Conditions: Epilepsy
Keywords: interictal state ictal/peri-ictal state
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: no

Brief summary:
Open-label study to assess the pharmacokinetics of a single diazepam buccal film (DBF) dose in 3 age cohorts of pediatric patients with epilepsy (age 2-5 years, age 6-11 years, and age 12-16 years). Subjects in the 6-11 years and 12-16 years age cohorts received a single DBF dose during the interictal period (Period A) and ictal/peri-ictal period (Period B) with at least 14 days washout between doses. Subjects in the age 2-5 years age cohort received a single DBF dose only during the ictal/peri-ictal period (Period B).

Detailed description:
This was a Phase 2 multicenter, open-label, two-way study conducted in male and female pediatric subjects (aged 2 to 16 years) with a clinical diagnosis of epilepsy who were scheduled to be admitted to an Epilepsy Monitoring Unit (EMU), a general clinical research center (GCRC), or similar facility for evaluation of seizures and who complied with all remaining protocol eligibility criteria. To ensure that 16 to 18 subjects would complete the study across 3 age ranges (2 to 5 years, 6 to 11 years, and 12 to 16 years), a minimum of 24 subjects were to be enrolled (8 in each age cohort).

Subjects in the 6 to 11 years and 12 to 16 years age cohorts received a single dose of DBF during the interictal period (Period A) and ictal/peri-ictal period (Period B) with at least 14 days washout between doses. Subjects in the age 2 to 5 years age cohort received a single dose of DBF only during the ictal/peri-ictal period (Period B). DBF was provided in a range of doses from 5 to 17.5 mg. The appropriate dose of DBF was assigned on the basis of age and weight using an interactive web response system during check-in.

Period A (interictal administration): Subjects were considered to be in an interictal state if an interval of at least 3 hours had elapsed since any clinically observable postictal signs or symptoms (from the last observed seizure) and the subject had been seizure-free over this period. Subjects on electroencephalogram (EEG) monitoring were to be considered to be in an interictal state if an interval of at least 3 hours had elapsed since there were any postictal electrical findings on EEG.

Period B (ictal/peri-ictal administration): For the purpose of this study, the ictal state was defined as an ongoing clinically observable seizure or seizure activity as verified via EEG. The peri-ictal state was defined clinically as the subject's immediate postictal state following a generalized tonic-clonic (GTC) seizure or focal seizure with impaired awareness, and within 5 minutes following the last clonic jerk. For subjects on EEG monitoring, the peri-ictal state was to be defined as less than 5 minutes after cessation of seizure activity as verified via EEG.

.

Arms:
arm 1: Each subject received a single dose of DBF based on the subject's age and weight. arm 2: Each subject received a single dose of DBF based on the subject's age and weight.

Interventions: intervention 1: Diazepam Buccal Film
Intervention descriptions: intervention 1: Subjects received a single DBF dose determined by age and body weight during the interictal state and during the ictal/peri-ictal period with at least 14 days washout between doses.

Protocol document:
Prot_000.pdf: 
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Aquestive Therapeutics 
Pediatric EMU Protocol 
Amendment 4, March 6, 2020  
 
 
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Page 1 
 
 
 
A Multicenter, Open Label Crossover Study to Assess the Pharmacokinetics and 
Safety of Diazepam Buccal Soluble Film (DBF) in Pediatric Subjects with Epilepsy  
 
 
 
Protocol Number: 160325 (Crossover) 
 
Amendment 4 
 
Protocol Amendment 4 Date: March 6, 2020 
Protocol Amendment 3 Date: September 6, 2018 
Protocol Amendment 2 Date: April 16, 2018 
Protocol Amendment 1 Date: August 4, 2017 
Original Protocol Date: April 16, 2018 
Sponsor:  
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA 
 
Phase 2 
 
IND Number: 129068 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Aquestive Therapeutics except to the extent that disclosure would be 
required by law and for the purpose of evaluating and/or conducting a clinical study for 
Aquestive Therapeutics. You are allowed to disclose the contents of this document only to 
your Institutional Review Board (IRB) and study personnel directly involved with 
conducting this protocol. Persons to whom the information is disclosed must be informed 
that the information is confidential and proprietary to Aquestive Therapeutics and that it 
may not be further disclosed to third parties. 
 


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PROTOCOL AMENDMENT: SUMMARY OF CHANGES 
Previous Protocol Versions 
Protocol 
Date 
Original 
June 5, 2017 
Amendment 1 
August 4, 2017 
Amendment 2 
April 16, 2018 
Amendment 3 
September 6, 2018 
Protocol 160325 Amendment 4 
Date of Amendment: March 6, 2020 
Amendment Summary 
This summary provides the changes made to Protocol 160325 Amendment 3 (September 
6, 2018) as Amendment 4. 
The Protocol 160325 Amendment 3 is being amended to: 1) update Diazepam Buccal 
Soluble Film to Diazepam Buccal Film for consistency with current nomenclature; 
2) include the end-date for study enrollment; 3) amend inclusion criterion #3 statement of 
weight range for study enrollment 
Following is a summary of content-oriented changes made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Throughout  
Diazepam Buccal Soluble Film has 
been changed to Diazepam Buccal Film  
The generic name of the 
Investigative Product has been 
updated for consistency with 
current nomenclature. 
Section 3 Synopsis 
New section added: Enrollment End-
Date : Enrollment end date is 05 March 
2020.  
Enrollment end-date is 05 March 
2020. 
Section 8.1.3 Treatment 
Periods 
Bulleted text added in the section 
Check-in Procedures: Enrollment end 
date is 05 March 2020.  
 


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Section 
Revision 
Rationale 
Table 8 Schedule of Events 
Footnotes added to the Schedule of 
Assessments: Check-in 
† Enrollment end date is 05 March 
2020.  
Enrollment end-date is 05 March 
2020. 
Continued→ 
Section 9 Subject Selection  
Sentence added: Enrollment end date is 
05 March 2020.  
 
Section 3 Synopsis 
Experimental Design and Study 
Population Note added to the 
description of the study population: 
Subjects will be 2 to 16 years of age, 
inclusive, with a body weight of ≥6 kg 
and ≤111 kg. NOTE: Subjects with 
body weight in the range 112 to 134 kg 
(247 to 295 pounds) may participate in 
the study at the discretion of the 
Investigator. 
Subjects with body  weight in the 
range of 112 to 134 kg are allowed 
to participate in the study at the 
discretion of the Investigator. 
Table 3 Rationale for 
Dosage of Diazepam Buccal 
Film in Section 6.5 
Rationale for the Dose 
Regimen of Diazepam 
Buccal Film 
Note added to the table:  
a Subjects with body weight in the 
range 112 to 134 kg (247 to 295 
pounds) may participate in the study at 
the discretion of the Investigator. 
 
Table 9 Calculated 
Prescribed Dose of 
Diazepam Buccal Film 
Note added to the table:  
a 
Subjects with body weight in the 
range 112 to 134 kg (247 to 295 
pounds) may participate in the study at 
the discretion of the Investigator. 
 
Section 9.2.1 Inclusion 
Criteria 
Note added to criterion #3: 
3.Subjects have a body weight of ≥6 kg 
and ≤111 kg.† 
† Subjects with body weight in the 
range 112 to 134 kg (247 to 295 
pounds) may participate in the study at 
the discretion of the Investigator. 
 
 


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Amendment 4, March 6, 2020  
 
 
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Page 4 
 
1. 
PROTOCOL APPROVAL  
 
STUDY TITLE: A Multicenter, Open Label Crossover Study to Assess the 
Pharmacokinetics and Safety of Diazepam Buccal Soluble Film (DBSF) in Pediatric 
Subjects with Epilepsy 
 
SPONSOR APPROVAL 
I have read this protocol and agree that the sponsor will use appropriate control processes 
to ensure that the sponsor’s activities meet the requirements of applicable regulatory 
agencies. 
 
 
 
 
 
 
Gary Slatko MD 
 
Date 
Senior Vice President, Chief Medical Officer 
 
 
Aquestive Therapeutics 
 
 
 
 
 
 
 
 


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Page 5 
 
 
INVESTIGATOR PROTOCOL AGREEMENT  
I have read this protocol and agree to comply with all of the procedures contained within 
this protocol and requirements of applicable regulatory agencies. 
 
 
 
 
 
Investigator  
 
Date: 
 
 
Institution:  
Address:  
 
 
 


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2. 
CONTACT INFORMATION AND FACILITIES 
Sponsor: 
Gary Slatko MD 
Senior Vice President, Chief Medical officer 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ, 07059 USA 
Sponsor’s Responsible Study 
Manager: 
Frances Ekweonu 
Clinical Trail Manager, Clinical Operations 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 USA 
Telephone: 1-908-941-1941 
Clinical Research 
Organization: 
Syneos Health 
202 Carnegie Center 
Princeton, NJ 08540 USA 
Tel.: 1-609-951-6800 
Clinical Laboratory: 
Covance Central Laboratory Services 
8211 Scicor Drive 
Indianapolis, IN 46214 USA 
Tel.: 1-888-268-2623 or 1-317-271-1200 
Analytical Facility: 
Syneos Health Clinique 
2500, rue Einstein  
Québec City, Québec, Canada, G1P 0A2  
Tel.: 1-418-527-4000  
Pharmacokinetic/Statistical 
Facility: 
Syneos Health Clinique 
2500, rue Einstein  
Québec City, Québec, Canada, G1P 0A2  
Tel.: 1-418-527-4000  


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Contract Research 
Organization Safety 
(Pharmacovigilance) 
Reporting: 
Syneos Health Global Safety & Pharmacovigilance 
Facsimile: 1-866-856-1649 
Telephone Hotline No.: +1-888-750-8020 
E-mail: saereceipt.international@syneoshealth.com 


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3. 
SYNOPSIS 
Title: 
A Multicenter, Open Label Crossover Study to Assess the 
Pharmacokinetics and Safety of Diazepam Buccal Soluble Film (DBSF) 
in Pediatric Subjects with Epilepsy 
Objectives: 
The primary objective is to assess the pharmacokinetics of Diazepam 
Buccal Film (DBF) in pediatric subjects with epilepsy (A) in the interictal 
state, and (B) in the ictal/peri-ictal state.  
 
(A) Subjects are considered to be in an interictal state if an interval of at 
least 3 hours has elapsed since any clinical observable postictal signs 
or symptoms (from the last observed seizure) and the subject has 
been seizure free over this period. Subjects on electroencephalogram 
(EEG) monitoring can be considered to be in an interictal state if an 
interval of at least 3 hours has elapsed since any postictal electrical 
findings on EEG. 
(B) For the purposes of this study, the ictal state is defined as an ongoing 
clinically observable seizure or seizure activity as verified via EEG. 
The peri-ictal state is defined as the subject’s immediate postictal 
state following a generalized tonic-clonic (GTC) seizure or focal 
seizure with impaired awareness, and within 5 minutes after the last 
clonic jerk. For subjects on EEG monitoring, the peri-ictal state may 
be defined as less than 5 minutes after cessation of seizure activity 
(GTC or focal seizure with impaired awareness) as verified via EEG. 
Secondary objectives: 
• Evaluate the safety/tolerability of DBF in pediatric subjects with 
epilepsy  
• Evaluate the usability of DBF  
Experimental 
Design and Study 
Population: 
Multicenter, open-label crossover study in pediatric epilepsy subjects to 
assess the pharmacokinetics and safety of DBF during the interictal state 
(Treatment Period A) and during the ictal/peri-ictal state (Treatment 
Period B). 
 
Male or female pediatric subjects with a clinical diagnosis of epilepsy 
admitted to an Epilepsy Monitoring Unit (EMU) or a General Clinical 
Research Center (GCRC) or similar facility for evaluation of seizures. 
Subjects will be 2 to 16 years of age, inclusive, with a body weight of 


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≥6 kg and 111 kg. NOTE: Subjects with body weight in the range 112 
to 134 kg (247 to 295 pounds) may participate in the study at the 
discretion of the Investigator. 
Subjects aged 2 to 5 years will undergo Treatment B only and will not 
undergo Treatment A. Subjects aged 6 to 16 years will undergo both 
Treatment A and Treatment B. 
Number of 
Subjects: 
To provide adequate pharmacokinetic, safety, and usability assessment of 
DBF in the pediatric population, 16 to 18 subjects should complete the 
study, distributed across three age ranges as follows: 6 subjects aged 2 to 
5 years, 6 subjects aged 6 to 11 years, and 4 to 6 subjects aged 12 to 16 
years. To ensure an adequate number of completed subjects by age range, 
efforts will be made to enroll approximately 8 subjects in each range, for 
a total of 24 enrolled subjects. 
Enrollment End-
Date: 
Enrollment end-date is 05 March 2020.  
Phase: 
2 
Test Drugs: 
Diazepam Buccal Film 5 mg (Aquestive Therapeutics) 
Diazepam Buccal Film 7.5 mg (Aquestive Therapeutics) 
Diazepam Buccal Film 10 mg (Aquestive Therapeutics) 
Diazepam Buccal Film 12.5 mg (Aquestive Therapeutics) 
Diazepam Buccal Film 15 mg (Aquestive Therapeutics) 
Diazepam Buccal Film 17.5 mg (Aquestive Therapeutics) 
Treatments: 
In each of the two treatment periods, subjects will receive a single dose 
of DBF. DBF is provided in a range of doses from 5 to 17.5 mg. The 
appropriate dose of DBF will be assigned on the basis of age and weight 
using an interactive web response system (IWRS) during check-in for the 
subject’s first treatment period. The dose for the second treatment period 
will be the same as that for the first treatment period. 
Duration of 
Treatment Periods: 
Each treatment period will last from admission to the EMU/GCRC until 4 
hours after DBF administration. 


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Study Duration: 
• The minimum study duration will be approximately 30 days for 
subjects aged 6 to 16 years (inclusive)*and 15 days for subjects aged 
2 to 5 years (inclusive)**, with a maximum of approximately 58 days, 
consisting of Screening Period: 0 to 28 days prior to Day 1. 
* Age range 6 to 16 years (inclusive): beginning at the year 6 birthday 
until the year 17 birthday. 
**Age range 2 to 5 years (inclusive): beginning at the year 2 birthday 
until the year 6 birthday. 
• Treatment Period A (interictal, subjects aged 6 to 16 years): 1 day 
(from admission to the EMU/GCRC until 4 hours after DBF 
administration).  
• Minimum washout period of 14 days between DBF treatment periods 
• Treatment Period B* (ictal/peri-ictal, all subjects): 1 day (from 
admission to the EMU/GCRC until 4 hours after DBF administration). 
* Period A and Period B may occur in either order, depending on 
seizure occurrence (i.e., if subject experiences a seizure during the 
first visit to the EMU or GCRC, the Investigator may regard that 
period as Treatment Period B). 
• 
Follow-up Visit: A follow-up visit will be scheduled to obtain safety 
data 14 days (±2 days) after the second treatment period. 
Dosing Time: 
The treatment periods will begin at a time of day consistent with usual 
EMU/GCRC protocol. In Treatment Period A, DBF will be administered 
as soon as check-in procedures have been completed. In Treatment 
Period B, the subject will be monitored for seizure activity, and DBF will 
be administered as soon as possible after detection of seizure activity, 
within 5 minutes after the last clonic jerk or within 5 minutes of cessation 
of the seizure as verified via EEG. 
Safety Monitoring 
and Endpoints: 
Clinical seizure monitoring (both treatment periods) will start prior to 
DBF treatment and will continue for 4 hours after dosing, or longer at the 
discretion of the EMU or GCRC Investigator. Continuous video EEG 
monitoring for seizure detection will be performed as indicated by EMU 
or GCRC protocol. Sites will maintain the EEG recordings with the study 
documents, but data from the EEG recordings will not be collected for 
the study dataset.  
The following safety assessments will be performed during the study: 


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• 
Columbia Suicide Severity Rating scale (C-SSRS; age-
appropriate version) in subjects age 7 and older at Screening, 
before dosing during Treatment Periods A and B, and at Follow-
up 
For non-verbal subjects, the C-SSRS assessments should be 
personally completed by the subject using non-verbal methods 
with assistance of site staff trained for these assessments. If the 
scales cannot be completed, the site must document this.  
• 
Serum pregnancy test in females of childbearing potential, urine 
drug screen, and breath alcohol test at Screening. Urine 
pregnancy test, urine drug screen, and breath alcohol test before 
dosing (Treatment Periods A and B), and at Follow-up 
• 
12-lead ECG at Screening, and for each treatment period before 
DBF administration and 4 hours after dose administration. 
• 
Vital signs (blood pressure [BP], heart rate [HR], respiratory rate 
[RR], and temperature) will be recorded at Screening and 
(Treatment Periods A and B) prior to DBF administration. BP, 
HR, and RR will be recorded post dose at 0.25 hours 
(15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 
hours (90 minutes), 2 hours (120 minutes), 3 hours (180 
minutes), and 4 hours (240 minutes) and at Follow-up. 
• 
Oxygen saturation (SaO2) measured via pulse oximetry, 
Screening and (Treatment Periods A and B) prior to DBF 
administration and at 5, 10, 20, 30, 40, 50 minutes post dose and 
thereafter at each time vital signs are recorded: 1 hour 
(60 minutes), 1.5 hours (90 minutes), 2 hours (120 minutes), 
3 hours (180 minutes), and 4 hours (240 minutes) and at 
Follow-up. 
• 
Clinical laboratory tests (hematology, serum chemistry, and 
urinalysis) at Screening and at Follow-up or at early termination. 
• 
Physical and neurological examination at Screening and at 
Follow-up or at early termination. 
• 
Oral mucosal inspection to assess for any local irritation 
conducted by the Investigator at the following times: 


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- 
At Screening;  
- 
During Treatment Periods A and B prior to dosing and at 
approximately 0.25 hours (15 minutes), 0.5 hours (30 
minutes), and 1 hour (60 minutes) after application of 
DBF; and  
- 
At Follow-up or early termination visit* 
* If an enrolled subject’s participation is terminated 
prematurely or the subject withdraws from the study, 
the procedures scheduled for the follow-up visit will 
be performed. 
• 
Any abnormalities detected after dosing will be followed as 
treatment emergent adverse events (TEAEs) until resolution.  
• 
Type, incidence, and severity of adverse events (AEs) at all visits 
The Investigator or physician designee will be present from 
approximately 30 minutes prior to dosing until at least 2 hours post dose 
for each subject for each treatment period. The Investigator or physician 
designee will remain on call throughout the duration of each study 
subject’s visit. The Investigator will be responsible for ensuring that a 
study subject is sufficiently medically stable to be safely discharged from 
the clinical unit (EMU or GCRC) regardless of whether the subject has 
received study drug. 
Usability Endpoints: The following usability assessments will be performed during the study: 
• 
Oral cavity placement assessment 
• 
Oral cavity insertion and retention assessment 
Pharmacokinetic 
Endpoints: 
The following pharmacokinetic parameters for diazepam will be 
determined: 
• 
Observed peak drug concentration (Cmax)  
• 
Observed time to reach maximum drug concentration (Tmax) 
PK Blood Sampling 
Time points: 
In both treatment periods, plasma samples for diazepam and the active 
metabolite desmethyldiazepam will be obtained before DBF 
administration and post dose at the following time points (±5 minutes): at 
0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 
hours (90 minutes), 2 hours (120 minutes), and 4 hours (240 minutes). 


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Collection of plasma samples will continue even if the administration of 
another anti-eptileptic drug (AED) is needed for rescue. 
Total Blood 
Volume: 
A total of approximately 35.4 mL of blood will be taken during the entire 
study for clinical chemistry, hematology, and pharmacokinetics: 3.7 mL 
at Screening, 14 mL during Treatment Period A, 14 mL during Treatment 
Period B, and 3.7 ml at the Follow-up Visit.  
Analyte(s) To Be 
Measured: 
Plasma samples will be assayed for diazepam and desmethyldiazepam 
using a validated analytical method according to the principles of Good 
Laboratory Practice. 
Statistical Analysis: 
 
 
 
Summary statistics will be reported for pharmacokinetic, safety, and 
usability endpoints. No formal statistical tests will be performed to 
compare Period A vs. Period B on pharmacokinetic, safety, or usability 
endpoints. All analyses will be descriptive and exploratory.  
Summary statistics of pharmacokinetic data will include intra-subject 
comparisons of Cmax and Tmax for diazepam.  
Summary statistics will be presented by age category and weight 
category, and data will be explored for the potential influence of 
concomitant medications. No efficacy analysis will be performed. 
The following age categories will be used for analysis: ages 2 to 5 years, 
ages 6 to 11 years, and ages 12 to 16 years. 
 
