visit (6-11 years old 
subject) -  Safety Population 
Table 14.2.4.5 
Nasal Discharge - Shift Tables by Treatment and Visit (>= 12 years 
old subject) -  Safety Population 
Table 14.2.4.6 
Nasal Discharge - Shift Tables by Treatment and Visit  (All subject) -  
Safety Population 
Table 14.2.5.1 
Mucosal Crusting by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Table 14.2.5.2 
Mucosal Crusting by Treatment and Visit (>= 12 years old subject) -  
Safety Population 
Table 14.2.5.3 
Mucosal Crusting by Treatment and Visit  (All subject) -  Safety 
Population 
Table 14.2.5.4 
Mucosal Crusting - Shift Tables by Treatment and Visit (6-11 years 
old subject) -  Safety Population 
Table 14.2.5.5 
Mucosal Crusting - Shift Tables by Treatment and Visit (>= 12 years 
old subject) -  Safety Population 
Table 14.2.5.6 
Mucosal Crusting- Shift Tables by Treatment and Visit  (All subject) -  
Safety Population 
Table 14.2.6.1 
Mucosal Epistaxis by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Table 14.2.6.2 
Mucosal Epistaxis by Treatment and Visit (>= 12 years old subject) -  


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Safety Population 
Table 14.2.6.3 
Mucosal Epistaxis by Treatment and Visit  (All subject) -  Safety 
Population 
Table 14.2.6.4 
Mucosal Epistaxis - Shift Tables by Treatment and Visit (6-11 years 
old subject) -  Safety Population 
Table 14.2.6.5 
Mucosal Epistaxis - Shift Tables by Treatment and Visit (>= 12 years 
old subject) -  Safety Population 
Table 14.2.6.6 
Mucosal Epistaxis - Shift Tables by Treatment and Visit  (All subject) 
- Safety Population
Table 14.2.7.1 
NIH TOOLBOX ODOR IDENTIFICATION TEST by Treatment and 
Visit  (6-11 years old subject) -  Safety Population 
Table 14.2.7.2 
NIH TOOLBOX ODOR IDENTIFICATION TEST by Treatment and 
Visit  (>= 12 years old subject) -  Safety Population 
Table 14.2.7.3 
NIH TOOLBOX ODOR IDENTIFICATION TEST by Treatment and 
Visit  (All subject) -  Safety Population 
Table 14.2.8.1 
QOLIE-31 (age 18 years or older) by Treatment and Visit -  Safety 
Population 
Table 14.2.8.2 
QOLIE-AD-48  (ages 11-17 years) by Treatment and Visit -  Safety 
Population 
Table 14.2.9.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( All subjects) -  Safety Population 
Table 14.2.9.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month) -  Safety 
Population 
Table 14.2.9.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure 6 - 12 month) -  Safety 
Population 
Table 14.2.9.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month) -  Safety 
Population 
Table 14.2.10.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment(  6-11 years old subject) -  Safety Population 
Table 14.2.10.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month and 6-11 years 
old subject) -  Safety Population 
Table 14.2.10.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure 6 - 12 month and  6-11 
years old subject) -  Safety Population 
Table 14.2.10.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month and  6-11 
years old subject) -  Safety Population 
Table 14.2.11.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( 12-17 years old subject) -  Safety Population 
Table 14.2.11.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month and 12-17 
years old subject) -  Safety Population 
Table 14.2.11.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  


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Treatment( subjects whose time of exposure 6 - 12 month and 12-17 
years old subject) -  Safety Population 
Table 14.2.11.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month and 12-17 
years old subject) -  Safety Population 
Table 14.2.12.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment(>= 18 years old subject) -  Safety Population 
Table 14.2.12.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month and >= 18 
years old subject) -  Safety Population 
Table 14.2.12.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure 6 - 12 month and >= 18 
years old subject) -  Safety Population 
Table 14.2.12.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month and >= 18 
years old subject) -  Safety Population 
Table 14.2.13.1 
Pattern of use for Single -> Second Dose by TIME-POINT(Female) -  
Safety Population 
Table 14.2.13.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month and Female) -  
Safety Population 
Table 14.2.13.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure 6 - 12 month and Female) 
- Safety Population
Table 14.2.13.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month and Female) 
- Safety Population
Table 14.2.14.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment(Male) -  Safety Population 
Table 14.2.14.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure <6 month and Male) -  
Safety Population 
Table 14.2.14.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure 6 - 12 month and Male) -  
Safety Population 
Table 14.2.14.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose time of exposure > 12 month and Male) -  
Safety Population 
Table 14.2.15.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose mean dose is < 1 dose/month) -  Safety 
Population 
Table 14.2.15.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose mean dose is 1-2 dose/month) -  Safety 
Population 
Table 14.2.15.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment( subjects whose mean dose is 2 -5 dose/month) -  Safety 
Population 


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Table 14.2.15.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment(subjects whose mean dose is > 5 dose/month) -  Safety 
Population 
Table 14.2.16.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is < 1 dose/month and 
subjects have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.2.16.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 1-2 dose/month and 
subjects have used more than 5 doses within a 30 days period)Safety 
Population 
Table 14.2.16.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 2 -5 dose/month and 
subjects have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.2.16.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment  -  (subjects whose mean dose is > 5 dose/month and 
subjects have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.2.17.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is < 1 dose/month and 
subjects have not used more than 5 doses within a 30 days 
period)Safety Population 
Table 14.2.17.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 1-2 dose/month and 
subjects have not used more than 5 doses within a 30 days 
period)Safety Population 
Table 14.2.17.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 2 -5 dose/month and 
subjects have not used more than 5 doses within a 30 days period) 
Safety Population 
Table 14.2.17.4 
Pattern of use for Single -> Second Dose by TIME-POINT by 
Treatment -  (subjects whose mean dose is > 5 dose/month and 
subjects have not used more than 5 doses within a 30 days period) 
Safety Population 
Table 14.2.18.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is < 1 dose/month and 
subjects have used at least once a second dose of NRL-1 within less 
than 4 hours) Safety Population 
Table 14.2.18.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 1-2 dose/month and 
subjects have used at least once a second dose of NRL-1 within less 
than 4 hours) Safety Population 
Table 14.2.18.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 2 -5 dose/month and 
subjects have used at least once a second dose of NRL-1 within less 
than 4 hours) Safety Population 


