Clinical trial NCT02724423
Conditions: Acute Repetitive Seizures
Keywords: epilepsy seizure
Sponsor: Neurelis, Inc.
Start date: 2016-06-30; Completion date: 2019-09-10
Enrollment: 57 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the pharmacokinetic and safety of NRL-1 in epilepsy subjects. Subjects will receive a single intranasal dose of NRL-1 of either 5 mg, 10 mg, 15 mg or 20 mg and will be based on the subject's body weight.

Detailed description:
Diazepam rectal gel (Diastat) is the only formulation of diazepam indicated for the management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs (AEDs) who require intermittent use of diazepam to control bouts of increased seizure activity, i.e., Acute Repetitive Seizures (ARS).

A diazepam nasal spray is being developed for patients who experience ARS to provide an alternative more convenient and acceptable route of diazepam administration.

Arms: arm 1: During the ictal or peri-ictal setting, a single 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. arm 2: During the inter-ictal setting, a single 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. 
 
INVESTIGATIONAL NEW DRUG PROTOCOL 
 
NRL-1 (INTRANASAL DIAZEPAM) 
 
PROTOCOL NUMBER DIAZ.001.04 
VERSION 5 
02 MAY 2017 
 
 
AN OPEN-LABEL, REPEAT-DOSE PHARMACOKINETIC STUDY OF NRL-1 IN 
EPILEPSY SUBJECTS UNDER SEIZURE AND NORMAL CONDITIONS 
 
SPONSOR: 
 
NEURELIS INC. 
1042-B N. EL CAMINO REAL 
ENCINITAS, CA  92024-1322 
 
 
CONFIDENTIAL 
 
 


Neurelis, Inc. 
Protocol DIAZ.001.04 
NRL-1 (Diazepam Intranasal) 
Version:  5 
 
02 May 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 
 
Bioanalytical Laboratory  
inVentiv Health Clinique Inc. 
Bioanalytical Laboratory 
2500, rue Einstein  
Québec (Québec), G1P 0A2 
CANADA 
Tel.:  (418) 527-4000 
Fax:  (418) 688-5242 
  
Serious Adverse Event Reporting 
Fax:  1-858-436-1401 
Email:  NeurelisSafety@pacificlinkconsulting.com 
 


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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 ............................................................................................. 11 
PROTOCOL SYNOPSIS ............................................................................................................. 13 
1.0 
INTRODUCTION........................................................................................................... 23 
1.1 
Nonclinical Assessments ................................................................................................... 24 
1.1.1 
Pharmacology ........................................................................................................................ 25 
1.1.2 
Toxicology of NRL-1 and Diazepam .................................................................................... 25 
1.1.2.1 
Single Dose Toxicity Studies ............................................................................................ 25 
1.1.2.2 
Repeated-Dose Toxicology Studies .................................................................................. 26 
1.1.2.3 
Genotoxicity and Carcinogenicity Studies ........................................................................ 26 
1.1.2.4 
Reproductive and Developmental Studies ........................................................................ 27 
1.1.3 
Pharmacology and Toxicology of Intravail A3 ..................................................................... 27 
1.2 
Clinical Experience (Diazepam and NRL-1) .................................................................... 28 
1.2.1 
Clinical Trials with NRL-1 ................................................................................................... 29 
1.2.2 
Pharmacokinetics and Product Metabolism in Humans ........................................................ 32 
1.3 
Study Rationale ................................................................................................................ 34 
2.0 
PURPOSE AND STUDY OBJECTIVES ..................................................................... 35 
2.1 
Purpose............................................................................................................................. 35 
2.2 
Study Objectives.............................................................................................................. 35 
2.2.1 Primary Objective ........................................................................................................... 35 
2.2.2 Secondary Objectives...................................................................................................... 35 
2.3 
Description of Study Design ........................................................................................... 35 
2.4 
Study Endpoints .............................................................................................................. 37 
2.4.1 Primary Endpoint ........................................................................................................... 37 
2.4.2 Secondary Endpoints ...................................................................................................... 37 
2.4.3 Randomization/Assignment to Study Drug .................................................................. 38 
2.5 
Study Drugs ..................................................................................................................... 38 
2.5.1 Test Product .................................................................................................................... 38 


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2.5.2 Dose and Dose Justification............................................................................................ 38 
2.5.3 Pharmacokinetic Plasma Sampling ............................................................................... 39 
2.5.4 Bioanalytical Method ...................................................................................................... 40 
2.6 
Concomitant Medications .............................................................................................. 40 
2.6.1 Prior and Concomitant Medications ............................................................................. 40 
2.6.2 Restricted Concomitant Medications ............................................................................ 40 
2.7 
Procedures for Monitoring Subject Compliance ......................................................... 40 
3.0 
STUDY POPULATION ................................................................................................. 41 
3.1 
Inclusion Criteria ............................................................................................................ 41 
3.2 
Exclusion Criteria ........................................................................................................... 41 
3.3 
Other Restrictions ........................................................................................................... 43 
4.0 
SAFETY ASSESSMENTS ............................................................................................. 43 
4.1 
Collection of Adverse Events Data ................................................................................ 43 
4.2 
Clinical Laboratory Evaluations ................................................................................... 43 
4.2.1 Hematology ...................................................................................................................... 44 
4.2.2 Serum Chemistry ............................................................................................................ 44 
4.2.3 Urinalysis ......................................................................................................................... 44 
4.2.4 Urine Drug and Alcohol Screen ..................................................................................... 44 
4.2.5 Other Blood Tests ........................................................................................................... 45 
4.3 
Physical Examinations and Medical History ................................................................ 45 
4.3.1 Physical and Neurological Examinations...................................................................... 45 
4.3.2 Medical History ............................................................................................................... 45 
4.4 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................................... 45 
4.5 
ECG .................................................................................................................................. 45 
4.6 
Height and Weight .......................................................................................................... 46 
4.7 
EEG .................................................................................................................................. 46 
4.8 
Vital Signs ........................................................................................................................ 46 
4.9 
Smell Test ......................................................................................................................... 46 
4.10 
Nasal Irritation Assessments .......................................................................................... 46 
4.11 
Pregnancy Test ................................................................................................................ 46 


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5.0 
PHARMACOKINETICS ............................................................................................... 47 
6.0 
PHARMACODYNAMICS............................................................................................. 47 
7.0 
EFFICACY ...................................................................................................................... 47 
8.0 
STUDY VISITS ............................................................................................................... 48 
8.1 
Screening .......................................................................................................................... 48 
8.2 
Screening Evaluations (Days -21 to -1) ......................................................................... 48 
8.3 
Baseline Evaluations (Day -7 to 0, pre-dose period 2) ................................................. 49 
8.4 
Drug Administration ...................................................................................................... 50 
8.5 
Collection of Blood Samples ........................................................................................... 50 
8.6 
Day 0 (post-dose) up to Discharge ................................................................................. 52 
8.7 
Follow-up Telephone Contact ........................................................................................ 52 
8.8 
Termination Procedures ................................................................................................. 53 
9.0 
PREMATURE DISCONTINUATION FROM STUDY ............................................. 53 
10.0 
PRODUCT SPECIFICATIONS .................................................................................... 53 
10.1 
Description ....................................................................................................................... 53 
10.2 
Formulation, Packaging, and Labeling ......................................................................... 54 
10.3 
Receipt, Storage and Stability of NRL-1....................................................................... 54 
10.4 
Preparation of Study Drug ............................................................................................. 54 
10.5 
Administration of Study Drug ....................................................................................... 54 
10.6 
Ordering and Distribution of Study Drug .................................................................... 55 
10.7 
Accountability of Study Drugs ....................................................................................... 55 
11.0 
SAFETY MONITORING AND ADVERSE EVENTS ............................................... 56 
11.1 
Adverse Events ................................................................................................................ 56 
11.2 
Serious Adverse Events .................................................................................................. 58 
11.2.1 
Reporting Requirements for Serious Adverse Events ............................................. 58 
11.2.2 
Recording of Serious Adverse Events ....................................................................... 59 
12.0 
STATISTICAL CONSIDERATIONS .......................................................................... 59 
12.1 
Sample Size Determination ............................................................................................ 59 
12.2 
Analysis Data Sets ........................................................................................................... 60 
12.3 
Pharmacokinetic Data Analyses .................................................................................... 60 


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12.4 
Safety ................................................................................................................................ 61 
13.0 
DATACOLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ...... 64 
13.1 
Data Collection and Reporting ...................................................................................... 64 
13.2 
Study Monitoring ............................................................................................................ 65 
13.3 
Data Disclosure and Subject Confidentiality ............................................................... 65 
14.0 
PROTECTION OF HUMAN SUBJECTS ................................................................... 66 
14.1 
Basic Principles ............................................................................................................... 66 
14.2 
Institutional Review Board/Ethics Committee ............................................................. 66 
15.0 
REFERENCE LIST ........................................................................................................ 67 
 
LIST OF TABLES 
Table 1:  Intravail A3 Safety Margins Based on Current NRL-1 Formulation ............................ 28 
Table 2:  Summary of Pharmacokinetic Data from the DIAZ.001.01 Study ............................... 30 
Table 3:  Severity Assessment Terminology for Reporting Adverse Events (CTCAE v 4.03) .... 57 
Table 4:  Contact Information for SAE Reporting ........................................................................ 59 
 
LIST OF FIGURES 
Figure 1:  Diazepam ...................................................................................................................... 23 
Figure 2:  Arithmetic Mean Plasma Diazepam Concentrations (Inset Illustrates the Initial 
24 Hours) ...................................................................................................................................... 30 
 
LIST OF APPENDICES 
APPENDIX A: 
SCHEDULE OF STUDY PROCEDURES ..................................................... 69 
APPENDIX B: 
SEDATION SCORING ................................................................................... 74 
APPENDIX C: 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ................ 76 
APPENDIX D: 
NIH TOOLBOX ODOR IDENTIFICATION TEST ...................................... 95 
APPENDIX E: 
LIST OF PROHIBITED MEDICATION........................................................ 96 
 


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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 
AUC(0-6) 
area under the plasma concentration time-curve to 6 hours post dose 
AUD(0-∞) 
area under the plasma concentration time-curve to infinity  
ß-hCG 
serum pregnancy test 
BLQ 
below the limit of quantitation  
BMI 
body mass index 
BUN 
blood urea nitrogen 
ºC 
Degrees Celsius 
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 
CI 
Confidence interval 
cm 
Centimeter 
Cmax 
Maximum plasma concentration 


Neurelis, Inc. 
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ABBREVIATION 
DEFINITION 
CNS 
central nervous system 
CO2 
bicarbonate/carbon dioxide 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cofficient of variation 
ECG 
Electrocardiogram 
E.coli 
Escherichia coli 
EEG 
Electroencephalogram 
EDTA 
ethylenediaminetetraacetic acid 
EMU 
Epilepsy Monitoring Unit 
EPA 
Environmental Protection Agency 
ºF 
Degrees Farenheit 
FDA 
US Food and Drug Administration 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMR 
Geometric mean ratio 
GRAS 
generally recognized as safe 
H 
Hour 
HbSAg 
Hepatitis B surface antigen 
HED 
human equivalent dose 
HEENT 
head, ears, eyes, nose, and throat 


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Version:  5 
 
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ABBREVIATION 
DEFINITION 
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) 
L 
Liter 
LC/MS/MS 
Liquid chromatography tandem mass spectrometry 
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) 
min 
Minute 
mL 
milliliter 
mm 
Millimeter 
NIH 
National Institutes of Health 
NOEL 
no observable effect level 
NRL-1.A 
100 mg/mL diazepam nasal spray suspension manufactured for Neurelis, 
Inc. 


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Protocol DIAZ.001.04 
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ABBREVIATION 
DEFINITION 
NRL-1.B 
100 mg/mL diazepam nasal spray solution manufactured for Neurelis, Inc. 
OTC 
Over-the-counter 
OECD 
Organisation for Economic Co-operation and Development 
PBMC 
blood peripheral mononuclear cells 
PI 
principal investigator 
PK 
pharmacokinetics 
QTcF 
Corrected QT interval, Fridericia’s formula 
RBC 
red blood cell 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SD 
Standard deviation 
TEAE 
treatment-emergent adverse event 
t1/2 
Half-life 
tmax 
time to maximum plasma concentration 
UDS 
Unit dose sprayer 
µL 
microliter 
US/USA 
United States of America 
VAS 
Visual Analog Scale 
WBC 
white blood cell 
WHODD 
World Health Organization Drug Dictionary 
 


Neurelis, Inc. 
Protocol DIAZ.001.04 
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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. 
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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.001.04 
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PROTOCOL SYNOPSIS 
Study Title 
An Open-Label, Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects Under 
Seizure and Normal Conditions (DIAZ.001.04) 
Phase 
Phase 1 (Pharmacokinetics in Epilepsy Subjects) 
Study Drug 
NRL-1 (Intranasal Diazepam) 
Objectives 
Primary objective:  
• 
The primary objective of this study is to assess the pharmacokinetics (PK) of diazepam after 
single intranasal doses of NRL-1 administered to Epilepsy subjects during the ictal or peri-
ictal period (defined as either during or immediately following a seizure), where the seizure 
involved motor activity or alteration of awareness.  The primary PK variables to determine 
absorption will be the maximum plasma concentration (Cmax) and the area under the curve 
through 6 hours (AUC(0-6)).  
Secondary objective:  
• 
To compare the diazepam Cmax, time to peak concentration (tmax) and AUC(0-6) after single 
administration of NRL-1 in Epilepsy subjects during the ictal or peri-ictal period to that after 
administration of NRL-1 to the same subjects under normal conditions; 
• 
To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of NRL-1 
between Epilepsy subjects ages 6 to 11 and those greater than 12 years of age; 
• 
To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of NRL-1 in 
Epilepsy subjects during the ictal or peri-ictal period and that of healthy normal subjects from 
PK data obtained in the DIAZ.001.02 and DIAZ.001.03 studies; 
• 
To assess the safety and tolerability of diazepam after intranasal administration of NRL-1. 


Neurelis, Inc. 
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Study Design 
This is a Phase 1, open-label, PK and safety study in Epilepsy subjects under ictal or peri-ictal 
(involving motor activity and/or altered awareness) and normal conditions.  Two doses of 
intranasal NRL-1 will be administered at either 5 mg, 10 mg, 15 mg, or 20 mg based on the 
subject’s body weight.  The study consists of a screening period, a baseline period, and a post-dose 
follow-up period. The NRL-1 dose will be administered during the ictal or peri-ictal period 
(Treatment 1), and again under normal non-seizing (intra-ictal) conditions (Treatment 2). The 
dosing may be done in either order (Treatment 1 or 2 first) with approximately 14-day wash-out 
between doses. Follow-up telephone contacts will be conducted 7-days and 14-days after the last 
dose of NRL-1.  Between doses of NRL-1, subjects and caregivers should avoid the use of other 
diazepam containing products.  For subjects who will roll over to the DIAZ.001.05 long term 
safety study, the Day 14 (second dosing day for NRL-1) assessments can be used as baseline 
assessments for DIAZ.001.05 to allow subjects to initiate long term treatment under that protocol. 
Baseline in period 1 for this study is considered the period within 7 days of admission.  The subject 
will be admitted and observed in the clinical site (i.e. Epilepsy Monitoring Unit [EMU] or Clinical 
Trial Research Center [CTRC]) and dosing will occur at the time of a seizure that is considered 
suitable for administration of NRL-1.  All subjects will be monitored by EEG, which is considered 
standard of care in the EMU but part of the study procedure in the CTRC, with the start and stop 
time of the seizure being recorded based on the EEG. Time point 0 will be defined as the time of 
dosing of NRL-1 and initiation of PK blood sampling. Subjects with diazepam blood levels at 
baseline that are equal or greater than 10% of the Cmax will be excluded from the primary PK 
analysis set.  
Treatment 1 with NRL-1 will be administered under ictal or peri-ictal conditions in a clinical 
setting to subjects having partial or generalized Epilepsy with motor seizures or seizures with clear 
alterations of awareness.  Since the primary objective is to obtain diazepam plasma concentrations 
and PK information when the drug is given in the ictal or peri-ictal period, dosing of NRL-1 will 
ideally occur within 5 minutes after the onset of the seizure.  The stop time of the seizure and any 
recurrence of seizure activity within the first 12 hours after dosing NRL-1 will also be recorded. 
A 3 mL blood sample for PK will be collected at the baseline and at the post-dose period once 
admitted to the clinical site.  During the post-dose period, 3 mL blood samples will be collected at 
predetermined times after NRL-1 dosing to determine the diazepam plasma concentration versus 
time profile.  If the baseline pre-dose blood sample is unable to be collected, i.e., subject 
experiences a seizure prior to collection, then the pre-dose assessment closest to dosing will be 
included in the analysis. 
If the subject experiences a seizure after NRL-1 dosing (during the blood sampling period), PK 
blood draws will be suspended as long as required for the subject’s medical care and should 
resume when clinically feasible.  Subjects may be treated with any other medication that does not 
contain diazepam that is standard of care. If the subject experiences a seizure after NRL-1 dosing 
and is administered an exclusionary medication (such as intravenous [IV], oral or rectal diazepam), 
PK blood draws will be stopped time of dosing diazepam recorded, and the Sponsor will be 
notified.  All other safety procedures will be performed as per the protocol Schedule of Study 
Procedures (APPENDIX A).   