 


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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AED 
anti-epileptic drug 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUCt 
area under the concentration-time curve from time zero until the last 
measurable concentration or last sampling time t, whichever occurs 
first. AUCt is estimated using the trapezoidal method. 
AUCinf 
area under the concentration-time curve from time zero to infinity, 
calculated as AUCt + Clast/λ, where Clast is the last measurable 
concentration. 
BLQ  
below the limit of quantitation / below quantitation limit 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CI 
confidence interval 
Clast 
the measured last quantifiable concentration. 
Cmax 
the maximal observed plasma concentration. 
eCRF 
electronic case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
CYP 
cytochrome 
DBF 
Diazepam Buccal Film, formerly referred to as Diazepam Buccal 
Soluble Film 
ECG 
electrocardiogram 
EMU 
Epilepsy Monitoring Unit 
FDA 
Food and Drug Administration 
GABAA 
gamma-Aminobutyric acid, or γ-aminobutyric acid type A 
GCP 
Good Clinical Practice 
GCRC 
General Clinical Research Center 
GTC 
generalized tonic-clonic (seizure) 


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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
Informed Consent Form 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliters  
ms 
millisecond 
mmHg 
millimeter of mercury 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
RBC 
red blood cell 
RPM 
revolutions per minute 
RR 
respiratory rate 
SAE 
serious adverse event 
SAS® 
Statistical Analysis System 
SaO2 
(blood) oxygen saturation  
SOC 
System Organ Classification 
SOP 
Standard Operating Procedure 
T1/2 
terminal elimination half-life, estimated as ln(2)/λ 
THC 
tetrahydrocannabinol 
Tmax 
time when the maximal plasma concentration is observed 
UBG 
urobilinogen 
WBC 
white blood cell 
 
 


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5. 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT: SUMMARY OF CHANGES ................................... 2 
1. 
PROTOCOL APPROVAL ..................................................................... 4 
2. 
CONTACT INFORMATION AND FACILITIES ................................ 6 
3. 
SYNOPSIS ............................................................................................. 8 
4. 
LIST OF ABBREVIATIONS............................................................... 14 
5. 
TABLE OF CONTENTS ..................................................................... 16 
LIST OF TABLES ................................................................................................... 21 
LIST OF FIGURES ................................................................................................. 21 
6. 
BACKGROUND AND PHARMACOKINETICS ............................... 22 
6.1. 
Treatment and Management of Refractory Patients with Epilepsy ...... 22 
6.2. 
Diazepam .............................................................................................. 23 
6.2.1. 
Mechanism of Action ........................................................................... 23 
6.2.2. 
Metabolism and Elimination................................................................. 24 
6.2.3. 
Pharmacokinetics .................................................................................. 24 
6.3. 
Diastat® AcuDial™ Rectal Gel in the Treatment of Seizures .............. 24 
6.4. 
Diazepam Buccal Film ......................................................................... 25 
6.4.1. 
Pilot Studies 1899 and 1900 ................................................................. 26 
6.4.2. 
Study 162013 – Dose-Proportionality .................................................. 28 
6.4.3. 
Study 162021 – Pivotal Bioavailability Study...................................... 29 
6.4.4. 
Food Effect Studies ............................................................................... 31 
6.5. 
Rationale for the Dose Regimen of Diazepam Buccal Film ................. 32 
6.6. 
Safety .................................................................................................... 35 
6.6.1. 
Diastat® AcuDial™ Rectal Gel ............................................................ 35 


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6.6.2. 
Diazepam Buccal Film ......................................................................... 36 
6.6.3. 
Overdosage ........................................................................................... 37 
7. 
STUDY OBJECTIVES ........................................................................ 39 
8. 
STUDY DESIGN ................................................................................. 40 
8.1. 
Discussion of Study Design .................................................................. 40 
8.1.1. 
Study Design ......................................................................................... 40 
8.1.2. 
Screening Period ................................................................................... 40 
8.1.3. 
Treatment Periods ................................................................................. 40 
8.1.4. 
Post-treatment ....................................................................................... 43 
8.1.5. 
Follow-up Visit ..................................................................................... 43 
8.1.6. 
Pharmacokinetic and Safety Assessments ............................................ 43 
8.2. 
Study Duration and Washout ................................................................ 44 
8.3. 
Randomization and Blinding ................................................................ 44 
9. 
SUBJECT SELECTION ....................................................................... 45 
9.1. 
Screening Procedures ............................................................................ 45 
9.2. 
Inclusion/Exclusion Criteria ................................................................. 46 
9.2.1. 
Inclusion Criteria .................................................................................. 46 
9.2.2. 
Exclusion Criteria ................................................................................. 47 
9.3. 
Permitted and Restricted Items ............................................................. 50 
9.4. 
Sample Size .......................................................................................... 51 
9.5. 
Dropout and Withdrawal/Termination ................................................. 52 
10. 
INVESTIGATIONAL PRODUCT ...................................................... 53 
10.1. 
Drug Information .................................................................................. 53 
10.1.1. 
Controlled Substance Documentation .................................................. 53 


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10.1.2. 
Description of Investigational Product ................................................. 53 
10.2. 
Labeling, Maintenance, and Retention of Study Drugs ........................ 54 
11. 
STUDY PROCEDURES ...................................................................... 55 
11.1. 
Schedule of Events ............................................................................... 55 
11.2. 
Treatment Periods A and B................................................................... 58 
11.2.1. 
Check-in Procedures ............................................................................. 58 
11.2.2. 
Treatment Period A (Subjects Age 6-16 Years) ................................... 59 
11.2.3. 
Treatment Period B (All Subjects) ....................................................... 59 
11.2.4. 
Dosing ................................................................................................... 60 
11.2.5. 
Post-treatment ....................................................................................... 63 
11.3. 
Follow-up .............................................................................................. 63 
11.4. 
Blood Sampling Schedule, Sample Collection, Processing, and Storage
 .............................................................................................................. 63 
11.4.1. 
Pharmacokinetic Assessments .............................................................. 63 
11.4.2. 
Clinical Laboratory Assessment ........................................................... 64 
11.4.3. 
Number and Volume of Blood Samples ............................................... 65 
11.5. 
Columbia-Suicide Severity Rating Scale .............................................. 66 
11.6. 
Vital Signs ............................................................................................ 67 
11.7. 
12-Lead Electrocardiogram .................................................................. 68 
11.8. 
Physical/Neurological Examination ..................................................... 68 
11.9. 
Oral Safety Assessments ....................................................................... 68 
11.10. 
Usability ................................................................................................ 68 
11.11. 
Food and Fluid Intake ........................................................................... 69 
11.12. 
Physical Activity ................................................................................... 69 
12. 
ADVERSE EVENTS............................................................................ 70 


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12.1. 
Adverse Event Recording and Follow-up ............................................. 70 
12.1.1. 
Seizures ................................................................................................. 70 
12.1.2. 
Serious Adverse Events ........................................................................ 70 
12.1.3. 
Evaluation of Severity of AEs .............................................................. 71 
12.1.4. 
Assessing Relationship to Study Drug ................................................. 71 
12.1.5. 
Investigator Presence ............................................................................ 72 
12.1.6. 
Follow-up of AEs ................................................................................. 72 
12.2. 
Procedures for Reporting Adverse Events ............................................ 73 
13. 
BIOANALYTICAL ANALYSIS ......................................................... 75 
13.1. 
Analytical Procedures ........................................................................... 75 
13.2. 
Samples to be Assayed ......................................................................... 75 
13.3. 
Analyte(s) in Biological Matrix ............................................................ 75 
14. 
PHARMACOKINETIC AND STATISTICAL ANALYSIS ............... 76 
14.1. 
Pharmacokinetic Analysis Data Set ...................................................... 76 
14.2. 
Data Analyzed ...................................................................................... 76 
14.2.1. 
Pharmacokinetic Analysis .................................................................... 76 
14.2.2. 
Statistical Analysis ................................................................................ 77 
14.2.3. 
Safety Endpoints ................................................................................... 77 
14.2.4. 
Usability Endpoints .............................................................................. 78 
14.3. 
Statistical Analyses ............................................................................... 79 
15. 
ETHICAL CONSIDERATIONS.......................................................... 80 
15.1. 
Basic Principles .................................................................................... 80 
15.2. 
Informed Consent ................................................................................. 80 
15.3. 
Revisions and/or Amendments to the Protocol .................................... 80 


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15.4. 
Delegation of Investigator Tasks .......................................................... 81 
16. 
REFERENCES ..................................................................................... 82 
APPENDIX A .......................................................................................................... 84 
 
 
 
 


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LIST OF TABLES 
Table 1. 
Study 162013 – Dose-Proportionality of DBF at Doses of 5, 10, and 15 
mg ..............................................................................................................29 
Table 2: 
Study 162021: Ratios (DBF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUC0-t, AUC0-inf, and Cmax 
- PK Population ..........................................................................................30 
Table 3. 
Rationale for Dosage of Diazepam Buccal Film .......................................34 
Table 4. 
Treatment-Emergent Adverse Events That Occurred in >1% of Patients 
Enrolled in Parallel-Group, Placebo-Controlled Trials and were 
Numerically More Common in the Diazepam Rectal Group ....................36 
Table 5: 
Pooled Data for Most Frequently Reported Treatment-Emergent Adverse 
Events in Six Completed Studies (1899, 1900, 162013, 162021, 162022, 
172018) ......................................................................................................37 
Table 6 
Study Restrictions ......................................................................................51 
Table 7. 
Study Drug Information .............................................................................53 
Table 8. 
Schedule of Events .....................................................................................55 
Table 9. 
Calculated Prescribed Dose of Diazepam Buccal Film .............................61 
Table 10 
Clinical Laboratory Assessments ...............................................................65 
Table 11 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject .................................................................................66 
LIST OF FIGURES 
Figure 1. 
Cmax Values by Nominal Dose for DBF vs. Diastat® .................................28 
 


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6. 
BACKGROUND AND PHARMACOKINETICS 
Diazepam Buccal Film (DBF), formerly referred to as Diazepam Buccal Soluble Film 
(DBSF), is being developed as an alternative dosage form to Diastat® AcuDial™ rectal 
gel, a gel formulation of diazepam. The proposed indication is identical to that of 
Diastat® AcuDial™ rectal gel: the treatment and management of selected, refractory 
patients with epilepsy who are on stable regimens of antiepileptic drugs (AEDs) and who 
require intermittent use of diazepam to control bouts of increased seizure activity 
(Diastat® AcuDial™ rectal gel prescribing information). Diastat® AcuDial™ rectal gel 
has been marketed in the United States since 1997 and currently is the only Food and 
Drug Administration (FDA) approved drug in the US for this indication. 
6.1. 
Treatment and Management of Refractory Patients with 
Epilepsy 
Acute repetitive seizures, including breakthrough seizures, repetitive seizures, and seizure 
clusters occur in a significant number of epilepsy patients who are on established 
antiepileptic drug treatment. These types of seizures have distinguishable characteristics 
that are usually recognized by patients, caregivers, and physicians.  
Although patients typically recover between seizures, these seizures can last from 
minutes to hours (Cereghino, 2007). When these seizures occur outside a hospital, the 
patient is often transported to an acute care facility for treatment to prevent prolonged 
seizures (Lowenstein and Alldredge, 1998). If treatment is not prompt and effective there 
is a risk that seizure activity will continue, and may become life threatening, including 
the risk of status epilepticus (Bergen, 2006; Matheson et al, 2000; Sankar and Rho, 
2007).  
In these cases, the primary goals of the treatment are seizure cessation and prevention of 
seizure recurrence (Cereghino, 2007). Usually, acute benzodiazepine treatment is 
effective for seizure control and often results in rapid seizure termination. Nevertheless, 
many treatment options rely on appropriate intervention by medical personnel, and 
treatment may be delayed while the patient is transported to a medical facility (Glauser, 
2007).  
Outpatient treatment for these types of seizures may reduce emergency medical 
intervention, decrease seizure duration, prevent general deterioration due to the repeated 
seizures and improve the quality of life of these patients. While rectal diazepam gel is 
currently available in the United States, a portion of the population does not benefit from 


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this treatment, partly because the rectal route of administration is inappropriate or 
unacceptable (Fisgin et al, 2002). Therefore, there is an unmet medical need for an 
effective treatment with a rapid onset of action that is easily administered in the 
outpatient setting.  
6.2. 
Diazepam  
Diazepam is a long-acting “classical” benzodiazepine with potent inhibitory activity at 
the γ-Aminobutyric acid type A (GABA-A) receptor and demonstrates anticonvulsant 
properties. It is commonly used to treat a range of conditions including seizures, anxiety, 
alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, 
trouble sleeping, and restless legs syndrome (Calcaterra and Barrow, 2014). It can be 
taken by mouth, inserted into the rectum, injected into muscle, or injected intravenously. 
When given intravenously, effects begin in 1 to 5 minutes. When diazepam is taken 
orally, effects may be delayed as long as 40 minutes (Riss et al, 2008). 
Intravenous diazepam is a first-line treatment for status epilepticus (Riss et al, 2008). 
Diazepam rectal gel has been demonstrated superior to placebo gel in reducing the risk of 
continuing seizures. Diazepam is rarely used for the long-term treatment of epilepsy 
because tolerance to its anticonvulsant effects develops over time with continuous 
treatment (Riss et al, 2008). However, diazepam is effective when used intermittently for 
the prevention of repeated seizures. Like other benzodiazepines, diazepam administration 
may cause sedation, anxiolysis, and amnesia (Riss et al, 2008). 
6.2.1. 
Mechanism of Action  
Although the precise mechanism by which diazepam exerts its anti-seizure effects is 
unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures 
through an interaction with γ-aminobutyric acid (GABA) receptors of the A-type 
(GABAA). GABA, the major inhibitory neurotransmitter in the central nervous system, 
acts at this receptor to open the membrane channel allowing chloride ions to flow into 
neurons (Tan et al, 2011). Entry of chloride ions causes an inhibitory potential that 
reduces the ability of neurons to depolarize to the threshold potential necessary to 
produce action potentials. Excessive depolarization of neurons is implicated in the 
generation and spread of seizures. It is believed that diazepam enhances the actions of 
GABA by causing GABA to bind more tightly to the GABAA receptor. 


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6.2.2. 
Metabolism and Elimination  
Diazepam is extensively metabolized to one major active metabolite 
(desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam 
(temazepam) and 3-hydroxy-N-diazepam (oxazepam) (Diastat® AcuDial™ rectal gel 
prescribing information). With steady state dosing, desmethyldiazepam is found in 
plasma at concentrations equivalent to those of diazepam while oxazepam and 
temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic 
and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 
3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The 
marked inter- individual variability in the clearance of diazepam reported in the literature 
is probably attributable to variability of CYP2C19 (which is known to exhibit genetic 
polymorphism; about 3-5% of Caucasians have little or no CYP2C19 activity and are 
“poor metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of 
inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating 
that these enzymes are not significantly involved in metabolism of diazepam 
(Dean, 2016).  
6.2.3. 
Pharmacokinetics  
Per the prescribing information, rectal administration of a 15 mg dose of Diastat® 
AcuDial™ rectal gel produces peak plasma concentrations in 1.5 hours, with absolute 
bioavailability of 90% relative to Valium® injectable. The volume of distribution of 
diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half-
life 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 (Coefficient of Variation [CV] = 37%), respectively. Both diazepam and its 
major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-
98%). 
6.3. 
Diastat® AcuDial™ Rectal Gel in the Treatment of Seizures 
Although the Diastat® AcuDial™ rectal gel formulation is considered generally safe and 
effective, the route of administration is less than ideal. The mechanics of administering a 
rectal gel can be a difficult, time-consuming, and embarrassing experience for both 
patient and care-givers alike. For example, the patient or care-giver must first remove 
articles of clothing and then place the patient in an appropriate position. The Diastat® 
AcuDial™ rectal gel syringe tip is inserted into the rectum to a specific depth and the gel 
expressed into the rectal vault. However, improper technique can lead to patient injury 


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and leakage of gel from the rectum can result in incomplete dosing and the need for an 
additional dose to compensate for any loss. Additionally, the attitude of some patients 
toward a rectal route of drug administration is unfavorable which may negatively impact 
compliance to treatment (Tatum, 2002). Each of these factors has a potential influence on 
patient morbidity. Persistent seizure activity is associated with worse outcomes across a 
spectrum of precipitating conditions (Haut, 2006; Waterhouse et al, 1999). Further, it has 
been demonstrated that if seizures are not terminated quickly, escalating doses of 
benzodiazepines are required to achieve seizure cessation and seizures may become 
refractory to anticonvulsant therapy (Kapur and Macdonald, 1997). 
6.4. 
Diazepam Buccal Film 
The new route of diazepam administration is via buccal film. Aquestive Therapeutics 
initiated development of DBF, specifically intended for buccal delivery for patients who 
require control of intermittent bouts of seizure activity. DBF contains the FDA approved 
active ingredient diazepam, a benzodiazepine, as a treatment for the management of 
selected, refractory patients with epilepsy, on stable regimens of antiepileptic drugs who 
require intermittent use of diazepam to control bouts of increased seizure activity. The 
DBF products, with a planned dose range of 5 mg to 15 mg, are expected to achieve peak 
plasma concentrations of diazepam equivalent to the reference therapy, Diastat® 
AcuDial™ rectal gel. The DBF product is intended for submission as a 505(b)(2) NDA 
using Diastat® AcuDial™ rectal gel as the reference therapy.  
Buccal diazepam may be particularly well-suited for administration in outpatient settings. 
The DBF is administered by placing the film against the inner aspect of the cheek, where 
it adheres, dissolves, and releases the drug onto the buccal mucosa. Although buccal 
absorption is expected to be the primary route of absorption of the drug, some absorption 
through the gastrointestinal (GI) tract may be possible due to swallowing of the saliva. It 
is expected that use of the buccal film will be similar to the use of Diastat® AcuDial™ 
rectal gel, i.e., the film would be administered during or immediately after a seizure with 
characteristics for which the Diastat rectal gel would be indicated, and the goal of 
treatment would be the same as that of the rectal gel—to reduce the overall frequency of 
acute repetitive seizures.  
There is no need to disrobe the patient during administration. Additionally, there is less 
potential for delay in treatment, and greater patient and caregiver acceptance with 
improved compliance may be expected. For patients with bouts of increased seizure 
activity, the development of a DBF will meet the treatment need for a form of diazepam 
that is effective, safe, allows reliable dose administration, and is easier to administer than 


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the rectal gel. Patients, caregivers, and physicians have indicated that this type of product 
would be desirable for acute, intermittent treatment of breakthrough, repetitive or cluster 
seizures.  
The Phase 1 clinical studies of DBF have focused on assessing its bioavailability relative 
to the reference therapy, Diastat® AcuDial™ rectal gel, assessment of dose 
proportionality, and assessment of food effect. Overall safety and tolerability have been 
assessed in all clinical trials conducted with DBF. The results of Phase 1 studies to date 
are summarized in this section. 
6.4.1. 
Pilot Studies 1899 and 1900 
The two pilot studies were randomized, open label, single-dose, fasting condition, 
crossover studies in healthy male and female volunteers to assess the bioavailability of 
DBF in comparison to the same nominal dose of Diastat® AcuDial™ rectal gel. Study 
1899 compared DBF 5 mg to Diastat® AcuDial™ rectal gel 5 mg, with 11 subjects 
completing both treatments. Study 1900 compared DBF 20 mg to Diastat® AcuDial™ 
rectal gel 20 mg, with 10 subjects completing both treatments.  
Study 1899 compared DBF 5 mg to Diastat® AcuDial™ rectal gel 5 mg. Among the 11 
subjects who completed both treatments, DBF 5 mg was bioequivalent to Diastat® 
AcuDial™ rectal gel 5 mg with respect to area under the curve from time zero until the 
last measurable concentration or last sampling time t (AUCt) and AUC from time 0 
extrapolated to infinity (AUCinf), i.e., the 90% confidence interval (CI) for the ratio of 
geometric means was within the acceptable range of 80-125%. For the observed peak 
drug concentration (Cmax), the ratio of geometric means was 1.07 with the 90% CI 
87.1 131.5%. The median observed time to reach maximum drug concentration (Tmax) 
was 0.67 hours for the DBF (range 0.33-1.50 hours) and 0.25 hours for the Diastat® 
AcuDial™ rectal gel (range 0.15-1.00 hours). The difference in Tmax values was not 
statistically significant. 
Study 1900 compared DBF 20 mg to Diastat® AcuDial™ rectal gel 20 mg. Evaluable 
data from 10 subjects who completed both treatments showed that the extent of the 
absorption of DBF 20 mg was comparable to Diastat® 20 mg rectal gel, with the ratio of 
geometric means for AUCt and AUCinf within the acceptable range of 80-125%. For Cmax, 
the ratio of geometric means was 158.72% with 90% CI 122.81-205.14. The median Tmax 
was 1.25 hours for the DBF (range 0.36-2.05 hours) and 1.00 hours for the Diastat® 
AcuDial™ rectal gel (range 0.25-2.00 hours). The difference in Tmax values was not 
statistically significant. Examination of the mean plasma curves for DSBF and Diastat® 
showed that although the Cmax was higher for the DSBF relative to Diastat®, the 


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pharmacokinetics were comparable in terms of rapid rate of absorption, duration of 
plateau, and the rate of elimination. 
Figure 1 shows the Cmax values for DBF vs. Diastat® at nominal doses of 5 mg in Study 
1899 and 20 mg in Study 1900. These early data suggested that DBF 5 mg was nearly 
bioequivalent to Diastat® 5 mg. In contrast, because the Cmax after administration of 
Diastat® 20 mg is lower than the Cmax after DBF 20 mg, DBF 20 mg is not bioequivalent 
to Diastat® 20 mg. While it is difficult to assess dose-proportionality based on pilot 
studies conducted in separate groups of subjects, the pilot studies suggested that for DBF, 
both Cmax and AUC are dose-proportional over the 5 mg to 20 mg dose range, whereas, 
for Diastat®, although AUC is dose-proportional (data not shown), Cmax is less than dose-
proportional. In light of this observation, at doses above 5 mg, the nominal dose of 
diazepam administered as DBF was expected to be lower than the therapeutically 
equivalent nominal dose of Diastat®. 
 


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Figure 1. Cmax Values by Nominal Dose for DBF vs. Diastat® 
 
 Data are Cmax values (geometric means) from pilot Studies 1899 (N=11) and Study 1900 (N=10). As 
shown in the figure, Cmax values for DBF were approximately dose-proportional while Cmax values for 
Diastat® were less than dose-proportional. (AUC(0-t) and AUC(0-inf) were approximately dose-proportional 
for both DBF and Diastat® – data not shown.) Analysis of the individual data by linear regression 
indicated that the observed Cmax values for DBF were consistent with a direct linear relationship between 
Cmax and nominal dose, while the observed Cmax values for Diastat® appeared to be linearly related to dose 
to the 2/3 power. 
 
6.4.2. 
Study 162013 – Dose-Proportionality 
Study 162013 was a single-dose, randomized, open-label, three-period, six-sequence, 
crossover study conducted to assess dose-proportionality of DBF at doses of 5, 10, and 15 
mg. A total of 30 subjects were randomized and dosed in the study. Analysis of the 
pharmacokinetic data confirmed that DBF is dose-proportional over the dose range 5 mg 
to 15 mg (Table 1). The criteria for dose proportionality were met for diazepam since for 
both comparisons (A/B: DBF 5 mg/DBF 10 mg and C/B: DBF 15 mg/DBF 10 mg), the 
geometric mean 90% CI of the ratios of Least-Squares means from the analysis of 


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variance (ANOVA) of the ln-transformed AUC0-t, AUC0-inf, and Cmax were within 80.0% 
- 125.0%.  
Table 1. Study 162013 – Dose-Proportionality of DBF at Doses of 5, 10, and 15 mg  
Parameter1 
Treatment Comparisons  
Geometric Mean 
Ratio2 
90% Confidence 
Interval3 
AUC0-t 
DBF 5 mg (A) – DBF 10 mg (B) 
103.53% 
99.51% 
107.72% 
AUC0-inf 
DBF 5 mg (A) – DBF 10 mg (B) 
104.08% 
99.43% 
108.96% 
Cmax 
DBF 5 mg (A) – DBF 10 mg (B) 
104.57% 
97.92% 
111.67% 
 
 
 
 
 
AUC0-t 
DBF 15 mg (C) – DBF 10 mg (B) 
101.94% 
97.62% 
106.44% 
AUC0-inf 
DBF 15 mg (C) – DBF 10 mg (B) 
103.64% 
98.52% 
109.02% 
Cmax 
DBF 15 mg (C) – DBF 10 mg (B) 
98.84% 
92.36% 
105.78% 
AUC0-inf = area under the concentration-time curve from time zero to infinity; AUC0-t = area under the 
concentration-time curve from time zero until the last measurable concentration or last sampling time t; 
Cmax= the maximal observed plasma concentration; DBF= Diazepam Buccal Film. 
1 Dose-normalized to 10 mg 
2 Calculated using least-squares means according to the formula eDIFFERENCE X 100 
3 90% Geometric Confidence Interval using ln-transformed data. 
6.4.3. 
Study 162021 – Pivotal Bioavailability Study 
This pivotal relative bioavailability study was a four-period, four-sequence randomized 
crossover in 36 healthy adult males and females. The four treatments were DBF 15 mg 
and three doses of Diastat® rectal gel: 5 mg, 12.5 mg, and 20 mg. These Diastat® doses 
span the approved dose range for the rectal gel. The objective of this study was to gain a 
thorough and precise understanding of the comparative exposure to diazepam and 
nordiazepam (both AUC and Cmax) after administration of DBF or Diastat®.  
Pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-inf) were compared pairwise. DBF 
15 mg with each of the three doses of the rectal gel (Table 2). The results suggest that the 
dose of DBF expected to match the diazepam Cmax following 20 mg Diastat® gel is lower 
than 12.5 mg (closer to 11 mg); the dose expected to match the diazepam Cmax following 
a 12.5 mg dose of Diastat® gel is lower than 9 mg; and the dose of DBF expected to 
match the diazepam Cmax following a 5 mg dose of Diastat® gel is lower than 5 mg 


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(closer to 4 mg). Results demonstrate that AUC (both AUC0-t and AUC0-inf) are 
dose proportional following single doses for both DBF and for Diastat® gel over the 
studied dose. These results, normalized for dose in mg, suggest that the relative 
bioavailability of diazepam administered as DMSF compared with Diastat® gel is 118% 
to 128%.   
Table 2: Study 162021: Ratios (DBF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUC0-t, AUC0-inf, and Cmax 
- PK Population 
Treatment  
 
 
Geometric 
Geometric 
 
90% Geometric CI2 
Comparison 
N 
Parameter 
LSM A 
LSM B 
Ratio1 
Lower 
Upper 
DBF 15 mg (A) 
24 
AUC0-t 
11310.33 
3181.98 
355.45% 
292.89% 
431.37% 
Diastat  
24 
AUC0-inf 
13204.10 
3730.87 
353.91% 
295.32% 
424.14% 
rectal gel 5 mg (B) 
24 
Cmax 
461.88 
116.88 
395.18% 
291.06% 
536.54% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM C 
 
 
 
DBF 15 mg (A) 
23 
AUC0-t 
11381.05 
7314.63. 
155.59% 
127.26% 
190.24% 
Diastat  
23 
AUC0-inf 
12871.61 
8370.26 
153.78% 
126.56% 
186.86% 
rectal gel 12.5 mg 
(C) 
23 
Cmax 
490.93 
206.30 
237.97% 
176.72% 
320.45% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM D 
 
 
 
DBF 15 mg (A) 
21 
AUC0-t 
11186.57 
12392.66 
90.27% 
42.23% 
112.80% 
Diastat  
20 
AUC0-inf 
13191.81 
14824.85 
88.98% 
69.28% 
114.29% 
rectal gel 20 mg 
(D) 
21 
Cmax 
458.51 
327.86 
139.85% 
140.92% 
186.42% 
 
 
 
 
 
 
 
 
AUC0-inf = area under the concentration-time curve from time zero to infinity; AUC0-t = AUC from time zero until the 
last measurable concentration or last sampling time t, whichever occurs first; Cmax = the maximal observed plasma 
concentration; CI = confidence interval; DBF = Diazepam Buccal Film; LSM = Least-Squares Mean 
1 Calculated least-squares means according to the formula: e (Difference) X 100;  
2 90% Geometric Mean Confidence Interval using ln-transformed data. 