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Table 14.2.18.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is > 5 dose/month and 
subjects have used at least once a second dose of NRL-1 within less 
than 4 hours) Safety Population 
Table 14.2.19.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is < 1 dose/month and 
subjects have not used at least once a second dose of NRL-1 within 
less than 4 hours) Safety Population 
Table 14.2.19.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 1-2 dose/month and 
subjects have not used at least once a second dose of NRL-1 within 
less than 4 hours) Safety Population 
Table 14.2.19.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is 2 -5 dose/month and 
subjects have not used at least once a second dose of NRL-1 within 
less than 4 hours) Safety Population 
Table 14.2.19.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subjects whose mean dose is > 5 dose/month and 
subjects have not used at least once a second dose of NRL-1 within 
less than 4 hours) Safety Population 
Table 14.2.20.1 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time ( 6-11 years old subject) -  Safety Population 
Table 14.2.20.2 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time ( 12-17 years old subject) -  Safety Population 
Table 14.2.20.3 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time (18 <  years old subject) -  Safety Population 
Table 14.2.20.4 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time (All subjects) -  Safety Population 
Table 14.2.20.5 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time ( Female) -  Safety Population 
Table 14.2.20.6 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time (Male) -  Safety Population 
Table 14.2.20.7 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time ( Super User) -  Safety Population 
Table 14.2.20.8 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time (Infrequent User) -  Safety Population 
Table 14.2.21.1 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose ( 6-11 years old subject) -  Safety Population 
Table 14.2.21.2 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose ( 12-17 years old subject) -  Safety Population 
Table 14.2.21.3 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose (18 <  years old subject) -  Safety Population 
Table 14.2.21.4 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose (All subjects) -  Safety Population 
Table 14.2.21.5 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose ( Female) -  Safety Population 
Table 14.2.21.6 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 


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second dose (Male) -  Safety Population 
Table 14.2.21.7 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose ( Super User) -  Safety Population 
Table 14.2.21.8 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose (Infrequent User) -  Safety Population 
Table 14.2.21.9 
Mean doses use per patient per month by treatment (6-11 years old 
subject) -  Safety Population 
Table 14.2.21.10 
Mean doses use per patient per month by treatment (12-17 years old 
subject) -  Safety Population 
Table 14.2.21.11 
Mean doses use per patient per month by treatment (< 18 years old 
subject) -  Safety Population 
Table 14.2.21.12 
Mean doses use per patient per month by treatment (All subjects) -  
Safety Population 
Table 14.2.21.13 
Mean doses use per patient per month by treatment (Female) -  Safety 
Population 
Table 14.2.21.14 
Mean doses use per patient per month by treatment (Male) -  Safety 
Population 
Table 14.2.22.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subject with concomitant use of other benzodiazepines) 
Safety Population 
Table 14.2.22.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subject not concomitant use of other benzodiazepines) 
Safety Population 
Table 14.2.22.3 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time  -  (subject with concomitant use of other 
benzodiazepines) Safety Population 
Table 14.2.22.4 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - first seizure 
that occurred time  -  (subject not concomitant use of other 
benzodiazepines) Safety Population 
Table 14.2.22.5 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose  -  (subject with concomitant use of other 
benzodiazepines) Safety Population 
Table 14.2.22.6 
Diurnal Pattern of Seizure Cluster treated with NRL-1 - required a 
second dose  -  (subject not concomitant use of other benzodiazepines) 
Safety Population 
Table 14.2.23.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subject who have Status Epilepticus or seizures as AE 
that leading to hospitalization) Safety Population 
Table 14.2.23.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment -  (subject who don't have Status Epilepticus or seizures as 
AE that leading to hospitalization) Safety Population 
Table 14.2.24.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (All subject) -  (Patients who used a second dose sooner 
than 4 hours for at least one seizure cluster event)  Safety Population 
Table 14.2.24.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment ( 6-11 years old subject) -  (Patients who used a second 
dose sooner than 4 hours for at least one seizure cluster event)  Safety 


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Population 
Table 14.2.24.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (12-17 years old subject) -  (Patients who used a second 
dose sooner than 4 hours for at least one seizure cluster event)  Safety 
Population 
Table 14.2.24.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (18 <  years old subject) -  (Patients who used a second 
dose sooner than 4 hours for at least one seizure cluster event)  Safety 
Population 
Table 14.2.24.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (All subject) -  (Patients who used a second dose >  4 hours 
for at least one seizure cluster event)  Safety Population 
Table 14.2.24.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment ( 6-11 years old subject) -  (Patients who used a second 
dose >  4 hours for at least one seizure cluster event)  Safety 
Population 
Table 14.2.24.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (12-17 years old subject) -  (Patients who used a second 
dose >  4 hours for at least one seizure cluster event)  Safety 
Population 
Table 14.2.24.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (18 <  years old subject) -  (Patients who used a second 
dose >  4 hours for at least one seizure cluster event)  Safety 
Population 
Table 14.2.25.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects who has seasonal allergies/rhinitis history) -  
(Patients who used a second dose sooner than 4 hours for at least one 
seizure cluster event)  Safety Population 
Table 14.2.25.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects who don't have seasonal allergies/rhinitis history) 
- (Patients who used a second dose sooner than 4 hours for at least
one seizure cluster event)  Safety Population
Table 14.2.25.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects who has seasonal allergies/rhinitis history) -  
(Patients who used a second dose >  4 hours for at least one seizure 
cluster event)  Safety Population 
Table 14.2.25.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects who don't have seasonal allergies/rhinitis history) 
- (Patients who used a second dose >  4 hours for at least one seizure
cluster event)  Safety Population
Table 14.2.26.1 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects not used  benzodiazepines as Concomitant 
medication)) -  (Patients who used a second dose sooner than 4 hours 
for at least one seizure cluster event)  Safety Population 
Table 14.2.26.2 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects not used  benzodiazepines as Concomitant 
medication) -  (Patients who used a second dose sooner than 4 hours 


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for at least one seizure cluster event)  Safety Population 
Table 14.2.26.3 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects not used  benzodiazepines as Concomitant 
medication)) -  (Patients who used a second dose >  4 hours for at least 
one seizure cluster event)  Safety Population 
Table 14.2.26.4 
Pattern of use for Single -> Second Dose by TIME-POINT by  
Treatment (subjects not used  benzodiazepines as Concomitant 
medication) -  (Patients who used a second dose >  4 hours for at least 
one seizure cluster event)  Safety Population 
Table 14.3.1.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment (6-11 
years old subject) -  Safety Population 
Table 14.3.1.1.2 
Summary of Treatment-Emergent Adverse Events by Treatment (>= 
12 years old subject) -  Safety Population 
Table 14.3.1.1.3 
Summary of Treatment-Emergent Adverse Events by Treatment (All 
subject) -  Safety Population 
Table 14.3.1.2.1 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (6-11 years old 
subject) -  Safety Population 
Table 14.3.1.2.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (>= 12 years old 
subject) -  Safety Population 
Table 14.3.1.2.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (All subject) -  
Safety Population 
Table 14.3.1.3.1 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (6-11 years old 
subject) -  Safety Population 
Table 14.3.1.3.2 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (>= 12 years old 
subject) -  Safety Population 
Table 14.3.1.3.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (All subject) -  
Safety Population 
Table 14.3.1.4.1 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (6-11 years old subject) -  Safety Population 
Table 14.3.1.4.2 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (>= 12 years old subject) -  Safety Population 
Table 14.3.1.4.3 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (All subject) -  Safety Population 
Table 14.3.1.5.1 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (6-11 years 
old subject) -  Safety Population 
Table 14.3.1.5.2 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (>= 12 