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The second treatment (Treatment 2) with NRL-1 will occur when the subject is in a normal state 
(intra-ictal period). Please note that it is not anticipated that subjects will be admitted to the clinical 
site for Treatment 2 and the site will select an appropriate clinical facility for this portion of the 
study.  Subjects should be seizure free for at least 12 hours prior to dosing.  A 3 mL blood sample 
for PK will be collected at the post-dose period in the clinic prior to administration of NRL-1.  
During the post-dose period, 3 mL blood samples will be collected at predetermined times after 
NRL-1 dosing to determine the diazepam plasma concentration versus time profile. 
Treatment 1 and Treatment 2 may be given in either order, provided there is at least a 14-day wash 
out period between doses of NRL-1 and no other diazepam containing products are used between 
the two NRL-1 administrations.  
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 (AE) assessment.  Concomitant medications 
will be recorded.  Columbia-Suicide Severity Rating Scale (C-SSRS for adults or children), nasal 
irritation assessment, assessment of mucosalerythema, mucosal edema, nasal discharge, mucosal 
crusting and mucosal epistaxis, sedation score assessment, and smell test (National Institutes of 
Health [NIH] Toolbox Odor Identification Test, (1, 2) will be conducted. 
Extension 
Study 
Subjects completing both periods of dosing and PK assessments as a participant in this protocol, 
are eligible for the long-term safety study (DIAZ.01.05) and may receive treatment with NRL-1 
under that protocol. 
Sample Size 
Approximately 45 subjects, 15 subjects age 6 to 11 years, and 30 subjects over 12 years of age, are 
to be enrolled as part of this study with dosing during the ictal or peri-ictal period of a seizure. Of 
these, at least 10 adult subjects and 5 pediatric subjects will have PK assessments after dosing 
during the ictal period.  
Study 
Population 
Subjects with a clinical diagnosis of epilepsy who, in the opinion of the Investigator, may need a 
benzodiazepine for seizure control. 


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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. Body mass index (BMI) not to exceed 35 kg/m², inclusive. 
4. Subject has a clinical diagnosis of Epilepsy and, in the opinion of the Investigator, may need 
benzodiazepine intervention for seizure control. 
5. Subjects having either partial or generalized Epilepsy with motor seizures or seizures with 
clear alteration of awareness are eligible for enrollment. 
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).   
7. No clinically significant abnormal findings in the medical history, on the physical 
examination, ECG (corrected QT interval [QTcF] < 450 msec for males and QTcF < 470 msec 
for females), or clinical laboratory results during screening. 
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. 


Neurelis, Inc. 
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Main 
Exclusion 
Criteria  
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. Subject is undergoing intracranial EEG monitoring. 
2. A history of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, severe 
seasonal or non-seasonal allergies, nasal polyps or any nasal passage abnormality that could 
interfere with nasal spray administration, or any other condition which, in the opinion of the 
Investigator, would jeopardize the safety of the subject or impact the validity of the study 
results. 
3. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days prior 
to study screening. 
4. Subjects with active major depression or a past suicide attempt documented on the 
Baseline/Screening C-SSRS.  The children 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. 
5. Any Suicidal Ideation of 3, 4, or 5 or any Suicidal Behavior in Lifetime using C-SSRS. 
6. A history of allergic or adverse responses to diazepam or any comparable or similar product. 
7. Subjects who (for whatever reason) have been on an abnormal diet (such as one that severely 
restricts specific basic food groups [e.g., ketogenic diet], limits calories [e.g., fast], and/or 
requires the use of daily supplements as a substitute for the foods typically eaten at 
mealtimes), during the four (4) weeks preceding the study.   
8. Subjects who donated blood or plasma within 30 days of the first dose of study drug. 
9. Participation in a clinical trial within 30 days prior to the first dose of study drug.  
Participation in an observational (non-interventional) study is not excluded as long as there are 
no scheduling conflicts with this study. 
10. Inadequate or difficult venous access that may jeopardize the quality or timing of the PK 
samples. 
11. Female subjects who are trying to conceive, are pregnant, or are lactating. 
12. Positive serum pregnancy test (ß-hCG) at screening or urine pregnancy test prior to each 
administration of study drug for all women of childbearing potential. 
13. Positive blood screen on subjects age 12 or greater for human immunodeficiency virus (HIV), 
Hepatitis B surface antigen (HbSAg), or Hepatitis C, or a positive urine screen for alcohol, 
drugs of abuse, or cotinine.  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.  
14. Treatment with phenobarbital or primidone within 30 days of the anticipated dosing visit (i.e., 
baseline). 
15. Treatment with warfarin or dabigatran or other blood thinners within 30 days of the anticipated 
dosing visit (i.e., baseline). 
16. Treatment with any diazepam containing products within 14 days of the anticipated dosing 
visit (i.e., baseline). 


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17. Use of nasal decongestants or nasal steroids within 7 days prior to the screening visit or during 
the study.  
18. Subject does not have the flu, rhinitis or any other nasal condition that would impact 
absorption of intranasal diazepam. 
Other 
Restrictions 
1. Treatment with any known strong or moderate inhibitors or inducers of metabolizing enzymes 
(e.g., CYP-P450 enzymes or MAO) within fourteen (14) days prior to the first dose of NRL-1, 
or during the study, is prohibited without approval from the Medical Monitor (See 
APPENDIX E for list of prohibited medications).  
2. Use of OTC oral and/or nasal decongestants within 7 days prior to the first dose of study drug 
or during the study. 
3. Smoking and the use of tobacco products in excess of 10 cigarettes or 1 cigar per day is not 
permitted for one (1) month prior to the first dose of Study Drug and for the duration of the 
study.  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. Subjects should not engage in strenuous exercise during the confinement period of the study. 


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Dosage and 
Administrati
on of Study 
Drug 
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). 
• 
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). 


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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. AE collection will begin after baseline assessments 
are complete prior to the initial treatment with NRL-1 and continue for 14-days after the final dose.  
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.  Subjects will receive follow-up phone calls approximately 7 days (± 2 days) 
and 14 days (± 3 days) after the second dose of NRL-1 dosing 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. 
Objective evaluations of nasal irritation will be assessed by a trained observer after administration 
of the intranasal formulation.  Nasal irritation will also be evaluated prior to each administration of 
NRL-1 (baseline) and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at 
discharge. Mucosal erythema, mucosal edema, nasal discharge, mucosal crusting and mucosal 
epistaxis will be evaluated on separate scales prior to each dose of NRL-1 (baseline), and at 30 (± 
10 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, 
and at discharge. The subjects will also be required to report any incident of nasal irritation or 
mucosal epistaxis in-between evaluation time points and during follow up contacts. 
Objective evaluations of sedation will be made using a 6-point (0 → 5) sedation scoring system 
that will be used to assess the degree of drowsiness of the subjects after administration of the 
intranasal formulation.  Sedation scores will be reported by the subject (if awake) as well as by a 
trained observer, using the same rating scale, prior to (baseline) and at 15 (± 5 min) and 
30 (± 10 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post 
dose after each administration, and at discharge.  Subjects will be also be questioned by the trained 
observer regarding their degree of drowsiness.  
An unconstrained visual analog scale (VAS) that consists of a 10 cm (100 mm) horizontal straight 
line will be used to assess acute pain following administration of study drug.  The ends of the scale 
are defined as extremes limits of pain sensation:  0 = no pain, 10 = extreme pain.  The subjects will 
be asked to mark a point on the scale which best describes their intensity of pain and discomfort 
prior to (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, 1 (± 10 min), 2 (± 15 min), 
4 (± 30 min), and 6 (± 30 min) hours post-dose, and at discharge.  The location of the marking at 
each time point will be measured and noted as the reported score.   
The C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality in 
order to classify suicidal events.  The children 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.  Suicidality will be 
assessed at screening and baseline (pre-dose) and post-dosing at 6 hours.  The screening and 
baseline assessments will use the Baseline/Screening Phase 1 version of the C-SSRS.  The Since 
Last Visit version of the C-SSRS will be used for post-dosing assessments. 
Smell tests will be conducted at baseline, at 1 (± 15 min) hour, 4 (± 30 min) hours, and 24 (± 30 
min) hours (before discharge) following NRL-1 administration.  The NIH Toolbox Odor 
Identification Test will be used as smell tests. 


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Safety data will be summarized and descriptive statistics will be provided for actual values and 
change from baseline values for physical and neurological examination including HEENT, vital 
signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and C-SSRS 
assessments. 
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. 
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. 
Pharmaco-
kinetic 
Analysis 
Blood samples (3 mL) will be collected in this study to measure diazepam plasma concentrations 
following the intranasal administration of NRL-1.  All subjects will have samples collected through 
at least 6 hours after each of the two doses of NRL-1.  Blood samples for PK will be obtained at 
baseline upon admission to the clinical site (EMU or CTRC) for each treatment, and at 15, 30, and 
45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing.  Blood samples should also 
be obtained if feasible at 8 and 12 hours after dosing.  If a blood sample collection is delayed, then 
the collection will occur as soon as feasible and should not be skipped even if close to the next 
blood draw. Actual blood collection times can vary as follows: 1) ± 10 minutes for the 15 to 60 
minute samples, 2) ± 15 minutes for the 1.25 to 6 hour samples, and 3) ± 30 minutes for the 
optional 8 and 12 hour sample. 
The following PK parameters for diazepam will be calculated using non-compartmental analysis:  
Cmax, tmax, AUC(0-6) with a concentration equal to or greater than the lower limit of quantitation.  
If a second dose of NRL-1 is administered due to a subsequent seizure between 4 and 12 hours 
after the initial dose, when clinically feasible, PK samples should be collected based on the time of 
the second dose at 0 (immediately after the 2nd dose), 30 minutes, and 1, 2, and 4 hours after 
dosing.  
For Treatment 1, the actual time of seizure onset, dose of NRL-1, time of seizure stop, and time of 
each blood sample will be recorded.  PK parameters will be determined using actual times of 
sample collection relative to the administration of NRL-1.  


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Statistical 
Analysis 
Individual subject plasma concentrations, actual sampling times, and PK parameters will be listed 
by analyte and treatment.  Descriptive statistics will be calculated by analyte, age group (6 to 11 
years being one group and those 12 years of age and over being the other group) and treatment for 
plasma concentrations and PK parameters.  Additional exploratory analyses will be conducted to 
provide descriptive statistics on subjects age 6 to 8 years, 9 to 11 years, 12 to 16 years and over 16 
years of age.  Individual subject and mean plasma concentrations will be displayed on linear and 
semi-logarithmic axes. 
A separate but identical analysis will be performed on the observed PK parameters depending on 
which age group the subject belongs.  The PK parameters Cmax and AUC(0-6) for diazepam will be 
compared for the first dose of NRL-1 under seizing conditions to the second dose of NRL-1 under 
non-seizing conditions using a linear mixed effect model with treatment period if appropriate and 
clinical site as the classification variables using the natural logarithms of the data.  Cmax and AUC(0-
6) will be normalized to the 10 mg dose prior to analysis.  Confidence intervals (CI) (90%) will be 
constructed for the geometric mean ratios (GMR) of the two parameters between the two 
treatments using the log-transformed data and the two one-sided t-tests procedure.  The point 
estimates and confidence limits will be exponentiated back to the original scale.  Dose equivalence 
will be concluded if the 90% CI for the GMRs among the two comparisons of the two parameters 
fall within 80% to 125%. 
For AUC(0-6) and Cmax, the geometric mean (inverse log-transformed) and the 90% CI for geometric 
means will be compared to those observed in DIAZ.001.02 and DIAZ.001.03 studies. 
The Cmax and AUC(0-6) determined in epilepsy subjects in the ictal and peri-ictal period will be 
compared between the same subject in a normative state.  The Cmax, tmax, and AUC(0-6) determined 
in epilepsy subjects will also be compared to those results in healthy, non-seizing, volunteers. 
The Cmax and AUC(0-6) will be visually compared between the two age groups in both seizure/non-
seizure conditions. 
Study 
Duration 
It is planned that each subject will participate in the study for approximately 49 to 65 days, which 
comprises a 21 day screening period, first treatment period and wash out of 14 days (28 days if on 
oral contraceptives), second treatment period and follow up period of 14-days.  The actual 
treatment periods will be approximately 28 to 42 days. 
Study 
Centers 
Up to sixteen (16) experienced 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 


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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 
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 PK 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 PK 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 this study. 


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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-
aminobuytric (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 mg/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 µL dose volume of 100 mg diazepam per 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/kg 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 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 


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concentration tested 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 to < 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 observable 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 intravenous 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 intravenous 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 intramuscular (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 (if subjects are 
on oral contraceptives (OC) the period between dosing should be extended to approximately 28-
days to ensure that the subject is dosed at the same approximate time of the OC cycle).  
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 


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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 
gastrointestinal tract after swallowing any “run off” from the back of the nose. 
A summary of the PK data from the DIAZ.001.01 study is provided in Table 2 and Figure 2. 
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 
Figure 2:  Arithmetic Mean Plasma Diazepam Concentrations (Inset Illustrates the Initial 
24 Hours) 
 


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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. 
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 TEAEs 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 AE.  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. 


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Conclusion 
Overall, the results of past clinical studies and the long history of diazepam use in patients, 
support the proposed Phase 1 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. 
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 (Coefficient of variation [CV]= 43%) and 71 hours 
(CV = 37%), respectively (17). 


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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 mg and 7 mg in 
polyethylene glycol 300 in seven healthy volunteers as compared to a 5 mg intravenous dose.  
The intranasal formulation had a relative bioavailability of 45% and 42%, a Cmax of 99 ng/mL 
and 179 ng⁄mL and a tmax of 18 and 42 minutes for the 4 mg 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 mg and 10 mg intranasal diazepam doses of their 
investigational formulation with a 5 mg dose of diazepam solution intravenously.  Following the 
5 mg and 10 mg doses, the median tmax were 20 and 30 minutes respectively and the mean Cmax 
were 134.3 ± 62 ng/mL 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 US 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 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 US 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. 


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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. 
A diazepam nasal spray is being developed for patients who experience ARS to provide an 
alternative more convenient and acceptable route of diazepam administration. 