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6.4.4. 
Food Effect Studies 
The Sponsor conducted two food effect studies (Study 162022 in Section 6.4.4.1 and 
Study 172018 in Section 6.4.4.2). Results for a high fat meal were consistent across the 
two studies.  
The food effect studies indicate that a high fat or moderate fat meal within 30 minutes 
prior to dosing of DBF has no effect on diazepam AUC but reduces diazepam Cmax on 
average of 45% and 33%, respectively. Bimodal peaks were observed under fed 
conditions due to the combination of oral transmucosal absorption and intestinal 
absorption of DBF. The first peak (mean concentration curves) for both high fat and 
moderate fat meals is observed at 45 minutes (mean of 199.04 ng/mL and 222.37 ng/mL, 
respectively) and the second peak of the mean concentration curves is observed at 3 hours 
(mean of 196.22 ng/mL and 261.79 ng/mL, respectively).  
6.4.4.1. 
Study 162022 
Study 162022 was a single-dose, open-label, two-period, randomized two-sequence 
crossover study with DBF 15 mg administered under fasted conditions and within 30 
minutes following a high-fat meal. The washout period between doses was 28 days. The 
study was conducted with 18 healthy male and female subjects aged 18 to 62 years, 
inclusive. AUC0-t and AUC0-inf were not affected by food; however, Cmax after a high fat 
meal was approximately 55% of the fasting value, 90% CI 48.6% – 62.7% (ratio of 
geometric means). Median Tmax fasting was approximately 0.75 hour with range of 
0.25 hour to 2 hours whereas median Tmax after a high fat meal was 3.0 hours with range 
0.5 hour to 6.0 hours, p = 0.0008.  
6.4.4.2. 
Study 172018 
Study 172018 was a four-period, randomized four-sequence crossover study in 24 male 
and female adults with four treatments: (A) DBF 15 mg fasted, administered upright; 
(B) DBF 15 mg fasted, administered reclining; DBF 15 mg within 30 minutes following a 
standardized high-fat meal, administered reclining; and DBF 15 mg within 30 minutes of 
a standardized moderate-fat meal, administered reclining.  
The primary objective was to assess the effect of a moderate-fat meal on the diazepam 
PK profile. A secondary objective was to assess the effect of administration of DBF with 
the subject reclining on his/her side (application site downward) for 15 minutes after 
application. This was based on aligning treatment administration with the typical posture 
assumed by patients in a postictal state and the Sponsor’s interest in investigating 
whether position affected diazepam PK following administration of DBF.  


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Analysis comprised pairwise comparisons of Treatment C (high-fat meal, reclining) and 
Treatment D (moderate-fat meal, reclining) with Treatment B (fasting, reclining) as well 
as a comparison between Treatment B (fasting, reclining) with Treatment A (fasting, 
upright). 
Overall, AUC0-t and AUC0-inf were not affected by either food or position. Cmax after the 
high fat meal (reclining) was approximately 53% of the fasting value (reclining), 
90% CI: 41.1% - 59.5% (ratio of geometric means). Cmax after the moderate fat meal 
(reclining) was approximately 67% of the fasting value (reclining), 90% CI 59.8%-74.6% 
(ratio of geometric means). Comparison of Treatment B with Treatment A demonstrated 
that position in the fasting condition (reclining versus upright) had no meaningful effect 
on either Cmax or AUC. Diazepam profiles (reclining versus upright) met bioequivalence 
criteria for the upright and fasting condition. There was no difference in Tmax, p = 0.4979. 
Median Tmax fasting, upright was 1.00 hour with range 0.28 hour to 2.03 hours. Median 
Tmax fasting, reclining was 0.80 hour with range 0.50 hour to 2.03 hours whereas median 
Tmax after a high fat meal, reclining was 2.01 hours with range 0.50 hour to 4.06 hours 
(p = 0.0147 versus fasting, reclining). and median Tmax  after a moderate fat meal, 
reclining was 3.00 hours with range 0.50 hour to 4.02 hours (p = 0.0005 versus fasting, 
reclining).  
6.5. 
Rationale for the Dose Regimen of Diazepam Buccal Film 
As described above, the data from Study 162013 and Study 162021 demonstrate that 
DBF is dose-proportional over the studied dose-range, while Diastat® is less than dose-
proportional with respect to Cmax. Also, as described above, the data from Study 162022 
and Study 172018 demonstrate that food taken within 30 minutes prior to dosing affects 
the rate (but not the extent) of absorption of diazepam administered as DBF. 
Accordingly, Aquestive used population PK modeling to select a dosing regimen to 
compensate for the differences in PK between DBF and Diastat®.  
Using data from Study 162013, Study 162021, and Study 172018, population PK 
modeling was used to model the PK profiles for DBF and Diastat® under fasted and fed 
conditions (DBF). In brief, the recommended DBF dose for each weight class as defined 
in the Diastat® label was selected (1) to provide a dose sufficiently high to ensure that 
the predicted median of the resulting diazepam Cmax following a moderate fat meal was 
similar to the median Cmax following the labeled dose of Diastat® , and (2) to provide a 
dose for which the predicted median of the resulting diazepam Cmax under fasting 
conditions would not exceed the median Cmax values observed and demonstrated as safe 
in Phase 1 studies with DBF. It was demonstrated that the predicted median diazepam 


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Cmax values with the proposed regimen administered under fasting conditions did not 
meaningfully exceed the median Cmax values observed in the 115 healthy volunteers 
(adult men and women) who received DBF 15 or 20 mg under fasting conditions in Phase 
1 studies conducted Aquestive. The median Cmax among these 115 healthy subjects (138 
DBF administrations) was 486 ng/mL. Under conditions of a moderate fat meal, the 
proposed DBF dosing regimen produces a Cmax similar to the Cmax expected following the 
labeled dose of Diastat®. 
For the current pediatric study, the DBF dose will be determined according to age and 
weight category in a manner analogous to the Diastat® label (Diastat® AcuDial™ rectal 
gel prescribing information December 2016) (Table 3). The proposed dosing regimen is 
predicted to produce a Cmax under fasting conditions that is approximately 150% of the 
Cmax expected following the labeled dose of Diastat®.   


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Table 3. Rationale for Dosage of Diazepam Buccal Film 
Weight (kg) 
Diastat® Dose (mg) 
Protocol-Specified Dose (mg) 
Age 2–5 Years 
6 to 10 
5 
5 
11 to 15 
7.5 
7.5 
16 to 20 
10 
10 
21 to 25 
12.5 
12.5 
26 to 30 
15 
15 
31 to 35 
17.5 
15 
36 to 44 
20 
17.5 
Age 6–11 Years 
10 to 16 
5 
5 
17 to 25 
7.5 
7.5 
26 to 33 
10 
10 
34 to 41 
12.5 
12.5 
42 to 50 
15 
15 
51 to 58 
17.5 
15 
59 to 74 
20 
17.5 
Age 12–16 Years 
14 to 25 
5 
5 
26 to 37 
7.5 
7.5 
38 to 50 
10 
10 
51 to 62 
12.5 
12.5 
63 to 75 
15 
15 
76 to 87 
17.5 
15 
88 to 111a 
20 
17.5 
a Subjects with body weight in the range 112 to 134 kg (247 to 295 pounds) may participate in the study at 
the discretion of the Investigator. 
 


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6.6. 
Safety 
It is anticipated that the adverse event (AE) profile from systemic exposure observed with 
DBF will resemble the already well-known profile for diazepam in general and the 
reference therapy, Diastat® AcuDial™ rectal gel, in particular.  
6.6.1. 
Diastat® AcuDial™ Rectal Gel 
Diazepam rectal gel was administered to 573 patients with epilepsy during Diastat® 
clinical trials, only some of which were placebo-controlled (Diastat® AcuDial™ rectal 
gel prescribing information December 2016). The controlled trials of Diastat® AcuDial™ 
rectal gel included children 2 years of age and older. Clinical studies have not been 
conducted to establish the efficacy and safety of Diazepam rectal gel in children under 2 
years of age. 
Most AEs were mild-to-moderate in severity and transient in nature. The most frequent 
AE reported with diazepam rectal gel in the two double-blind, placebo-controlled studies 
was somnolence (23%). Less frequent AE were headache (≤5%), diarrhea (≤4%), ataxia 
(≤3%), dizziness (≤3%), euphoria (≤3%), incoordination (≤3%), rash (≤3%), 
vasodilatation (≤2%), and asthma (≤2%). 
Table 4 below lists treatment-emergent adverse events (TEAEs) that occurred in >1% of 
patients enrolled in parallel-group, placebo-controlled trials and that were numerically 
more common in the diazepam rectal gel group.  


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Table 4. Treatment-Emergent Adverse Events That Occurred in >1% of Patients 
Enrolled in Parallel-Group, Placebo-Controlled Trials and were 
Numerically More Common in the Diazepam Rectal Group 
Body System 
COSTART Term 
Diastat 
n=101  
% 
Placebo 
n=104 
% 
Body as a Whole 
Headache 
5% 
4% 
Cardiovascular 
Vasodilatation 
2% 
0% 
Digestive 
Diarrhea 
4% 
<1% 
Nervous  
Ataxia 
3% 
<1% 
Dizziness 
3% 
2% 
Euphoria 
3% 
0% 
Incoordination 
3% 
0% 
Somnolence 
23% 
8% 
Respiratory 
Asthma 
2% 
0% 
Skin and Appendages 
Rash 
3% 
0% 
COSTART = Coding Symbols for a Thesaurus of Adverse Reaction Terms  
Source: (Diastat® AcuDial™ rectal gel prescribing information December 2016) 
Approximately 1.4% of the 573 patients who received diazepam rectal gel in clinical 
trials of epilepsy discontinued treatment because of an AE. The AE most frequently 
associated with discontinuation (occurring in three patients) was somnolence. Other AEs 
most commonly associated with discontinuation and occurring in two patients were 
hypoventilation and rash. AEs occurring in one patient were asthenia, hyperkinesia, 
incoordination, vasodilation, and urticaria. These events were judged to be related to 
diazepam rectal gel.  
6.6.2. 
Diazepam Buccal Film 
A total of 9 clinical studies have been conducted with DBF (6 completed, 3 ongoing). 
Pooled data for the most frequently reported TEAEs in the 6 completed studies are 
provided in Table 5. Somnolence was the most frequently reported TEAE in all DBF 
dose groups followed by dizziness.  
Three subjects discontinued study due to a TEAE, all in 15 mg dose groups: blood 
pressure increased assessed as not related to study drug in Study 162013; severe and 
serious depressed level of consciousness and severe somnolence in Study 162021. 


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Table 5: Pooled Data for Most Frequently Reported Treatment-Emergent Adverse 
Events in Six Completed Studies (1899, 1900, 162013, 162021, 162022, 
172018) 
 
DBF 
MedDRA 
5 mg 
10 mg 
15 mg 
20 mg 
System Organ Class 
N = 38 
N = 26 
N = 105 
N = 12 
Preferred Term 
n (%) 
n (%) 
n (%) 
n (%) 
Any TEAE 
15 (39.5) 
15 (57.7) 
92 (87.6) 
12 (100) 
Nervous System Disorders 
 
Somnolence 
13 (34.2) 
10 (38.5) 
75 (71.4) 
22 (57.9) 
Dizziness 
1 (2.6) 
1 (3.8) 
12 (11.4) 
1 (8.3) 
Headache 
0 
0 
0 
1 (8.3) 
Gastrointestinal Disorders 
 
Hiccups 
0 
0 
8 (7.6)a 
1 (8.3) 
General Disorders and Administration Site Conditions 
 
Gait disturbance 
0 
0 
0 
1 (8.3) 
Asthenia 
0 
0 
0 
1 (8.3) 
Feeling of relaxation 
0 
0 
9 (11.1) 
0 
Investigations 
Aspartate aminotransferase increased 
0 
0 
2 (2.5) 
0 
Blood creatine phosphokinase increased 
0 
0 
2 (2.5) 
0 
Psychiatric Disorders 
 
 
 
 
Euphoric mood 
0 
0 
3 (2.8) 
0 
DBF = diazepam buccal  film; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = 
treatment-emergent adverse event 
a Coded to System Organ Class Respiratory, Thoracic, and Mediastinal Disorders 
6.6.3. 
Overdosage 
According to the prescribing information for Diastat® AcuDial™ rectal gel (December 
2016), previous reports of diazepam overdosage have shown that manifestations of 
diazepam overdosage include somnolence, confusion, coma, and diminished reflexes. 


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Respiration, pulse, and blood pressure should be monitored, as in all cases of drug 
overdosage, although, in general, these effects have been minimal. General supportive 
measures should be employed, along with intravenous fluids, and an adequate airway 
maintained. Hypotension may be combated by the use of levarterenol or metaraminol. 
Dialysis is of limited value. 
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete 
or partial reversal of the sedative effects of benzodiazepines and may be used in 
situations when an overdose with a benzodiazepine is known or suspected. Prior to the 
administration of flumazenil, necessary measures should be instituted to secure airway, 
ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a 
substitute for, proper management of benzodiazepine overdose. Patients treated with 
flumazenil should be monitored for re-sedation, respiratory depression and other residual 
benzodiazepine effects for an appropriate period after treatment. The prescriber should be 
aware of a risk of seizure in association with flumazenil treatment, particularly in long-
term benzodiazepine users and in cyclic antidepressant overdose. Caution should be 
observed in use of flumazenil in epileptic patients treated with benzodiazepines. The 
complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, 
and PRECAUTIONS, should be consulted prior to use. 


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7. 
STUDY OBJECTIVES  
The primary objective is to assess the pharmacokinetics of DBF in pediatric subjects with 
epilepsy in (A) the interictal state and (B) the ictal/peri-ictal state.  
(A) Subjects are considered to be in an interictal state if an interval of at least 3 hours 
has elapsed since any clinical observable postictal signs or symptoms (from the 
last observed seizure) and the subject has been seizure free over this period. 
Subjects on electroencephalogram (EEG) monitoring can be considered to be in 
an interictal state if an interval of at least 3 hours has elapsed since any postictal 
electrical findings on EEG. 
(B) For the purposes of this study, the ictal state is defined as an ongoing clinically 
observable seizure or seizure activity as verified via EEG. The peri-ictal state is 
defined clinically as the subject’s immediate postictal state following a 
generalized tonic-clonic (GTC) seizure or focal seizure with impaired awareness, 
and within 5 minutes following the last clonic jerk. For subjects on EEG 
monitoring, the peri-ictal state may be defined as less than 5 minutes after 
cessation of seizure activity as verified via EEG. 
Secondary objectives: 
• Evaluate the safety/tolerability of DBF in pediatric subjects with epilepsy  
• Evaluate the usability of DBF  
Data from this study are intended to support a 505(b)(2) New Drug Application for the 
test product. 


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8. 
STUDY DESIGN 
8.1. 
Discussion of Study Design 
8.1.1. 
Study Design  
This study uses a multicenter, open-label, crossover design with the following periods: 
Screening Visit, Treatment Period A (interictal DBF dosing and pharmacokinetic 
evaluation, subjects aged 6-16 years), minimum washout period of 14 days between DBF 
treatment periods, Treatment Period B (ictal/peri-ictal DBF dosing and pharmacokinetic 
evaluation, all subjects), and Follow-up 14 (±2) days after treatment. Definitions of the 
interictal and ictal/peri-ictal states are given in Section 7. If the subject must remain in the 
Epilepsy Monitoring Unit (EMU) or General Clinical Research Center (GCRC) for 
medical reasons after the end of Treatment Period A or B, this time will be designated as 
Post-treatment. The treatment periods may occur in either order depending on occurrence 
of seizures.  
Male or female pediatric subjects (age 2-16 years) who are scheduled to enter the EMU 
or GCRC for evaluation and treatment of their epilepsy and who meet the inclusion and 
exclusion criteria are eligible to participate in this study. Subjects aged 2 to 5 years will 
undergo Treatment B only. Subjects aged 6 to 16 years will undergo both Treatment A 
and Treatment B. 
8.1.2. 
Screening Period  
The Screening Period (Section 9.1) will occur 0 to 28 days prior to the first treatment 
period. The subject or subject’s legally authorized representative must provide written 
informed consent prior to the initiation of any screening procedures, and subjects must 
provide oral and/or written assent as required by the Institutional Review Board (IRB). 
During the Screening Period, the subject will be evaluated for study participation as 
described in Section 9.1 and Section 9.2.  
8.1.3. 
Treatment Periods  
The treatment periods (Section 11.2) will begin at a time of day consistent with usual 
EMU/GCRC protocol. Subjects will arrive at the EMU, GCRC, or similar facility on their 
scheduled day and time. Subjects are to continue taking their regular AEDs prior to and 
throughout each Treatment Period (in accordance with EMU or GCRC protocol).  


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Check-in Procedures: Subjects will undergo standard admission procedures, including 
the placement of an indwelling cannula for intravenous access, assessment of medical 
history, medications, vital signs (oxygen saturation [SaO2) via pulse oximetry, respiratory 
rate [RR], heart rate [HR], blood pressure [BP], temperature), 12-lead electrocardiogram 
(ECG), and the Columbia Suicide Severity Rating scale (C-SSRS) as age-appropriate. At 
the Investigator’s discretion, urine drug tests and a breath alcohol test will be performed 
on all subjects. Urine pregnancy tests will also be performed for women of childbearing 
potential. 
The Investigator or medical staff will review results from the Screening Period and, if 
applicable, results from the previous treatment period, including vital signs (SaO2 via 
pulse oximetry, RR, HR, BP, temperature), 12-lead ECG, clinical laboratory tests, and 
AEs. The subject’s informed consent and/or assent as applicable, medical history, 
medications, use of restricted substances, and results from the current visit assessments 
will be reviewed for eligibility and safety. If this is a first treatment visit, subjects who do 
not meet the inclusion and exclusion criteria will not be enrolled. Subjects who meet 
inclusion and exclusion criteria will be enrolled.  
• Enrollment end-date is 05 March 2020.  
If enrolled subjects who have completed a previous treatment visit no longer meet 
inclusion and exclusion criteria, they will be discontinued from the study.  
A study drug kit will be assigned by the Interactive Web Response System (IWRS). 
Appropriately delegated clinical staff at each clinical site will use the IWRS to assign a 
kit of the appropriate dose (from the available 5, 7.5, 10, 12.5, 15, and 17.5 mg DBF 
doses) based on the subject’s weight and age.  
Clinical monitoring will be initiated. Continuous video EEG monitoring for seizure 
detection will also be initiated as indicated by EMU or GCRC protocol Sites will 
maintain the EEG recordings with the study documents, but data from the EEG 
recordings will not be collected for the study dataset.  
Treatment Period A (Subjects aged 6-16 years): Subjects will enter Treatment Period 
A as scheduled if at least a 3-hour interval has elapsed since any clinical postictal signs or 
symptoms (from the last observed seizure) have been observed and the subject has been 
seizure free over this period. If clinical assessment (and EEG monitoring, if applicable) 
show no seizure activity, the subject will receive a single dose of 5 mg, 7.5 mg, 10 mg, 
12.5, 15, or 17.5 mg DBF, based on the subject’s weight and age (Table 9) (see 
placement diagram in Appendix A). Safety and PK assessments will be performed as 


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described below. Clinical monitoring will continue until the end of the treatment period 
(4 hours), and video EEG monitoring will continue as specified by EMU or GCRC 
protocol.  
If the subject experiences a seizure before dosing during Treatment Period A, and if it has 
been determined that the subject meets the inclusion and exclusion criteria, the 
Investigator may regard this visit as Treatment Period B, and Treatment A will be 
rescheduled. If no seizure occurs and Treatment Period A is completed, the subject will 
be scheduled for Treatment Period B. 
Treatment Period B (All Subjects): Monitoring for the occurrence of seizures as per 
EMU or GCRC protocol will continue until the subject experiences a qualifying (GTC 
seizure or focal seizure with impaired awareness). If the subject’s AEDs are to be tapered 
(e.g., if per EMU or GCRC protocol), the Investigator will determine and record the time 
to begin tapering the AEDs, including the doses administered or prescribed, percent dose 
reduction, and tapering rate.  
Seizure management and the required intervention will be determined by the Investigator. 
Subjects with a GTC seizure or focal seizure with impaired awareness who are 
determined to be medically appropriate to receive study drug (DBF) will receive a single 
dose of 5 mg, 7.5 mg, 10 mg, 12.5, 15, or 17.5 mg DBF, based on the subject’s weight 
and age (Table 9)  
• during the seizure, OR 
• within 5 minutes after the last clonic jerk, AND/OR  
• within 5 minutes after cessation of the seizure as verified via EEG.  
If the subject’s seizure persists after the single dose of DBF, an alternative anti-epileptic 
drug (AED) (rescue medication) may be administered as medically required according to 
the standard-of-care EMU or GCRC treatment protocol. Any alternative AED 
medications will be recorded in the study CRF. The physician in charge will be 
encouraged but not required to use intravenous lorazepam for rescue in preference to 
intravenous diazepam. The Investigator is permitted to discontinue the subject from the 
study protocol at any time throughout the study protocol. At the end of the treatment 
period, clinical seizure assessment, AEDs and concomitant medications, and AEs will be 
reviewed. If AEDs were tapered previously, the Investigator will determine and record 
the time to restart the subject’s AED medications, including the doses administered or 
prescribed and the schedule for percent dose increase. 


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8.1.4. 
Post-treatment  
If the subject remains in the EMU, GCRC, or similar facility following the end of the 
treatment period, that time will be regarded as a post-treatment period. While the subject 
remains in the EMU, GCRC, or similar facility, general seizure activity, administration of 
additional AEDs, surgical treatment of their epilepsy, and AEs will be recorded. The 
subject will be discharged when medically stable.  
8.1.5. 
Follow-up Visit  
Safety data (including concomitant medications, vital signs including SaO2 via pulse 
oximetry, clinical laboratory tests including urine pregnancy test in females of 
childbearing potential, AEs, physical and neurological examinations, C-SSRS, and 
inspection of oral mucosa) will be obtained at a follow-up visit in an outpatient setting (to 
be determined by Investigator or Staff) at 14 ± 2 days after the last treatment period (A or 
B). 
8.1.6. 
Pharmacokinetic and Safety Assessments 
The following assessments will be performed (see Section 11.4 for details):  
Diazepam PK (Section 11.4.1). In the two pilot studies conducted by the Sponsor in 
healthy male and female volunteers to assess the bioavailability of DBF, the median Tmax 
for DBF was 0.67 hours (range 0.33-1.50 hours) in Study 1899 and 1.5 hours (range 0.36-
2.05 hours) in Study 1900. Therefore, in both treatment periods in the present study, 
plasma samples for diazepam and the active metabolite desmethyldiazepam PK will be 
obtained before DBF administration and post dose at the following time points (±5 
minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours 
(90 minutes), 2 hours (120 minutes), and 4 hours (240 minutes). Collection of plasma 
samples will continue regardless of whether another AED is administered for rescue. 
Vital Signs. The subject’s SaO2, BP, HR, RR, and temperature will be recorded at 
Screening, at check-in predose, during the treatment visits and post dose, and at Follow-
up as described in Section 11.6. 
Oral Mucosal Inspection. As described in Section 11.9, to check for any mucosal 
irritation, an illumination-assisted visual inspection of the DBF application site will be 
performed at Screening; at each treatment visit prior to study drug administration and 
approximately 0.25 hours (15 minutes), 0.5 hours (30 minutes), and 1 hour (60 minutes) 
after application of the film (±5 minutes for all time points); and at Follow-up.  