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years old subject) -  Safety Population 
Table 14.3.1.5.3 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (All 
subject) -  Safety Population 
Table 14.3.1.6.1 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (6-11 
years old subject) -  Safety Population 
Table 14.3.1.6.2 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (>= 12 
years old subject) -  Safety Population 
Table 14.3.1.6.3 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (All 
subject) -  Safety Population 
Table 14.3.1.7.1 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (6-11 years old subject) 
- Safety Population
Table 14.3.1.7.2 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (>= 12 years old subject) 
- Safety Population
Table 14.3.1.7.3 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (All subject) 
- Safety Population
Table 14.3.1.8.1 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment (6-11 
years old subject) -  Safety Population 
Table 14.3.1.8.2 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment (>= 
12 years old subject) -  Safety Population 
Table 14.3.1.8.3 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment (All 
subject) -  Safety Population 
Table 14.3.1.9 
Treatment-Emergent Adverse Events leading to Discontinuation by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
Safety Population 
Table 14.3.1.10.1 
Summary of Treatment-Emergent Adverse Events by Treatment (12-
17 years old subject) -  Safety Population 
Table 14.3.1.10.2 
Summary of Treatment-Emergent Adverse Events by Treatment (>= 
18 years old subject) -  Safety Population 
Table 14.3.1.10.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (12-17 years old 
subject) -  Safety Population 
Table 14.3.1.10.4 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (>= 18 years old 
subject) -  Safety Population 


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Table 14.3.1.10.5 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (12-17 years old 
subject) -  Safety Population 
Table 14.3.1.10.6 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (>= 18 years old 
subject) -  Safety Population 
Table 14.3.1.10.7 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (12-17 years old subject) -  Safety Population 
Table 14.3.1.10.8 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (>= 18 years old subject) -  Safety Population 
Table 14.3.1.10.9 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (12-17 
years old subject) -  Safety Population 
Table 14.3.1.10.10 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (>= 18 
years old subject) -  Safety Population 
Table 14.3.1.10.11 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (12-17 
years old subject) -  Safety Population 
Table 14.3.1.10.12 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (>= 18 
years old subject) -  Safety Population 
Table 14.3.1.10.13 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (12-17 years old subject) 
- Safety Population
Table 14.3.1.10.14 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (>= 18 years old subject) 
- Safety Population
Table 14.3.1.10.15 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment (12-
17 years old subject) -  Safety Population 
Table 14.3.1.10.16 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment (>= 
18 years old subject) -  Safety Population 
Table 14.3.1.11.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(Female) -  Safety Population 
Table 14.3.1.11.2 
Summary of Treatment-Emergent Adverse Events by Treatment 
(Male) -  Safety Population 
Table 14.3.1.11.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (Female) -  Safety 
Population 
Table 14.3.1.11.4 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (Male) -  Safety 


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Population 
Table 14.3.1.11.5 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (Female) -  Safety 
Population 
Table 14.3.1.11.6 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (Male) -  Safety 
Population 
Table 14.3.1.11.7 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (Female) -  Safety Population 
Table 14.3.1.11.8 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (Male) -  Safety Population 
Table 14.3.1.11.9 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (Female) -  
Safety Population 
Table 14.3.1.11.10 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (Male) -  
Safety Population 
Table 14.3.1.11.11 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment 
(Female) -  Safety Population 
Table 14.3.1.11.12 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (Male) 
- Safety Population
Table 14.3.1.11.13 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (Female) 
- Safety Population
Table 14.3.1.11.14 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (Male) 
- Safety Population
Table 14.3.1.11.15 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(Female) -  Safety Population 
Table 14.3.1.11.16 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(Male) -  Safety Population 
Table 14.3.1.12.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
Safety Population 
Table 14.3.1.12.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is < 1 dose/month) Safety Population 
Table 14.3.1.12.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is < 1 dose/month) Safety Population 


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Table 14.3.1.12.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects whose mean dose is < 1 dose/month) Safety 
Population 
Table 14.3.1.12.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
whose mean dose is < 1 dose/month) Safety Population 
Table 14.3.1.12.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects whose mean dose is < 1 dose/month) Safety Population 
Table 14.3.1.12.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects whose mean dose is < 1 dose/month) Safety Population
Table 14.3.1.12.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects whose mean dose is < 1 dose/month) Safety Population 
Table 14.3.1.13.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.13.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.13.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.13.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects whose mean dose is 1-2  dose/month) Safety 
Population 
Table 14.3.1.13.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.13.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.13.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects whose mean dose is 1-2  dose/month) Safety Population
Table 14.3.1.13.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects whose mean dose is 1-2  dose/month) Safety Population 
Table 14.3.1.14.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects whose mean dose is 2-5 dose/month) Safety Population 
Table 14.3.1.14.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is 2-5 dose/month) Safety Population 


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Table 14.3.1.14.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is 2-5 dose/month) Safety Population 
Table 14.3.1.14.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects whose mean dose is 2-5 dose/month) Safety 
Population 
Table 14.3.1.14.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
whose mean dose is 2-5 dose/month) Safety Population 
Table 14.3.1.14.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects whose mean dose is 2-5 dose/month) Safety Population 
Table 14.3.1.14.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects whose mean dose is 2-5 dose/month) Safety Population
Table 14.3.1.14.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects whose mean dose is 2-5 dose/month) Safety Population 
Table 14.3.1.15.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.15.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.15.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects 
whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.15.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects whose mean dose is > 5 dose/month) Safety 
Population 
Table 14.3.1.15.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.15.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.15.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects whose mean dose is > 5 dose/month) Safety Population
Table 14.3.1.15.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects whose mean dose is > 5 dose/month) Safety Population 
Table 14.3.1.16.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(Patients who used a second dose sooner than 4 hours for at least one 