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2.0 PURPOSE AND STUDY OBJECTIVES 
2.1 
Purpose 
The purpose of this study is to assess the PK and safety in Epilepsy subjects under both seizure 
and normal conditions. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
The primary objective of this study is to assess the PK of diazepam after single intranasal doses 
of NRL-1 administered to Epilepsy subjects during the ictal or peri-ictal period (defined as either 
during or immediately following a seizure), where the seizure involved motor activity or 
alteration of awareness.  The primary PK variables to determine absorption will be the Cmax and 
the area under the curve through 6 hours (AUC0-6). 
2.2.2 
Secondary Objectives 
The secondary objectives of this study include: 
• To compare the diazepam Cmax, tmax and AUC(0-6) after single administration of NRL-1 in 
Epilepsy subjects during the ictal or peri-ictal period to that after administration of 
NRL-1 to the same subjects under normal conditions; 
• To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of NRL-1 
between Epilepsy subjects ages 6 to 11 and those greater than 12 years of age;  
• To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of NRL-1 in 
Epilepsy subjects during the ictal or peri-ictal period (defined as either during or 
immediately following a seizure), where the seizure involved motor activity or alteration 
of awareness and that of healthy normal subjects from PK data obtained in the 
DIAZ.001.02 and DIAZ.001.03 studies; 
• To assess the safety and tolerability of diazepam after intranasal administration of 
NRL-1. 
2.3 
Description of Study Design 
This is a Phase 1, open-label, PK and safety study in Epilepsy subjects under both ictal or peri-
ictal (involving motor activity and/or altered awareness) and normal conditions.  Two doses of 
intranasal NRL-1 will be administered at either 5 mg, 10 mg, 15 mg, or 20 mg based on the 
subject’s body weight. 
The study consists of a screening period, a baseline period, and a post-dose follow-up period. 
The NRL-1 dose will be administered during the ictal or peri-ictal period (Treatment 1) and 
again under normal non-seizing (intra-ictal) conditions (Treatment 2). The dosing may be done 


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in either order (Treatment 1 or Treatment 2 first) with approximately 14-day wash-out between 
doses. Follow-up telephone contacts will be conducted 7-days and 14-days after the last dose of 
NRL-1.  Between doses of NRL-1, subjects and caregivers should avoid the use of other 
diazepam containing products. For subjects who will roll over to the DIAZ.001.05 long term 
safety study, the Day 14 (second dosing for NRL-1) assessments can be used as baseline 
assessments for DIAZ.001.05 to allow subjects to initiate long term treatment under the protocol.  
Baseline in period 1 for this study is considered the period within 7 days of admission.  The 
subject will be admitted and observed in the clinical site (i.e. Epilepsy Monitoring Unit [EMU] 
or Clinical Trial Research Center [CTRC]) and dosing will occur at the time of a seizure that is 
considered suitable for administration of NRL-1.  All subjects will be monitored by EEG, which 
is considered standard of care in the EMU but part of study procedure in the CTRC, with the 
start and stop time of the seizure being recorded based on the EEG. Time point 0 will be defined 
as the time of dosing of NRL-1 and initiation of PK blood sampling. Subjects with diazepam 
blood levels at baseline that are equal to or greater than 10% of the Cmax will be excluded from 
the primary PK analysis set.  
Treatment 1 with NRL-1 will initially be administered under ictal or peri-ictal conditions in a 
clinical setting to subjects having partial or generalized Epilepsy with motor seizures or seizures 
with clear alterations of awareness.  Since the primary objective is to obtain diazepam plasma 
concentrations and PK information when the drug is given in the ictal or peri-ictal period, dosing 
of NRL-1 will ideally occur during or within 5 minutes after the onset of the seizure. The stop 
time of the seizure and any recurrence of seizure activity within the first 12 hours after dosing 
NRL-1 will also be recorded.  
A 3 mL blood sample for PK will be collected at the baseline and at the post-dose period once 
admitted to the clinical site.  During the post-dose period, 3 mL blood samples will be collected 
at predetermined times after NRL-1 dosing to determine the diazepam plasma concentration 
versus time profile.  If the baseline pre-dose blood sample is unable to be collected, i.e., subject 
experiences a seizure prior to collection, then the pre-dose assessment closest to dosing will be 
included in the analysis. 
If the subject experiences a seizure after NRL-1 dosing (during the blood sampling period), PK 
blood draws will be suspended as long as required for the subject’s medical care and should 
resume when clinically feasible.  Subjects may be treated with any other medication that does not 
contain diazepam that is standard of care. If the subject experiences a seizure after NRL-1 dosing 
and is administered an exclusionary medication (such as IV, oral or rectal diazepam), PK blood 
draws will be stopped, time of dosing diazepam recorded, and the Sponsor will be notified.  All 
other safety procedures will be performed as per the protocol Schedule of Study Procedures 
(APPENDIX A). 
The second treatment (Treatment 2) with NRL-1 will occur when the subject is in a normal state 
(intra-ictal period). Please note that it is not anticipated that subjects will be admitted to the 


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clinical site for Treatment 2 and the site will select an appropriate clinical facility for this portion 
of the study.  Subjects should be seizure free for at least 12 hours prior to dosing.  A 3 mL blood 
sample for PK will be collected at the post-dose period in the clinic prior to administration of 
NRL-1.  During the post-dose period, 3 mL blood samples will be collected at predetermined 
times after NRL-1 dosing to determine the diazepam plasma concentration versus time profile. 
Treatment 1 and Treatment 2 may be given in either order, provided there is at least a 14-day 
wash out period between doses of NRL-1 and no other diazepam containing products are used 
between the two NRL-1 administrations.  
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 children), nasal irritation 
assessment, assessment of mucosalerythema, mucosal edema, nasal discharge, mucosal crusting 
and mucosal epistaxis, sedation score sssessment, and smell test (National Institutes of Health 
[NIH] Toolbox Odor Identification Test, (1, 2) will be conducted. 
2.4 
Study Endpoints 
2.4.1 
Primary Endpoint 
The primary endpoint of this study is the PK outcome.  There are no efficacy measures evaluated 
in this study.  The PK endpoint of this trial is to determine the relative bioavailability of 
diazepam from NRL-1 (Cmax, tmax, AUC(0-6)) in epilepsy subjects. 
2.4.2 
Secondary Endpoints 
The secondary endpoints in this study include: 
• A secondary PK endpoint of this trial is to compare the diazepam Cmax, tmax, and AUC(0-6) 
after single administration of NRL-1 between Epilepsy subjects ages 6 to 11 and those 
greater than 12 years of age in both seizure and non-seizure conditions. 
• A secondary PK endpoint of this trial is to determine the relative bioavailability of 
diazepam from NRL-1 (Cmax, tmax, AUC(0-6)) in epilepsy subjects during the ictal or peri-
ictal period (defined as either during or immediately following a seizure), where the 
seizure involved motor activity or alteration of awareness compared to that of normal 
conditions and healthy normal subjects from PK data obtained in the DIAZ.001.02 and 
DIAZ.001.03 studies. 
• Assessment of the safety events from NRL-1. 
• To visually compare the Cmax and AUC(0-6) between the 2 age groups under seizure and 
non-seizure conditions. 


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2.4.3 
Randomization/Assignment to Study Drug 
There are no randomization/assignments to study drug as this is an open-label study. 
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 
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). 
• 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). 
In patients, the usual dose of diazepam rectal gel (Diastat) is 0.3 mg/kg, or ~9 mg in a 30 kg 
child and 0.2 mg/kg or ~14 mg in a 70 kg adult.  The diazepam doses selected of 5 mg to 20 mg 
is the low to high dose in the typical weight range for a patient.  These doses are also expected to 
provide plasma diazepam concentrations sufficient for comparing the PK of diazepam after 
administration of the doses while minimizing risk to the subjects. 
2.5.3 
Pharmacokinetic Plasma Sampling 
Blood samples (3 mL) will be collected in this study to measure diazepam plasma concentrations 
following the intranasal administration of NRL-1.  All subjects will have samples collected 
through at least 6 hours after each of the two doses of NRL-1.  Blood samples for PK will be 
obtained at baseline upon admission to the clinical site (EMU or CTRC) for each treatment and 
at 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing.  Blood 
samples should also be obtained if feasible at 8 and 12 hours after dosing.  If a blood sample 
collection is delayed, then the collection will occur as soon as feasible and should not be skipped 
even if close to the next blood draw. 
Actual blood collection times can vary as follows: 1) ± 10 minutes for the 15 to 60 minute 
samples, 2) ± 15 minutes for the 1.25 to 6 hour samples, and 3) ± 30 minutes for the optional 8 
and 12 hour samples. 
The following PK parameters for diazepam will be calculated using non-compartmental analysis: 
Cmax, tmax, AUC(0-6), with a concentration equal to or greater than the lower limit of quantitation.  
If a second dose of NRL-1 is administered due to a subsequent seizure between 4 and 12 hours 
after the initial dose, when clinically feasible, PK samples should be collected based on the time 
of the second dose at 0 (immediately after the 2nd dose), 30 minutes, and 1, 2, and 4 hours after 
dosing.  


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For Treatment 1, the actual time of seizure onset, dose of NRL-1, time of seizure stop, and time 
of each blood sample will be recorded. PK parameters will be determined using actual times of 
sample collection relative to the administration of NRL-1. 
2.5.4 
Bioanalytical Method 
Plasma samples will be evaluated by a validated liquid chromatography tandem mass 
spectrometry (LC/MS/MS) method capable of detecting diazepam. 
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 discharge at the end of the Treatment period 2. 
The use of over-the-counter (OTC) oral and/or nasal decongestants is not permitted for the 7 
days prior to the screening period or during the study.  Other OTC medications are not allowed 
within seven (7) days of the first dose.  All prescription medications are not allowed within 
fourteen (14) days of the first dose of NRL-1. 
2.6.2 
Restricted Concomitant Medications 
Treatment with any known strong or moderate inhibitors or inducers of metabolizing enzymes 
(e.g., CYP-P450 enzymes or MAO) within fourteen (14) days prior to the first dose of NRL-1, or 
during the study, is prohibited without approval from the Medical Monitor (See APPENDIX E 
for list of prohibited medications).  
Use of OTC oral and/or nasal decongestants within 7 days prior to the first dose of study drug or 
during the study. 
Treatment with any other diazepam containing product within 14 days prior to the first dose of 
study drug or during the study. 
2.7 
Procedures for Monitoring Subject Compliance 
Subjects will be in the clinical trial site for the dosing and blood sampling portion of the trial.  
Between dosing periods, subjects will be allowed to return home.  Subjects will return to the 
clinic for subsequent dosing periods and for clinical assessments. 


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3.0 STUDY POPULATION 
The study population will be subjects with a clinical diagnosis of epilepsy who, in the opinion of 
the Investigator, may need a benzodiazepine for seizure control. 
3.1 
Inclusion Criteria 
For a subject to be eligible for this study, s/he must meet ALL of the following criteria:  
1. Male and female subjects between the ages of 6 and 65 years, inclusive. 
2. Written informed consent to participate in the study. 
3. Body mass index (BMI) not to exceed 35 kg/m², inclusive. 
4. Subject has a clinical diagnosis of Epilepsy and, in the opinion of the Investigator, may 
need benzodiazepine intervention for seizure control. 
5. Subjects having either partial or generalized Epilepsy with motor seizures or seizures 
with clear alteration of awareness are eligible for enrollment. 
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).   
7. No clinically significant abnormal findings in the medical history, on the physical 
examination, ECG (corrected QT interval [QTcF] < 450 msec for males and QTcF < 470 
msec for females), or clinical laboratory results during screening. 
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. 
3.2 
Exclusion Criteria 
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. Subject is undergoing intracranial EEG monitoring. 
2. A history of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, 
severe seasonal or non-seasonal allergies, nasal polyps or any nasal passage abnormality 
that could interfere with nasal spray administration, or any other condition which, in the 
opinion of the Investigator, would jeopardize the safety of the subject or impact the 
validity of the study results. 


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3. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days 
prior to study screening. 
4. Subjects with active major depression or a past suicide attempt documented on the 
Baseline/Screening C-SSRS.  The children 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.   
5. Any Suicidal Ideation of 3, 4, or 5 or any Suicidal Behavior in Lifetime using C-SSRS. 
6. A history of allergic or adverse responses to diazepam or any comparable or similar 
product. 
7. Subjects who (for whatever reason) have been on an abnormal diet (such as one that 
severely restricts specific basic food groups [e.g., ketogenic diet], limits calories [e.g., 
fast], and/or requires the use of daily supplements as a substitute for the foods typically 
eaten at mealtimes), during the four (4) weeks preceding the study. 
8. Subjects who donated blood or plasma within 30 days of the first dose of study drug. 
9. Participation in a clinical trial within 30 days prior to the first dose of study drug.  
Participation in an observational (non-interventional) study is not excluded as long as 
there are no scheduling conflicts with this study. 
10. Inadequate or difficult venous access that may jeopardize the quality or timing of the PK 
samples. 
11. Female subjects who are trying to conceive, are pregnant, or are lactating. 
12. Positive serum pregnancy (ß-hCG) test at screening or urine pregnancy test prior to each 
administration of study drug for all women of childbearing potential. 
13. Positive blood screen on subjects age 12 or greater for human immunodeficiency virus 
(HIV), Hepatitis B surface antigen (HbSAg), or Hepatitis C, or a positive urine screen for 
alcohol, or drugs of abuse, or cotinine.  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. 
14. Treatment with phenobarbital or primidone within 30 days of the anticipated dosing visit 
(i.e., baseline). 
15. Treatment with warfarin or dabigatran or other blood thinners within 30 days of the 
anticipated dosing visit (i.e., baseline). 
16. Treatment with any diazepam containing products within 14 days of the anticipated 
dosing visit (i.e. baseline). 
17. Use of nasal decongestants or nasal steroids within 7 days prior to the screening visit or 
during the study.  
18. Subject does not have the flu, rhinitis or any other nasal condition that would impact 
absorption of intranasal diazepam. 


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3.3 
Other Restrictions 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Treatment with any known strong or moderate inhibitors or inducers of metabolizing 
enzymes (e.g., CYP-P450 enzymes or MAO) within fourteen (14) days prior to the first 
dose of NRL-1, or during the study, is prohibited without approval from the Medical 
Monitor (See APPENDIX E for list of prohibited medications).  
2. Use of OTC oral and/or nasal decongestants for the 7 days prior to the first dose of study 
drug or during the study. 
3. Smoking and the use of tobacco products in excess of 10 cigarettes or 1 cigar per day is 
not permitted for one (1) month prior to the first dose of Study Drug and for the duration 
of the study.  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. Subjects should not engage in strenuous exercise during the confinement period of the 
study. 
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 during the 
blood sampling period and until follow-up phone calls.  
Any AE reported by the subject or noted by the Investigator or his/her designee will be recorded 
on the case report form (CRF) regardless of the Investigator opinion of causality. The following 
information will be recorded for each AE: description of the event, date and time of onset, date 
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, ECGs, 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. 


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Baseline blood and urine samples in period 1 must be collected within 7 days of admission to the 
clinical site.  Results must be evaluated prior to dosing.  If an abnormal test result of clinical 
significance is obtained at baseline that was not clinically significant at screening, the test will be 
repeated within 7 days and dosing will be delayed until the value is no longer clinically 
significant. 
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 baseline 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.  
4.2.4 
Urine Drug and Alcohol Screen 
Urine samples will be collected at screening and baseline for amphetamines, barbiturates, 
cocaine metabolites, methadone, opiate metabolites, phencyclidine, marijuana metabolites, and 
alcohol.  When marijuana used for medical reasons in the opinion of the invesigator, it is not 


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considered a 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 as a concomitant medication. 
4.2.5 
Other Blood Tests 
The presence of HIV antibody, HbSAg, and Hepatitis C antibody will be assessed at screening. 
4.3 
Physical Examinations and Medical History 
4.3.1 
Physical and Neurological Examinations 
The Investigator or designee will perform a physical and neurological examination at screening 
and baseline.  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.).  The C-SSRS, a measure of 
suicidal ideation and behavior, will be used to document suicidality at screening, baseline, and at 
6 hours post dose in order to classify suicidal events using the Columbia Classification 
Algorithm of Suicide Assessment.  The children 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. 
4.4 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality 
in order to classify suicidal events. Suicidality will be accessed at screening and baseline (pre-
dose) and post-dosing at 6 hours. For adults, screening and baseline assessments will use the 
Baseline/Screening Phase 1 version of the C-SSRS.  The Since Last Visit version of the C-SSRS 
will be used for post-dosing assessments.  For children, screening and baseline assessments will 
use Children’s Baseline/Screening and Children’s Since Last Visit will be used for post-dosing 
assessments (APPENDIX C) 
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. 
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.  One duplicate copy of the ECG tracing and the evaluation report will be printed 
and sent to the Sponsor after de-identifying the subject for inclusion with the CRF.  The original 
ECG results will be kept on file at the site as source documentation. 