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Usability. The usability of DBF will be evaluated by assessing oral cavity insertion, 
retention, and placement after each administration during the treatment periods as 
described in Section 11.10.  
Laboratory Safety. Blood samples will be collected for laboratory safety at Screening 
and at Follow-up or upon early termination (Section 11.4.2).  
ECG. A 12-lead ECG will be obtained at Screening and at each treatment period, both 
predose and 4 hours after dosing (Section 11.7). 
8.2. 
Study Duration and Washout 
The study includes the Screening Period 0-28 days before Day 1; Treatment Period A 
(interictal, for subjects aged 6 to 16 years (inclusive) 1 day; a minimum washout period 
of 14 days between DBF treatment periods; Treatment Period B (ictal/peri-ictal, for all 
subjects) 1 day; and Follow-up 14 days (±2 days) after the second treatment period. Thus, 
the minimum study duration will be approximately 30 days for subjects aged 6 to 16 
years (inclusive) and 15 days for subjects aged 2 to 5 years (inclusive). The maximum 
study duration (including screening) will be approximately 58 days for subjects aged 6 to 
16 years and 43 days for subjects aged 2 to 5 years. 
8.3. 
Randomization and Blinding 
This is an open-label study. Neither subjects nor clinic staff will be blinded. The 
treatment order (order of Treatment Period A and Treatment Period B) will not be 
randomized. 


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9. 
SUBJECT SELECTION 
Enrollment end-date is 05 March 2020. 
9.1. 
Screening Procedures 
Screening procedures will be conducted 0 to 28 days prior to the first treatment period. 
The following screening procedures will be conducted for each potential subject: 
• Obtain written informed consent as evidenced by potential subject’s parent(s) or 
legally authorized representative signing an Informed Consent Form (ICF). 
Obtain verbal and/or written assent from the subject as required by the IRB. 
Subjects, parents, and legally authorized representatives will be given an 
opportunity to ask questions about the study before giving consent/assent.  
• Register subject in IWRS. 
• Record medical/medication history (including diazepam or benzodiazepines, 
smoking history, etc), and demographic information based on existing medical 
records and an interview with the potential subject. 
• Administer age-appropriate versions of the Columbia-Suicide Severity Rating 
Scale (subjects age 7 and older – see Section 11.5). For non-verbal subjects, the 
C-SSRS assessments should be personally completed by the subject using non-
verbal methods with assistance of site staff trained for these assessments. If the 
scales cannot be completed, the site must document this.  
• Collect urine samples for urinalysis and drug screening (see Section 11.4.2).  
• Receiving any dosage form of diazepam or other benzodiazepines with the 2 
weeks prior to the screening is not a reason to postpone screening procedures. 
However, if the subject or subjects’ parent(s) or legally authorized representative 
reports that the subject has received any dosage form of diazepam (all other 
benzodiazepines are allowed) within the 2 weeks prior to the day of admission to 
clinic, then the clinic admission for treatment should be deferred for a minimum 
of 2 weeks and a maximum of 4 weeks. If the subject or parent(s) or legally 
authorized representative reports that the subject has taken no diazepam and the 
urine test is positive for benzodiazepines, then the Investigator should review the 
medication history to determine whether it is consistent with the positive urine 
test for benzodiazepines.  


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• To allow a subject who tests positive for tetrahydrocannabinol (THC) at screening 
to continue in the study, verify and affirm in writing that the use of a medical 
marijuana product is part of the subject’s treatment plan as recommended by a 
physician for treatment of a medical condition.  
• Obtain height and body weight. 
• Obtain vital signs (SaO2, temperature, RR, HR, BP) and 12-lead ECG. 
• Collect blood samples for hematology, chemistry, and pregnancy testing (for 
females of childbearing potential). For a complete listing of all tests to be 
performed, see Section 11.4.2. 
• Perform breath alcohol test in subjects.  
• Perform a physical and neurological examination. 
• Dispense seizure diaries, with instructions to subjects or parent(s) or legally 
authorized representatives to record the number of seizures, AED dosing, use of 
rescue, and any AEs. 
• Investigator reviews inclusion/exclusion criteria and all screening results/data to 
assess eligibility of each potential subject. 
9.2. 
Inclusion/Exclusion Criteria 
9.2.1. 
Inclusion Criteria 
Potential subjects meeting all of the following criteria may be included in the study: 
1. Subjects have a clinical diagnosis of epilepsy (GTC seizures or focal seizures with 
impaired awareness) and are scheduled for admission to an Epilepsy Monitoring 
Unit (EMU), General Clinical Research Center (GCRC), or similar facility for 
evaluation. 
2. Male and female subjects between 2 and 16 years of age, inclusive. 
3. Subjects have a body weight of ≥6 kg and 111 kg.† 
†  Subjects with body weight in the range 112 to 134 kg (247 to 295 pounds) may 
participate in the study at the discretion of the Investigator. 
4. Subjects have an average frequency of >1 clinically apparent seizures every 3 
days or >10 clinically apparent seizures per month, with alteration of 


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consciousness as documented by reliable subject report, personal seizure diary 
records, and/or by seizure diaries dispensed at Screening and verified prior to 
Treatment Period A or Treatment Period B. 
5. Female subjects of childbearing potential (i.e., are having periods, are not 
surgically sterile) must have a negative serum pregnancy test (ß-hCG) at 
Screening and a negative urine pregnancy test on Day 1 prior to drug dosing. 
Female subjects of childbearing potential must agree to abstinence, have a partner 
who is sterile, or be practicing double barrier contraception or have been using an 
FDA-approved contraceptive (e.g., licensed hormonal or barrier methods) for 
greater than 2 months prior to screening visit, and must commit to an acceptable 
form of birth control for the duration of the study and for 30 days after 
participation in the study. 
6. Male subjects with a female sexual partner of childbearing potential must agree to 
abstinence or practice adequate birth control during the study, including at least 1 
barrier method such as a condom, diaphragm, or spermicide for greater than 2 
months prior to screening visit, and must commit to an acceptable form of birth 
control for the duration of the study and for 30 days after participation in the 
study. Also, male subjects must agree to not donate sperm during the study and 
for 90 days after the follow-up visit. 
7. Subjects are currently receiving at least one antiepileptic medication. 
8. Subject’s parent or legally authorized representative must be willing and able to 
complete informed consent and HIPAA authorization. Subjects must be willing to 
give assent as required by the IRB. 
9. Subject must agree to be available or subject’s parent(s) or legally authorized 
representative must agree to have the subject be available for both treatment 
periods and the follow-up visit and must be willing to comply with all required 
study procedures and adhere to all protocol requirements. 
10. Subject or subject’s parent(s) or legally authorized representative must be able to 
comprehend and be informed of the nature of the study, as assessed by the 
Investigator. 
9.2.2. 
Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded: 


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1. Subjects with a progressive neurological disorder such as a brain tumor, 
demyelinating disease, or degenerative central nervous system (CNS) disease that 
is likely to progress in the next 12 months. 
2. Subject has respiratory failure (or is at risk for respiratory failure) or other severe 
cardiorespiratory disease with New York Heart Association Class III or IV 
functional status or requires supplemental oxygen. 
3. Female subjects who are lactating, have a positive serum pregnancy test (ß-hCG) 
at screening, or have a positive urine pregnancy test at Check-in for treatment 
periods. 
4. Subjects with psychiatric disease that in the Investigator's judgment would 
prevent the subject's successful completion of the study. 
5. Subject has a recent history of suicide attempt (defined as an active, interrupted, 
or aborted attempt with the past five years) or reports suicidal ideation in the past 
six months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the C-SSRS performed at the Screening Visit. 
6. Subjects with known history or presence of any clinically significant hepatic (e.g., 
hepatic impairment), renal/genitourinary (renal impairment, kidney stones), 
psychiatric, dermatological, or hematological disease or condition, unless 
determined as not clinically significant by the Investigator or designee and 
confirmed by Sponsor via written communication prior to subject enrollment. 
Abnormal laboratory results considered clinically significant by the Investigator 
or designee will be evaluated by the Investigator in consultation with the Medical 
Monitor. 
7. Subjects with any clinically significant illness other than epilepsy within 30 days 
prior to study drug administration, as determined by the Investigator. 
8. Subjects with any significant physical or organ abnormality or other condition 
that would interfere with study participation or constitute a safety risk in the 
judgment of the Investigator.  
9. Subjects with any significant lesion of the oral cavity or having oral prophylactic 
or dental procedures within 30 days prior to study drug administration. 
10. Subjects with a QTcF (QT with Fredericia's correction) interval ≥450 msec for 
males or QTcF 470 msec for females on screening ECG, unless determined to be 
not clinically significant by the Investigator. 


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11. Subjects with a positive test result for any of the following drugs of abuse: 
amphetamines, cocaine, opiates, phencyclidine, or a positive breath alcohol test. 
Subjects who test positive for tetrahydrocannabinol (THC) at screening will be 
excluded unless the Principal Investigator is able to affirm in writing that the use 
of a medical marijuana product is part of the subject’s treatment plan as 
recommended by a physician for treatment of a medical condition. In such case, 
the subject will be allowed to continue with screening, and the medical marijuana 
product will be recorded as a concomitant medication. 
12. Subjects with a known history or presence of: 
a. Substance abuse or dependence (including alcohol) within one year prior to 
first study drug administration 
b. Hypersensitivity or idiosyncratic reaction to diazepam, its excipients, 
sodium phosphates, and/or related substances, e.g., benzodiazepines 
c. Glaucoma (open or acute narrow angle) 
d. Severe allergic reactions (e.g., anaphylactic reactions, angioedema) to 
investigational product and excipients  
13. Subjects who have participated in another clinical trial or who received an 
investigational drug within 30 days prior to study drug administration or 5 half-
lives of the investigational drug—whichever is the longer period.  
14. Subjects with presence of mouth jewelry, dentures, oral implants, braces, or 
piercings in the mouth or tongue that, in the opinion of the Principal Investigator, 
would be likely to interfere with successful completion of the dosing procedure. 
15. Subjects with a blood or plasma donation within 30 days prior to Screening. 
16. Subjects not willing or unable to tolerate blood draws. 
17. Consumption of alcohol within 48 hours before dosing; or food or beverages 
containing grapefruit, star fruit, Seville oranges, and/or pomelo, or their derived 
products (e.g., fruit juice) within 10 days prior to study drug administration. 
18. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome 
(CYP) 450 enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, 
ciprofloxacin, fluconazole, ketoconazole, diltiazem, or human immunodeficiency 
virus [HIV] antivirals) and strong inducers of CYP enzymes (e.g., 
glucocorticoids, St. John´s Wort, or rifampicin), in the previous 30 days prior to 


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study drug administration. (Barbiturates, carbamazepine, phenytoin, and other 
enzyme-modifying AEDs that are medically needed are permitted.)  
19. Use of any monoamine oxidase (MAO) inhibitors (e.g., phenelzine, 
tranylcypromine), phenothiazines (chlorpromazine) within 30 days prior to first 
study drug administration. 
20. Employee or immediate relative of an employee of Aquestive Therapeutics, any 
of its affiliates or partners, or Syneos Health. 
9.3. 
Permitted and Restricted Items 
Study restrictions are summarized in Table 6. If any subject does not comply with these 
restrictions, at any time prior to or during the study, continued eligibility will be re-
assessed by the Investigator in consultation with the Sponsor. 
Subjects may take concomitant drug or non-drug treatment as needed during study 
participation, unless specified within the protocol as excluded or restricted. Any excluded 
or restricted concomitant drug or non-drug treatments taken will be reported as soon as 
possible to the Sponsor or designee and will be reviewed on a case by case basis to 
determine the subject’s further participation in the study. 
Treatment with a medical marijuana product during the course of the study is acceptable 
as concomitant medication if the Principal Investigator is able to affirm in writing that 
such treatment is a part of the subject’s treatment plan as recommended by a physician 
for treatment of a medical condition. 
All cases of concomitant medication, herbal/dietary supplement administration, or 
consumption of restricted food or beverages from Screening through Follow-up will be 
documented in the CRF. 
 


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Table 6 Study Restrictions 
Restriction Period 
Item Restricted 
Examples 
30 days prior to drug 
administration until after the 
last blood draw in the final 
study period 
Enzyme-modifying drugs  
Strong inhibitors of CYP enzymes (e.g., 
cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, diltiazem, or HIV antivirals) 
Strong inducers of CYP enzymes (e.g., 
glucocorticoids, St. John´s Wort, or 
rifampicin). [Barbiturates, carbamazepine, 
phenytoin, and other AEDs affecting CYP 
enzymes are allowed if medically 
indicated. 
Monoamine oxidase (MAO) 
inhibitors 
Phenelzine, tranylcypromine 
Phenothiazines 
Chlorpromazine 
Note: Spermicidal/barrier 
contraceptive products may 
be permitted. 
 
10 days prior to drug 
administration until after the 
last blood draw in the final 
study period 
Foods and/or beverages 
containing grapefruit 
Grapefruit, grapefruit juice, grapefruit 
candies, star fruit, Seville oranges, and/or 
pomelo, or their derived products (e.g., 
fruit juice)   
48 hours prior to drug 
administration until after the 
last blood draw in each 
study period 
Alcohol of any kind 
Wine, beer, liquor, cocktails 
1 hour after dosing 
Food and water intake  
 
 
9.4. 
Sample Size 
To provide adequate pharmacokinetic, safety, and usability assessment of DBF in the 
pediatric population, 16 to 18 subjects should complete the study, distributed across three 
age ranges as follows: 6 subjects aged 2 to 5 years, 6 subjects aged 6 to 11 years, and 4 to 
6 subjects aged 12 to 16 years. To ensure adequate numbers of completed subjects, 


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efforts will be made to enroll 8 subjects in each age group, for a total of 24 enrolled 
subjects.  
9.5. 
Dropout and Withdrawal/Termination 
Subjects whose participation in the study is discontinued (for any reason) will not be 
replaced. 
A subject is free to withdraw at any time, for any reason. Every attempt will be made to 
record reasons for withdrawal. 
Enrolled subjects who have an episode of status epilepticus at any time during either 
treatment period may be excluded from further study participation at the Investigator’s 
discretion in consultation with the Sponsor. Subjects experiencing emesis after dosing 
will be evaluated (to assess subject safety) on a case-by-case basis by the Investigator and 
the Sponsor, and they will decide on the subject's continued participation. A subject may 
also be removed if necessary to protect their health or the integrity of the study. This 
determination will be made by the Investigator in consultation with the Medical Monitor. 
Removal of a subject from the study will only be permitted prior to commencement of 
bioanalysis. 
If an enrolled subject’s participation is terminated prematurely or the subject withdraws 
from the study, the cause, date, and time of the early termination or withdrawal will be 
documented on the source documents and in the final study report. Efforts will be made 
to obtain an early discontinuation visit at which clinical seizure assessment will be done, 
vital signs including SaO2 will be recorded, physical and neurological examination and 
clinical laboratory tests will be performed, an oral mucosal inspection will be performed, 
and any concomitant medications, including AEDs, will be recorded. 


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10. INVESTIGATIONAL PRODUCT 
10.1. 
Drug Information 
Information on the study drug is given in Table 7.  
Table 7. Study Drug Information 
Drug Name: 
Diazepam 
Strengths: 
5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, and 17.5 
Dosage Form: 
Buccal Film 
Manufacturer: 
Aquestive Therapeutics 
Dose: 
1 x 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 17.5 mg, depending on 
weight and age (see Table 3)  
10.1.1. 
Controlled Substance Documentation 
Diazepam Buccal Film is designated as a Schedule IV controlled substance with abuse 
potential by the US Controlled Substances Act (21 Code of Federal Regulations [CFR] 
§1308). Because the study drug is a controlled substance, drug supplies must be kept in a 
secure, double-locked, substantially constructed enclosure with restricted access. 
Prior to shipment of study drug, the Investigator must provide the Sponsor with a copy of 
a controlled substance license that clearly identifies the registrant and address of the 
registrant. Study drug supplies will be shipped to the registrant and address noted on the 
certificate. 
10.1.2. 
Description of Investigational Product 
Diazepam Buccal Film (DBF) contains the active ingredient diazepam incorporated into a 
polymer-based film matrix utilizing Aquestive Therapeutics’ PharmFilm® technology. 
For the purposes of this pediatric study, the investigational product will be provided at 
the following strengths: 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg and 17.5 mg. 
The film is intended for application to the inner aspect of the cheek where the film 
immediately adheres and begins to hydrate. During the hydration process, the drug, along 
with associated solubility enhancers, are rapidly released onto the buccal mucosa for 
dissolution and absorption. The DBF doses up to 20 mg were tested in a pilot clinical 
study. The inactive ingredient composition, the film dimensions, and the manufacturing 


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process selected for this drug product are based on the information gained from the 
development of the DBF and other film products produced by Aquestive Therapeutics 
(ZUPLENZ® 4 and 8 mg and SUBOXONE® 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 
mg/3mg Sublingual Films). The DBF product is a green rectangular film.  
The primary package used for DBF is a polyester/foil laminate provided by Amcor 
Flexibles (Madison, WI). The material (product code RFE-013) is a multi-layer 
composite consisting of (1) a 12.2-micron layer of polyethylene phthalate, (2) a 
25.4-micron layer of low-density polyethylene, (3) an 8.9-micron layer of aluminum foil, 
and (4) a 38.1-micron layer of low-density polyethylene, and is heat sealed at the edges. 
Each pouch contains one DBF. 
10.2. 
Labeling, Maintenance, and Retention of Study Drugs 
It is the responsibility of the Sponsor to ensure that all drug supplies provided for the 
study are manufactured under current Good Manufacturing Practices and are suitable for 
human use. The Sponsor will supply an authorized clinical supplies vendor with a 
sufficient quantity of the study formulation(s) to allow completion of this study, 
including some spares for replacement drugs. The clinical supply vendor will ship the 
packaged and labeled study drugs for each participating investigator to the Pharmacy or 
Investigator at the address specified on the DEA Controlled Substance certificate.  
The study drugs will be sent to the Site Pharmacy already packed in individual unit-dose 
packages. Each unit-dose package will be labeled in English containing at a minimum the 
Protocol Number, Drug Name, Strength, Kit Identification Number, Route of 
Administration, and a statement “For clinical trial use only.” 
Upon receipt of the study drugs, the Investigator, Pharmacist, or designee will inspect the 
shipment to ensure study drugs are received in good condition. Study drug receipt and 
condition will be promptly registered in the IWRS. The Investigator, Pharmacist, or 
designee will ensure records of receipt and dispensing of study drugs supplied are 
maintained for the duration of the study.  
The Investigator or designee will log into the IWRS to register the subject’s visit and 
have the study drug kit number assigned to the subject. Only this kit will be removed 
from inventory.  
At the completion of the study, all unused study drugs, including the spares, will be 
retained by the Study Site until the authorization to return or destroy is received from the 
Sponsor. 


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11. 
STUDY PROCEDURES 
11.1. 
Schedule of Events 
The schedule of study events is given in Table 8.  
Table 8. Schedule of Events 
 
 
Treatment Aa 
Treatment Ba 
FU 
Procedure/Activity 
Screening  
(Day -28  
to Day 0) 
Check-in†  
(predose) 
Dosing/ 
(postdose) 
Check-in  
(predose) 
Dosing/ 
(postdose) 
(14 ±2 d 
post last 
treatment) 
ICF and assentb 
X 
 
 
 
 
 
Inclusion/Exclusion 
assessment 
X 
X 
 
X 
 
 
IWRS: Register subject, 
determine DBF dose, 
update status 
X 
X 
 
X 
 
X 
Medical 
history/demographics 
X 
X 
 
X 
 
 
Concomitant medication 
review 
X 
X 
 
X 
 
X 
Date/time of the 
subject’s last meal 
before DBF dose 
 
X 
 
X 
 
 
Review of restrictions  
X 
Xc 
Xc 
Xc 
Xc 
 
C-SSRS (age-
appropriate versions) 
X 
X 
 
X 
 
X 
Height and body weight 
Xd 
X 
 
X 
 
 
Oxygen saturation  
X 
Xe 
Xe 
Xe 
Xe 
X 
Blood pressure 
X 
Xf 
Xf 
Xf 
Xf 
X 
Heart rate 
X 
Xf 
Xf 
Xf 
Xf 
X 
Respiratory rate 
X 
Xf 
Xf 
Xf 
Xf 
X 
Temperature 
X 
Xf 
 
Xf 
 
X 
Physical/neurological 
exam 
Xg 
 
 
 
 
X 
ECG 
Xh 
Xh 
Xh 
Xh 
Xh 
 
Pregnancy test 
Xi 
Xi 
 
Xi 
 
Xi 
Clinical laboratory tests 
X  
 
 
 
 
X 


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Treatment Aa 
Treatment Ba 
FU 
Procedure/Activity 
Screening  
(Day -28  
to Day 0) 
Check-in†  
(predose) 
Dosing/ 
(postdose) 
Check-in  
(predose) 
Dosing/ 
(postdose) 
(14 ±2 d 
post last 
treatment) 
Drug screen (urine) 
Xj 
Xj 
 
Xj 
 
 
Breath alcohol test  
X 
X 
 
X 
 
X 
Oral mucosal inspection 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Dispense/collect seizure 
diaries  
X 
X 
 
X 
 
X 
Continuous video EEG 
 
Xl 
Xl 
Xl 
Xl 
 
Study drug dosing 
 
 
X 
 
X 
 
PK sampling 
 
X 
Xm 
X 
Xm 
 
Assessment of usability 
 
 
Xn 
 
Xn 
 
Adverse event reporting 
 
Xo 
Xo 
Xo 
Xo 
Xo 
C-SSRS = Columbia-Suicide Severity Rating Scale; DBF = Diazepam Buccal Film; ECG = 
electrocardiogram; EEG = electroencephalogram; FU = Follow-up; ICF = informed consent form; PK = 
pharmacokinetics.  
† Enrollment end date is 05 March 2020.  
a. 
Only subjects aged 6-16 will undergo Treatment Period A. Treatment Periods A and B may occur 
in either order, depending on seizure occurrence, e.g., if a subject experiences a seizure during the 
first visit to the EMU or GCRC. In such cases, if feasible after IWRS registration, dose 
determination, and review of inclusion/exclusion criteria, the Investigator may regard that period 
as Treatment Period B and schedule another visit for Treatment Period A. 
b. Obtain written informed consent from parent(s) or legally authorized representative. Obtain verbal 
and/or written assent from subjects as required by Institutional Review Board. 
c. 
Confirmed at each ambulatory blood draw, if applicable. 
d. Height measured at Screening only. 
e. 
At both treatment visits, SaO2 via pulse oximetry will be recorded predose and at 5, 10, 20, 30, 40, 
50 minutes post dose and thereafter at each time vital signs are recorded: 1 hour (60 minutes), 1.5 
hours (90 minutes), 2 hours (120 minutes), 3 hours (180 minutes), and 4 hours (240 minutes). 
f. 
At both treatment visits, vital signs (BP, HR, RR, and temperature) are to be recorded predose. 
BP, HR, and RR are to be recorded post dose at the following time points (±5 minutes): 0.25 hours 
(15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours (90 minutes), 2 hours (120 
minutes), 3 hours (180 minutes, even though no blood will be drawn at this time point), and 4 
hours (240 minutes) after dosing. The subject’s position may be seated or supine but should be 
consistent throughout. 