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seizure cluster event) Safety Population 
Table 14.3.1.16.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Patients who 
used a second dose sooner than 4 hours for at least one seizure cluster 
event) Safety Population 
Table 14.3.1.16.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Patients who 
used a second dose sooner than 4 hours for at least one seizure cluster 
event) Safety Population 
Table 14.3.1.16.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (Patients who used a second dose sooner than 4 hours for 
at least one seizure cluster event) Safety Population 
Table 14.3.1.16.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (Patients 
who used a second dose sooner than 4 hours for at least one seizure 
cluster event) Safety Population 
Table 14.3.1.16.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Patients who used a second dose sooner than 4 hours for at least one 
seizure cluster event) Safety Population 
Table 14.3.1.16.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (Patients who used a second dose sooner than 4 hours for at least
one seizure cluster event) Safety Population
Table 14.3.1.16.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(Patients who used a second dose sooner than 4 hours for at least one 
seizure cluster event) Safety Population 
Table 14.3.1.17.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -   
(where subject's the NRL-1 treatment was sooner than the 5 days in-
between events) Safety Population 
Table 14.3.1.17.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -   (where 
subject's the NRL-1 treatment was sooner than the 5 days in-between 
events) Safety Population 
Table 14.3.1.17.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -   (where 
subject's the NRL-1 treatment was sooner than the 5 days in-between 
events) Safety Population 
Table 14.3.1.17.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -   (where subject's the NRL-1 treatment was sooner than 
the 5 days in-between events) Safety Population 
Table 14.3.1.17.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment  -   (where 


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subject's the NRL-1 treatment was sooner than the 5 days in-between 
events) Safety Population 
Table 14.3.1.17.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -   
(where subject's the NRL-1 treatment was sooner than the 5 days in-
between events) Safety Population 
Table 14.3.1.17.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (where subject's the NRL-1 treatment was sooner than the 5 days
in-between events) Safety Population
Table 14.3.1.17.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -   
(where subject's the NRL-1 treatment was sooner than the 5 days in-
between events) Safety Population 
Table 14.3.1.18.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(Subject who have used more than 5 doses within a 30 days period) 
Safety Population 
Table 14.3.1.18.2 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(Subject who have not used more than 5 doses within a 30 days 
period) Safety Population 
Table 14.3.1.18.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Subject who 
have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.4 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Subject who 
have not used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.5 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Subject who 
have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.6 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Subject who 
have not used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.7 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -  (Subject who have used more than 5 doses within a 30 
days period) Safety Population 
Table 14.3.1.18.8 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -  (Subject who have not used more than 5 doses within a 
30 days period) Safety Population 
Table 14.3.1.18.9 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment  -  (Subject 


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who have used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.10 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment  -  (Subject 
who have not used more than 5 doses within a 30 days period) Safety 
Population 
Table 14.3.1.18.11 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Subject who have used more than 5 doses within a 30 days period) 
Safety Population 
Table 14.3.1.18.12 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Subject who have not used more than 5 doses within a 30 days 
period) Safety Population 
Table 14.3.1.18.13 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (Subject who have used more than 5 doses within a 
30 days period) Safety Population 
Table 14.3.1.18.14 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment -  (Subject who have not used more than 5 doses within 
a 30 days period) Safety Population 
Table 14.3.1.18.15 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(Subject who have used more than 5 doses within a 30 days period) 
Safety Population 
Table 14.3.1.18.16 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(Subject who have not used more than 5 doses within a 30 days 
period) Safety Population 
Table 14.3.1.19.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects used  benzodiazepines as Concomitant medication) Safety 
Population 
Table 14.3.1.19.2 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects not used  benzodiazepines as Concomitant medication) 
Safety Population 
Table 14.3.1.19.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment -  (subjects used  
benzodiazepines as Concomitant medication) Safety Population 
Table 14.3.1.19.4 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects not 
used  benzodiazepines as Concomitant medication) Safety Population 
Table 14.3.1.19.5 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects used  
benzodiazepines as Concomitant medication) Safety Population 
Table 14.3.1.19.6 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects not 


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used  benzodiazepines as Concomitant medication) Safety Population 
Table 14.3.1.19.7 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -  (subjects used  benzodiazepines as Concomitant 
medication) Safety Population 
Table 14.3.1.19.8 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -  (subjects not used  benzodiazepines as Concomitant 
medication) Safety Population 
Table 14.3.1.19.9 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
used  benzodiazepines as Concomitant medication) Safety Population 
Table 14.3.1.19.10 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
not used  benzodiazepines as Concomitant medication) Safety 
Population 
Table 14.3.1.19.11 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment -  
(subjects used  benzodiazepines as Concomitant medication) Safety 
Population 
Table 14.3.1.19.12 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment -  
(subjects not used  benzodiazepines as Concomitant medication) 
Safety Population 
Table 14.3.1.19.13 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects used  benzodiazepines as Concomitant medication) Safety
Population
Table 14.3.1.19.14 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (subjects not used  benzodiazepines as Concomitant 
medication) Safety Population 
Table 14.3.1.19.15 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects used  benzodiazepines as Concomitant medication) Safety 
Population 
Table 14.3.1.19.16 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects not used  benzodiazepines as Concomitant medication) 
Safety Population 
Table 14.3.1.20.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.2 
Summary of Treatment-Emergent Adverse Events by Treatment -  
(subjects who don't have seasonal allergies/rhinitis history) Safety 
Population 
Table 14.3.1.20.3 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 


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System Organ Class, Preferred Term and Treatment  -  (subjects who 
has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.4 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects who 
don't have seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.5 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment -  (subjects who 
has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.6 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects who 
don't have seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.7 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment  -  (subjects who has seasonal allergies/rhinitis history) 
Safety Population 
Table 14.3.1.20.8 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects who don't have seasonal allergies/rhinitis 
history) Safety Population 
Table 14.3.1.20.9 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment  -  (subjects 
who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.10 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment  -  (subjects 
who don't have seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.11 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.12 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects who don't have seasonal allergies/rhinitis history) Safety 
Population 
Table 14.3.1.20.13 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects who has seasonal allergies/rhinitis history) Safety
Population
Table 14.3.1.20.14 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (subjects who don't have seasonal allergies/rhinitis 
history) Safety Population 
Table 14.3.1.20.15 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.20.16 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment -  
(subjects who don't have seasonal allergies/rhinitis history) Safety 