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4.6 
Height and Weight 
Height will be measured in centimeters at screening.  Body weight will be measured in kilograms 
at screening and baseline.  Height and weight will be recorded on the CRF. 
4.7 
EEG 
Subjects will be monitored for seizure activity with a continuous EEG evaluation. The EEG is 
considered standard of care when in the EMU setting, but is part of the study procedure if in 
CTRC setting. The start time, stop time, and type of seizure will be recorded based on the EEG 
results. The time of NRL-1 dosing will also be recorded as part of the study database.  
4.8 
Vital Signs 
Vital signs (temperature, pulse, respiration rate and blood pressure) are to be obtained at 
screening, baseline, and at 45 (± 5 min) minutes, 2 (± 15 min), 4 (± 30 min), 6 (± 30 min), 
8 (± 30 min), and 12 (± 30 min) post dosing and at discharge.  Vital signs at 8 (± 30 min) and 
12 (± 30 min) hours are optional.  Vital signs will be recorded on the CRF. 
4.9 
Smell Test  
Smell tests will be conducted at baseline, at 1 hour (± 15 min), 4 hours (± 30 min) post dosing, 
and at discharge.  The NIH Toolbox Odor Identification Test will be used as smell tests (1, 2).  
4.10 
Nasal Irritation Assessments 
Objective evaluations of nasal irritation will be assessed by a trained observer after 
administration of the intranasal formulation.  Nasal irritation will also be evaluated prior to each 
administration of NRL-1 (baseline) and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours 
post dose, and at discharge.  Mucosal erythema, mucosal edema, nasal discharge, mucosal 
crusting and mucosal epistaxis will be evaluated on separate scales prior to each dose of NRL-1 
(baseline), and at 30 (± 10 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 
30 min) hours post dose, and at discharge. The subjects will also be required to report any 
incident of nasal irritation or mucosal epistaxis in-between evaluation time points and during 
follow up contacts.  See Section 12.4 for assessment scales. 
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 prior to each treatment with NRL-1.  Please note that subjects 
age 6 to 11 are not required to take a pregnancy test.   
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 


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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 
The following PK parameters for diazepam will be calculated using non-compartmental analysis:  
Cmax, tmax, and AUC(0-6).  Blood samples (3 mL) will be collected in this study to measure 
diazepam plasma concentrations following the intranasal administration of NRL-1.  All subjects 
will have samples collected through at least 6 hours after each of the two doses of NRL-1.  Blood 
samples for PK will be obtained at baseline, upon admission to the clinical site (EMU or CTRC) 
for each treatment, and at 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours 
after dosing.  Blood samples should also be obtained if feasible at 8 and 12 hours after dosing.  If 
a blood sample collection is delayed, then the collection will occur as soon as feasible and should 
not be skipped even if close to the next blood draw.  Actual blood collection times can vary as 
follows:  1) ± 10 minutes for the 15 to 60 minute samples, 2) ± 15 minutes for the 1.25 to 6 hour 
samples, and 3) ± 30 minutes for the optional 8 and 12 hour samples. 
For subjects that have blood samples collected beyond 6 hours, the area under the diazepam 
plasma concentration versus time curve through the last sample (AUCt) will be calculated.  For 
subjects that have blood samples collected through 12 hours, the area under the diazepam plasma 
concentration versus time curve through 12 hours (AUC12h) will be calculated.  
If a second dose of NRL-1 is administered due to a subsequent seizure between 4 and 12 hours 
after the initial dose, when clinically feasible, PK samples should be collected based on the time 
of the second dose at 0 (immediately after the 2nd dose), 30 minutes, and 1, 2, and 4 hours after 
dosing. 
For Treatment 1, the actual time of seizure onset, dose of NRL-1, time of seizure stop, and time 
of each blood sample will be recorded.  PK parameters will be determined using actual times of 
sample collection relative to the administration of NRL-1. 
6.0 PHARMACODYNAMICS 
No pharmacodynamic measures will be assessed during this trial. 
7.0 EFFICACY 
No efficacy measures will be assessed during this study. 


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8.0 STUDY VISITS 
Refer to APPENDIX A for the Schedule of Study Procedures. 
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-specified 
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 in advance of dosing, but must be completed at least one (1) day 
prior to dosing.   
• The following study evaluations and procedures are required to determine eligibility: 
Medical history including seizure history, demographics, prior medications, and 
concomitant medications. 
• The C-SSRS, a measure of suicidal ideation and behavior, will be used to document 
suicidality at screening, baseline, and post-dosing at 6 hours.  The children 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 screening assessment will use the Baseline/Screening 
Phase 1 version of the C-SSRS.  If the subject has active major depression or a past 
suicide attempt, she/he is not eligible for the study.  


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• Physical and neurological examination, including height (at screening only) and weight 
measurements.   
• Vital signs consisting of temperature, pulse, and blood pressure. 
• 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) 
8.3 
Baseline Evaluations (Day -7 to 0, pre-dose period 2) 
Following the screening visit, subjects determined to be eligible for participation in the study 
will undergo baseline assessments after admission to the clinical site and within 7 days prior to 
dosing in period 1 and 48 hours for period 2. 
Baseline assessments include the following: 
• Any restricted concomitant medications  
• Medical history (at baseline period 1 only) 
• Physical and neurological examinations including weight 
• Vital signs consisting of temperature, pulse, respiratory rate and blood pressure. 
• Blood and serum samples for the following laboratory evaluations: 
o Hematology 
o Serum chemistry 
o PK 
• Urine samples 
o Urine pregnancy test 
o Urine drug and alcohol screen 
o Urinalysis 
• 12-lead ECGs 


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• Smell Test (1, 2)  
• C-SSRS.  The children 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 
• Nasal examination and irritation assessments (The following will be assessed on separate 
scales: nasal irritation, erythema, edema, nasal discharge, mucosal erythema, mucosal 
edema, nasal discharge, mucosal crusting and mucosal epistaxis) 
• Sedation score assessment 
• Visual analog scale (VAS) 
• EEG Monitoring (continuous) 
8.4 
Drug Administration 
Treatment 1 with NRL-1 will be administered under ictal or peri-ictal conditions in a clinical 
setting to subjects having partial or generalized Epilepsy with motor seizures or seizures with 
clear alterations of awareness.  Since the primary objective is to obtain diazepam plasma 
concentrations and PK information when drug is administered in the ictal or peri-ictal period, 
dosing of NRL-1 will occur within 5 minutes after the onset of the seizure. The stop time of the 
seizure and any recurrence of seizure activity within the first 12 hours after dosing NRL-1 will 
also be recorded.  
The second treatment (Treatment 2) with NRL-1 will occur when the subject is in a normal state 
(intra-ictal period). Please note that it is not anticipated that subjects will be admitted to the 
clinical site for Treatment 2 dosing and the site will select an appropriate clinical facility for this 
portion of the study. Subjects should be seizure free for at least 12 hours prior to dosing.  A 3 mL 
blood sample for PK will be collected at the post-dose period in the clinic prior to administration 
of NRL-1.  During the post-dose period, 3 mL blood samples will be collected at predetermined 
times after NRL-1 dosing to determine the diazepam plasma concentration versus time profile. 
Treatment 1 and Treatment 2 may be given in either order, provided there is at least a 14-day 
wash out period between doses of NRL-1 and no other diazepam containing products are used 
between the two NRL-1 administrations.  
Study site personnel are responsible for administering all study drugs.  The calendar date and 
24-hour clock time of all doses will be recorded on the CRF. 
8.5 
Collection of Blood Samples 
Blood samples (3 mL) for the measurement of plasma concentrations of diazepam will be 
collected in blood collection tubes (e.g.,Vacutainers) containing K2-ethylenediaminetetraacetic 
acid (EDTA) [1 x 6 mL]. 


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All subjects will have 3 mL samples collected through at least 6 hours after each of the two doses 
of NRL-1.  If clinically feasible, additional samples will be collected through 12 hours post-dose.  
Blood samples for PK will be obtained at Baseline upon admission to the clinical site (EMU or 
CTRC) for each treatment, Pre-dose (prior to each treatment of NRL-1), and at 15, 30, and 45 
minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 8, and 12 hours after dosing.  Blood samples at 8 (± 
30 min) and 12 (± 30 min) hours are optional.  If a blood sample collection is delayed, then the 
collection will occur as soon as feasible and should not be skipped even if close to the next blood 
draw. 
Actual blood collection times can vary as follows:  1) ± 10 minutes for the 15 to 60 minute 
samples, 2) ± 15 minutes for the 1.25 to 6 hour samples, and 3) ± 30 minutes for the optional 8 
and 12 hour. 
If a second dose of NRL-1 is administered due to a subsequent seizure between 4 and 12 hours 
after the initial dose, when clinically feasible, PK samples should be collected based on the time 
of the second dose at 0 (immediately after the 2nd dose), 30 minutes, and 1, 2, and 4 hours after 
dosing.  
The calendar date and 24-hour clock time of all blood samples will be recorded on the CRF. 
Blood samples will be stored on ice prior to processing, which will begin within 60 minutes of 
collection.  Plasma will be separated by centrifugation (e.g., 3000 rpm x 10 minutes at 0°C to 
approximately 4°C) and equal aliquots transferred to two (2) clearly labeled tubes and stored in a 
freezer at approximately -20°C.  Temperature excursions will be allowed as per the current 
standard operating procedure (SOP) at the clinic or laboratory. 
Samples will be packed in Styrofoam shipping containers with a sufficient amount of dry ice to 
maintain frozen conditions for at least 72 hours (3 days). 
One aliquot of each sample will be sent by courier to: 
inVentive Health Clinique, Inc. 
Attn: Sample Coordinator 
2500 Einstein Street 
Quebec, Canada GIP 0A2  
 
Telephone: 418-688-5212 
Fax: 1-858-436-1401 
The remaining aliquots will be sent to the analytical laboratory after the site receives written 
confirmation that the originals have been received and inventoried. 


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8.6 
Day 0 (post-dose) up to Discharge 
Post-dose assessments include the following (Refer Appendix A1 and A2 for the timing of each 
assessment): 
• Vital signs consisting of temperature, pulse, respiratory rate and blood pressure 
• Blood samples for PK 
• C-SSRS.  The children 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 
• Nasal examination and irritation assessments (The following will be assessed on separate 
scales: nasal irritation, erythema, edema, nasal discharge, mucosal erythema, mucosal 
edema, nasal discharge, mucosal crusting and mucosal epistaxis) 
• Sedation score assessment 
• Smell Test (1)  
• VAS 
• Concomitant medications  
• AEs 
There will be at least a 14 day wash-out period between the treatments (if subjects are on oral 
contraceptives (OC) the period between dosing should be extended to approximately 28-days to 
ensure that the subject is dosed at the same approximate time of the OC cycle).  Subjects may 
discharge from the clinic after blood sample at 6 hours (or optional 8 and 12 hours) post dose is 
complete followed by the discharge assessments. When discharge occurs after 6 hours post dose, 
the assessments at discharge that overlap with the assessments at 6 hours post dose do not have 
to be repeated. 
Treatment 1 and Treatment 2 may be given in either order, provided there is at least a 14-day 
wash out period between doses of NRL-1 and no other diazepam containing products have been 
used between the two NRL-1 administrations.  
For subjects who will roll over to the DIAZ.001.05 long term safety study, the Day 14 (second 
dosing day for NRL-1) assessments can be used as baseline assessments for DIAZ.001.05 to 
allow subjects to initiate long term treatment under that protocol.  
8.7 
Follow-up Telephone Contact 
Follow-up phone calls 7 days (± 2 days) and 14 days (± 3 days) will be conducted after the last 
dose of NRL-1 to determine if any AE has occurred and to follow-up on any TEAEs ongoing 
since last communication with the subject.   


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8.8 
Termination Procedures 
At early termination, all subjects will be contacted by phone calls approximately 7 days 
(± 2 days) after the final dose of NRL-1.   
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 
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 experienced pregnancy 
• 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; 


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• 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. 
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 
dispensed to study staff responsible for administration to study subjects and reconciliation will 
occur after dosing. 
10.5 
Administration of Study Drug 
Study drug shall be administered in the clinical site on days where subjects will be held for PK 
evaluations.  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: 


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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). 
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). 
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 


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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 
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 the 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 non-serious AEs starts after the first administration of study drug on 
Day 0 and ends at telephone contact on Day 28. 
If an AE remains unresolved at the telephone contact on Day 28, the subject will 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 


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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, 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. 
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 may be 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. 


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CTCAE 
Grade 
Common Term 
Description 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL. 
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 (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. 


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The Investigator also must report all SAEs promptly to the appropriate IRB/EC as required by 
the institution. 
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.com 
Email: 
rhasson@pacificlinkconsulting.com 
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 
Approximately forty-five (45), male and female subjects, 15 subjects age 6 to 11 years and 30 
subjects over 12 years of age, are to be enrolled as part of this study with dosing during the ictal 
or peri-ictal period of a seizure.  Of these, at least 10 adult subjects and 5 pediatric subjects will 
have PK assessments after dosing during the ictal period. 
Individual subject plasma concentrations, actual sampling times, and PK parameters will be 
listed by analyte and treatment.  Descriptive statistics will be calculated by analyte, age group (6 
to 11 years being one group and those over 12 years of age being the other group) and treatment 
for plasma concentrations and PK parameters.  Additional exploratory analyses will be 
conducted to provide descriptive statistics on subjects age 6 to 8 years, 9 to 11 years, 12 to 16 
years and over 16 years of age.  Individual subject and mean plasma concentrations will be 
displayed on linear and semi-logarithmic axes. 


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A separate but identical analysis will be performed on the observed PK parameters depending on 
which age group the subject belongs.  The PK parameters Cmax and AUC(0-6) for diazepam will be 
compared for the first dose of NRL-1 under seizing conditions to the second dose of NRL-1 
under non-seizing conditions using a linear mixed effect model with treatment period if 
appropriate and clinical site as the classification variables using the natural logarithms of the 
data.  Cmax and AUC(0-6) will be normalized to the 10 mg dose prior to analysis.  Confidence 
intervals (CI) (90%) will be constructed for the geometric mean ratio (GMR) of the two 
parameters between the two treatments using the log-transformed data and the two one-sided t-
tests procedure.  The point estimates and confidence limits will be exponentiated back to the 
original scale.  Dose equivalence will be concluded if the 90% CI for the GMRs among the two 
comparisons of the two parameters fall within 80% to 125%. 
For AUC0-6 and Cmax, the geometric mean (inverse log-transformed) and the 90% CI for 
geometric means will be compared to those observed in DIAZ.001.02 and DIAZ.001.03. 
The Cmax and AUC0-6 determined in epilepsy subjects in the ictal and peri-ictal period will be 
compared between the same subject in a normative state.  The Cmax, tmax, and AUC0-6 determined 
in epilepsy subjects will also be compared to those results in healthy, non-seizing, volunteers. 
The Cmax and AUC(0-6) will be visual compared between the two age groups in both seizure/non-
seizure conditions. 
The number of subjects is based on the results of Study DIAZ.001.01 in which the coefficient of 
variation for natural log-transformed Cmax for diazepam (excluding the IV treatment) was 38%.  
Cmax was the parameter with the greatest variability.  Assuming half of this value is a result of the 
intra-subject variability (%CV = 19%), approximately 27 subjects would be required per age 
group.  The sample size assumes 80% power to obtain 90% CI for the GMR within 80% and 
125% with α = 0.05, and a true mean treatment ratio (µT/µr) = 0.95.  Given the nature of this 
study population, up to 45 subjects will be enrolled to obtain at least 30 evaluable subjects who 
complete both PK sampling periods of the study. 
12.2 
Analysis Data Sets 
Subjects who receive at least one dose of NRL-1 will be included in the safety analyses.  Subjects 
who complete the study through the 6 hours PK sampling periods on at least one of the dosing 
days will be included in the primary PK analysis and preliminary efficacy assessment.  For the 
comparative bioavailability assessment, plasma samples from all subjects that complete the two 
periods of the study will be analyzed. 
12.3 
Pharmacokinetic Data Analyses 
The following PK parameters for diazepam will be calculated using non-compartmental analysis:  
Cmax, tmax, and AUC(0-6) with a concentration equal to or greater than the lower limit of 
quantitation. 