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g. Physical/neurological examination will be performed at Screening and at Follow-up or at an early 
discontinuation visit. 
h. A 12-lead ECG will be obtained at Screening, at the beginning of each treatment period, and at 4 
hours after dose administration. 
i. 
A serum pregnancy test will be performed for females of childbearing potential at Screening; a 
urine pregnancy test will be performed at each treatment period Check-in and at Follow-up. 
j. 
Screening: Receiving any dosage form of diazepam or other benzodiazepines within the 2 weeks 
before screening is not a reason to postpone screening.  
Treatment periods: If the subject or parent(s) or legally authorized representative reports that the 
subject received any dosage form of diazepam (all other benzodiazepines are acceptable) within 2 
weeks prior to the day of admission to the clinic when Treatment Period A or B may be conducted, 
then the admission should be deferred for a minimum of 2 weeks and a maximum of 4 weeks. If the 
subject or parent(s) or legally authorized representative reports that the subject has taken no 
diazepam in the previous 2 weeks but the urine test is positive for benzodiazepines at Check-in the 
Investigator should consider the subject’s drug history and evaluate whether the drug history is 
consistent with the positive urine result. Considering both the drug history and the urine test 
positive for benzodiazepines, the Investigator may choose to reschedule the clinical admission, but 
the protocol does not require the Investigator to reschedule. Subjects who test positive for THC at 
screening may participate if the Principal Investigator is able to affirm in writing that the use of a 
medical marijuana product is part of the subject’s treatment plan as recommended by a physician 
for treatment of a medical condition. In such case, the medical marijuana product will be recorded 
as a concomitant medication. 
k. The Investigator will make an illumination-assisted visual inspection of the oral mucosa during 
Screening and during each treatment period prior to study drug administration and at 
approximately 15 minutes, 30 minutes, and 60 minutes after film placement. A further inspection 
of oral mucosa will be made at Follow-up. 
l. 
If indicated by EMU or GCRC protocol, continuous video EEG monitoring for seizure detection 
will be performed throughout each treatment period (4 hours). Sites will maintain the EEG 
recordings with the study documents, but data from the EEG recordings will not be collected for 
the study dataset.  
m. For both treatment periods, plasma samples for determination of diazepam and 
desmethyldiazepam PK samples are to be obtained at predose and post dose at the following time 
points (±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 
hours (90 minutes), 2 hours (120 minutes), and 4 hours (240 minutes) after dosing. Collection of 
plasma samples will continue even if the administration of another AED is needed for rescue. 
n. The study staff will evaluate the insertion process to determine usability of the film as described in 
Section 11.10. 
o. AEs are to be collected from time of consent throughout the study.  


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11.2. 
Treatment Periods A and B 
11.2.1. 
Check-in Procedures  
For each treatment period, subjects will undergo standard admission procedures as 
described below, including the placement of an indwelling cannula for intravenous 
access, assessment of medical history, medications, date/time of the subject’s last meal 
before the DBF dose, vital signs, urine pregnancy test in females of childbearing 
potential, urine drug screen, breath alcohol test, 12-lead ECG, and the Columbia Suicide 
Severity Rating scale (C-SSRS), as age appropriate.  
Subjects and their parent(s) or legally authorized representatives will be questioned about 
whether they have complied with the study restrictions. If a restricted drug or non-drug 
therapy specified in the protocol was used, a decision to continue or discontinue the 
subject’s participation will be made by the Investigator and/or by the Sponsor.  
If the subject or subjects’ parent(s) or legally authorized representative reports that the 
subject received any dosage form of diazepam (all other benzodiazepines are acceptable) 
within the 2 weeks prior to the day of admission, then the admission should be postponed 
for a minimum of 2 weeks and a maximum of 4 weeks. If the subject, parent(s) or legal 
representative reports that the subject has taken no diazepam and the urine test is positive 
for benzodiazepines, then the Investigator may choose to postpone the clinic admission 
after considering both the subject’s drug history and the urine test positive for 
benzodiazepines. 
At each period check-in, the Investigator will review results from the Screening Period 
and, if applicable, results from the previous treatment period, including vital signs (SaO2, 
BP, HR, RR, temperature), 12-lead ECG, and clinical laboratory tests, informed consent, 
medical history, medications, seizure diaries, use of restricted substances, results of drug 
tests, breath alcohol test, and pregnancy test. Results from the current visit assessments 
will also be reviewed for eligibility and safety. If this is a first treatment visit, subjects 
who do not meet the inclusion and exclusion criteria will not be enrolled. Subjects who 
meet inclusion and exclusion criteria will be enrolled. If enrolled subjects who have 
completed a previous treatment visit no longer meet inclusion and exclusion criteria, they 
will be discontinued from the study.  
A study drug kit will be assigned by the Interactive Web Response System (IWRS). 
Appropriately delegated clinical staff at each clinical site will use the IWRS to assign a 
kit of the appropriate dose (from the available 5, 7.5, 10, 12.5, 15, and 17.5 mg DBF 
doses) based on the subject’s weight and age.  


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Clinical monitoring will be initiated. Continuous video EEG monitoring for seizure 
detection will be initiated as indicated by EMU or GCRC protocol. Sites will maintain 
the EEG recordings with the study documents, but data from the EEG recordings will not 
be collected for the study dataset.  
11.2.2. 
Treatment Period A (Subjects Age 6-16 Years) 
Subjects will enter Treatment Period A as scheduled if at least a 3-hour interval has 
elapsed since any clinical postictal signs or symptoms (from the last observed seizure) 
have been observed and the subject has been seizure free over this period. If clinical 
and/or EEG monitoring show no seizure activity, the subject will receive a single dose of 
DBF as assigned by the IWRS (see placement diagram in Appendix A). Safety and PK 
assessments will be performed as described below. Clinical monitoring will continue 
until the end of the treatment period (4 hours post dose), and video EEG monitoring will 
continue as specified by EMU or GCRC protocol.  
If the subject experiences a seizure before dosing during Treatment Period A, and if 
feasible after IWRS registration, dose determination, and review of inclusion/exclusion 
criteria, the Investigator may regard this visit as Treatment Period B, and Treatment A 
will be rescheduled. If no seizure occurs and Treatment Period A is completed, the 
subject will be scheduled for Treatment Period B.  
11.2.3. 
Treatment Period B (All Subjects)  
During Treatment Period B, the subject will be monitored until a GTC or focal seizure 
with impaired awareness is detected or the Investigator terminates the monitoring period. 
If the subject’s AEDs are to be tapered as per EMU or GCRC protocol, and the 
Investigator will determine and record the time to begin tapering the AEDs, including the 
percent dose reduction and tapering rate.  
Seizure management and the required intervention will be determined by the Investigator. 
Subjects with a GTC seizure or focal seizure with impaired awareness who are 
determined to be medically appropriate to receive study drug (DBF) will receive a single-
dose of DBF (dose level determined via the IWRS) during the seizure or within 5 minutes 
after the last clonic jerk or within 5 minutes after cessation of the seizure as verified via 
EEG.  
If the subject’s seizure persists after the single dose of DBF, an alternative AED 
medication (rescue medication) can be administered as medically required and according 
to the standard-of-care EMU or GCRC treatment protocol and recorded in the study CRF. 


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The physician in charge will be encouraged but not required to use intravenous lorazepam 
for rescue and to avoid using intravenous diazepam. The Investigator will be allowed to 
discontinue the subject from the study protocol at any time throughout the study.  
11.2.4. 
Dosing 
DBF is provided in a range of doses from 5 to 17.5 mg to facilitate optimal dosing (see 
Section 6.5). The recommended dose of DBF is dependent on the subject’s age and 
weight. The Investigator or attending EMU or GCRC medical staff will use the IWRS 
(based on Table 9) to choose appropriate doses for pediatric subjects.  


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Table 9. Calculated Prescribed Dose of Diazepam Buccal Film 
Weight (kg) 
Protocol-Specified Dose (mg) 
Age 2–5 Years 
6 to 10 
5 
11 to 15 
7.5 
16 to 20 
10 
21 to 25 
12.5 
26 to 30 
15 
31 to 35 
15 
36 to 44 
17.5 
Age 6–11 Years 
 
10 to 16 
5 
17 to 25 
7.5 
26 to 33 
10 
34 to 41 
12.5 
42 to 50 
15 
51 to 58 
15 
59 to 74 
17.5 
Age 12–16 Years 
14 to 25 
5 
26 to 37 
7.5 
38 to 50 
10 
51 to 62 
12.5 
63 to 75 
15 
76 to 87 
15 
88 to 111a 
17.5 
a Subjects with body weight in the range 112 to 134 kg (247 to 295 pounds) may participate in the study at 
the discretion of the Investigator. 
 
 


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Before administration of the DBF, the Investigator will perform an oral safety inspection 
as described in Section 11.9. The dosing process will consist of the following steps: 
• When opening the foil pouch containing the study drug, staff are to use scissors to 
carefully cut along the wide edge of the pouch and use gloves when handling and 
administering the study drug to the subject.  
• Subjects will be instructed to swallow saliva and then open their mouth.  
• If the predose oral safety assessment reveals evidence of mucosal injury or 
irritation (e.g., a cheek bite resulting from a seizure), care should be taken to 
avoid placement of DBF in that area.  
• Staff will place the film on the tip of a finger and then use the finger to insert the 
film into the subject’s mouth. 
• The film is to be centered against the inner aspect of the right or left cheek, so that 
it adheres to the buccal mucosa (refer to Appendix A for a diagram of film 
placement).  The film may be placed without regard to the location of the parotid 
duct.  
• Subjects should be placed in a comfortable position. 
• The subject will be instructed to close his/her mouth in a natural way, without 
swallowing, chewing, biting, or breaking the DBF. 
• Staff will observe the patient during this 15-minute period. It should be noted 
whether the subject chews, talks, moves the film, spits it out, or blows it out of his 
or her mouth. If the subject spits the film out or blows it out of his or her mouth, 
Staff should try to reinsert the film, if possible. No second film should be applied. 
• Dosing time will be set to the time the film is placed on the buccal mucosa. At 15 
minutes after film placement, the subject will be asked to swallow any remaining 
film remnants, and the subject’s hands will be inspected to check whether the 
subject had removed the film (or a part of the film) from the mouth.  
• The study staff will evaluate the insertion process to determine usability of the 
film as described in Section 11.10. As noted in Section 11.9, the Investigator will 
again perform post-dose oral safety assessments at 15, 30, and 60 minutes after 
film placement. 


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11.2.5. 
Post-treatment  
If the subject remains in the EMU, GCRC, or similar facility following the end of 
Treatment Period A or B, that time will be regarded as a post-treatment period. While the 
subject remains in the EMU, GCRC, or similar facility, general seizure activity, 
administration of additional AEDs, surgical treatment of their epilepsy, and AEs will be 
recorded. The subject will be discharged when medically stable. 
11.3. 
Follow-up  
Safety data including concomitant medication, vital signs, clinical laboratory tests 
(hematology, serum chemistry, urinalysis, including urine pregnancy test, as described in 
Section 11.4.2), AEs, physical and neurological examinations, C-SSRS, inspection of oral 
mucosa), and review of personal seizure diary records will be obtained at a follow-up visit 
in an outpatient setting (to be determined by Investigator or Staff) at 14 ± 2 days after the 
last treatment period (A or B), or after withdrawal/ discontinuation of a subject from the 
study (where possible). 
11.4. 
Blood Sampling Schedule, Sample Collection, Processing, and 
Storage 
Blood will be obtained by direct venipuncture in the arm, or via an indwelling cannula. 
Subjects may use up to a total of 2 indwelling cannulas in each study period. A third 
indwelling cannula may only be used upon authorization by the Investigator or qualified 
designee. If the cannula fails to work (i.e., it becomes clogged), the remaining samples 
will be taken by direct venipuncture.  
Blood sample collection times will be recorded on the appropriate source documents and 
reported for each subject. 
11.4.1. 
Pharmacokinetic Assessments 
During both treatment periods, plasma samples for determination of diazepam and the 
active metabolite, desmethyldiazepam PK will be obtained at predose (0 hours), and at 
the following time points (±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 
1 hour (60 minutes), 1.5 hours (90 minutes), 2 hours (120 minutes), and 4 hours (240 
minutes) after dosing. Collection of plasma samples will continue even if the 
administration of another AED is needed for rescue. 


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Blood PK samples will be placed in a refrigerated centrifuge within 30 minutes from the 
time of collection and centrifuged at approximately 3000 revolutions per minute (RPM) 
for 10 minutes under refrigerated (approximately 4°C) conditions.  
After centrifugation, the plasma will be aspirated and aliquoted into 2 pre-chilled clear 
polypropylene tubes. A minimum of 1 mL plasma will be transferred to the first tube, and 
the remaining plasma (if any) will be aliquoted into a second tube. Samples that are 
disturbed during the separation process will be re-spun under the same conditions in an 
attempt to obtain the maximum amount of plasma from each sample. Polypropylene 
tubes will be pre-chilled and pre-labeled with at least the following information: Time 
point, Protocol Number, Study Period, Aliquot Number, Matrix, and Subject Number. 
The samples will be stored at -20°C or colder in a freezer pending shipment. Samples 
must be placed in the freezer within 70 minutes from the start of centrifugation. 
Throughout sample collection and following centrifugation, the samples will be 
maintained in an ice-bath until stored in the freezer. 
Details regarding the proper collection, preparation, labeling, storage, and shipment of 
plasma samples for PK analysis will be provided by the central laboratory in a lab 
manual. 
11.4.2. 
Clinical Laboratory Assessment 
Blood samples will be collected for laboratory safety tests at Screening and at Follow-up 
or upon early study discontinuation. 
Blood and urine specimens will be collected by qualified study center personnel at all 
visits and sent to a central laboratory for analysis of the parameters specified in Table 10. 
Abnormal laboratory test results will be flagged by the central laboratory. Detailed 
instructions of sample collection, storage, and shipping will be provided by the central 
laboratory in a lab manual. 
All clinically important abnormal laboratory tests occurring during the study will be 
repeated and followed until they resolve (return to normal or baseline values) or stabilize, 
or until they are considered by the Investigator to be no longer clinically significant. 
 


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Table 10 Clinical Laboratory Assessments 
TYPE OF TEST 
COMPONENTS 
Hematology 
• Hemoglobin 
• Hematocrit 
• RBC 
• Platelet count  
• WBC and differential  
• Peripheral blood smear 
Serum chemistry 
• Glucose 
• Calcium 
• Sodium 
chloride 
• Albumin 
• Protein 
• Bilirubin 
• Lactate 
dehydrogenase 
• AST 
• ALT 
• Potassium 
• Alkaline 
phosphatase 
• BUN 
• Uric acid 
• Creatinine 
• Creatine kinase 
• Pregnancy (ß-hCG)a 
Urinalysis 
• Bilirubin 
• Blood  
• Glucose 
• pH  
• Ketones 
• Leukocytes 
• Nitrites 
• Protein 
• Pregnancya 
• Specific gravity 
• UBG  
Additional tests 
Breath alcohol test as per EMU/GCRC protocol 
Urine drug tests  
Amphetamines, Phencyclidine, Cocaine, Opiates, Benzodiazepines, THC  
Diazepam & 
desmethyldiazepa
m 
Active drug and metabolite in DBF formulation 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
RBC = red blood cells; THC = tetrahydrocannabinol; UBG = urobilinogen; WBC = white blood cells.  
aSerum and urine pregnancy tests for females of child-bearing potential only 
 
11.4.3. 
Number and Volume of Blood Samples 
The number and volume of blood samples and total blood volume collected per subject 
are shown in Table 11.  


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Table 11 Number and Volume of Blood Samples and Total Blood Volume Collected 
per Subject 
 
 
Maximum # Samples 
 
 
Volume 
(mL) per 
sample 
Screening 
Period A 
Period B 
Follow-up 
TOTAL 
Blood (mL) 
Clinical Chemistry a 
2.5 
1 
- 
- 
1 
5 
Hematology a 
1.2 
1 
- 
- 
1 
2.4 
PK b, c 
2 
 
7 b 
7 b 
 
28 
 
 
 
 
 
 
 
 
 
Maximum Blood Volume (mL) 
 
TOTAL (mL) 
  
3.7 
14 
14 
3.7 
35.4 
 
 
 
 
 
 
 
Type of Vacutainer 
(pediatric) 
PK – pre-chilled K2EDTA Vacutainer®, 2 mL 
Chemistry – Vacutainer®, 2.5 mL 
Hematology – Vacutainer®, 1.2 Ml 
Blood sampling time points 
a. Samples for the clinical laboratory tests will be obtained at Screening and at 
Follow-up (or at early discontinuation). 
b. Plasma samples for diazepam and desmethyldiazepam PK will be obtained 
during both treatment periods at predose (0 hours) and at the following time 
points (±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour 
(60 minutes), 1.5 hours (90 minutes), 2 hours (120 minutes), and 4 hours 
(240 minutes) after dosing.  
c. The actual time of blood sample collection will be used for PK and 
statistical analysis. 
 
11.5. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS, which assesses suicidal behavior and ideation, will be administered at 
Screening, at check-in for each treatment period, and at the Follow-up Visit to subjects 
aged 7 or older. Qualified, trained staff will administer age-appropriate versions of the C-
SSRS: Subjects aged 7-11 will be administered the Children’s Baseline-Screening 
version and Children’s Since Last Contact versions. Subjects aged 12-16 will be 
administered the Baseline-Screening and Since Last Visit versions. 
For non-verbal subjects, the C-SSRS assessments should be personally completed by the 
subject using non-verbal methods with assistance of site staff trained for these 
assessments. If the scales cannot be completed, the site must document this.  


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Subjects with Type 4 (active suicidal ideation with some intent to act, without specific 
plan) or Type 5 (active suicidal ideation with specific plan and intent) suicidal ideation 
are exclusionary for enrollment and, if found during the study, the subject will be 
discontinued from the study and referred to a mental health professional. 
11.6. 
Vital Signs  
The subject’s vital signs (oxygen saturation [SaO2] measured via pulse oximetry, BP, 
HR, RR, and temperature) will be recorded at Screening and during both treatment 
periods, and at the Follow-up Visit.  
Vital signs (BP, HR, RR, and temperature) will be recorded at Screening and (Treatment 
Periods A and B) prior to DBF administration. BP, HR, and RR will be recorded post 
dose at 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours 
(90 minutes), 2 hours (120 minutes), 3 hours (180 minutes), and 4 hours (240 minutes) 
and at the follow-up visit. The subject’s position may be seated or supine but should be 
consistent throughout. 
SaO2 measured via pulse oximetry, will be recorded Screening and (Treatment Periods A 
and B) prior to DBF administration and at 5, 10, 20, 30, 40, 50 minutes post dose and 
thereafter at each time vital signs are recorded: 1 hour (60 minutes), 1.5 hours (90 
minutes), 2 hours (120 minutes), 3 hours (180 minutes), and 4 hours (240 minutes) and at 
the follow-up visit. 
For subjects with pre- or post-dose vital signs outside of the acceptable range for systolic 
blood pressure (90-140 mmHg, inclusive), diastolic blood pressure (50-90 mmHg, 
inclusive), or heart rate (50-100 bpm, inclusive), the measurement will be repeated up to 
two times (at rest, after 5 minutes in a sitting position). If vital signs are still outside of 
the acceptable range, the Investigator will determine the appropriate course of action. 
Methods for the administration of oxygen should be readily available for saturation 
dropping below 90%. The Investigator will determine management of hypoxemia until 
recovery.  
Additional measurements of vital signs will be made if deemed necessary by the 
Investigator. Should a timing conflict arise, blood draws will take precedence over vital 
sign measurements and other scheduled activities, unless deemed otherwise by the 
Investigator. 


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11.7. 
12-Lead Electrocardiogram 
A 12-lead ECG will be obtained at Screening and at the beginning and end of each 
treatment period. 
11.8. 
Physical/Neurological Examination 
A physical and neurological examination will be performed at Screening and at Follow-
up or prior to early termination. 
11.9. 
Oral Safety Assessments 
The Investigator will make an illumination-assisted visual inspection of the oral mucosa, 
including the DBF application site, at the following times: 
• At Screening;  
• During Treatment Periods A and B prior to dosing and at approximately 0.25 
hours (15 minutes), 0.5 hours (30 minutes), and 1 hour (60 minutes) after 
application of the film (±5 minutes for all time points); and  
• At Follow-up.  
Mucosal irritation and any injuries to the oral cavity (e.g., tongue or mucosa laceration, 
broken tooth, bleeding) will be recorded using criteria specified in a checklist in the CRF. 
Any de novo post dose mucosal irritation or other abnormalities will be reported as AEs 
and followed as described in Section 12.1.3. 
11.10. 
Usability 
To assess usability of DBF, oral cavity insertion, retention, and placement will also be 
evaluated for each administration. The following usability endpoints will be reported: 
• Whether successful placement was achieved (Placement is judged to be successful 
when the film adheres to the center of the buccal mucosa of either the right or the 
left cheek, as shown in Appendix A). 
• Location of film placement (right or left) 
• Time of successful film placement. 
• Number of attempts needed to successfully insert the film (An attempt is defined 
as inserting the finger with the film into the subject’s mouth.) 


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• Whether any remnant of the film remained 15 minutes after placement.  
(If yes, the subject should be instructed to swallow the remaining film and 15 
minutes will be the time of complete film disintegration/dissolution that is 
reported in the CRF.) 
• Whether the subject spit or blew the film out of their mouth. If yes, whether an 
attempt was made to reinsert it. 
• Whether any saliva exited the subject’s mouth. If yes, time of exit and estimated 
total amount (in mL).  
• Whether a check of the subject’s hands at 15 minutes after film placement 
revealed that the film (or a part of the film) was removed by subject.  
Where applicable, categorical explanations of the circumstances will be given (e.g., 
uncooperative or confused patient in a peri-ictal state). 
11.11. 
Food and Fluid Intake 
The date/time of the patient’s last meal before DBF dose (both treatment periods) will be 
recorded. Food and water intake will be restricted for 1 hour after dosing. Food and water 
will be allowed ad libitum at all other times. 
11.12. 
Physical Activity 
Subjects will be required to abstain from strenuous activities for the duration of each 
study period.  


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12. 
ADVERSE EVENTS 
The CRO, Syneos Health, has established standard operating procedures (SOPs) in 
conformity with regulatory requirements to ensure the timely, accurate, and complete 
reporting of safety information.  
12.1. 
Adverse Event Recording and Follow-up 
Subjects will be instructed to inform clinic personnel of any untoward medical symptoms 
and/or events that may arise during the course of the study.  
At the treatment and follow-up visits, subjects will be questioned concerning symptoms 
that may have occurred after administration of the study drug. The incidence, seriousness, 
severity, duration, and relationship to study drug of all AEs will be recorded.  
12.1.1. 
Seizures 
Subjects should record all seizures from the time of consent through the Follow-up Visit 
in their personal seizure diary records, and/or in seizure diaries dispensed at Screening 
and verified prior to Treatment Period A or Treatment Period B and at the Follow-up 
Visit. 
Seizures will be reported as AEs using the AE electronic Case Report Form (eCRF) 
pages if they occur during the period from clinic admission for Treatment A or Treatment 
B up to 24 hours after administration of the study drug. Seizures occurring more than 24 
hours after administration of the study drug will be reported as AEs only if the seizure is 
more severe than normal or is a change from the subject’s normal seizure activity.  
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event as 
it occurred; this does not include an event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death) 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 


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• Is a congenital anomaly or birth defect (in the child of a subject who was exposed 
to the study drug) 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in such situations. 
If the subject has a planned or elective hospitalization due to a pre-existing condition, this 
will not result in a reportable SAE as defined in the criteria listed above.  
12.1.3. 
Evaluation of Severity of AEs 
Severity of AEs will be evaluated as follows: 
Mild 
Adverse event resulting in discomfort, but not sufficient to cause 
interference in normal daily activities. 
Moderate 
Adverse event resulting in discomfort that is sufficient to cause 
interference in daily activities.  
Severe 
Adverse event resulting in discomfort causing an inability to carry out 
normal daily activities.  
12.1.4. 
Assessing Relationship to Study Drug 
The Investigator will assess the relationship of all AEs to the drug, using the following 
scale: 


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Probable 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to drug administration, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to drug administration, but which could also be explained 
by concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and which other drugs, chemicals or underlying disease 
provide plausible explanation. 
Unrelated 
This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (diseases, environment, etc.) 
and do not meet the criteria for drug relationship listed for the above-
mentioned conditions. 
 