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Population 
Table 14.3.1.21.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(subjects who has seasonal allergies/rhinitis history and second dose 
of NRL-1 was used prior to 4 hours) Safety Population 
Table 14.3.1.21.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects who 
has seasonal allergies/rhinitis history and second dose of NRL-1 was 
used prior to 4 hours) Safety Population 
Table 14.3.1.21.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (subjects who 
has seasonal allergies/rhinitis history and second dose of NRL-1 was 
used prior to 4 hours) Safety Population 
Table 14.3.1.21.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (subjects who has seasonal allergies/rhinitis history and 
second dose of NRL-1 was used prior to 4 hours) Safety Population 
Table 14.3.1.21.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (subjects 
who has seasonal allergies/rhinitis history and second dose of NRL-1 
was used prior to 4 hours) Safety Population 
Table 14.3.1.21.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(subjects who has seasonal allergies/rhinitis history and second dose 
of NRL-1 was used prior to 4 hours) Safety Population 
Table 14.3.1.21.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
- (subjects who has seasonal allergies/rhinitis history and second
dose of NRL-1 was used prior to 4 hours) Safety Population
Table 14.3.1.21.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(subjects who has seasonal allergies/rhinitis history and second dose 
of NRL-1 was used prior to 4 hours) Safety Population 
Table 14.3.1.22.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.22.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.22.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.22.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Winter : Jan-Mar) -  (subjects 


Neurelis, Inc. Protocol DIAZ.001.05 
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who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.22.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.22.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.22.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Winter : Jan-Mar) 
- (subjects who has seasonal allergies/rhinitis history) Safety
Population
Table 14.3.1.22.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.23.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.23.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.23.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.23.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Spring : Apr-Jun) -  (subjects 
who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.23.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.23.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.23.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Spring : Apr-Jun) 
- (subjects who has seasonal allergies/rhinitis history) Safety
Population
Table 14.3.1.23.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 


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Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.24.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.24.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.24.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.24.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Summer : Jul-Sep) -  (subjects 
who has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.24.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.24.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.24.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Summer : Jul-Sep) 
- (subjects who has seasonal allergies/rhinitis history) Safety
Population
Table 14.3.1.24.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.25.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.25.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.25.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.25.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 


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Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Fall : Oct-Dec) -  (subjects who 
has seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.25.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.25.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history) Safety Population 
Table 14.3.1.25.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Fall : Oct-Dec) 
- (subjects who has seasonal allergies/rhinitis history) Safety
Population
Table 14.3.1.25.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history) Safety Population 
Table 14.3.1.26.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.1.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.1.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.1.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Winter : Jan-Mar) -  (subjects 
who has seasonal allergies/rhinitis history and age is 6-11) Safety 
Population 
Table 14.3.1.26.1.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.1.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.1.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Winter : Jan-Mar) 


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 -  (subjects who has seasonal allergies/rhinitis history and age is 6-11) 
Safety Population 
Table 14.3.1.26.1.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.26.2.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.2.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.2.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.2.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Winter : Jan-Mar) -  (subjects 
who has seasonal allergies/rhinitis history and age is 12-18) Safety 
Population 
Table 14.3.1.26.2.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.2.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.2.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Winter : Jan-Mar) 
 -  (subjects who has seasonal allergies/rhinitis history and age is 12-
18) Safety Population 
Table 14.3.1.26.2.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.26.3.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.26.3.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.26.3.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 


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System Organ Class, Preferred Term and Treatment (where AE onset 
month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.26.3.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Winter : Jan-Mar) -  (subjects 
who has seasonal allergies/rhinitis history and age is > 18) Safety 
Population 
Table 14.3.1.26.3.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.26.3.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Winter : Jan-Mar) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.26.3.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Winter : Jan-Mar) 
- (subjects who has seasonal allergies/rhinitis history and age is > 18)
Safety Population
Table 14.3.1.26.3.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Winter : Jan-Mar) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.27.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.1.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.1.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.1.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Spring : Apr-Jun) -  (subjects 
who has seasonal allergies/rhinitis history and age is 6-11) Safety 
Population 
Table 14.3.1.27.1.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.1.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 


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AE onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.1.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Spring : Apr-Jun) 
 -  (subjects who has seasonal allergies/rhinitis history and age is 6-11) 
Safety Population 
Table 14.3.1.27.1.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.27.2.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.2.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.2.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.2.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Spring : Apr-Jun) -  (subjects 
who has seasonal allergies/rhinitis history and age is 12-18) Safety 
Population 
Table 14.3.1.27.2.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.2.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.2.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Spring : Apr-Jun) 
 -  (subjects who has seasonal allergies/rhinitis history and age is 12-
18) Safety Population 
Table 14.3.1.27.2.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.27.3.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 


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Table 14.3.1.27.3.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.27.3.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.27.3.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Spring : Apr-Jun) -  (subjects 
who has seasonal allergies/rhinitis history and age is > 18) Safety 
Population 
Table 14.3.1.27.3.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.27.3.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Spring : Apr-Jun) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.27.3.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Spring : Apr-Jun) 
- (subjects who has seasonal allergies/rhinitis history and age is > 18)
Safety Population
Table 14.3.1.27.3.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Spring : Apr-Jun) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.1.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.1.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.1.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Summer : Jul-Sep) -  (subjects 
who has seasonal allergies/rhinitis history and age is 6-11) Safety 
Population 
Table 14.3.1.28.1.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 


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Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.1.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.1.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Summer : Jul-Sep) 
- (subjects who has seasonal allergies/rhinitis history and age is 6-11)
Safety Population
Table 14.3.1.28.1.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.28.2.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.2.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.2.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.2.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Summer : Jul-Sep) -  (subjects 
who has seasonal allergies/rhinitis history and age is 12-18) Safety 
Population 
Table 14.3.1.28.2.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.2.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.2.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Summer : Jul-Sep) 
- (subjects who has seasonal allergies/rhinitis history and age is 12-
18) Safety Population
Table 14.3.1.28.2.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 


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(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.28.3.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.3.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.3.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.3.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Summer : Jul-Sep) -  (subjects 
who has seasonal allergies/rhinitis history and age is > 18) Safety 
Population 
Table 14.3.1.28.3.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.3.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Summer : Jul-Sep) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.28.3.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Summer : Jul-Sep) 
 -  (subjects who has seasonal allergies/rhinitis history and age is > 18) 
Safety Population 
Table 14.3.1.28.3.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Summer : Jul-Sep) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.1.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.1.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.1.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.1.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 


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Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Fall : Oct-Dec) -  (subjects who 
has seasonal allergies/rhinitis history and age is 6-11) Safety 
Population 
Table 14.3.1.29.1.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.1.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.1.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Fall : Oct-Dec) 
 -  (subjects who has seasonal allergies/rhinitis history and age is 6-11) 
Safety Population 
Table 14.3.1.29.1.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is 6-11) Safety Population 
Table 14.3.1.29.2.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.2.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.2.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.2.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Fall : Oct-Dec) -  (subjects who 
has seasonal allergies/rhinitis history and age is 12-18) Safety 
Population 
Table 14.3.1.29.2.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.2.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.2.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 