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If a second dose of NRL-1 is administered due to a subsequent seizure between 4 and 12 hours 
after the initial dose, when clinically feasible, PK samples should be collected based on the time 
of the second dose at 0 (immediately after the 2nd dose), 30 minutes, and 1, 2, and 4 hours after 
dosing. 
For Treatment 1, the actual time of seizure onset, dose of NRL-1, time of seizure stop, and time 
of each blood sample will be recorded.  PK parameters will be determined using actual times of 
sample collection relative to the administration of NRL-1. 
Individual subject plasma concentrations, actual sampling times, and PK parameters will be 
listed by analyte and treatment.  Any plasma concentration below the limit of quantitation (BLQ) 
will be reported as zero prior to tmax and as “BLQ” after tmax, which essentially treats it as a 
missing value. 
Descriptive statistics will be calculated by analyte and treatment for plasma concentrations and 
PK parameters.  Individual subject and mean plasma concentrations will be displayed on linear 
and semi-logarithmic axes. 
12.4 
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 physical and 
neurological examination including HEENT, vital signs, clinical laboratory tests (serum 
chemistry, hematology, and urinalysis), and C-SSRS assessments (children and adult).   
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. 
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. 
Assessment of Nasal Irritation: 
Objective evaluations of nasal irritation will be assessed after administration of the intranasal 
formulation based on the following assessment scale: 


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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 scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose after 
each administration, and at discharge.  The subjects will also be required to report any incident of 
nasal irritation or mucosal epistaxis in-between evaluation time points and during follow up 
contacts. 
Assessment of Mucosal Erythema: 
Objective evaluations of mucosal erythema will be assessed after administration of the intranasal 
formulation based on the following assessment 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)  
The scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post dose after each administration, and at discharge.   
Assessment of Mucosal Edema: 
Objective evaluations of mucosal edema will be assessed after administration of the intranasal 
formulation 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  
The scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post dose after each administration, and at discharge. 
Assessment of Nasal Discharge: 


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Objective evaluations of nasal discharge will be assessed after administration of the intranasal 
formulation 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  
The scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post dose after each administration, and at discharge. 
Assessment of Mucosal Crusting: 
Objective evaluations of mucosal crusting will be assessed after administration of the intranasal 
formulation 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  
The scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post dose after each administration, and at discharge. 
Assessment of Mucosal Epistaxis: 
Objective evaluations of mucosal epistaxis will be assessed after administration of the intranasal 
formulation 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   
The scoring will be done by a trained observer based on an assessment of the nasal mucosa prior 
to each dose of NRL-1 and at 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post dose after each administration, and at discharge. 
Assessment of Sedation: 
Objective evaluations of sedation will be made using a 6-point (0 → 5) sedation scoring system 
that will be used to assess the degree of drowsiness of the subjects after administration of the 
intranasal formulation.  Sedation scores will be reported by the subject (if awake) as well as by a 


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trained observer, using the same rating scale, prior to each dosing period, at 15 (± 5 min) and 
30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post 
dose after each administration, and at discharge.  Subjects will be also be questioned by the 
trained observer regarding their degree of drowsiness. 
Assessment of Nasal Mucosal Pain: 
An unconstrained VAS that consists of a 10 cm (100 mm) horizontal straight line will be used to 
assess acute pain following administration of study drug.  The ends of the scale are defined as 
extreme limits of pain sensation:  0 = no pain, 10 = extreme pain.  The subjects will be asked to 
mark a point on the scale which best describes their intensity of pain and discomfort prior to each 
dosing period, at 15 (± 5 min) and 30 minutes (± 10 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 
min), and 6 (± 30 min) hours post-dose, and at discharge.  The location of the marking at each 
time point will be measured and noted as the reported score. 
Columbia Suicide Severity Rating Scale: 
The C-SSRS, a measure of suicidal ideation and behavior, will be used to document suicidality.  
Suicidality will be assessed at screening (period 1 only), prior to each dosing, and post-dosing at 
6 hours.  The baseline C-SSRS should be performed within 3 hours prior to dosing of NRL-1.  
The screening and baseline assessments will use the Baseline/Screening Phase 1 version of the 
C-SSRS.  The Since Last Visit version of the C-SSRS will be used for post-dosing assessments. 
Smell Test: 
A test to evaluate changes in smell will be conducted prior to each dosing, and at 1 hour 
(± 15 min), 4 hours (± 30 min) post-dose, and at 24 hours (± 30 min) or discharge.  The NIH 
Toolbox for Odor Identification Test will be used as smell tests (1, 2).  
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 and neurological 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 SOPs 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 verified against corresponding source documentation (e.g., office and clinical 
laboratory records) for each subject on a risk based approach.  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 US 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 Good 
Clinical Practice (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. 
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. 


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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 Procedures (Treatment 1): NRL-1 Dose Treatment (During Clinical Site Visit – Seizing Conditions) 
(Treatment period 1) 
Study Procedure 
Screeninga 
Baselineb 
Post-Dose Procedures 
Study Day 
Day -21 to 
Day -1 
Day -7 to 
Day 0 
0min 
15min 
30min 
45min 
1hr 
1.25hrs 
1.5hrs 
1.75hrs 
2hrs 
3hrs 
4hrs 
5hrs 
6hrs 
8hrs* 
12hrs* 
Dischargec 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to Clinical Site 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history including 
seizure history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Columbia-Suicide 
Severity Rating Scaled 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Physical and Neurological 
exam (including HEENT) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X* 
X* 
X 
Height and Weight 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEG (continuous) g 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
 
Hematology, Serum 
Chemistry and Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ß-hCG 
(Pregnancy)h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody and 
Hepatitis Testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug and Alcohol 
Screenj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medication assessment 
X 
X 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Adverse event assessmentk 
 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
ECG (12-Lead in 
triplicate)l 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRL-1 administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for PKm,n 
 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
 
Nasal Irritationo 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
Nasal Examinationsp 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
Sedation Scoreq 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
Smell Test r 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
VAS for Pains 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
* 
Optional assessment if feasible. 


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a. 
Screening evaluations must be performed within 21 days prior to dosing on Day 0.  Screening evaluations performed within 7 days (Day -7 to Day 0) of dosing do not need to be repeated if subjects are 
maintained in house. Screening procedures are performed only once prior to the first dose of study medication (Treatment 1 or 2). 
b. 
Baseline evaluations will be performed upon admission to the clinical site and within 7 days of dosing if maintained in house.  Time point 0 will be considered the time of dosing NRL-1 and initiation 
of PK blood sampling.  Subjects may be dosed in either Treatment 1 or Treatment 2 first. The second treatment with NRL-1 will be separated by a minimum 14-day wash out period and baseline 
evaluation will be repeated for each treatment period (if subjects are on oral contraceptives (OC) the period between dosing should be extended to approximately 28-days to ensure that the subject is 
dosed at the same approximate time of the OC cycle). 
c. 
Discharge occurs anytime after the PK blood sample is taken at 6 hours post dose (or optional 8 and 12 hours). When discharge occurs after 6 hours post dose, the assessments at discharge that overlap 
with the assessments at 6 hours post dose do not have to be repeated.  In that case, check the check box in the CRF at 6 hours post dose to confirm that the assessments that overlap with the assessments 
at discharge is not going to be repeated.   
d. 
Suicidal events will be assessed using the C-SSRS (adult or children) at screening, baseline, and at 6 hours post dose.  The baseline C-SSRS should be performed within 3 hours prior to dosing of NRL-
1 (see APPENDIX C). 
e. 
Vital signs (temperature, pulse, respiratory rate and blood pressure) are to be obtained at screening, baseline, and at 45 (± 5 min) minutes, 2 (± 15 min), 4 (± 30 min), 6 (± 30 min), 8 (± 30 min), and 12 
(± 30 min) hours post dosing, and at discharge.  Vital signs at 8 and 12 hours are optional.   
f. 
Weight only. 
g. 
Subjects will be monitored for seizure activity with a continuous EEG evaluation. The EEG is considered standard of care when in the EMU setting, but is part of the study procedures if in a CTRC 
setting. The start time, stop time, and type of seizure will be recorded based on the EEG results. The time of NRL-1 dosing will also be recorded as part of the study database.  
h. 
A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at screening.  Urine pregnancy test is only required for female subjects of child bearing potential.  If a serum 
pregnancy test is done on Day -1, urine pregnancy test does not have to be repeated on Day 0 (baseline).  Pregnancy testing does not have to be done on subjects age 6 to 11. 
i. 
Hepatitis B surface antigen (HbSAg), or Hepatitis C 
j. 
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 should be entered in the CRF page for concomitant medication. 
k. 
Adverse event assessment is continuous from time of first dose of NRL-1. 
l. 
ECG is to be performed in triplicate.  Three consecutive ECGs (each approximately 1-2 minutes apart) are performed. 
m. 
Blood samples (3 mL each) are to be obtained before dosing (0, pre-dose) and at 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours.  Blood samples should also be obtained if feasible 
at 8 and 12 hours after dosing.  If a blood sample collection is delayed, then the collection will occur as soon as feasible and should not be skipped even if close to the next blood draw.  Actual blood 
collection times can vary as follows: 1) ± 10 minutes for the 15 to 60 minute samples, 2) ± 15 minutes for the 1.25 to 6 hour samples, and 3) ± 30 minutes for the optional 8 and 12 hour samples. 
n. 
If a second dose of NRL-1 is administered due to a subsequent seizure btween 4 and 12 hours after the initial dose, when clinically feasible, PK samples should be collected based on the time of the 
second dose at 0, 30 minutes, and 1, 2, and 4 hours after dosing.  
o. 
Nasal Irritation assessments are performed prior to dosing (baseline) and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
p. 
Nasal examination and scoring for mucosal erythema, mucosal edema, nasal discharge, mucosal crusting and mucosal epistaxis will be performed prior to dosing (baseline) and at 30 (± 10 min) 
minutes, 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
q. 
Sedation Scores are just prior to dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
r. 
Smell tests and examination of the nasal mucosa will be conducted at baseline, and at 1 hour (± 15 min), 4 hours (± 30 min) post dose, and at discharge.  The NIH Toolbox Odor Identification Test will 
be used as smell tests (1, 2).  
s. 
VAS Scores are just prior to dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, 1(± 10 min), 2 (± 15 min), 4 (± 30 min), 6 (± 30 min) hours post dose, and at discharge. 
 
 


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Appendix A2:  Schedule of Study Procedures (Treatment 2): NRL-1 Dose Treatment (Non-Seizing [Normative] Conditions) 
Study Procedure 
Baselinea 
Post-Dose Procedures 
Follow-up 
Telephone 
Contactm 
Study Day 
Day 14 
0 min 
15min 
30min 
45min 
1hr 
1.25hrs 
1.5hrs 
1.75hrs 
2hrs 
3hrs 
4hrs 
5hrs 
6hrs 
8hrs* 
12hrs* 
Dischargel 
Day 
21 
Day 
28 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to Clinical 
Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Columbia-Suicide 
Severity Rating Scalek 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Physical and 
Neurological exam 
(including HEENT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X* 
X* 
X 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum 
Chemistry and 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug, Alcohol 
and Cotinine Screeno 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medication assessment 
X 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
Adverse event 
assessmentd 
X 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------- 
ECG (12-Lead in 
triplicate)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRL-1 
administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for PKf 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
 
 
 
Nasal Irritationg 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Nasal Examinationsh 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Sedation Score 
Assessmenti 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Smell Test n 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
VAS for Painj 
X 
 
Xk 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
* 
Optional assessment if feasible.  
 


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a. 
Baseline evaluations will be performed within 48 hours prior to dosing NRL-1.  The Day 14 visit may be between 14 and 28 days after the initial dosing of NRL-1. 
b. 
Follow-up phone calls 7 days (± 2 days) and 14 days (± 3 days) after the second dose of NRL-1 dosing to determine if any AE has occurred and to follow-up on any TEAEs ongoing since last 
communication with the subject.  Subjects who prematurely discontinued will be followed up by phone calls approximately 7 days (± 2 days) after the last dose of NRL-1.  
c. 
Discharge occurs anytime after the PK blood sample is taken at 6 hours post dose (or optional 8 and 12 hours). When discharge occurs after 6 hours post dose, the assessments at discharge that overlap 
with the assessments at 6 hours post dose do not have to be repeated.  In that case, check the check box in the CRF at 6 hours post dose to confirm that the assessments that overlap with the assessments 
at discharge is not going to be repeated.   
d. 
Suicidal events will be assessed using the C-SSRS (adult or children) at screening and baseline, and at 6 hours post dose.  The baseline C-SSRS should be performed within 3 hours of administering the 
dose (see APPENDIX C). 
e. 
Vital signs (temperature, pulse, respiratory rate and blood pressure) are to be obtained at baseline and at 45 (± 5 min), 2 (± 15 min), 4 (± 30 min), 6 (± 30 min), 8 (± 30 min), and 12 (± 30 min) hours 
post dosing and at discharge. Vital signs at 8, 12 hours are optional.   
f. 
Pregnancy test is only required for female subjects of child bearing potential.  Pregnancy test does not have to be done on subjects age 6 to 11.  
g. 
When marijuana is used for medical reason 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. 
h. 
Adverse event assessment is continuous. 
i. 
ECG is to be performed in triplicate. Three consecutive ECGs (each approximately 1-2 minutes apart) are performed as part of the screening process. 
j. 
Blood samples are to be obtained before dosing (0, pre-dose) and at 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours.  Blood samples should also be obtained if feasible at 8, 12 
hours.  Actual blood collection times can vary as follows: 1) ± 10 minutes for the 15 to 60 minute samples, 2) ± 15 minutes for the 1.25 to 8 hour samples, 3) and ± 30 minutes for the 8 and12 hour 
sample. 
k. 
Nasal Irritation assessments are performed prior to dosing (baseline) and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
l. 
Nasal examination and scoring for mucosal erythema, mucosal edema, nasal discharge, mucosal crusting and mucosal epistaxis will be performed prior to dosing (baseline) and at 30 (± 10 min) 
minutes, 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
m. 
Sedation Scores are just prior to dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
n. 
Smell tests and examination of the nasal mucosa will be conducted at baseline, and at 1 hour (± 10 min), 4 hours (± 30 min), and at discharge. The NIH Toolbox Odor Identification Test will be used as 
smell tests (1, 2). 
o. 
VAS Scores are just prior to dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
 


 
 
APPENDIX B: 
SEDATION SCORING 
 


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Appendix B:  Sedation Scoring 
A sedation scale will be used to assess the degree of drowsiness of the subjects after 
administration of the intranasal and intravenous diazepam formulations.  
Sedation scores will be reported by the subject (if awake) as well as by a trained observer using 
the same rating scale, just at (baseline) and at 15 and 30 minutes, and 1, 2, 4, and 6 hours post 
dose and at discharge.  
Sedation Scale 
0 - Alert, not drowsy; normal conversation 
1 - Awake, talking; but somewhat drowsy 
2 - Napping or sleeping, but easily awakened 
3 - Sleeping, awakened only with loud voice or shaking 
4 - Sleeping, very difficult to awaken; promptly returns to sleep 
5 - Sleeping, cannot awaken