All AEs will be evaluated by the Investigator, who must approve the subject for 
subsequent dosing. 
12.1.5. 
Investigator Presence 
The Investigator or physician designee will be present approximately 30 minutes prior to 
dosing until at least 2 hours post dose for each subject. The Investigator or physician 
designee will remain on call throughout the duration of each study subject’s treatment 
visit. The Investigator will be responsible for ensuring that a study subject is sufficiently 
medically stable to be safely discharged from the clinical unit (EMU or GCRC) regardless of 
whether the subject has received study drug. 
12.1.6. 
Follow-up of AEs 
All AEs, whether serious or non-serious, will be monitored throughout the study and 
followed to resolution or for up to 2 weeks following completion of the study, after which 
the Investigator will decide the course of action. 


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12.2. 
Procedures for Reporting Adverse Events 
Subjects will be instructed to inform clinic personnel of any AEs that may arise during 
the study. Treatment of AEs will be administered under the direction of the Investigator. 
All symptoms will be recorded by clinic staff and will be reviewed by the Investigator 
prior to any subsequent dosing.  
When appropriate, medical tests and examinations will be performed to document 
resolution of the event(s). 
Adverse events will be coded into the Preferred Term (PT), classified according to 
Version 20.0 of the Medical Dictionary for Regulatory Activities (MedDRA) with 
System Organ Classification (SOC) and reported with severity, duration, onset time and 
relationship to study drug and action taken. 
Female subjects of child-bearing potential must have a negative pregnancy test before 
study drug administration at each Treatment Visit. Any cases of pregnancy in female 
subjects or in female sexual partners of male subjects that become known after 
administration of study drug will be reported immediately by phone and by 
faxing/emailing a completed Pregnancy Report to the Sponsor (or designee) within 24 
hours of knowledge of the event. The pregnancy will not be processed as an SAE; 
however, the Investigator will follow the subject until completion of the pregnancy and 
must assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy. The Investigator should notify the Sponsor (or designee) of 
the pregnancy outcome by submitting a follow-up Pregnancy Report. If the outcome of 
the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus 
is to be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator 
will report the event by phone and by faxing a completed SAE form to the Sponsor (or 
designee) within 24 hours of knowledge of the event. 
All SAEs, whether or not the event is deemed drug-related, will be reported on the SAE 
Report Form by email or fax to the designated Clinical Research Organization, Syneos 
Health, within 24 hours of the Investigator or site staff becoming aware of the SAE.  
The safety address where SAE report forms and other SAE related documents should be 
sent is: 


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Fax No. +1 866 856 1649 
Email In case of emergency or fax failure the report can also be submitted by 
email to saereceipt.international@syneoshealth.com  
If notification cannot be made via these means due to technical delivery problems, initial 
notification may be made by phone, using the Syneos Health GSPV “SAE Hotline” 
number. A telephone call to the SAE Hotline does not substitute for the site’s 
responsibility to submit a written SAE Report Form to Syneos Health. SAEs reported via 
the Hotline number must be followed with the SAE report the same day. 
Hotline No.: +1 888-750-8020 
In the event of any fatal or life-threatening SAE, the Investigator must also inform a 
Medical Monitor at Syneos Health by telephone or email: 
Dr. Marcel Reichert 
Senior Medical Director  
Medical Management and Scientific Services 
Clinical Solutions,  
Syneos Health, USA  
Mobile +1 650-554-1706 
Fax ++1 650-550-1706 
marcel.reichert@syneoshealth.com 
Dr. Bruce Rubin  
Medical Director, CNS  
Medical Management and Scientific Services 
Clinical Solutions,  
Syneos Health, 
Regionally Based – Florida USA  
Tel: +1 984-459-4470 
Mobile: +1 305-213-7639  
bruce.rubin@syneoshealth.com 
 
The Investigator will be responsible for notifying the IRB. The Sponsor will be 
responsible for notifying the regulatory agencies, as appropriate. 


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13. 
BIOANALYTICAL ANALYSIS 
13.1. 
Analytical Procedures 
Data management, quality review and reporting of study data pertaining to laboratory 
analysis of study data will be the responsibility of the following facility: 
 
Syneos Health 
2500, rue Einstein 
Québec City, Québec G1P 0A2 Canada 
Tel.: 1-418-527-4000 
 
13.2. 
Samples to be Assayed 
Samples from all subjects dosed in this bioavailability/observational study will be 
analyzed. 
13.3. 
Analyte(s) in Biological Matrix 
Plasma samples will be assayed for diazepam and desmethyldiazepam using a validated 
analytical method according to the principles of Good Laboratory Practice.  


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14. 
PHARMACOKINETIC AND STATISTICAL ANALYSIS 
14.1. 
Pharmacokinetic Analysis Data Set 
The data from the following subjects will be included in the final PK and statistical 
analysis: 
• Subjects who complete at least one treatment period. 
• Subjects who have missed samples but for whom it has been predicted prior to the 
start of bioanalytical analysis that reliable estimates of the PK parameters should 
be possible. 
Data from subjects who were dismissed/withdrawn (for any reason other than non-
compliance) or who withdrew will be evaluated by a Syneos Health PK specialist and/or 
the Sponsor for inclusion in the PK and statistical analysis. If reliable estimation of PK 
parameters is judged possible, the data will be included in the analysis. If removed from 
the analysis, the data will be presented separately. 
Any decision for excluding data from the final data set will be provided with a detailed 
explanation and will be properly recorded and dated. 
The final data set will be defined prior to sample analysis. 
14.2. 
Data Analyzed 
Pharmacokinetic and statistical analysis will be performed by Syneos Health/third party 
as determined by the Sponsor.  
Pharmacokinetic and statistical analysis will be performed on all data from all subjects in 
the final data set (Intent-to-Treat population). The actual time of blood samples collection 
will be used for PK and statistical analysis. 
The PK and/or statistical analyses outlined in this protocol may be altered with 
appropriate justification. 
A final Statistical Analysis Plan will be issued prior to database lock. 
14.2.1. 
Pharmacokinetic Analysis 
The following PK parameters will be estimated (where possible) for diazepam and 
included in the PK and statistical analysis for the subjects in the final data set: 


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Cmax 
The maximal observed plasma concentration 
Tmax 
Time when the maximal plasma concentration is observed 
For PK and statistical analyses, drug concentrations below the lower limit of quantitation 
(BLQ) of an assay will be considered as zero except when they occur between two non-
BLQ concentrations where they will be considered as missing during PK calculations and 
estimations. 
Missed samples and non-reportable concentrations (e.g., quantity not sufficient) from the 
analytical laboratory will be treated as missing in the PK analysis. 
14.2.2. 
Statistical Analysis 
Summary statistics will be reported for pharmacokinetic, safety, and usability endpoints. 
No formal statistical tests will be performed to compare Period A vs. Period B on 
pharmacokinetic, safety, or usability endpoints. All analyses will be descriptive and 
exploratory.  
Summary statistics of pharmacokinetic data will include intra-subject comparisons of 
Cmax and Tmax for diazepam.  
Summary statistics will be presented by age category and weight category, and data will 
be explored for the potential influence of concomitant medications. No efficacy analysis 
will be performed. 
The following age categories will be used for analysis: ages 2 to 5 years, ages 6 to 11 
years, and ages 12 to 16 years. 
14.2.3. 
Safety Endpoints 
Frequency of the following safety endpoints will be reported: 
• Type, incidence, and severity of AEs  
• TEAEs related to study drug  
• TEAEs leading to discontinuation 
• SAEs 
• Columbia Suicide Severity Rating scale (age-appropriate versions) 


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• Vital signs (oxygen saturation, blood pressure, heart rate, respiratory rate, and 
temperature) 
• Physical/neurological examination at Screening and at the Follow-up Visit. 
• 12-lead ECG 
• Clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
• Oral mucosa inspection  
For purposes of the analysis, it is intended that seizures reported as AEs as described in 
Section 12.1.1 will be handled as unrelated to the study drug. 
14.2.4. 
Usability Endpoints 
Frequency of the following usability endpoints will be reported for each treatment 
period: 
• Oral cavity placement assessment 
- 
Whether placement was successfully achieved  
- 
Time of successful film placement. 
- 
Placement location (right or left side) 
• Oral cavity insertion and retention assessment 
- 
Number of attempts needed to achieve successful placement  
▪ An attempt is defined as inserting the finger with the film into the 
subject’s mouth. Placement is judged to be successful when the film 
adheres to the center of the buccal mucosa of either the right or the left 
cheek, as shown in Appendix A.) 
▪ Categorical explanations will be captured for attempt failures 
- 
Whether any remnant of the film remained 15 minutes after placement. 
- 
Number of occurrences of DBF being spit out or blown out by the subject 
after adherence to the buccal mucosa 
▪ Categorical explanations will be provided for each occurrence  
▪ Whether film was reinserted  
- 
Number of occurrences of saliva exiting the subject’s mouth 
▪ Recorded time and estimated amount of saliva (in mL) 
▪ Categorical explanations will be recorded for each occurrence 
- 
Whether subject had removed film or parts of film from the subject’s mouth 
(as revealed by check of the subject’s hands).  


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14.3. 
Statistical Analyses 
No formal statistical tests will be performed to compare Period A vs. Period B on 
pharmacokinetic, safety, or usability endpoints 
Additional statistical and alternate tests will be performed if necessary. The PK and 
statistical analysis will be performed using an appropriate Statistical Analysis System 
(SAS®) Version. 


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15. 
ETHICAL CONSIDERATIONS 
15.1. 
Basic Principles 
This research will be carried out in accordance with Good Clinical Practice (GCP) as set 
out by the International Council for Harmonization (ICH), the basic principles defined in 
the U.S. Code of Federal Regulations (21 CFR Part 312), the Belmont Report, Directive 
2001/20/EC (Europe), The Tri-Council Policy Statement and the principles enunciated in 
the most recent version of the World Medical Association Declaration of Helsinki. 
15.2. 
Informed Consent 
Informed consent will be performed by the site PI and/or their IRB-approved designee. 
As noted in Section 8.1.2 and Section 9.1, written informed consent will be obtained from 
the parent(s) or legally authorized representative of each potential subject before any 
study-specific procedures or assessments are performed and after the aims, methods, 
anticipated benefits, and potential hazards are explained. The willingness of the parent(s) 
or legally authorized representative to have the subject participate in the study will be 
documented in writing in a consent form, approved by the IRB, which will be signed by 
the subject’s parent(s) or legally authorized representative and the Investigator or 
designee, with the date of signature indicated. The Investigator will keep the original 
consent forms, and copies will be given to the subject’s parent(s) or legally authorized 
representative. Verbal and/or written assent will be obtained from the subject as required 
by the IRB. It will also be explained to the parent(s) or legally authorized representative 
and the subject that they are free to refuse entry into the study and free to withdraw from 
the study at any time without prejudice to future treatment. Written and/or oral 
information about the study will be given to the parent(s) or legally authorized 
representative and, if appropriate, to the subject, in a language they can understand. 
HIPAA guidelines for confidentiality and the principles of medical ethics will be adhered 
to during the study. 
15.3. 
Revisions and/or Amendments to the Protocol 
Revisions and/or amendments to the protocol must be documented and approved by the 
Principal Investigator and Sponsor. If the revision/amendment will affect subject safety 
and/or study design, then the amendment will be re-submitted to the IRB for approval. 
Administrative changes (i.e., change of analytical facility, typographical errors, 
discrepancies, clarifications) will also be submitted to the IRB, but may not require 
approval. A copy of the IRB’s approval documents will be included in the final report. 


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For revisions or amendments to the protocol that substantially alter the study design after 
initiation of the study, the Principal Investigator and Sponsor will decide whether a 
revised Informed Consent Form (ICF) will be needed for continued participation. 
It is the Sponsor’s responsibility to submit, or to assign responsibility to submit, all 
revisions and amendments to the appropriate regulatory authorities when necessary. 
15.4. 
Delegation of Investigator Tasks 
The Investigator may delegate tasks as appropriate to individuals who are qualified by 
education, training, and experience (and state licensure where relevant) to perform the 
delegated task, as described in the FDA Guidance for Industry on Investigator 
Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, October 
2009.  
 
 


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Page 82 
 
16. 
REFERENCES 
Bateman LM, Li C-S, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis 
of incidence, severity and risk factors. Brain. 2008;131:3239-3245. 
 
Bergen DC. Do seizures harm the brain? Epilepsy Curr. 2006;6(4):117-118. 
 
Calcaterra NE, Barrow JC. Classics in chemical neuroscience: diazepam (valium). ACS 
Chem Neurosci. 2014;5(4):253-260. 
 
Cereghino JJ. Identification and treatment of acute repetitive seizures in children and 
adults. Curr Treat Options Neurol. 2007;9(4):249-255. 
 
Dean L. Diazepam Therapy and CYP2C19 Genotype In: Pratt V, McLeod H, Dean L, 
editors. Medical Genetics Summaries [Internet]. Bethesda MD: National Center for 
Biotechnology Information (US); 2016. Accessed 22 May 2017. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK379740 
 
DelRosso LM, Hoque R, Mitchell C, Ly NP. Severe postictal hypoxemia-associated 
seizure in a 12-year-old child. J Clin Sleep Med.2016;12(12):1691–1693 
 
Diastat® AcuDial™ rectal gel prescribing information. December 2016. Accessed 2 May 
2017. Available from: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=A84A73A7-8E3A-4985-
8BE0-04B3028F5E49 
 
Fisgin T, Gurer Y, Tezic T, Senbil N, Zorlu P, Okuyaz C, Akgun D. Effects of intranasal 
midazolam and rectal diazepam on acute convulsions in children: prospective randomized 
study. J Child Neurol. 2002;17(2):123-126. 
 
Glauser TA. Designing practical evidence-based treatment plans for children with 
prolonged seizures and status epilepticus. J Child Neurol. 2007;22(5 Suppl):38S-46S. 
 
Haut SR. Seizure clustering. Epilepsy & Behavior. 2006;8(1):50-55. 
 
Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ 
sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci. 
1997;17(19):7532-7540. 


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Page 83 
 
 
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338(14):970-976. 
 
Matheson AJ, Lowe MN, Palmer KJ, Wilde MI. Management of Acute Repetitive 
Seizures. Disease Management and Health Outcomes. 2000;8(6):355-368. 
 
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and 
pharmacokinetics. Acta Neurol Scand. 2008;118(2):69-86. 
 
Sankar R, Rho JM. Do seizures affect the developing brain? Lessons from the laboratory. 
J Child Neurol. 2007;22(5 Suppl):21S-29S. 
 
Singh K, Katz ES, Zarowski M, Loddenkemper T, Llewellyn N, Manganaro S, et al. 
Cardiopulmonary complications during pediatric seizures: A prelude to understanding 
SUDEP. Epilepsia. 2013;54(6):1083-1091. 
 
Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes 
and addiction. Trends Neurosci. 2011;34(4):188-197. 
 
Tatum WO. Adult patient perceptions of emergency rectal medications for refractory 
seizures. Epilepsy Behav. 2002;3(6):535-538. 
 
Waterhouse EJ, Garnett LK, Towne AR, Morton LD, Barnes T, Ko D, DeLorenzo RJ. 
Prospective population-based study of intermittent and continuous convulsive status 
epilepticus in Richmond, Virginia. Epilepsia. 1999;40(6):752-758. 
 
 
 
 


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Appendix A 
Placement Diagram for Aquestive Therapeutics 
Diazepam Buccal Film (DBF) 
Test Drug: Placement against the buccal mucosa (either side can be against mucosa): 
The DBF film is to be centered against the inner aspect of the right or left cheek, as 
illustrated by the Figure below.  Film may be placed without regard to the location of 
the parotid duct. 
Ensure film is completely adhered to the mucosal surface. 
Note: Figure is for illustrative purposes and not drawn to scale. 
Figure: Test Drug: Placement of Aquestive Therapeutics Buccal Film against the 
buccal mucosa of the mouth. 
Subjects are not required to lie on their side after administration; AE reports in PK 
studies in healthy adults indicate an increased incidence of somnolence when the subject 
lies on their side.   
 

SAP_001.pdf: 
 
 
 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
Page 1 of 50 
 
Statistical Analysis Plan 
 
Sponsor Name: Aquestive Therapeutics 
 
Protocol Number: 160325 (Crossover) 
Protocol Title: A Multicenter, Open Label Crossover Study to Assess the Pharmacokinetics and Safety 
of Diazepam Buccal Soluble Film (DBF) in Pediatric Subjects with Epilepsy 
 
Protocol Version and Date: Protocol Amendment 4 Date: March 6, 2020 
 
Syneos Health Project Code: 16MO1R-0025 
 
Authors: Jit Mitra, Biostatistician 
                                             
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Aquestive Therapeutics. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Aquestive Therapeutics. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics Committees 
or duly authorized representatives of a national regulatory authority under the condition that they are 
requested to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos 
Health should be notified promptly. 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
Page 2 of 50 
 
Revision History 
Version # 
Date 
(DD-Mmm-
YYYY) 
Document Owner 
Revision Summary 
01 
21-Nov-2017 
Yogesh Pokharkar /  
Priya D’silva 
Release Version 1.0, 
Based on Protocol Amendment 1 Dated: August 4, 2017 
02 
21-Feb-2020 
Jit Mitra 
Based on protocol Amendment 3 Dated: September 6, 
2018 
03 
11-Jun-2020 
Jit Mitra 
 Added new weight category in footnote of table 1 and 
added as a note in inclusion criteria 3. 
 Added definition of Phase of study in section 6.2.3. 
 Added definition for several baselines in section 6.2.1. 
 Added strategy for PK analysis for new weight category 
in section 5.3.1. 
 Added individual plots for PK parameters without dose 
normalization and some term changes in section 9.4. 
 Used the term Nordiazepam instead of 
desmethyldiazepam everywhere and added 
sectionwise presentation of data for it. 
 


July 1st 2020


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
Page 4 of 50 
 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................... 3 
 
Glossary of Abbreviations ................................................................................................... 6 
 
Purpose .............................................................................................................................. 8 
 
Study Objectives ................................................................................................................ 9 
 
Endpoints ......................................................................................................................... 18 
 
Analysis Sets .................................................................................................................... 20 
 
General Aspects for Statistical Analysis ........................................................................... 22 
 
Demographic, Other Baseline Characteristics and Medication ......................................... 24 
 
Efficacy ............................................................................................................................ 26 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
Page 5 of 50 
 
 
Analysis of Pharmacokinetics ........................................................................................... 27 
 
Safety ............................................................................................................................... 30 
 
Interim Analyses ............................................................................................................... 35 
 
Changes from Analysis Planned in Protocol ..................................................................... 36 
 
Reference List .................................................................................................................. 37 
 
Programming Considerations ........................................................................................... 38 
 
Quality Control ................................................................................................................. 43 
 
Index of Tables ................................................................................................................. 44 
 
Index of Figures................................................................................................................ 47 
 
Index of Listings ............................................................................................................... 49 
 
Shells ............................................................................................................................... 50 
 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
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 Glossary of Abbreviations 
Abbreviation 
Description 
AE 
Adverse event 
AED 
Antiepileptic drug 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC0-xh 
Area under the concentration-time curve from time zero until x hours 
estimated using the trapezoidal method 
β-hCG 
Beta-human chorionic gonadotropin 
BLQ 
Below the lower limit of quantitation 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
Cmax 
Maximal observed plasma concentration 
CNS 
Central nervous system 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicidal Severity Rating Scale 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DBF 
Diazepam Buccal Film 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEG 
Electroencephalogram  
EMU 
Epilepsy Monitoring Units 
FDA 
Food and Drug Administration 
GCRC 
General Clinical Research Centers 
GLM 
General linear model 
GTC 
Generalized tonic-clonic 
H 
Above normal range 
HR 
Heart rate 
ICF 
Informed consent form 
IRB 
Institutional review board 
IWRS 
Interactive Web Response System 
L 
Below normal range 
ln 
Natural logarithm 
LS 
Least squares 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N 
Number of observations 
PK 
Pharmacokinetic 


Statistical Analysis Plan 
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SAP Version: 03, Date: 16-Jun-2020 
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Abbreviation 
Description 
PT 
Preferred Term 
QRS 
A structure on the ECG that corresponds to the depolarization of the 
ventricles 
QT 
Time from electrocardiogram Q wave to the end of the T wave 
corresponding to electrical systole 
QTcB 
QT corrected with Bazett’s formula 
QTcF 
QT corrected with Fridericia’s formula 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SaO2 
Oxygen saturation 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SD 
Standard deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol  
Tmax 
Time of maximal observed plasma concentration 
vs 
Versus 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
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 Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality control 
of all tables, figures and listings. 
 Timings of Analyses 
The primary analysis of safety and pharmacokinetics is planned after all subjects complete the final study 
visit or terminate early from the study. 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
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 Study Objectives 
 Primary Objective 
The primary objective is to assess the pharmacokinetics of Diazepam Buccal Soluble Film (currently 
referred to as Diazepam Buccal Film [DBF]) in pediatric subjects with epilepsy in (A) the interictal state and 
(B) the ictal/peri-ictal state, defined as follows:  
(A) Subjects are considered to be in an interictal state if an interval of at least 3 hours has elapsed 
since any clinical observable postictal signs or symptoms (from the last observed seizure) and the 
subject has been seizure free over this period. Subjects on electroencephalogram (EEG) 
monitoring can be considered to be in an interictal state if an interval of at least 3 hours has elapsed 
since any postictal electrical findings on EEG.  
(B) For the purposes of this study, the ictal state is defined as an ongoing clinically observable seizure 
or seizure activity as verified via EEG. The peri-ictal state is defined clinically as the subject’s 
immediate postictal state following a generalized tonic-clonic (GTC) seizure or focal seizure with 
impaired awareness, and within 5 minutes following the last clonic jerk. For subjects on EEG 
monitoring, the peri-ictal state may be defined as less than 5 minutes after cessation of seizure 
activity as verified via EEG.  
 Secondary Objective(s) 
Secondary objectives are as follows: 
 
Evaluate the safety/tolerability of DBF in pediatric subjects with epilepsy  
 
Evaluate the usability of DBF  
Data from this study are intended to support a 505(b)(2) New Drug Application for the test product. 
 Brief Description 
Diazepam Buccal Film (DBF) is being developed as an alternative dosage form to Diastat® AcuDial™ rectal 
gel, a gel formulation of diazepam. The proposed indication is identical to that of Diastat AcuDial rectal gel: 
the treatment and management of selected, refractory patients with epilepsy who are on stable regimens 
of antiepileptic drugs (AEDs) and who require intermittent use of diazepam to control bouts of increased 
seizure activity (Diastat AcuDial package insert, 2016). Diastat AcuDial rectal gel has been marketed in the 
United States since 1997 and currently is the only Food and Drug Administration (FDA) approved drug in 
the US for this indication. 
This study uses a multicenter, open-label, crossover design with the following periods: Screening Visit, 
Treatment Period A (interictal DBF dosing and pharmacokinetic (PK) evaluation, subjects aged 6-16 years), 
minimum washout period of 14 days between DBF treatment periods, Treatment Period B (ictal/peri-ictal 
DBF dosing and PK evaluation, all subjects), and Follow-up visit 14 (±2) days after treatment. If the subject 
must remain in the Epilepsy Monitoring Unit (EMU) or General Clinical Research Center (GCRC) for 
medical reasons after the end of Treatment Period A or B, this time will be designated as Post-treatment. 
The treatment periods may occur in either order depending on the occurrence of seizures.  