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and Treatment (where AE onset month is Fall : Oct-Dec) 
- (subjects who has seasonal allergies/rhinitis history and age is 12-
18) Safety Population
Table 14.3.1.29.2.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is 12-18) Safety Population 
Table 14.3.1.29.3.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.3.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.3.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where AE onset 
month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.3.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where AE onset month is Fall : Oct-Dec) -  (subjects who 
has seasonal allergies/rhinitis history and age is > 18) Safety 
Population 
Table 14.3.1.29.3.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where AE 
onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.3.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
AE onset month is Fall : Oct-Dec) -  (subjects who has seasonal 
allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.29.3.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where AE onset month is Fall : Oct-Dec) 
- (subjects who has seasonal allergies/rhinitis history and age is > 18)
Safety Population
Table 14.3.1.29.3.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where AE onset month is Fall : Oct-Dec) -  (subjects who has 
seasonal allergies/rhinitis history and age is > 18) Safety Population 
Table 14.3.1.30.1 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (where PT are 
Cardiorespiratory/, Nasal/nasopharyngeal) Safety Population 
Table 14.3.1.30.2 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (where PT are 
Cardiorespiratory/, Nasal/nasopharyngeal) -  (where PT are 
Cardiorespiratory/, Nasal/nasopharyngeal) Safety Population 


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Table 14.3.1.30.3 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment (where PT are Cardiorespiratory/, Nasal/nasopharyngeal) -  
(where PT are Cardiorespiratory/, Nasal/nasopharyngeal) Safety 
Population 
Table 14.3.1.30.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment (where PT 
are Cardiorespiratory/, Nasal/nasopharyngeal) -  (where PT are 
Cardiorespiratory/, Nasal/nasopharyngeal) Safety Population 
Table 14.3.1.30.5 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (where 
PT are Cardiorespiratory/, Nasal/nasopharyngeal) -  (where PT are 
Cardiorespiratory/, Nasal/nasopharyngeal) Safety Population 
Table 14.3.1.30.6 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (where PT are Cardiorespiratory/, 
Nasal/nasopharyngeal) 
 -  (where PT are Cardiorespiratory/, Nasal/nasopharyngeal) Safety 
Population 
Table 14.3.1.30.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(where PT are Cardiorespiratory/, Nasal/nasopharyngeal) -  (where PT 
are Cardiorespiratory/, Nasal/nasopharyngeal) Safety Population 
Table 14.3.1.31.1 
 Incidence of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  (AE 
event that requires/Prolongs Hospitalization) Safety Population 
Table 14.3.1.31.2 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment -  (AE 
event that requires/Prolongs Hospitalization) Safety Population 
Table 14.3.1.31.3 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (AE event that requires/Prolongs Hospitalization) 
Safety Population 
Table 14.3.1.31.4 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(AE event that requires/Prolongs Hospitalization) Safety Population 
Table 14.3.1.32.1 
 Incidence of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Status Epilepticus, Recurrent Seizures - which led to 
ER/Hospitalization and within the 48 hours after first NRL-1 dose ) 
Safety Population 
Table 14.3.1.32.2 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Status Epilepticus, Recurrent Seizures - which led to 
ER/Hospitalization and within the 48 hours after first NRL-1 dose ) 
Safety Population 
Table 14.3.1.32.3 
Treatment-Emergent Serious Adverse Events by MedDRA System 


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Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (Status Epilepticus, Recurrent Seizures - which led 
to ER/Hospitalization and within the 48 hours after first NRL-1 dose ) 
Safety Population 
Table 14.3.1.32.4 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment -  
(Status Epilepticus, Recurrent Seizures - which led to 
ER/Hospitalization and within the 48 hours after first NRL-1 dose ) 
Safety Population 
Table 14.3.1.33.1 
 Incidence of Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  (AE 
event that requires/Prolongs Hospitalization but not related) Safety 
Population 
Table 14.3.1.33.2 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment  -  (AE event that requires/Prolongs Hospitalization but 
not related) Safety Population 
Table 14.3.1.33.3 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(AE event that requires/Prolongs Hospitalization but not related) 
Safety Population 
Table 14.3.1.34.1 
Summary of Treatment-Emergent Adverse Events by Treatment 
(SELF-ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment (SELF-
ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment ( SELF-
ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment ( SELF-ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment ( SELF-
ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment (SELF-
ADMINISTRATORS) -  Safety Population 
Table 14.3.1.34.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment (SELF-ADMINISTRATORS) 
- Safety Population
Table 14.3.1.34.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment 
(SELF-ADMINISTRATORS) -  Safety Population 
Table 14.3.1.35.1 
Summary of Treatment-Emergent Adverse Events by Treatment  -  
(Patients who used a second dose is 4-24 hours for at least one seizure 


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cluster event) Safety Population 
Table 14.3.1.35.2 
 Incidence of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Patients who 
used a second dose is 4-24 hours for at least one seizure cluster event) 
Safety Population 
Table 14.3.1.35.3 
Treatment-Emergent Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term and Treatment  -  (Patients who 
used a second dose is 4-24 hours for at least one seizure cluster event) 
Safety Population 
Table 14.3.1.35.4 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Strongest Relationship to Study Drug and 
Treatment -  (Patients who used a second dose is 4-24 hours for at 
least one seizure cluster event) Safety Population 
Table 14.3.1.35.5 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, Maximum Severity and Treatment -  (Patients 
who used a second dose is 4-24 hours for at least one seizure cluster 
event) Safety Population 
Table 14.3.1.35.6 
Treatment-Emergent Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class, Preferred Term and Treatment  -  
(Patients who used a second dose is 4-24 hours for at least one seizure 
cluster event) Safety Population 
Table 14.3.1.35.7 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study Drug 
and Treatment 
 -  (Patients who used a second dose is 4-24 hours for at least one 
seizure cluster event) Safety Population 
Table 14.3.1.35.8 
Treatment-Emergent Serious Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and Treatment  -  
(Patients who used a second dose is 4-24 hours for at least one seizure 
cluster event) Safety Population 
Table 14.3.2.1 
Serious Adverse Events  -  Safety Population 
Table 14.3.2.2 
Adverse Event leading to Discontinuation  -  Safety Population 
Table 14.3.2.3 
Adverse Event leading to Death  -  Safety Population 
Table 14.3.4.1 
Listing of Abnormal values of the Laboratory Test  -  Safety 
Population 
Table 14.3.4.2 
Listing of Abnormal values of the Laboratory Test - Urinalysis  -  
Safety Population 
Table 14.3.5.1.1.1 
Laboratory: Hematology by Treatment and Visit (6-11 years old 
subject) -  Safety Population 
Table 14.3.5.1.1.2 
Laboratory: Hematology by Treatment and Visit (>= 12 years old 
subject) -  Safety Population 
Table 14.3.5.1.1.3 
Laboratory: Hematology by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.5.1.2.1 
Laboratory: Hematology (Categorical result) by Treatment and Visit 
(6-11 years old subject)  -  Safety Population 
Table 14.3.5.1.2.2 
Laboratory: Hematology (Categorical result) by Treatment and Visit 
(>= 12 years old subject) -  Safety Population 