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


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Appendix C:  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 suicidality.  For adults, screening and baseline assessments will use the 
Baseline/Screening Phase 1 version of the C-SSRS.  The Since Last Visit version of the C-SSRS 
will be used for post-dosing assessments.  For children, screening and baseline assessments will use 
Children’s Baseline/Screening 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 
____ 
 
____ 
 
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) 
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 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. 
Post-
Dose 
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 
 
 
 
 
____ 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Post-
Dose 
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 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 D: 
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 E: 
LIST OF PROHIBITED MEDICATION 
Amiodarone 
Ketoconazole 
Amprenavir 
Lopinavir/Ritonavir 
Aprepitant 
Methoxsalen 
Atazanavir 
Mexiletine 
Boceprevir 
Mibefradil 
Bupropion 
Miconazole 
Cinacalcet 
Moclobemide 
Ciprofloxacin 
Nefazodone 
Clarithromycin 
Nelfinavir 
Conivaptan 
Omeprazole 
Darunavir/Ritonavir 
Oxandrolone 
Diltiazem 
Paroxetine 
Duloxetine 
Phenylpropanolamine 
Enoxacin 
Posaconazole 
Erythromycin 
Quinidine 
Esomeprazole 
Ritonavir 
Fluconazole 
Saquinavir 
Fluoxetine 
Telaprevir 
Fluvoxamine 
Telithromycin 
Fosamprenavir 
Terbinafine 
Gemfibrozil 
Thiabendazole 
Grapefruit Juice 
Ticlopidine 
Imatinib 
Verapamil 
Indinavir 
Voriconazole 
Itraconazole 
Zileuton 
 

SAP_001.pdf: 
Page 1 of 30
NEURELIS, INC.
STATISTICAL ANALYSIS PLAN
Section 14 and 16
Protocol No.: DIAZ.001.04
An Open-Label, Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects 
Under Seizure and Normal Conditions (DIAZ.001.04)
CONFIDENTIAL
Version:  1.0
Date: May 25, 2018


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 2 of 30
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)
(yyyy/mm/dd)
Approved By:
Enrique Carrazana
Signature
Date
(yyyy/mm/dd)
2018/05/25
2018/05/25
2018/05/25
2018/07/03
Jaekwan 
Kim
디지털 서명자Jaekwan Kim 
DN: cn=Jaekwan Kim, o=gsg-us.com, 
ou, email=jaekwan.kim@gsg-us.com, 
c=US 
날짜: 2018.05.25 11:53:42 +09'00'
chaeyong 
chang
Digitally signed by chaeyong chang 
DN: cn=chaeyong chang, o=gsg-
us.com, ou=gsg-us.com, 
email=chaeyong.chang@gsg-us.com, 
c=US 
Date: 2018.07.02 10:12:06 -04'00'
Richard 
Lowenthal
Digitally signed by Richard Lowenthal 
DN: cn=Richard Lowenthal, o=Pacific 
Link Consulting, ou=President, 
email=richard@pacificlinkconsulting.
com, c=US 
Date: 2018.07.02 21:13:56 -07'00'
Enrique 
Carrazana, M.D.
Digitally signed by Enrique 
Carrazana, M.D. 
DN: cn=Enrique Carrazana, M.D., 
o, ou, email=ecarrazana@aol.com, 
c=US 
Date: 2018.07.03 00:18:20 -04'00'


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 3 of 30
TABLE OF CONTENTS
LIST OF ABBREVIATIONS.............................................................................................5 
1. 
INTRODUCTION......................................................................................................6 
2. 
STUDY OBJECTIVES AND ENDPOINTS................................................................6 
2.1. 
Study Objectives...........................................................................................6 
Primary objective ..........................................................................................6 
Secondary objective .....................................................................................6 
2.2. 
Study Endpoints............................................................................................6 
2.2.1. 
Efficacy endpoint(s) .......................................................................6 
2.2.2. 
Safety Endpoint(s) .........................................................................7 
2.2.3. 
Pharmacokinetic Endpoints ...........................................................7 
3. 
STUDY DESIGN ......................................................................................................8 
4. 
PLANNED ANALYSES ..........................................................................................14 
4.1. 
Interim Analysis ..........................................................................................14 
4.2. 
Final Analysis .............................................................................................14 
5. 
SAMPLE SIZE CONSIDERATIONS.......................................................................14 
5.1. 
Sample Size Determination ........................................................................14 
5.2. 
Sample Size Re-estimation.........................................................................14 
6. 
ANALYSIS POPULATIONS ...................................................................................14 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................15 
7.1. 
Multicenter Studies .....................................................................................15 
7.2. 
Other Strata and Covariates .......................................................................15 
7.3. 
Examination of Subgroups..........................................................................15 
7.4. 
Multiple Comparisons and Multiplicity .........................................................15 
8. 
DATA HANDLING CONVENTIONS .......................................................................16 
8.1. 
Premature Withdrawal and Missing Data ....................................................16 
8.2. 
Derived and Transformed Data...................................................................16 
8.3. 
Values of Clinical Concern..........................................................................16 
9. 
STUDY POPULATION...........................................................................................16 
9.1. 
Disposition of Subjects................................................................................16 
9.2. 
Protocol Deviations.....................................................................................16 
9.3. 
Demographic and Baseline Characteristics.................................................17 
10. EFFICACY ANALYSIS ...........................................................................................17 
11. SAFETY ANALYSES .............................................................................................17 
11.1. 
Extent of Exposure .....................................................................................17 
11.2. 
Adverse Events...........................................................................................17 
11.3. 
Deaths and Serious Adverse Events...........................................................18 
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 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 4 of 30
11.6. 
Clinical Laboratory Evaluations...................................................................18 
11.7. 
Other Safety Measures...............................................................................18 
11.7.1. 
Concomitant Medication ..............................................................18 
11.7.2. 
Vital Signs....................................................................................19 
11.7.3. 
Electrocardiograms......................................................................19 
11.7.4. 
Physical examination ...................................................................19 
11.7.5. 
C-SSRS assessments (children and adult) ..................................19 
11.7.6. 
Nasal Irritation, Mucosal Erythema, Mucosal Edema, 
Nasal Discharge, Mucosal Crusting and Mucosal Epistaxis .........19 
11.7.7. 
Visual Analogue Scale.................................................................20 
11.7.8. 
NIH Toolbox Odor Identification Test ...........................................20 
11.7.9. 
Sedation Score Assessment........................................................20 
12. TABLES, LISTINGS ...............................................................................................20 
12.1.1. 
Tables..........................................................................................20 
12.1.2. 
Listings ........................................................................................26 
12.1.3. 
Figures ........................................................................................27 
13. REFERENCES.......................................................................................................29 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 5 of 30
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
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


CONFIDENTIAL Page 6 of 30
Neurelis, Inc. Protocol DIAZ.001.04
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.001.04.
This SAP is based on the final amended protocol version 5 (2-May-2017).
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objectives
Primary objective
The primary objective of this study is to assess the pharmacokinetics (PK) of diazepam 
after single intranasal doses of NRL-1 administered to Epilepsy subjects during the ictal 
or peri-ictal period (defined as either during or immediately following a seizure), where 
the seizure involved motor activity or alteration of awareness. The primary PK variables 
to determine absorption will be the maximum plasma concentration (Cmax) and the area 
under the curve through 6 hours (AUC(0-6)). FDA has requested that analyses be 
presented by Overall and age group of 6-11; 12-16 and 16+ dosing in the Diastat labeling.
Secondary objective
The secondary objectives of this study include:
x
To compare the diazepam Cmax, time to peak concentration (tmax) and AUC(0-6)
after single administration of NRL-1 in Epilepsy subjects during the ictal or peri-
ictal period to that after administration of NRL-1 to the same subjects under 
normal conditions.
x
To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of 
NRL-1 between Epilepsy subjects ages 6 to 11 and those greater than 12 years of 
age.
x
To compare the diazepam Cmax, tmax, and AUC(0-6) after single administration of 
NRL-1 in Epilepsy subjects during the ictal or peri-ictal period and that of healthy 
normal subjects from PK data obtained in the DIAZ.001.02 and DIAZ.001.03 
studies.
x
To assess the safety and tolerability of diazepam after intranasal administration of 
NRL-1
2.2.
Study Endpoints
2.2.1.
Efficacy endpoint(s)
There are no efficacy endpoints for this study.


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 7 of 30
2.2.2.
Safety Endpoint(s)
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; 12-16 and 16+ descriptive statistics will be 
provided for actual values and change from baseline values for physical and neurological
examination including HEENT, vital signs, clinical laboratory tests (serum chemistry, 
hematology, and urinalysis) and C-SSRS assessments (children and adult).
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, mucosal epistaxis, VAS and NIH 
toolbox odor identification test.
For the actual incidence of seizure (it can occur period 1 or period 2), start time, stop time,
NRL-1 dosing time, phase of seizure, type of seizure, time to seizure stop from dose time 
to stop time for those subjects dosed in the Ictal Phase will be provided.    
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.
2.2.3.
Pharmacokinetic Endpoints
The following PK parameters for diazepam will be calculated using non-compartmental 
analysis:  Cmax, tmax, and AUC(0-6).
For the actual time of seizure (it can occur Period 1 or Period 2) onset prior to the first 
dose of NRL-1, and time of the blood sampling will be recorded. PK parameters will be 
determined using actual times of sample collection relative to the administration of NRL-
1.
Individual subject plasma concentrations, actual sampling times, and PK parameters will 
be listed by analyte and treatment.  Any plasma concentration below the limit of 
quantitation (BLQ) will be reported as zero prior to tmax and as “BLQ” after tmax, which 
essentially treats it as a missing value.
Descriptive statistics will be calculated by analyte and treatment for plasma 
concentrations and PK parameters.  Individual subject and mean plasma concentrations 
will be displayed on linear and semi-logarithmic axes.


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 8 of 30
3.
STUDY DESIGN
This is a Phase 1, open-label, PK and safety study in Epilepsy subjects under both ictal or 
peri-ictal (involving motor activity and/or altered awareness) and normal conditions. A 
single 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.
The study consists of a screening period, a baseline period, a post-dose period where 
dosing is done during the ictal or peri-ictal period (Treatment period 1), a baseline period 
and a post-dose period after a second single-dose treatment under normal non-seizing 
conditions approximately 14-days later (Treatment period 2), and follow-up telephone 
contacts 7-days and 14-days after the last dose of NRL-1.  Between doses of NRL-1,
subjects and caregivers should avoid the use of other diazepam containing products. For 
subjects who will roll over to the DIAZ.001.05 long term safety study, the Day 14 
(second dosing for NRL-1) assessments can be used as baseline assessments for 
DIAZ.001.05 to allow subjects to initiate long term treatment under the protocol. 
Baseline in period 1 for this study is considered the period within 7 days of admission.  
The subject will be admitted and observed in the clinical site (i.e. EMU or Clinical 
Research Center) and dosing will occur at the time of a seizure that is considered suitable 
for administration of NRL-1.  Time point 0 will be defined as the time of dosing of NRL-
1 and initiation of PK blood sampling. EEG monitoring was used to determine the 
seizure start, stop time and assessment of seizure type.
The first treatment with NRL-1 will initially be administered under ictal or peri-ictal 
conditions in a clinical setting to subjects having partial or generalized Epilepsy with 
motor seizures or seizures with clear alterations of awareness. Since the primary 
objective is to obtain diazepam plasma concentrations and PK information when the drug 
is given in the ictal or peri-ictal period, dosing of NRL-1 will ideally occur during or 
within 5 minutes after the onset of the seizure.
A 3 mL blood sample for PK will be collected at the baseline and at the post-dose period 
once admitted to the clinical site. During the post-dose period, 3 mL blood samples will 
be collected at predetermined times after NRL-1 dosing to determine the diazepam 
plasma concentration versus time profile. If the baseline pre-dose blood sample is unable 
to be collected, i.e., subject experiences a seizure prior to collection, then the pre-dose 
assessment closest to dosing will be included in the analysis.
In treatment period 1, if the subject experiences a seizure after NRL-1 dosing (during the 
blood sampling period), PK blood draws will be suspended as long as required for the 
subject’s medical care and will resume when clinically feasible. If the subject experiences 
a seizure after NRL-1 dosing and is administered an exclusionary medication (such as IV, 
oral or rectal diazepam), PK blood draws will be stopped, time of dosing diazepam 
recorded, and the Medical Monitor will be notified. All other safety procedures will be 
performed as per the protocol Schedule of Study Procedures.
The second treatment with NRL-1 will occur on a subsequent visit after at least a 14-day 
washout period(if subjects are on oral contraceptives (OC) the period between dosing 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 9 of 30
should be extended to approximately 28-days to ensure that the subject is dosed at the 
same approximate time of the OC cycle).  Subjects will return to the clinical site to 
receive a single dose of NRL-1 when in a normal state.  Please note that it is not 
anticipated that subjects will need to be admitted or held overnight for the second dosing, 
and the site will select an appropriate clinical facility for this portion of the study.  
Subjects should be seizure free for at least 12 hours prior to dosing.  A 3 mL blood 
sample for PK will be collected at the post-dose period in the clinic prior to 
administration of NRL-1.  During the post-dose period, 3 mL blood samples will be 
collected at predetermined times after NRL-1 dosing to determine the diazepam plasma 
concentration versus time profile.
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 children), nasal 
irritation assessment, assessment of mucosal erythema, mucosal edema, nasal discharge,
mucosal crusting and mucosal epistaxis, sedation score assessment, VAS and smell test 
(National Institutes of Health [NIH] Toolbox Odor Identification Test).