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
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Male or female pediatric subjects (aged 2-16 years) who are scheduled to enter the EMU or GCRC for 
evaluation and treatment of their epilepsy and who meet the inclusion and exclusion criteria are eligible to 
participate in this study. Subjects aged 2 to 5 years will enter Treatment Period B only. Subjects aged 6 to 
16 years will enter both Treatment Period A and Treatment Period B.  
Screening Period : The Screening Period will occur 0 to 28 days prior to the first treatment period. The 
subject or subject’s legally authorized representative must provide written informed consent prior to the 
initiation of any screening procedures, and subjects must provide oral and/or written assent as required by 
the Institutional Review Board (IRB).  
Check-in Procedures : Subjects will undergo standard admission procedures, including the placement of 
an indwelling cannula for intravenous access and assessment of medical history, medications, vital signs 
(oxygen saturation [SaO2] via pulse oximetry, respiratory rate [RR], heart rate [HR], blood pressure [BP], 
temperature), 12-lead electrocardiogram (ECG), oral mucosa, and the Columbia Suicide Severity Rating 
scale (C-SSRS) as age-appropriate. At the Investigator’s discretion, urine drug tests and a breath alcohol 
test will be performed. Urine pregnancy tests will also be performed for women of child bearing potential. 
Subjects who meet inclusion and exclusion criteria will be enrolled. If enrolled subjects who have completed 
a previous treatment visit no longer meet inclusion and exclusion criteria, they will be discontinued from the 
study. 
Treatment Periods : The treatment periods will begin at a time of day consistent with usual EMU/GCRC 
protocol. Subjects will arrive at the EMU, GCRC, or similar facility on their scheduled day and time. Subjects 
are to continue taking their regular AEDs prior to and throughout each Treatment Period (in accordance 
with EMU or GCRC protocol). Dosing is described in Section 3.7. 
Treatment Period A (Subjects aged 6-16 years) : Subjects will enter Treatment Period A as scheduled if at 
least a 3-hour interval has elapsed since any clinical postictal signs or symptoms (from the last observed 
seizure) have been observed and the subject has been seizure free over this period. If clinical assessment 
(and EEG monitoring, if applicable) show no seizure activity, the subject will receive a single dose of 5 mg, 
7.5 mg, 10 mg, 12.5 mg, 15 mg, or 17.5 mg DBF, based on the subject’s weight and age (Table 1).  
Treatment Period B (All Subjects) : Monitoring for the occurrence of seizures as per EMU or GCRC protocol 
will continue until the subject experiences a qualifying seizure (GTC seizure or focal seizure with impaired 
awareness). If the subject’s AEDs are to be tapered (e.g., if tapering should be done per EMU or GCRC 
protocol), the Investigator will determine and record the time to begin tapering the AEDs, including the 
doses administered or prescribed, percent dose reduction, and tapering rate.  
Seizure management and the required intervention will be determined by the Investigator. Subjects with a 
GTC seizure or focal seizure with impaired awareness who are determined to be medically appropriate to 
receive study drug (DBF) will receive a single dose of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 17.5 mg 
DBF, based on the subject’s weight and age (Table 1) (a) during the seizure, OR (b) within 5 minutes after 
the last clonic jerk, AND/OR (c) within 5 minutes after cessation of the seizure as verified via EEG. 
Post-treatment : If the subject remains in the EMU, GCRC, or similar facility following the end of the 
treatment period, that time will be regarded as a post-treatment period. While the subject remains in the 
EMU, GCRC, or similar facility, general seizure activity, administration of additional AEDs, surgical 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
This document is confidential. 
SAP Version: 03, Date: 16-Jun-2020 
Page 11 of 50 
 
treatment of their epilepsy, and AEs will be recorded. The subject will be discharged when medically stable. 
Follow-up Visit : Safety data (including concomitant medications, vital signs including SaO2 via pulse 
oximetry, clinical laboratory tests including urine pregnancy test in females of childbearing potential, AEs, 
physical and neurological examinations, C-SSRS, and inspection of oral mucosa) will be obtained at a 
follow-up visit in an outpatient setting (to be determined by Investigator or Staff) at 14 ± 2 days after the last 
treatment period (A or B). 
 Subject Selection 
Screening procedures will be conducted 0 to 28 days prior to the first treatment period. The following 
screening procedures will be conducted for each potential subject: 
• 
Obtain written informed consent as evidenced by potential subject’s parent(s) or legally authorized 
representative signing an Informed Consent Form (ICF). Obtain verbal and/or written assent from 
the subject as required by the IRB. Subjects, parents, and legally authorized representatives will 
be given an opportunity to ask questions about the study before giving consent/assent. 
• 
Register subject in the Interactive Web Response System (IWRS). 
• 
Record medical/medication history (including diazepam or benzodiazepines, smoking history, 
etc), and demographic information based on existing medical records and an interview with the 
potential subject. 
• 
Administer age-appropriate versions of the Columbia-Suicide Severity Rating Scale (subjects age 
7 and older – see Section 10.8). For nonverbal subjects, the C-SSRS assessments should be 
personally completed by the subject using nonverbal methods with assistance of site staff trained 
for these assessments. If the scales cannot be completed, the site must document this. 
• 
Collect urine samples for urinalysis and drug screening (see Section 10.3). 
• 
Receiving any dosage form of diazepam or other benzodiazepines with the 2 weeks prior to the 
screening is not a reason to postpone screening procedures. However, if the subject or subjects’ 
parent(s) or legally authorized representative reports that the subject has received any dosage 
form of diazepam (all other benzodiazepines are allowed) within the 2 weeks prior to the day of 
admission to clinic, then the clinic admission for treatment should be deferred for a minimum of 2 
weeks and a maximum of 4 weeks. If the subject or parent(s) or legally authorized representative 
reports that the subject has taken no diazepam and the urine test is positive for benzodiazepines, 
then the Investigator should review the medication history to determine whether it is consistent 
with the positive urine test for benzodiazepines. 
• 
To allow a subject who tests positive for tetrahydrocannabinol (THC) at screening to continue in 
the study, verify and affirm in writing that the use of a medicalmarijuana product is part of the 
subject’s treatment plan as recommended by a physician for treatment of a medical condition. 
• 
Obtain height and body weight. 
• 
Obtain vital signs (SaO2, temperature, RR, HR, BP) and 12-lead ECG. 
• 
Collect blood samples for hematology, chemistry, and pregnancy testing (for females of 
childbearing potential). For a complete listing of all tests to be performed, see Section 10.3. 
• 
Perform breath alcohol test in subjects. 
• 
Perform a physical and neurological examination. 
• 
Dispense seizure diaries, with instructions to subjects or parent(s) or legally authorized 
representatives to record the number of seizures, AED dosing, use of rescue, and any AEs. 


Statistical Analysis Plan 
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• 
Investigator reviews inclusion/exclusion criteria and all screening results/data to assess eligibility 
of each potential subject. 
 Inclusion Criteria 
Potential subjects meeting all of the following criteria may be included in the study: 
I-1. 
Subjects have a clinical diagnosis of epilepsy (GTC seizures or focal seizures with impaired 
awareness) and are scheduled for admission to an EMU, GCRC, or similar facility for evaluation. 
I-2. 
Male and female subjects between 2 and 16 years of age, inclusive. 
I-3. 
Subjects have a body weight of ≥6 kg and ≤111 kg. (Note: Subjects with body weight in range 
112 to 134 kg (247 to 295 pounds) may participate in the study at the discretion of the 
investigator). 
I-4. 
Subjects have an average frequency of >1 clinically apparent seizure every 3 days or >10 clinically 
apparent seizures per month, with alteration of consciousness as documented by reliable subject 
report, personal seizure diary records, and/or by seizure diaries dispensed at screening and 
verified prior to Treatment Period A or Treatment Period B. 
I-5. 
Female subjects of childbearing potential (i.e., are having periods, are not surgically sterile) must 
have a negative serum pregnancy test (beta human chorionic gonadotropin; β-hCG) at screening 
and a negative urine pregnancy test on Day 1 prior to drug dosing. Female subjects of 
childbearing potential must agree to abstinence, have a partner who is sterile, or be practicing 
double barrier contraception or have been using an FDA-approved contraceptive (e.g., licensed 
hormonal or barrier methods) for greater than 2 months prior to screening visit, and must commit 
to an acceptable form of birth control for the duration of the study and for 30 days after 
participation in the study. 
I-6. 
Male subjects with a female sexual partner of childbearing potential must agree to abstinence or 
practice adequate birth control during the study, including at least 1 barrier method such as a 
condom, diaphragm, or spermicide for greater than 2 months prior to screening visit, and must 
commit to an acceptable form of birth control for the duration of the study and for 30 days after 
participation in the study. Also, male subjects must agree to not donate sperm during the study 
and for 90 days after the follow-up visit. 
I-7. 
Subjects are currently receiving at least 1 AED. 
I-8. 
Subject’s parent or legally authorized representative must be willing and able to complete 
informed consent and HIPAA authorization. Subjects must be willing to give assent as required 
by the IRB. 
I-9. 
Subject must agree to be available or subject’s parent(s) or legally authorized representative must 
agree to have the subject be available for both treatment periods and the follow-up visit and must 
be willing to comply with all required study procedures and adhere to all protocol requirements. 
I-10. 
Subject or subject’s parent(s) or legally authorized representative must be able to comprehend 
and be informed of the nature of the study, as assessed by the Investigator. 
 Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded: 
E-1. 
Subjects with a progressive neurological disorder such as a brain tumor, demyelinating disease, 
or degenerative central nervous system (CNS) disease that is likely to progress in the next 12 
months. 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
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E-2. 
Subject has respiratory failure (or is at risk for respiratory failure) or other severe cardiorespiratory 
disease with New York Heart Association Class III or IV functional status or requires supplemental 
oxygen. 
E-3. 
Female subjects who are lactating, have a positive serum pregnancy test (β-hCG) at screening, 
or have a positive urine pregnancy test at check-in for treatment periods. 
E-4. 
Subjects with psychiatric disease that in the Investigator's judgment would prevent the subject's 
successful completion of the study. 
E-5. 
Subject has a recent history of suicide attempt (defined as an active, interrupted, or aborted 
attempt with the past 5 years) or reports suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS performed at 
screening. 
E-6. 
Subjects with known history or presence of any clinically significant hepatic (e.g., hepatic 
impairment), renal/genitourinary (renal impairment, kidney stones), psychiatric, dermatological, or 
hematological disease or condition, unless determined as not clinically significant by the 
Investigator or designee and confirmed by the sponsor via written communication prior to subject 
enrollment. Abnormal laboratory results considered clinically significant by the Investigator or 
designee will be evaluated by the Investigator in consultation with the Medical Monitor. 
E-7. 
Subjects with any clinically significant illness other than epilepsy within 30 days prior to study drug 
administration, as determined by the Investigator. 
E-8. 
Subjects with any significant physical or organ abnormality or other condition that would interfere 
with study participation or constitute a safety risk in the judgment of the Investigator. 
E-9. 
Subjects with any significant lesion of the oral cavity or having oral prophylactic or dental 
procedures within 30 days prior to study drug administration. 
E-10. 
Subjects with a QTcF (QT with Fredericia's correction) interval ≥450 msec for males or QTcF 
≥470 msec for females on screening ECG, unless determined to be not clinically significant by 
the Investigator. 
E-11. 
Subjects with a positive test result for any of the following drugs of abuse: amphetamines, cocaine, 
opiates, phencyclidine, or a positive breath alcohol test. Subjects who test positive for THC at 
screening will be excluded unless the Principal Investigator is able to affirm in writing that the use 
of a medical marijuana product is part of the subject’s treatment plan as recommended by a 
physician for treatment of a medical condition. In such case, the subject will be allowed to continue 
with screening, and the medical marijuana product will be recorded as a concomitant medication. 
E-12. 
Subjects with a known history or presence of: 
A. 
Substance abuse or dependence (including alcohol) within 1 year prior to first study drug 
administration 
B. 
Hypersensitivity or idiosyncratic reaction to diazepam, its excipients, sodium phosphates, 
and/or related substances, e.g., benzodiazepines 
C. 
Glaucoma (open or acute narrow angle) 
D. 
Severe allergic reactions (e.g., anaphylactic reactions, angioedema) to investigational 
product and excipients 
E-13. 
Subjects who have participated in another clinical trial or who received an investigational drug 
within 30 days prior to study drug administration or 5 half-lives of the investigational drug—
whichever is the longer period. 
E-14. 
Subjects with presence of mouth jewelry, dentures, oral implants, braces, or piercings in the 
mouth or tongue that, in the opinion of the Principal Investigator, would be likely to interfere with 
successful completion of the dosing procedure. 


Statistical Analysis Plan 
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E-15. 
Subjects with a blood or plasma donation within 30 days prior to screening. 
E-16. 
Subjects not willing or unable to tolerate blood draws. 
E-17. 
Consumption of alcohol within 48 hours before dosing; or food or beverages containing grapefruit, 
star fruit, Seville oranges, and/or pomelo, or their derived products (e.g., fruit juice) within 10 days 
prior to study drug administration. 
E-18. 
Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) 
enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, diltiazem, or human immunodeficiency virus antivirals) and strong inducers of CYP 
enzymes (e.g., glucocorticoids, St. John’s Wort, or rifampicin), in the previous 30 days prior to 
study drug administration. (Barbiturates, carbamazepine, phenytoin, and other enzyme-modifying 
AEDs that are medically needed are permitted.) 
E-19. 
Use of any monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine), phenothiazines 
(chlorpromazine) within 30 days prior to first study drug administration. 
E-20. 
Employee or immediate relative of an employee of Aquestive Therapeutics, any of its affiliates or 
partners, or Syneos Health. 
 Determination of Sample Size 
To provide adequate PK, safety, and usability assessments of DBF in the pediatric population, 16 to 18 
subjects should complete the study, distributed across 3 age ranges as follows: 6 subjects aged 2 to 5 
years, 6 subjects aged 6 to 11 years, and 4 to 6 subjects aged 12 to 16 years. To ensure adequate numbers 
of completed subjects, efforts will be made to enroll 8 subjects in each age group, for a total of 24 enrolled 
subjects. 
 Treatment Assignment and Blinding 
This is an open-label study. Neither subjects nor clinic staff will be blinded. The treatment order (order of 
Treatment Period A and Treatment Period B) will not be randomized. 
 Administration of Study Medication 
 Check-in Procedures  
For each treatment period, subjects will undergo standard admission procedures. A study drug kit will be 
assigned by the IWRS. Appropriately delegated clinical staff at each clinical site will use the IWRS to assign 
a kit of the appropriate dose (from the available 5, 7.5, 10, 12.5, 15, and 17.5 mg DBF doses) based on the 
subject’s weight and age. 
 Treatment Period A (Subjects aged 6-16 Years) 
Subjects will enter Treatment Period A as scheduled if at least a 3-hour interval has elapsed since any 
clinical postictal signs or symptoms (from the last observed seizure) have been observed and the subject 
has been seizure-free over this period. If clinical and/or EEG monitoring show no seizure activity, the subject 
will receive a single dose of DBF as assigned by the IWRS. 
If the subject experiences a seizure before dosing during Treatment Period A, and if feasible after IWRS 
registration, dose determination, and review of inclusion/exclusion criteria, the Investigator may regard this 
visit as Treatment Period B, and Treatment A will be rescheduled. If no seizure occurs and Treatment 
Period A is completed, the subject will be scheduled for Treatment Period B. 


Statistical Analysis Plan 
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 Treatment Period B (All Subjects) 
During Treatment Period B, the subject will be monitored until a GTC or focal seizure with impaired 
awareness is detected or the Investigator terminates the monitoring period. Seizure management and the 
required intervention will be determined by the Investigator.  
The physician in charge will be encouraged but not required to use intravenous lorazepam for rescue and 
to avoid using intravenous diazepam. The Investigator will be allowed to discontinue the subject from the 
study protocol at any time throughout the study. 
 Dosing 
DBF is provided in a range of doses from 5 to 17.5 mg to facilitate optimal dosing. The recommended dose 
of DBF is dependent on the subject’s age and weight. The Investigator or attending EMU or GCRC medical 
staff will use the IWRS (based on Table 1) to choose appropriate doses for pediatric subjects. 
Table 1 : Dosage of Diazepam Buccal Film 
Dose (mg) 
Weight (kg) 
 
Age 2–5 Years 
Age 6–11 Years 
Age 12–16 Years 
 
Original 
Amended 
Original 
Amended 
Original 
Amended 
5 
6 to 10 
6 to 10 
10 to 15 
10 to 16 
14 to 25 
14 to 25 
7.5 
11 to 20 
11 to 15 
16 to 33 
17 to 25 
26 to 50 
26 to 37 
10 
21 to 25 
16 to 20 
34 to 41 
26 to 33 
51 to 62 
38 to 50 
12.5 
26 to 44 
21 to 25 
42 to 74 
34 to 41 
63 to 111 
51 to 62 
15 
 
26 to 35 
 
42 to 58 
 
63 to 87 
17.5 
 
36 to 44 
 
59 to 74 
 
88 to 111 
Original: From the Original Protocol dated June 5, 2017. Amended: From the Protocol Amendment 3 Dated  September 6, 2018. 
Note: Subjects with body weight in range 112 to 134 kg (247 to 295 pounds) may participate in the study at the discretion of the 
investigator. 
 
 


Statistical Analysis Plan 
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 Study Procedures and Flowchart 
The schedule of study events is given in Table 2. 
Table 2 : Schedule of Assessments 
 
 
Treatment Aa 
Treatment Ba 
Follow-upU 
Procedure/Activity 
Screening  
(Day -28  
to Day -7) 
Check-in  
predose 
Dosing/ 
postdose 
Check-in  
predose 
Dosing/ 
postdose 
(14±2d 
postdose 
ICF and assentb 
x 
 
 
 
 
 
Inclusion/Exclusion assessment 
x 
x 
 
x 
 
 
IWRS: Register subject, determine 
DBF dose, update status 
x 
x 
 
x 
 
x 
Medical history/demographics 
x 
x 
 
x 
 
 
Concomitant medication review 
x 
x 
 
x 
 
x 
Date/time of the subject’s last meal 
before DBF dose 
 
x 
 
x 
 
 
Review of restrictions 
x 
xc 
xc 
xc 
xc 
 
C-SSRS (age-appropriate versions) 
x 
x 
 
x 
 
x 
Height and body weight 
xd 
x 
 
x 
 
 
Oxygen saturation 
x 
xe 
xe 
xe 
xe 
x 
Blood pressure 
x 
xf 
xf 
xf 
xf 
x 
Heart rate 
x 
xf 
xf 
xf 
xf 
x 
Respiratory rate 
x 
xf 
xf 
xf 
xf 
x 
Temperature 
x 
xf 
xf 
xf 
xf 
x 
Physical/neurological exam 
xg 
 
 
 
 
x 
ECG 
xh 
xh 
xh 
xh 
xh 
 
Pregnancy test 
xi 
xi 
 
xi 
 
xi 
Clinical laboratory tests 
x 
 
 
 
 
x 
Drug screen (urine) 
xj 
xj 
 
xj 
 
 
Breath alcohol test 
x 
x 
 
x 
 
x 
Oral mucosal inspection 
xk 
xk 
xk 
xk 
xk 
xk 
Dispense/collect seizure diaries 
x 
x 
 
x 
 
x 
Continuous video EEG 
 
xl 
xl 
xl 
xl 
 
Study drug dosing 
 
 
x 
 
x 
 
PK sampling 
 
x 
xm 
x 
xm 
 
Assessment of usability 
 
 
xn 
 
xn 
 
Adverse event reporting 
 
xo 
xo 
xo 
xo 
xo 
AE = Adverse event; BP = Blood Pressure; C-SSRS = Columbia-Suicide Severity Rating Scale; DBF = Diazepam Buccal Film; ECG = electrocardiogram; 
EEG = electroencephalogram; EMU = Epilepsy Monitoring Unit; GCRC = General Clinical Research Center; HR = Heart rate; ICF = informed consent 
form; IRB = Institutional review board; IWRS = Interactive Web Response System; PK = pharmacokinetic; RR = Respiratory rate; SaO2 = Oxygen 
saturation; THC = tetrahydrocannabinol; 
a. 
Only subjects aged 6-16 will undergo Treatment Period A. Treatment Periods A and B may occur in either order, depending on seizure occurrence, 
e.g., if a subject experiences a seizure during the first visit to the EMU or GCRC. In such cases, if feasible after IWRS registration, dose determination, 
and review of inclusion/exclusion criteria, the Investigator may regard that period as Treatment Period B and schedule another visit for Treatment 
Period A. 


Statistical Analysis Plan 
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b. 
Obtain written informed consent from parent(s) or legally authorized representative. Obtain verbal and/or written assent from subjects as required 
by IRB. 
c. 
Confirmed at each ambulatory blood draw, if applicable. 
d. 
Height measured at Screening only. 
e. 
At both treatment visits, SaO2 via pulse oximetry will be recorded predose and at 5, 10, 20, 30, 40, 50 minutes postdose and thereafter at each time 
vital signs are recorded: 1 hour (60 minutes), 1.5 hours (90 minutes), 2 hours (120 minutes), 3 hours (180 minutes), and 4 hours (240 minutes). 
f. 
At both treatment visits, vital signs (BP, HR, RR, and temperature) are to be recorded predose. BP, HR, and RR are to be recorded postdose at the 
following time points (±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours (90 minutes), 2 hours (120 
minutes), 3 hours (180 minutes, even though no blood will be drawn at this time point), and 4 hours (240 minutes) after dosing. The subject’s position 
may be seated or supine but should be consistent throughout. 
g. 
Physical/neurological examination will be performed at screening and at follow-up or at an early discontinuation visit. 
h. 
A 12-lead ECG will be obtained at screening, at the beginning of each treatment period, and at 4 hours after dose administration. 
i. 
A serum pregnancy test will be performed for females of childbearing potential at screening; a urine pregnancy test will be performed at each 
treatment period check-in and at follow-up. 
j. 
Screening: Receiving any dosage form of diazepam or other benzodiazepines within the 2 weeks before screening is not a reason to postpone 
screening. Treatment periods: If the subject or parent(s) or legally authorized representative reports that the subject received any dosage form of 
diazepam (all other benzodiazepines are acceptable) within 2 weeks prior to the day of admission to the clinic when Treatment Period A or B may 
be conducted, then the admission should be deferred for a minimum of 2 weeks and a maximum of 4 weeks. If the subject or parent(s) or legally 
authorized representative reports that the subject has taken no diazepam in the previous 2 weeks but the urine test is positive for benzodiazepines 
at check-in the Investigator should consider the subject’s drug history and evaluate whether the drug history is consistent with the positive urine 
result. Considering both the drug history and the urine test positive for benzodiazepines, the Investigator may choose to reschedule the clinical 
admission, but the protocol does not require the Investigator to reschedule. Subjects who test positive for THC at screening may participate if the 
Principal Investigator is able to affirm in writing that the use of a medical marijuana product is part of the subject’s treatment plan as recommended 
by a physician for treatment of a medical condition. In such case, the medical marijuana product will be recorded as a concomitant medication. 
k. 
The Investigator will make an illumination-assisted visual inspection of the oral mucosa during screening and during each treatment period prior to 
study drug administration and at approximately 15 minutes, 30 minutes, and 60 minutes after film placement. A further inspection of oral mucosa 
will be made at follow-up. 
l. 
If indicated by EMU or GCRC protocol, continuous video EEG monitoring for seizure detection will be performed throughout each treatment period 
(4 hours). Sites will maintain the EEG recordings with the study documents, but data from the EEG recordings will not be collected for the study 
dataset. 
m. For both treatment periods, plasma samples for determination of diazepam and Nordiazepam PK samples are to be obtained at predose and 
postdose at the following time points (±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours (90 minutes), 2 
hours (120 minutes), and 4 hours (240 minutes) after dosing. Collection of plasma samples will continue even if the administration of another AED 
is needed for rescue. 
n. 
The study staff will evaluate the insertion process to determine usability of the film. 
o. 
AEs are to be collected from time of consent throughout the study. 
 