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Table 14.3.5.1.2.3 
Laboratory: Hematology (Categorical result) by Treatment and Visit 
(All subject) -  Safety Population 
Table 14.3.5.1.3.1 
Laboratory: Hematology - Shift Tables by Treatment and Visit (6-11 
years old subject)  -  Safety Population 
Table 14.3.5.1.3.2 
Laboratory: Hematology - Shift Tables by Treatment and Visit (>= 12 
years old subject) -  Safety Population 
Table 14.3.5.1.3.3 
Laboratory: Hematology - Shift Tables by Treatment and Visit (All 
subject) -  Safety Population 
Table 14.3.5.2.1.1 
Laboratory: Chemistry by Treatment and Visit (6-11 years old 
subject)  -  Safety Population 
Table 14.3.5.2.1.2 
Laboratory: Chemistry by Treatment and Visit (>= 12 years old 
subject) -  Safety Population 
Table 14.3.5.2.1.3 
Laboratory: Chemistry by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.5.2.2.1 
Laboratory: Chemistry - Shift Tables by Treatment and Visit (6-11 
years old subject)  -  Safety Population 
Table 14.3.5.2.2.2 
Laboratory: Chemistry - Shift Tables by Treatment and Visit  (>= 12 
years old subject) -  Safety Population 
Table 14.3.5.2.2.3 
Laboratory: Chemistry - Shift Tables by Treatment and Visit (All 
subject) -  Safety Population 
Table 14.3.5.3.1.1 
Laboratory: Urinalysis by Treatment and Visit (6-11 years old subject)  
-  Safety Population 
Table 14.3.5.3.1.2 
Laboratory: Urinalysis by Treatment and Visit (>= 12 years old 
subject) -  Safety Population 
Table 14.3.5.3.1.3 
Laboratory: Urinalysis by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.5.3.2.1 
Laboratory: Urinalysis (Categorical result) by Treatment and Visit (6-
11 years old subject)  -  Safety Population 
Table 14.3.5.3.2.2 
Laboratory: Urinalysis (Categorical result) by Treatment and Visit (>= 
12 years old subject) -  Safety Population 
Table 14.3.5.3.2.3 
Laboratory: Urinalysis (Categorical result) by Treatment and Visit  -  
Safety Population 
Table 14.3.5.3.3.1 
Laboratory: Urinalysis - Shift Tables by Treatment and Visit (6-11 
years old subject)  -  Safety Population 
Table 14.3.5.3.3.2 
Laboratory: Urinalysis - Shift Tables by Treatment and Visit (>= 12 
years old subject) -  Safety Population 
Table 14.3.5.3.3.3 
Laboratory: Urinalysis - Shift Tables by Treatment and Visit (All 
subject) -  Safety Population 
Table 14.3.6.1.1 
ECG Parameters by Treatment and Visit (6-11 years old subject)  -  
Safety Population 
Table 14.3.6.1.2 
ECG Parameters by Treatment and Visit (>= 12 years old subject) -  
Safety Population 
Table 14.3.6.1.3 
ECG Parameters by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.6.2.1 
ECG Interpretation by Treatment and Visit (6-11 years old subject)  -  
Safety Population 
Table 14.3.6.2.2 
ECG Interpretation by Treatment and Visit (>= 12 years old subject) -  


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Safety Population 
Table 14.3.6.2.3 
ECG Interpretation by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.7.1 
Vital Signs by Treatment and Visit (6-11 years old subject)  -  Safety 
Population 
Table 14.3.7.2 
Vital Signs by Treatment and Visit (>= 12 years old subject) -  Safety 
Population 
Table 14.3.7.3 
Vital Signs by Treatment and Visit (All subject) -  Safety Population 
Table 14.3.8.1.1 
Physical Examination by Treatment and Visit (6-11 years old subject)  
-  Safety Population 
Table 14.3.8.1.2 
Physical Examination by Treatment and Visit (>= 12 years old 
subject) -  Safety Population 
Table 14.3.8.1.3 
Physical Examination by Treatment and Visit (All subject) -  Safety 
Population 
Table 14.3.8.2.1 
Physical Examination - Shift Tables by Treatment and Visit (6-11 
years old subject)  -  Safety Population 
Table 14.3.8.2.2 
Physical Examination - Shift Tables by Treatment and Visit (>= 12 
years old subject) -  Safety Population 
Table 14.3.8.2.3 
Physical Examination - Shift Tables by Treatment and Visit (All 
subject) -  Safety Population 
 
 
 