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 10 of 30
Appendix Al: Schedule of Study Procedures (Treatment 1): NRL-1 Dose Treatment (Dming Clinical Site Visit - Seizing Conditions) 
(Treatment period 1) 
StuclY Procedw·e 
Screeuinr' Baselineb 
Post-Dose Procedures 
Study Day 
Dn -21 ro 
ri.w-1 
D:n·-iro 
ria,· 0 
Omin 
15min 
30min 
..l.5min 
1hr 
1.25hrs 
1.5hrs 
1.75hrs 
!hrs 
3hrs 
.thrs 
5bJ'S 
6hrs 
Shrs"' 
11hrs* 
Signed informed consent 
X 
Inclusioo/Exclusion 
X 
X 
Criteria 
Admission to Qinical Site 
X 
Medical history including 
X 
X 
seizure historv 
Columbia-Suicide 
X 
X 
X 
Severity Rating Scale• 
Physical and Neurological 
X 
X 
exam (including HEENT) 
Vital siense 
X 
X 
X 
X 
X 
X 
x• 
x• 
Height and Weight 
X 
X' 
EEG (continuous)' 
X 
• 
Hematology, Serum 
X 
X 
Cbemisny and Urinalysis 
SernmB-hCG 
X 
rPre=•ncyl' 
Urine Pregnancy Test' 
X 
HIV Antibody and 
Herntitis Test' 
X 
Urine Drug and Alcohol 
X 
X 
Screeni 
Dist'h:ugf'' 
X 
Prior and Concomitant 
X 
X 
X 
-------------• 
medication assessment 
Adverse event assessment" 
X 
• 
ECG (12-Lead in 
lriolic.1te)1 
X 
X 
NRL-1 administration 
X 
Blood Samole for PK""" 
X 
X' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x• 
x• 
Nasal Irritation° 
X 
X 
X 
X 
X 
Nasal Examinations> 
X 
X 
X 
X 
X 
X 
X 
Sedation Score< 
X 
X 
X 
X 
X 
X 
X 
X 
Smell Testr 
X 
X 
X 
X 
VAS for Pain; 
X 
X 
X 
X 
X 
X 
X 
X 
OptJ.onal assessme,ot if feasible. 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 11 of 30
a. 
Screening evaluations nrust be perfonned within 21 days prior to dosing on Day 0. Screening evaluations perl'onned within 7 days (Day -7 to Day 0) of dosing do not need to be repeated if subjects are 
maintained in house. Sc.reening procedures are performed only once prior to the first dose of study medication (Treatment I or 2). 
b. 
Baseline evaluations will be perfonned upon ad.mission to the clinical site and within 7 days of dosing if maintained in house. Time point O will be considered the time of dosing NRL-1 and initiation 
of PK blood sampling. Subjects may be dosed in either Treatment I or Treatment 2 ftrst. The secoud treatment v..ith NRL-1 will be separated by a minimuru 14-daywash out period and baseline 
evaluation will be repeated for each treatment period (if subjects are ou oral contraceptives (OC) the period between dosing should be extended to approximately 28-da}~ to ensure that the subject is 
dosed at the same approximate time of the OC cycle). 
c. 
Discharge occttrs anytime after the PK blood sample is taken at 6 ho,us post dose (or optional 8 and 12 hoitrs). When discharge occ,us after 6 hoitrs post dose., the assessments at discharge that overlap 
with the assessments at 6 hours post dose do not have to be repeated. In that case., check the check box in the CRF at 6 hours post dose to confirm that the assessments that overlap with the assessments 
at discharge is not going to be repeated. 
d. 
Suic.idal events will be assessed using the C-SSRS (aditlt or children) at screening, baseline, and at 6 hours post dose. The baseline C-SSRS should be perfonned within 3 hours prior to dosing of NRL-
1 (se.e APPENDIX C). 
e. 
Vital signs (temperalltre, pulse, respiratory rate and blood pressure) are to be obtained at screening, baseline, and at 45 (± 5 min) minutes, 2 (± 15 min), 4 (± 30 min), 6 (± 30 min), 8 (± 30 min), and 12 
(± 30 min) hoitrs post dosing, and at discharge. Vital signs at 8 and 12 hours are optional. 
f. 
Weight only. 
g. 
Subjects will be monitored for seizure activity v..ith a c.ontinuous EEG evaluation. The EEG is considered standard of care when in the EMU setting, but is part of the study procedures if in a CTRC 
se,tting. The start time., stop time, and type of seizure will be recorded based on the EEG results. The time ofNRL-1 dosing will also be recorded as part of the sll1dy database. 
h. 
A serum (6-hCG) pregnancy test v..ill be administered to females of childbearing potential at screening. Urine pregnancy test is only required for female subjects of child bearing potential. If a senun 
pregnancy test is done on Day -1, urine pregnancy test does not have to be repeated on Day 0 (baseline). Pregnancy testing does not have to be done on subjects age 6 to 11. 
i. 
Hepatitis B surface antigen (HbSAg), or Hepatitis C 
j. 
When marijuana was used for medical reasons in the opinion of the investigator, it is not c.ouside.red as dmg abuse and the patient can be enrolled eve.n if the marijuana metabolites in the wine revealed 
as positive. In this case, information about marijuana use should be entered in the CRF page for concomitant medication. 
k. 
Adverse event asses-sment is continuous from time of first dose of NRL-1. 
I. 
ECG is to be perfonned in triplicate. Three consecutive ECGs (each approximately 1-2 minutes apart) are perl'ormed. 
m. 
Blood samples (3 mL each) are to be obtained before dosing (0, pre-dose) and at 15, 30, and 45 minutes, and I, 1.25, 1.5, I. 75, 2, 3, 4, 5, and 6 hours. Blood samples should also be obtained if feasible 
at 8 and 12 hours after dosing. If a blood sample collection is delayed, then the c.ollection will occttr as soon as feasible and shoitld not be skipped even if close to the next blood draw. Actual blood 
collection times can vary as follows: I) ± JO minutes for the 15 to 60 minute samples, 2) ± 15 minutes for the 1.25 to 6 hour samples, and 3) ± 30 minutes for the optional 8 and 12 hour samples. 
n. 
If a second dose ofNRL-1 is administered due to a subsequent seizme btween 4 and 12 hours after the initial dose., when clinically feasible, PK samples should be collected based on the time of the 
second dose at 0, 30 minutes, and I, 2, and 4 hours after dosing. 
o. 
Nasal lnitation assessments are perfonned prior to dosing (baseline) and at 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) ho,us post dose, and at discharge. 
p. 
Nasal examination and scoring for mucosa! erythema, mucosa! edema, nasal discharge, mucosa! crusting and mucosa! epistaxis will be perfonned prior to dosing (baseline) and at 30 (± 10 min) 
minutes, I (± JO min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) ho,us post dose, and at discharge. 
q. 
Sedation Scores are just prior to dosing (baseline) and at 15 (± 5 min) and 30 (± ! 0min) minutes,, I(± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge. 
r. 
Smell tests and eumination of the nasal mucosa will be conducted at baseline, and at I hour (± 1.5 min), 4 hours (± 30 min) post dose., and at disc.barge. The NIH Toolbox Odor Identification Test will 
be used as smell tests (I, 2). 
s. 
VAS Scores are just priorto dosing (baseline) and at 15 (± 5 min) and 30 (± JO min) minutes, 1(± 10 min), 2 (± 15 min), 4 (± 30 min), 6 (± 30 min) hours post dose, and at discharge. 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 12 of 30
Appendix A2: Srhednle of Study Prorednres (Treatment 2): NRL-1 Dose T reatment (]\"on-Seizing [riormative) Conditions) 
Follow-up 
Srudy P rocedure 
Baseline• 
Posr-Dose Proceduns 
T elE'phone 
Contact"' 
Study Day 
Da~-U 
0 mill 
15min 
30min 
45mi.n 
1hr 
1.25-llr'i 
l.5brs 
l.i 5hrs 
lh1·s 
3hrs 
4111-..; 
5brs 
6hrs 
Shri."' 
121us:;, 
Discharge! 
Day 
Day 
21 
28 
I.nctusion/E.'>.clusion 
X 
Criteria 
Admission to Clinical 
X 
Unit 
Columbia-Suicide 
X 
X 
Severity Rating: Scale.l 
Physical and 
Neurological exam 
X 
(induding HEEN1) 
Vital si~:l 
X 
X 
X 
X 
X 
x• 
x• 
X 
Weight 
X 
Hematology, Serum 
Chemistry and 
X 
Urinal~i-:: 
Urine Pre~cv T es.1" 
X 
Urine Drug, Alcohol 
X 
and Cotin.ine Screen'" 
Prior and Concomitant 
X 
X 
• 
medication assessment 
Adverse e.vent 
X 
X 
• 
asse.ssmenf 
ECG (12-Lead in 
X 
triplicate)' 
:S-RL-1 
X 
administration 
Blood $l'lmnle for PK! 
X 
X' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x• 
x• 
Nasal Irritation! 
X 
X 
X 
X 
X 
Nasal E.xaminationsb 
X 
X 
X 
X 
X 
X 
X 
Sedation Sc.ore 
X 
X 
X 
X 
X 
X 
X 
X 
As.sessment1 
Smell Testa. 
X 
X 
X 
X 
VAS for Pain' 
X 
x' 
X 
X 
X 
X 
X 
X 
Opnonal assessment if feasible. 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 13 of 30
a. 
Baseline evaluations will be performed within 48 hours prior to dosing NRL-1. The Day 14 visit may be between 14 and 2S days after the initial dosing ofNRL-1. 
b. 
Follow-up phone c.a11s 7 days (± 2 days) and 14 days(± 3 days) after the second dose. ofl\l'Rl-1 dosing to determine if any A.E has occurred and to foUow-up on any TEAEs ongoing since last 
comm1lllication 1,1,-itb lhe subject. Subjects who prematurely discontinued will be followed up by phone c.alls approximately 7 days (± 2 days) after the last dose ofNRL-1. 
c. 
Disc.barge occurs anytime after the PK blood sample is taken at 6 hours pos1 dose (or optional 8 and 12 hours). When discharge occurs after 6 ho11r.s post dose .• the assessments a1 discharge that overlap 
1,1,-ith the assessments at 6 hoUJ"S post dose do not have to be re.peated. Io that case., check the check box in the CRF at 6 hours post dose to confirm that the assessments that overlap with the assessments 
at discharge is not going to be repeated 
d. 
Suicidal events will be assessed using the C-SSRS (adult or children) at screening and baseline. and at 6 hours post dose. The baseline C-SSRS should be performed within 3 hours of administering the 
dose (see APPENDIX C). 
e. 
Vital signs (temperature, pulse, respiratory rate and blood pressure) are to be obtained at baseline and at 45 ("' 5 min), 2 ("' 15 min), 4 ("' 30 min), 6 (± 30 min), S ("' JO min), and 12 ("' 30 min) hours 
post dosing and at discharge. Vital signs at 8, 12 hours are optional. 
f. 
Pre.gnancy test is only required for female subjects of child bearing potential. Pregnancy test does not ha\·e to be done on subjec.ts age 6 to 11. 
g. 
When marijuana is used for medical reason in the opinion of the investigator, it is not considered as drug abuse and the patiem can be enroUed even if the marijuana metabolites in the mine revealed as 
positive. Io this case, infoIDJation about marijuana use should be entered in the CRF page for concomitant medication. 
h. 
Adverse e\•ent assessment is continuous. 
i. 
ECG is to be performed in triplicate. Three consecutive ECGs (each apprnximately 1-2 minutes apart) are performed as part of the screening process. 
j. 
Blood samples are to be obtained before dosing (0, pre-dose) and at 15, 30, and 45 minutes, and 1, 125, 1.5, 1.75, 2, 3, 4, 5, and 6 hours. Blood samples should also be obtained if feasible.at 8, 12 
hours. Actual blood collection ti.mes can vary as follows: 1) ± 10 minutes for the 15 to 60 minute samples, 2) ± l 5 minutes for the 1.25 to 8 hour samples, 3) and ± 30 minutes for the 8 andl2 hour 
sample. 
k. 
Nasal Irritation assessments are performed prior to dosing (baseline) and at 2 (± 15 min). 4 (± 30 min), and 6 (± 30 min) hoUIS post dose. and at discharge. 
I. 
Nasal e."tamination and scoring for mucosa) eryihema. mucosa! edema, nasal disc-.harge, mucosa! c.msting and mucosa! epistaxis will be pelformed prior to dosing (baseline) and at 30 (::: 10 min) 
minutes, I (± 10 min), 2 (± 15 min), 4 (± 30 min), aud 6 ("' 30 min) hoUIS post dose, and at discharge. 
m. 
Sedation Scores are just priorto dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, and I (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours post dose, and at discharge .. 
n. 
Sm.ell tests and examination of the nasal mucosa will be conducted at baseline~ and at 1 hour(± 10 min), 4 hours (± 30 min), and at discharge. The NIH Toolbox Odor Identification Test will be used as 
smell tests (l, 2). 
o. 
VAS Scores are justpriorto dosing (baseline) and at 15 (± 5 min) and 30 (± 10 min) minutes, and I ("' 10 min), 2 (± 15 min), 4 (± 30 min), and 6 ("' 30 min) hours post dose, and at discharge. 


Neurelis, Inc. Protocol DIAZ.001.04
CONFIDENTIAL Page 14 of 30
4.
PLANNED ANALYSES
4.1.
Interim Analysis
Total of two interim analysis will be performed.  First Interim analysis will be performed 
using soft lock data (cutoff date : April 30, 2018 ) for regulatory approval. Second interim
analysis will be performed after NDA submission for the 120 day safety update.
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
Approximately forty-five (45), male and female subjects, 15 age 6 to 11 years and 30 
over 12 years of age, are to be dosed as part of this study with dosing during the ictal or 
peri-ictal period of a seizure.  Of these at least 10 adult subjects and 5 pediatric subjects 
will have PK assessments after dosing during the ictal period.
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 receive at least one dose of NRL-1will be included in the safety analyses.
PK Analysis Population
Subjects who complete the study through the 6 hours PK sampling periods on at least one 
of the dosing days will be included in the primary PK analysis and preliminary efficacy 
assessment.  For the comparative bioavailability assessment, plasma samples from all 
subjects that complete the two periods of the study will be analyzed.


Neurelis, Inc. Protocol DIAZ.001.04
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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; 12-16 and 16+).
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; 12-16 and 16+ will be provided.
7.4.
Multiple Comparisons and Multiplicity
No adjustments for multiple comparisons are planned.


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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
QTc intervals will be calculated by Fridericia’s (QTcF) formulas. 
Fridericia’s formula is:
QTcF interval (msec) = QT interval (msec)/ (RR interval (sec))1/3
where RR interval (sec) = 1/(heart rate (bpm)/60)
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.
9.
STUDY POPULATION
Subjects with a clinical diagnosis of epilepsy 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. Subjects who have not been dosed due to 
lack of Seizure, will be summarized in the disposition table.  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.


Neurelis, Inc. Protocol DIAZ.001.04
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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.
Subject demographics will be summarized by treatment group.  Age, weight and height at 
screening will be summarized by descriptive statistics (n, mean, standard deviation, 
median, minimum and maximum).  Gender and race will be summarized by number and 
percentage in each category.  
Baseline characteristics such as laboratory evaluations, vital signs, ECGs at screening 
will be summarized by descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum).  Medical history (number and percentage of subjects with any 
condition and each condition) will be summarized by treatment group. Seizure types 
(number and percent of subjects) will be summarized by treatment group.
No statistical tests will be performed on the demographic and baseline characteristics.
10.
EFFICACY ANALYSIS
No efficacy measures will be assessed during this study.
Time to seizure stop from dose time (n, mean, standard deviation, median, minimum and 
maximum) will be summarized by treatment.   No formal statistical comparisons will be 
conducted.
11.
SAFETY ANALYSES
Safety assessments include adverse events, vital signs, 12-lead electrocardiograms and
clinical laboratory evaluations (hematology, serum chemistry, urinalysis, and serology). 
In addition, Columbia Suicide Severity Rating Scale (C-SSRS), Nasal Irritation
Assessment, Sedation Score Assessment, VAS and Smell Test and examination of nasal 
mucosa will be conducted.
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. 
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 


Neurelis, Inc. Protocol DIAZ.001.04
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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.
11.3.
Deaths and Serious Adverse Events
Any deaths and other serious adverse events will be summarized and listed as appropriate 
to the data.
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.