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12.1.2. 
Listings 
Listing No 
Title 
Listing 16.2.1.1 
Final Termination  -  All Population 
Listing 16.2.2.1 
Protocol deviations -  Safety Population 
Listing 16.2.3.1 
Patients excluded from the Safety Population -  
Listing 16.2.4.1 
Demographic Data -  Safety Population 
Listing 16.2.4.2 
Past Medical History -  Safety Population 
Listing 16.2.4.3 
Seizure Medical History -  Safety Population 
Listing 16.2.6.1 
Individual PK Summary Data of  -  PK Population 
Listing 16.2.6.2 
Individual  -  PK Population 
Listing 16.2.6.3.1 
Concentration Data of  - Plasma -  PK Population 
Listing 16.2.6.3.2 
Concentration Data of  - Urine -  PK Population 
Listing 16.2.7.1 
Adverse Events -  Safety Population 
Listing 16.2.8.1 
Laboratories Results - Chemistry/ Hematology Test Assessments -  
Safety Population 
Listing 16.2.8.2 
Urine Test Assessments : Continuous Results -  Safety Population 
Listing 16.2.8.3 
Urine Test Assessments : Categorical Results -  Safety Population 
Listing 16.2.8.4 
Laboratories Results - Urine Drug Screening -  Safety Population 
Listing 16.2.8.5 
Laboratories Results - Serology Assessments at Screening -  Safety 
Population 
Listing 16.2.8.6 
Laboratories Results - Pregnancy -  Safety Population 
Listing 16.2.9.1 
Vital Signs Results and Change from Baseline -  Safety Population 
Listing 16.2.9.2 
Physical Examination -  Safety Population 
Listing 16.2.9.3.1 
ECG Interpretation -  Safety Population 
Listing 16.2.9.3.2 
ECG Results  -  Safety Population 
Listing 16.2.9.3.3 
ECG Rhythms and Arrhythmias -  Safety Population 
Listing 16.2.9.4 
Concomitant Medication  -  Safety Population 
Listing 16.2.9.5.1 
Study Drug Prescription -  Safety Population 
Listing 16.2.9.5.2 
Exposure -  Safety Population 
Listing 16.2.9.5.3 
Dose per Subject -  Safety Population 
Listing 16.2.9.6 
Nasal Irritation Assessments -  Safety Population 
Listing 16.2.9.7.1 
Columbia-suicidality severity-Baseline /Screening Version -  Safety 
Population 
Listing 16.2.9.7.2 
Columbia-suicidality severity-Since Last Visit -  Safety Population 
Listing 16.2.9.7.3 
Columbia-suicidality severity-Children's Baseline/Screening -  Safety 
Population 
Listing 16.2.9.7.4 
Columbia-suicidality severity-Children's Since Last Visit -  Safety 
Population 
Listing 16.2.9.8.1 
QOLIE-31 (age 18 years or older) -  Safety Population 
Listing 16.2.9.8.2 
QOLIE-AD-48  (ages 11-17 years) -  Safety Population 
Listing 16.2.9.9 
NIH Toolbox Odor Identification Test -  Safety Population 
Listing 16.2.9.10 
Mucosal Erythema -  Safety Population 
Listing 16.2.9.11 
Mucosal Edema -  Safety Population 
Listing 16.2.9.12 
Nasal Discharge  -  Safety Population 
Listing 16.2.9.13 
Mucosal Crusting  -  Safety Population 


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Listing 16.2.9.14 
Mucosal  Epistaxis -  Safety Population 
Listing 16.2.9.15 
Seizure -  Safety Population 
Listing 16.2.9.16 
Eligibility -  Safety Population 
Listing 16.2.9.17 
Subject/Caregiver Assessment -  Safety Population 
Listing 16.2.9.18 
Telephone Contact -  Safety Population 
Listing 16.2.10.1 
Comments -  Safety Population 
12.1.3. 
Graphs 
Figure No 
Title 
Figure 14.2.1.1 
 Nasal Irritation Assessments Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) -  Safety Population 
Figure 14.2.1.2 
 Nasal Irritation Assessments Mean and Standard Deviation by 
Treatment and Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.1.3 
 Nasal Irritation Assessments Mean and Standard Deviation by 
Treatment and Visit (All subject) -  Safety Population 
Figure 14.2.2.1 
 Mucosal Erythema Mean and Standard Deviation by Treatment and 
Visit (6-11 years old subject) -  Safety Population 
Figure 14.2.2.2 
 Mucosal Erythema Mean and Standard Deviation by Treatment and 
Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.2.3 
 Mucosal Erythema Mean and Standard Deviation by Treatment and 
Visit (All subject) -  Safety Population 
Figure 14.2.3.1 
Mucosal Edema Mean and Standard Deviation by Treatment and Visit 
(6-11 years old subject) -  Safety Population 
Figure 14.2.3.2 
 Mucosal Edema Mean and Standard Deviation by Treatment and 
Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.3.3 
 Mucosal Edema Mean and Standard Deviation by Treatment and 
Visit (All subject) -  Safety Population 
Figure 14.2.4.1 
Nasal Discharge Mean and Standard Deviation by Treatment and Visit 
(6-11 years old subject) -  Safety Population 
Figure 14.2.4.2 
 Nasal Discharge Mean and Standard Deviation by Treatment and 
Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.4.3 
 Nasal Discharge Mean and Standard Deviation by Treatment and 
Visit (All subject) -  Safety Population 
Figure 14.2.5.1 
 Mucosal Crusting Mean and Standard Deviation by Treatment and 
Visit (6-11 years old subject) -  Safety Population 
Figure 14.2.5.2 
 Mucosal Crusting Mean and Standard Deviation by Treatment and 
Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.5.3 
 Mucosal Crusting Mean and Standard Deviation by Treatment and 
Visit (All subject) -  Safety Population 
Figure 14.2.6.1 
 Mucosal Epistaxis Mean and Standard Deviation by Treatment and 
Visit (6-11 years old subject) -  Safety Population 


Neurelis, Inc. Protocol DIAZ.001.05 
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Figure 14.2.6.2 
 Mucosal Epistaxis Mean and Standard Deviation by Treatment and 
Visit (>= 12 years old subject) -  Safety Population 
Figure 14.2.6.3 
 Mucosal Epistaxis Mean and Standard Deviation by Treatment and 
Visit (All subject) -  Safety Population 
Figure 14.2.7.1 
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean and 
Standard Deviation by Treatment and Visit (6-11 years old subject) -  
Safety Population 
Figure 14.2.7.2 
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean and 
Standard Deviation by Treatment and Visit (>= 12 years old subject) -  
Safety Population 
Figure 14.2.7.3 
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean and 
Standard Deviation by Treatment and Visit (All subject) -  Safety 
Population 
Figure 14.2.8.1 
KM plot for second dosed subject (first vs. second in each seizure 
cluster) by treatment -  Safety Population 
Figure 14.2.8.2 
KM plot for second dosed subject (first vs. second in each seizure 
cluster) by age -  Safety Population 
Figure 14.2.8.3 
KM plot for second dosed subject (first vs. second in each seizure 
cluster) by use pattern -  Safety Population 
Figure 14.2.8.4 
KM plot for second dosed subject (first vs. second in each seizure 
cluster) by usage time -  Safety Population 
Figure 14.2.8.5 
KM plot for second dosed subject (first vs. second in each seizure 
cluster) by gender -  Safety Population 
Figure 14.2.9.1 
KM plot for second dosed subject (first vs. last in each seizure cluster) 
by treatment -  Safety Population 
Figure 14.2.9.2 
KM plot for second dosed subject (first vs. last in each seizure cluster) 
by age -  Safety Population 
Figure 14.2.9.3 
KM plot for second dosed subject (first vs. last in each seizure cluster) 
by use pattern -  Safety Population 
Figure 14.2.9.4 
KM plot for second dosed subject (first vs. last in each seizure cluster) 
by usage time -  Safety Population 
Figure 14.2.9.5 
KM plot for second dosed subject (first vs. last in each seizure cluster) 
by gender -  Safety Population 


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13.
REFERENCES
1. U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation
and Research (CDER). Center for Biologics Evaluation and Research (CBER).
Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance. ICH,
1996, Rockville, Maryland.
2. U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation
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