Neurelis, Inc. Protocol DIAZ.001.04
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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.
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.
11.7.6.
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.
Assessment will be dichomized for each assements (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 


Neurelis, Inc. Protocol DIAZ.001.04
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epistaxis) mean and standard deviation by visit will be provided.  Same tables and figures 
by age group of 6-11; 12-16 and 16+ will be provided.
11.7.7.
Visual Analogue Scale
Visual Analogue Scale will be listed for each subject. Summary statistics (n(Number of 
subjects), mean, standard deviation, minimum, median, and maximum)for Visual 
Analogue Scale 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; 12-16 and 16+ 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; 12-16 and 16+ 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. Assessment will be 
dichomized. One category will be Score 0 and other category will be combination of any 
Non Score 0 assessments.  A shift summary of change from screening to time-point (visit)
will be produced. A figure showing mean and standard deviation by visit will be provided.
Same tables and figures by age group of 6-11; 12-16 and 16+ will be provided.
12.
TABLES, LISTINGS & FIGURES
12.1.1.
Tables
Table No
Title
Table 14.1.1
Subject Disposition-Safety Population
Table 14.1.2.1
Analysis Populations-Safety Population
Table 14.1.2.2.1
Demographics (6-11 years old subject)-Safety Population
Table 14.1.2.2.2
Demographics (12-16 years old subject)-Safety Population
Table 14.1.2.2.3
Demographics (> 16 years old subject)-Safety Population
Table 14.1.2.2.4
Demographics (All subject)-Safety Population
Table 14.1.2.3.1
Seizure Duration by Age group-Safety Population
Table 14.1.2.3.2
Seizure-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


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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 14.2.2.1
Nasal Irritation Assessments by Treatment and Visit (6-11
years old subject)-Safety Population
Table 14.2.2.2
Nasal Irritation Assessments by Treatment and Visit (12-16
years old subject)-Safety Population
Table 14.2.2.3
Nasal Irritation Assessments by Treatment and Visit (> 16 
years old subject)-Safety Population
Table 14.2.2.4
Nasal Irritation Assessments by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.2.5
Nasal Irritation Assessments - Shift Tables by Treatment and 
Visit (6-11 years old subject)-Safety Population
Table 14.2.2.6
Nasal Irritation Assessments - Shift Tables by Treatment and 
Visit (12-16 years old subject)-Safety Population
Table 14.2.2.7
Nasal Irritation Assessments - Shift Tables by Treatment and 
Visit (> 16 years old subject)-Safety Population
Table 14.2.2.8
Nasal Irritation Assessments - Shift Tables by Treatment and 
Visit (All subject)-Safety Population
Table 14.2.3.1
Visual Analogue Scale by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.3.2
Visual Analogue Scale by Treatment and Visit (12-16 years 
old subject)-Safety Population
Table 14.2.3.3
Visual Analogue Scale by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.3.4
Visual Analogue Scale by Treatment and Visit (All subject)-
Safety Population
Table 14.2.4.1
Mucosal Erythema by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.4.2
Mucosal Erythema by Treatment and Visit (12-16 years old 
subject)-Safety Population
Table 14.2.4.3
Mucosal Erythema by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.4.4
Mucosal Erythema by Treatment and Visit (All subject)-
Safety Population
Table 14.2.4.5
Mucosal Erythema - Shift Tables by Treatment and Visit (6-
11 years old subject)-Safety Population
Table 14.2.4.6
Mucosal Erythema - Shift Tables by Treatment and Visit (12-
16 years old subject)-Safety Population
Table 14.2.4.7
Mucosal Erythema - Shift Tables by Treatment and Visit (> 
16 years old subject)-Safety Population
Table 14.2.4.8
Mucosal Erythema - Shift Tables by Treatment and Visit (All 
subject)-Safety Population


Neurelis, Inc. Protocol DIAZ.001.04
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Table 14.2.5.1
Mucosal Edema by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.5.2
Mucosal Edema by Treatment and Visit (12-16 years old 
subject)-Safety Population
Table 14.2.5.3
Mucosal Edema by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.5.4
Mucosal Edema by Treatment and Visit (All subject)-Safety 
Population
Table 14.2.5.5
Mucosal Edema - Shift Tables by Treatment and Visit (6-11
years old subject)-Safety Population
Table 14.2.5.6
Mucosal Edema - Shift Tables by Treatment and Visit (12-16
years old subject)-Safety Population
Table 14.2.5.7
Mucosal Edema - Shift Tables by Treatment and Visit (> 16 
years old subject)-Safety Population
Table 14.2.5.8
Mucosal Edema - Shift Tables by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.6.1
Nasal Discharge by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.6.2
Nasal Discharge by Treatment and Visit (12-16 years old 
subject)-Safety Population
Table 14.2.6.3
Nasal Discharge by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.6.4
Nasal Discharge by Treatment and Visit (All subject)-Safety 
Population
Table 14.2.6.5
Nasal Discharge - Shift Tables by Treatment and Visit (6-11
years old subject)-Safety Population
Table 14.2.6.6
Nasal Discharge - Shift Tables by Treatment and Visit (12-16
years old subject)-Safety Population
Table 14.2.6.7
Nasal Discharge - Shift Tables by Treatment and Visit (> 16 
years old subject)-Safety Population
Table 14.2.6.8
Nasal Discharge - Shift Tables by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.7.1
Mucosal Crusting by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.7.2
Mucosal Crusting by Treatment and Visit (12-16 years old 
subject)-Safety Population
Table 14.2.7.3
Mucosal Crusting by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.7.4
Mucosal Crusting by Treatment and Visit (All subject)-Safety 
Population
Table 14.2.7.5
Mucosal Crusting - Shift Tables by Treatment and Visit (6-11
years old subject)-Safety Population
Table 14.2.7.6
Mucosal Crusting - Shift Tables by Treatment and Visit (12-
16 years old subject)-Safety Population
Table 14.2.7.7
Mucosal Crusting - Shift Tables by Treatment and Visit (> 16 
years old subject)-Safety Population


Neurelis, Inc. Protocol DIAZ.001.04
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Table 14.2.7.8
Mucosal Crusting - Shift Tables by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.8.1
Mucosal  Epistaxis by Treatment and Visit (6-11 years old 
subject)-Safety Population
Table 14.2.8.2
Mucosal  Epistaxis by Treatment and Visit (12-16 years old 
subject)-Safety Population
Table 14.2.8.3
Mucosal  Epistaxis by Treatment and Visit (> 16 years old 
subject)-Safety Population
Table 14.2.8.4
Mucosal  Epistaxis by Treatment and Visit (All subject)-
Safety Population
Table 14.2.8.5
Mucosal  Epistaxis - Shift Tables by Treatment and Visit (6-
11 years old subject)-Safety Population
Table 14.2.8.6
Mucosal  Epistaxis - Shift Tables by Treatment and Visit (12-
16 years old subject)-Safety Population
Table 14.2.8.7
Mucosal  Epistaxis - Shift Tables by Treatment and Visit (> 
16 years old subject)-Safety Population
Table 14.2.8.8
Mucosal  Epistaxis - Shift Tables by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.9.1
NIH TOOLBOX ODOR IDENTIFICATION TEST  by 
Treatment and Visit (6-11 years old subject)-Safety 
Population
Table 14.2.9.2
NIH TOOLBOX ODOR IDENTIFICATION TEST by 
Treatment and Visit (12-16 years old subject)-Safety 
Population
Table 14.2.9.3
NIH TOOLBOX ODOR IDENTIFICATION TEST by 
Treatment and Visit (> 16 years old subject)-Safety 
Population
Table 14.2.9.4
NIH TOOLBOX ODOR IDENTIFICATION TEST by 
Treatment and Visit (All subject)-Safety Population
Table 14.2.10.1
Sedation Score Assessment  by Treatment and Visit (6-11
years old subject)-Safety Population
Table 14.2.10.2
Sedation Score Assessment by Treatment and Visit (12-16
years old subject)-Safety Population
Table 14.2.10.3
Sedation Score Assessment by Treatment and Visit (> 16 
years old subject)-Safety Population
Table 14.2.10.4
Sedation Score Assessment by Treatment and Visit (All 
subject)-Safety Population
Table 14.2.10.5
Sedation Score Assessment - Shift Tables by Treatment and 
Visit (6-11 years old subject)-Safety Population
Table 14.2.10.6
Sedation Score Assessment - Shift Tables by Treatment and 
Visit (12-16 years old subject)-Safety Population
Table 14.2.10.7
Sedation Score Assessment - Shift Tables by Treatment and 
Visit (> 16 years old subject)-Safety Population
Table 14.2.10.8
Sedation Score Assessment - Shift Tables by Treatment and 
Visit (All subject)-Safety Population
Table 14.3.1.1
Summary of Treatment-Emergent Adverse Events by 
Treatment -Safety Population


Neurelis, Inc. Protocol DIAZ.001.04
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Table 14.3.1.2
Incidence of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term and 
Treatment -Safety Population
Table 14.3.1.3
Treatment-Emergent Treatment-Related Adverse Events by 
MedDRA System Organ Class, Preferred Term and 
Treatment-Safety Population
Table 14.3.1.4
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class, Preferred Term, Strongest Relationship to Study 
Drug and Treatment -Safety Population
Table 14.3.1.5
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class, Preferred Term, Maximum Severity and 
Treatment -Safety Population
Table 14.3.1.6
Treatment-Emergent Treatment-Related Serious Adverse 
Events by MedDRA System Organ Class, Preferred Term and 
Treatment -Safety Population
Table 14.3.1.7
Treatment-Emergent Serious Adverse Events by MedDRA 
System Organ Class, Preferred Term, Strongest Relationship 
to Study Drug and Treatment
-Safety Population
Table 14.3.1.8
Treatment-Emergent Serious Adverse Events by MedDRA 
System Organ Class, Preferred Term, Maximum Severity and 
Treatment -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 14.3.2.1
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 -16 years 
old subject) -Safety Population
Table 14.3.5.1.1.3
Laboratory: Hematology by Treatment and Visit (> 16 years 
old subject) -Safety Population
Table 14.3.5.1.1.4
Laboratory: Hematology 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 -16 years 
old subject) -Safety Population


Neurelis, Inc. Protocol DIAZ.001.04
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Table 14.3.5.2.1.3
Laboratory: Chemistry by Treatment and Visit (> 16 years old 
subject)  -Safety Population
Table 14.3.5.2.1.4
Laboratory: Chemistry 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 -16 years 
old subject) -Safety Population
Table 14.3.5.3.1.3
Laboratory: Urinalysis by Treatment and Visit (> 16 years old 
subject) -Safety Population
Table 14.3.5.3.1.4
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 -16 years old subject) -Safety Population
Table 14.3.5.3.2.3
Laboratory: Urinalysis (Categorical result) by Treatment and 
Visit (> 16 years old subject) -Safety Population
Table 14.3.5.3.2.4
Laboratory: Urinalysis (Categorical result) 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 -16 years old 
subject) -Safety Population
Table 14.3.6.1.3
ECG Parameters by Treatment and Visit (> 16 years old 
subject) -Safety Population
Table 14.3.6.1.4
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 -16 years old 
subject) -Safety Population
Table 14.3.6.2.3
ECG Interpretation by Treatment and Visit (> 16 years old 
subject) -Safety Population
Table 14.3.6.2.4
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 -16 years old subject) 
-Safety Population
Table 14.3.7.3
Vital Signs by Treatment and Visit (> 16 years old subject) -
Safety Population
Table 14.3.7.4
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


Neurelis, Inc. Protocol DIAZ.001.04
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Table 14.3.8.1.2
Physical Examination by Treatment and Visit (12 -16 years 
old subject) -Safety Population
Table 14.3.8.1.3
Physical Examination by Treatment and Visit (> 16 years old 
subject) -Safety Population
Table 14.3.8.1.4
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 -16 years old subject) -Safety Population
Table 14.3.8.2.3
Physical Examination - Shift Tables by Treatment and Visit 
(> 16 years old subject) -Safety Population
Table 14.3.8.2.4
Physical Examination - Shift Tables by Treatment and Visit 
(All subject) -Safety Population
12.1.2.
Listings
Listings 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 PK 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


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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
Study Drug Administration - Safety Population
Listing 16.2.9.6
Visual Analogue Scale - Safety Population
Listing 16.2.9.7
Nasal Irritation Assessments - Safety Population
Listing 16.2.9.8.1
Columbia-suicidality severity-Baseline /Screening Version -
Safety Population
Listing 16.2.9.8.2
Columbia-suicidality severity-Since Last Visit - Safety 
Population
Listing 16.2.9.8.3
Columbia-suicidality severity-Children's Baseline/Screening -
Safety Population
Listing 16.2.9.8.4
Columbia-suicidality severity-Children's Since Last Visit -
Safety Population
Listing 16.2.9.9
NIH Toolbox Odor Identification Test - Safety Population
Listing 16.2.9.10
Sedation Score Assessment - Safety Population
Listing 16.2.9.11
Mucosal Erythema - Safety Population
Listing 16.2.9.12
Mucosal Edema - Safety Population
Listing 16.2.9.13
Nasal Discharge  - Safety Population
Listing 16.2.9.14
Mucosal Crusting  - Safety Population
Listing 16.2.9.15
Mucosal  Epistaxis - Safety Population
Listing 16.2.9.16
Seizure - Safety Population
Listing 16.2.9.17
Eligibility - Safety Population
Listing 16.2.9.18
Admission to Clinical Site - Safety Population
Listing 16.2.10.1
Comments - Safety Population
12.1.3.
Figures
Figures
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 -16 years old subject) - Safety 
Population
Figure 14.2.1.3
Nasal Irritation Assessments Mean and Standard Deviation 
by Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.1.4
Nasal Irritation Assessments Mean and Standard Deviation 
by Treatment and Visit - Safety Population
Figure 14.2.2.1
Visual Analogue Scale Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) - Safety 
Population
Figure 14.2.2.2
Visual Analogue Scale Mean and Standard Deviation by 
Treatment and Visit (12 -16 years old subject) - Safety 
Population


Neurelis, Inc. Protocol DIAZ.001.04
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Figure 14.2.2.3
Visual Analogue Scale Mean and Standard Deviation by 
Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.2.4
Visual Analogue Scale Mean and Standard Deviation by 
Treatment and Visit - Safety Population
Figure 14.2.3.1
Mucosal Erythema Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) - Safety 
Population
Figure 14.2.3.2
Mucosal Erythema Mean and Standard Deviation by 
Treatment and Visit (12 -16 years old subject) - Safety 
Population
Figure 14.2.3.3
Mucosal Erythema Mean and Standard Deviation by 
Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.3.4
Mucosal Erythema Mean and Standard Deviation by 
Treatment and Visit - Safety Population
Figure 14.2.4.1
Mucosal Edema Mean and Standard Deviation by Treatment 
and Visit (6-11 years old subject) - Safety Population
Figure 14.2.4.2
Mucosal Edema Mean and Standard Deviation by Treatment 
and Visit (12 -16 years old subject) - Safety Population
Figure 14.2.4.3
Mucosal Edema Mean and Standard Deviation by Treatment 
and Visit (> 16 years old subject) - Safety Population
Figure 14.2.4.4
Mucosal Edema Mean and Standard Deviation by Treatment 
and Visit - Safety Population
Figure 14.2.5.1
Nasal Discharge Mean and Standard Deviation by Treatment 
and Visit (6-11 years old subject) - Safety Population
Figure 14.2.5.2
Nasal Discharge Mean and Standard Deviation by Treatment 
and Visit (12 -16 years old subject) - Safety Population
Figure 14.2.5.3
Nasal Discharge Mean and Standard Deviation by Treatment 
and Visit (> 16 years old subject) - Safety Population
Figure 14.2.5.4
Nasal Discharge Mean and Standard Deviation by Treatment 
and Visit - Safety Population
Figure 14.2.6.1
Mucosal Crusting Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) - Safety 
Population
Figure 14.2.6.2
Mucosal Crusting Mean and Standard Deviation by 
Treatment and Visit (12 -16 years old subject) - Safety 
Population
Figure 14.2.6.3
Mucosal Crusting Mean and Standard Deviation by 
Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.6.4
Mucosal Crusting Mean and Standard Deviation by 
Treatment and Visit - Safety Population
Figure 14.2.7.1
Mucosal Epistaxis Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) - Safety 
Population


Neurelis, Inc. Protocol DIAZ.001.04
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Figure 14.2.7.2
Mucosal Epistaxis Mean and Standard Deviation by 
Treatment and Visit (12 -16 years old subject) - Safety 
Population
Figure 14.2.7.3
Mucosal Epistaxis Mean and Standard Deviation by 
Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.7.4
Mucosal Epistaxis Mean and Standard Deviation by 
Treatment and Visit - Safety Population
Figure 14.2.8.1
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean 
and Standard Deviation by Treatment and Visit (6-11 years 
old subject) - Safety Population
Figure 14.2.8.2
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean 
and Standard Deviation by Treatment and Visit (12 -16 years 
old subject) - Safety Population
Figure 14.2.8.3
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean 
and Standard Deviation by Treatment and Visit (> 16 years 
old subject) - Safety Population
Figure 14.2.8.4
NIH TOOLBOX ODOR IDENTIFICATION TEST Mean 
and Standard Deviation by Treatment and Visit  - Safety 
Population
Figure 14.2.9.1
Sedation Score Assessment Mean and Standard Deviation by 
Treatment and Visit (6-11 years old subject) - Safety 
Population
Figure 14.2.9.2
Sedation Score Assessment Mean and Standard Deviation by 
Treatment and Visit (12 -16 years old subject) - Safety 
Population
Figure 14.2.9.3
Sedation Score Assessment Mean and Standard Deviation by 
Treatment and Visit (> 16 years old subject) - Safety 
Population
Figure 14.2.9.4
Sedation Score Assessment Mean and Standard Deviation by 
Treatment and Visit  - Safety Population
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
and Research (CDER). Center for Biologics Evaluation and Research (CBER).
Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance. ICH,
1996, Rockville, Maryland.


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