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 Endpoints 
 Pharmacokinetic Endpoints 
The following PK parameters for diazepam will be determined: 
• 
Observed peak drug concentration (Cmax) 
• 
Observed time to reach maximum drug concentration (Tmax) 
• 
AUC0-4h, AUC0-2h  
 Safety Endpoints 
Frequency of the following safety endpoints will be reported: 
• 
Type, incidence, and severity of AEs 
• 
Treatment emergent adverse events (TEAEs) related to study drug 
• 
TEAEs leading to discontinuation 
• 
SAEs 
• 
CSSRS (age-appropriate versions) 
• 
Vital signs (SaO2, BP, HR, RR, and temperature) 
• 
Physical/neurological examination at screening and at the follow-up visit. 
• 
12-lead ECG at screening, and for each treatment period before DBF administration and 4 hours 
after dose administration. 
• 
Clinical laboratory tests (hematology, serum chemistry, and urinalysis) at screening and at follow-
up or at early termination. 
• 
Oral mucosa inspection to assess for any local irritation 
Other tests used to ensure study eligibility and safety are as follows: serum pregnancy test in females of 
childbearing potential, urine drug screen, and breath alcohol test at screening;urine pregnancy test, urine 
drug screen, and breath alcohol test before dosing (Treatment Periods A and B), and at follow-up. 
For purposes of the analysis, it is intended that seizures reported as AEs as described below will be handled 
as unrelated to the study drug : 
 
Seizures will be reported as AEs using the AE electronic Case Report Form (eCRF) pages if they 
occur during the period from clinic admission for Treatment A or Treatment B up to 24 hours after 
administration of the study drug. 
 
Seizures occurring more than 24 hours after administration of the study drug will be reported as 
AEs only if the seizure is more severe than normal or is a change from the subject’s normal seizure 
activity. 
 Usability Endpoints 
Frequency of the following usability endpoints will be reported for each treatment period: 
• Oral cavity placement assessment 
 
Whether placement was successfully achieved 
 
Time of successful film placement. 
 
Placement location (right or left side) 


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• Oral cavity insertion and retention assessment 
 
Number of attempts needed to achieve successful placement 
 
An attempt is defined as inserting the finger with the film into the subject’s mouth. 
Placement is judged to be successful when the film adheres to the center of the buccal 
mucosa of either the right or the left cheek. 
 
Categorical explanations will be captured for attempt failures 
 
Whether any remnant of the film remained 15 minutes after placement. 
 
Number of occurrences of DBF being spit out or blown out by the subject after adherence to 
the buccal mucosa 
 
Categorical explanations will be provided for each occurrence 
 
Whether film was reinserted 
 
Number of occurrences of saliva exiting the subject’s mouth 
 
Recorded time and estimated amount of saliva (in mL) 
 
Categorical explanations will be recorded for each occurrence 
 
Whether subject had removed film or parts of film from the subject’s mouth (as revealed by 
check of the subject’s hands). 
 


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 Analysis Sets 
The following sections define the analysis sets to be used for analyzing the endpoints. Treatment 
assignment will be according to the actual treatment received. 
 Screened Set 
All subjects who have been screened will be included in this set. The analysis of disposition and protocol 
deviations will include all screened subjects. 
 Safety Set  
The safety population is defined as the group of subjects who receive at least 1 dose of the study 
medication. The analysis of safety or usability parameters will be based on the safety population. 
 Pharmacokinetic Set  
The PK population will include subjects who meet all of the following criteria:  
 
Do not have a major protocol deviation that would impact the reliability of PK parameter estimation, 
 
Have completed at least 1 treatment period (Period A or Period B)  
 
Have no missed samples, or have missed samples but for whom it has been predicted prior to the 
start of bioanalytical analysis that reliable estimates of the PK parameters should be possible. 
The analysis of PK parameters will be based on the PK population. 
 Pharmacokinetic Analysis Data Set 
Data from subjects who were dismissed/withdrawn (for any reason other than noncompliance) or who 
withdrew will be evaluated by Syneos Health PK scientist for inclusion in the PK and statistical analysis. If 
reliable estimation of PK parameters will be judged possible, the data will be included in the analysis. If 
removed from the analysis, the data will be presented in the tables but excluded from descriptive statistics.  
For a given analyte, any subject with pre-dose concentrations will be excluded from the PK and statistical 
analysis for the concerned analyte and period combination if the pre-dose concentration is greater than 5% 
of the Cmax value of that period and analyte for that subject.  
Data (concentrations and PK parameters) from subjects who are not included in the PK population (due to 
major protocol violation, reliable estimation was predicted to be impossible or excluded due to a pre-dose 
concentration greater than 5% of their Cmax) will be presented but excluded from the statistical analyses.  
Here are some aspects to be considered (but not to be limited to) when determining data availability for the 
PK population: inclusion and exclusion criteria, acceptable times for visit dates and measurements, 
compliance with treatment, the nature and quality of the data, withdrawal and any protocol deviation. The 
final responsibility of deciding which subjects are to be included or excluded lies with the investigator. The 
data from all subjects included in the PK population will be included in the final PK analysis data set. All PK 
summaries and the primary analyses will be performed using the final PK analysis data set.  
Note: The evaluation of PK parameters will be performed by the Syneos Health PK Scientist prior to the 
database lock after all PK samples are tested. The sponsor will not be involved in this evaluation to avoid 


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any bias. The PK scientist will be blinded to the subject level information such as age, weight, dose and 
treatment period in order to derive the PK parameters.  
Subjects with body weight in range 112 to 134 kg (247 to 295 pounds) may participate in the study at the 
discretion of the investigator. But since the primary analysis in 160325 is the AB comparison,  these subjects 
will not be excluded from paired analysis if the subject is otherwise valid for analysis. However, PK 
concentration and parameters for these subjects will not be included while calculating the summary 
statistics, with notification. These subjects will be included in the listings.   


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 General Aspects for Statistical Analysis 
 General Methods 
Percentages and Decimal Places : If not otherwise specified, the following rules are applied, with the 
exception of PK tables and listings: 
 
Percentages will be presented to 1 decimal place. 
 
Percentages equal to 0 or 100 will be presented as such without a decimal point. 
 
Minimum (Min) and maximum (Max) will be presented with the same precision as the original 
values; mean and median will be presented with 1 more decimal place than the original values; and 
standard deviation (SD) will be presented with 2 more decimal places than the original values. 
All digits will be used for PK and statistical PK calculations. For PK tables and listings, the final reportable 
results or data will be presented by rounding off to 2 decimal digits, except for the following situations (this 
applies to individual data and descriptive statistics): 
 
Kel and correlation  data: rounded off to 4 decimal places. 
 
Tmax will be reported with the same precision as the actual sampling time: rounded off to 3 decimal 
places. 
 
Concentration versus time data will be reported as they appear in the final summary concentration 
table provided by the bioanalytical laboratory. 
 
Ratios and 90% confidence intervals (Cis) will be presented to 2 decimal places. 
Analysis : Unless specified, all analyses will be performed overall or by associated current treatment period 
or more recent treatment period and age group, as appropriate. Subjects who discontinue during the 
washout period or during the baseline assessment will be included under the last or most recent treatment 
period in which the subject received treatment prior to discontinuation. 
The following age categories will be used for analysis: ages 2 to 5 years, ages 6 to 11 years, and ages 12 
to 16 years. 
 
Coding : Adverse events will be graded by the Investigator based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03 or later, and will be coded for summarization using 
the Medical Dictionary for Regulatory Activities (MedDRA Version 20.0 or later). Concomitant medications 
will be coded using the World Health Organization Drug Dictionary Enhanced (WHO DDE version March 
2017, Format B or later. 
 Key Definitions 
 Baseline Value 
Baseline for all period will be defined as the last available nonmissing observation/assessment prior to the 
first dose of study drug administration. 
Baseline for Period 1 will be defined as the last available nonmissing observation/assessment prior to the 
first dose of study drug administration. 


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Baseline for Period 2 will be defined as the last available nonmissing observation/assessment prior to the 
second dose of study drug administration. If missing at check-in procedures for period 2, it may include 
information from period 1 baseline or screening, with appropriate notification. 
Unknown, Not Done, Not Applicable and other classifications of missing data will not be considered when 
calculating baseline observations. However, valid categorical observations will be considered for baseline 
calculations. 
 Study Day 
Study day is the number of days since the first study drug administration, which is counted as Study Day 
1. Study day is calculated using the formula below: 
Study day = date of assessment - date of first study drug administration + 1, if date of assessment is after 
the date of first drug administration; or: 
Study day = date of assessment - date of first study drug administration, if date of assessment is prior to 
the date of first drug administration. 
 Study Phases for occurences 
For occurences, like adverse events and medications, three phases will be defined: 
1) Prior Phase: This will include any occurences from screening till the first dose of the study drug. 
2) Period 1 Phase: This will include any occurences from first dose of the study drug till 
a. if period 2 is administrated: prior to the second dose administrated. 
b. if period 2 not administrated: the last observed occurrence. 
3) Period 2 Phase (when period 2 is administrated): This will include any occurences from second 
dose of the study drug till the last observed occurrence. 
Note: Last observed occurrence can be beyond the end of study visit. 
 Missing Data 
Unless otherwise specified in the SAP, missing values will not be imputed. If missing values are imputed, 
the result of all imputation strategies and newly derived information must be stored in the ADaM (Analysis 
Data Model) dataset. 
Concentration values below the lower limit of quantitation (BLQ) and samples with no reportable value 
occurring prior to dosing will be handled as described in Section 9.3.1.1. 
 Pooling of Centers 
Pooling of investigative sites is not required in the statistical analysis for this study. 
 


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 Demographic, Other Baseline Characteristics and Medication 
 Subject Disposition and Withdrawals 
Subject disposition will be summarized by treatment period, age categories (2-5 years, 6-11 years, and 12-
16 years) and overall as indicated below. The following categories will be summarized by number and 
percentage. 
 
Screened and screen failures subjects (by age group and overall) 
 
Enrolled and not enrolled subjects (by age group and overall) 
 
Subjects who are dosed in each treatment period by age group and overall 
 
Subjects who are not dosed in each treatment period by age group 
 
Subjects who are included in the PK population for each treatment period by age group and overall 
 
Subjects who have completed each treatment period by age group and overall 
 
Subjects who were discontinued or did not complete the treatment period 
 
Reasons for absence/early termination. 
Subject disposition information will be listed. In addition, subjects who were discontinued from a treatment 
period or who did not complete a treatment period will also be presented in this listing, including 
absence/early termination reason and date and time of discontinuation. 
For subjects enrolled, not enrolled and screen failures, the percentage denominator will be the number of 
screened subjects. For all other calculations, the percentage denominator will be the number of subjects 
dosed in each treatment period or age category. For overall, percentages based on the overall number of 
subjects dosed (safety population). 
 Demographic and Other Baseline Characteristics 
Descriptive statistics (sample size, mean, median, SD, Min and Max) will be presented for continuous 
variables: age, body mass index (BMI), height, and weight. Frequency counts and percentages will be 
tabulated for categorical variables: age group (2-5, 6-11, 12-16 years), gender, ethnicity, and race.  
Results will be presented overall for the safety population and by treatment period and age group for the 
PK population. No statistical tests for comparison of demographic and baseline data between treatment 
periods will be performed.  
All demographic and baseline characteristics will be listed by subject. 
 Medical History 
Medical history will be collected at screening and reviewed at the check-in visit for each treatment period. 
MedDRA Version 20.0 or later will be used to classify all medical history findings to a System Organ Class 
(SOC) and Preferred Term (PT). 
All medical history data will be listed and sorted by subject and alphabetically according to SOC and PT. 
 Medication 
WHO DDE Version Mar2017, Format B or later will be used to classify all medications reported during the 
study to an Anatomical Therapeutic Chemical (ATC) Level 1 term and a standardized medication name. 


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Prior medication is defined as medication/therapy stopped prior to the first drug administration, regardless 
of medication start date. Concomitant medication is defined as any medication started at any time and not 
stopped before the first study drug administration in Treatment Period A or Treatment Period B, whichever 
occurs first. 
Medications will be summarized by age group and overall, separately for prior and concomitant medications 
by ATC category Level 1 and by standardized medication name. ATC Level 1 categories and standardized 
medication names will appear in an alphabetical order on the summary table. For each medication, the 
number of subjects and percentages will be displayed. 
The use of prior and/or concomitant medication will be listed by subject. 
 Protocol Deviations 
All protocol deviations will be collected and listed by subject, including start date, end date and impact of 
deviation. Study day will be presented along with start and end date of deviation. 


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 Efficacy 
No efficacy analysis is planned as per the protocol. 


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 Analysis of Pharmacokinetics 
Shells for all summary descriptive statistic tables and listings referred to in this section are displayed in a 
separate document; the shells may be revised as they are presented to illustrate the general layout of data 
to be included in the final report. 
 PK Sampling Schedule 
During both treatment periods, plasma samples for the determination of diazepam and nordiazepam (the 
active metabolite) pharmacokinetics will be obtained at predose (0 hours), and at the following time points 
(±5 minutes): 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours (90 minutes), 
2 hours (120 minutes), and 4 hours (240 minutes) after dosing. Collection of plasma samples will continue 
even if the administration of another AED is needed for rescue. 
 Plasma PK Endpoint 
The following PK parameters for diazepam will be determined: 
• 
Cmax, 0-2h, Cmax, 0-4h 
• 
Tmax, 0-2h, Tmax, 0-4h 
• 
AUC0-2h, AUC0-4h 
 Presentation of Concentration Data 
 Handling of Missing Data  
9.3.1.1. Handling of the BLQ and the No Reportable Concentration Values 
During PK and statistical analyses, drug concentration values that are BLQ of an assay will be considered 
as zero except when they occur between 2 non-BLQ concentrations when they will be considered as 
missing for PK calculations and estimations in a given period. A sample with a no reportable value occurring 
prior to the dosing for a given period will be replaced by zero. For tabulation, graphical representation and 
calculation purposes, all samples with no reportable value observed after dosing will be set to missing. 
9.3.1.2. Handling of the Difference Between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK samples will 
be recorded using the electronic data capture. For all sampling times, the actual sampling times will be 
calculated as the difference between the sample collection actual clock time and the actual clock time of 
dosing. The actual postdose sampling times expressed in hours and rounded off to 3 decimal places will 
be used to calculate the PK parameters; predose samples occurring prior to dosing will be reported as zero 
(0.000), regardless of the time difference. Scheduled sampling times will be presented in concentration 
tables and mean graphs and actual times will be presented for the individual graphs. A by-subject listing of 
the actual times for PK collections will be provided for PK samples. 
 Listing and Presentation of Individual PK Data 
Individual and mean plasma concentration versus time curves will be presented using linear and semi-log 
scales for diazepam and nordiazepam. Listings and descriptive statistics (number of observations, 
arithmetic mean, SD, coefficient of variation [CV], median, Min, Max, and geometric mean) of the 
concentrations for diazepam and nordiazepam over time will be provided. 


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 PK Parameter Derivation 
During both treatment periods, plasma samples for diazepam and the active metabolite nordiazepam will 
be obtained pre-dose (0 hours) and postdose administration at the following time points (±5 minutes): 0.25 
hours (15 minutes), 0.5 hours (30 minutes), 1 hour (60 minutes), 1.5 hours (90 minutes), 2 hours (120 
minutes), and 4 hours (240 minutes).  
Plasma samples from diazepam and nordiazepam will be used to calculate the following PK parameters by 
standard noncompartmental methods: 
AUC0-2h 
Area under the concentration-time curve from time zero to 2 hours. AUC0-2h is 
calculated using the trapezoidal method. For a subject with missing concentration data 
at the sampling time 2 hours postdose, the calculation of AUC0-2h will not be done for 
the concerned treatment period. AUC0-2h dose-normalized to 1 mg will also be provided 
(AUC0-2h /D) where D is the dose in mg. 
AUC0-4h 
Area under the concentration-time curve from time zero to 4 hours. AUC0-4h is 
calculated using the trapezoidal method. For a subject with missing concentration data 
at the sampling time 4 hours postdose, the calculation of AUC0-4h will not be done for 
the concerned treatment period. AUC0-4h dose-normalized to 1 mg will also be provided 
(AUC0-4h /D) where D is the dose in mg. 
Cmax, 0-2h 
Maximal observed plasma concentration, taken from the plasma concentration-time 
profile from time zero to 2 hours. Cmax, 0-2h dose-normalized to 1 mg will also be 
provided (Cmax, 0-2h/D) where D is the dose in mg. 
Cmax, 0-4h 
Maximal observed plasma concentration, taken from the plasma concentration-time 
profile from time zero to 4 hours. Cmax, 0-4h dose-normalized to 1 mg will also be 
provided (Cmax, 0-4h/D) where D is the dose in mg. 
Tmax, 0-2h 
Time when the maximal plasma concentration is observed, taken from the 
concentration-time profile from time zero to 2 hours. 
Tmax, 0-4h 
Time when the maximal plasma concentration is observed, taken from the 
concentration-time profile from time zero to 4 hours. 
For subjects with missing or nonreportable diazepam/nordiazepam concentrations, the data will be 
reviewed both prior to knowledge of the bioanalysis (without the plasma concentrations) and with 
knowledge of the bioanalysis (e.g., for predose elevated concentrations or unreasonable concentrations) 
on a case-by-case basis by the PK scientist to determine if the data are reliable for PK parameter estimation. 
The reviewers will be blinded to the subject level information such as age, weight, dose and treatment 
period. The blinded adjudication will be recorded before statistical analysis of the PK data. If the data are 
not considered reliable, PK parameters will not be presented and included in the statistical analysis. 
Explanations for PK parameters that could not be estimated will be provided in the CSR. 
 PK Parameter Summarization 
For diazepam and nordiazepam, plasma PK parameters will be listed for each treatment period (Period A 
and Period B) by age group (2-5, 6-11, 12-16 years) and dose levels and weight category. In order to 


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summarize, for each age group and by period, arithmetic mean, SD, Min, Max, median and CV will be 
calculated for PK parameters. Additionally, geometric means will be calculated for AUC0-2h, AUC0-2h/D, 
AUC0-4h, AUC0-4h/D, Cmax, 0-2h, Cmax, 0-2h/D, Cmax, 0-4h and Cmax, 0-4h/D.  
 
For Diazepam: 
 
For the comparison Period A vs Period B, additional tables presenting the individual ratios (A/B) for 
AUC0-2h, AUC0-4h, Cmax, 0-2h and Cmax, 0-4h  as well as individual differences (A-B) for Tmax, 0-2h and Tmax, 
0-4h will be provided. 
 
As an exploratory analysis period geometric mean ratios (B/A) and corresponding 90% CIs will be 
evaluated for AUC0-2h, AUC0-4h, Cmax, 0-2h and Cmax, 0-4h. Using the generalized linear model (GLM) 
procedure in SAS, an analysis of covariance (ANCOVA) will be performed on ln-transformed AUC0-
2h, AUC0-4h, Cmax, 0-2h and Cmax, 0-4h for diazepam only at the alpha level of 0.05. Factors incorporated 
in the statistical model will include Treatment (A and B) as a fixed factor and dose as a covariate. 
Also, Subject will be included as a random factor. The treatment effect will be tested against 
residual mean squares. The ANCOVA for each parameter, will include calculations of least-squares 
(LS) means for each treatment period, the LS-mean for treatment period differences using the 
ESTIMATE statement and the standard errors associated with these differences. Probability (p) 
values will be derived from Type III sums of squares. Tmax, 0-2h and Tmax, 0-4h will be analyzed using 
a nonparametric test (Wilcoxon signed-rank test). 
The ratios of geometric means (B/A) and corresponding 90% CIs, based on LS means from the 
ANCOVA of the ln-transformed data, will be calculated for AUC0-2h, AUC0-4h, Cmax, 0-2h and Cmax, 0-4h. 
Inter and intrasubject CVs will be estimated. Only subjects with valid PK data in both Treatment 
Period A and Treatment Period B will be included in ANCOVA analysis and statistical treatments 
comparison without considering the age-group. 
Individual plots of the Cmax, 0-2h/D, Cmax, 0-4h /D, AUC0-2h/D, AUC0-4h/D, Cmax, 0-2h, Cmax, 0-4h, AUC0-2h 
and AUC0-4h vs  age group and weight category will be presented, separate for each treatment 
period. Any patient with any valid profile for period A or B will be included in this plot. 
For Nordiazepam: 
PK parameters will not be compared or plotted for nordiazepam. 


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 Safety 
Safety data will be evaluated through the assessment of AEs, laboratory parameters (serum chemistry, 
hematology, and urinalysis), 12-lead ECG, clinical signs and symptoms from physical and neurological 
examination, C-SSRS and vital signs assessments. TEAEs, laboratory values, and vital signs, will be 
summarized by age group, dose levels within age groups and overall or according to the associated 
treatment period in which they were collected, as appropriate. Safety data will be summarized but not 
subjected to inferential analysis. 
Shells for all tables and listings referenced to in this section are displayed in a separate document. 
 Extent of Exposure 
The study drug administration details (including treatment received, start/end date, start/end time, route 
and frequency of administration) will be listed by subject. The dosing time will be set to the time the film is 
placed on the buccal mucosa. The total time taken for complete dissolution of film will be recorded in 
seconds and listed by subject. 
Treated seizure information collected during Treatment Period B will be listed by subject. Treated seizure 
start/stop date including seizure type will be included in the listing. 
 Adverse Events / Adverse Drug Reactions 
TEAEs and non-TEAEs (those occurring prior to administration of study medication or that first occurred 
prior to study drug administration and did not worsen in frequency or severity) will be listed. TEAEs will be 
defined as AEs that occur on or after the date and time of first study drug administration, or those that first 
occur pre-dose but worsen in frequency or severity after study drug administration. TEAEs will be captured 
through the end of the study. TEAEs will be attributed to the most recent treatment period in which study 
drug is taken. A TEAE with a start date and time during the wash-out period (ending at the time of study 
drug administration) will be attributed to the study drug taken during the previous treatment period.  
The incidence of TEAEs will be summarized using the safety population. MedDRA version 20.0 or later will 
be used to classify all AEs reported during the study by SOC and PT.  
Incidence of subjects who experienced TEAEs will be presented by age group, dose level, treatment period 
and overall, by each SOC and PT, and also by investigator-assessed relationship and severity. Each 
subject may only contribute once to each of the incidence rates, for a TEAE following a given treatment, 
regardless of the number of occurrences; the highest severity or highest relationship will be presented, as 
appropriate. In each table, SOC will be presented in descending order of overall incidence rate in terms of 
frequency of subjects and then in frequency of events (alphabetical order will be used in case of equal rates 
and frequency of events). For each SOC, PT will be presented the same way.  
Incidence of TEAEs (number of events) will also be presented by age group, treatment period, SOC, and 
PT, by investigator-assessed relationship and severity. 
The relationship of TEAEs to study drug will be classified according to the study protocol as unrelated, 
unlikely, possible, or probable. The severity of AEs will be rated as according to the study protocol as: mild, 
moderate, or severe. 


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A significant AE will be defined as any event (other than those reported as serious) that led to an 
intervention, including withdrawal of study drug, or significant additional concomitant therapy. 
Serious and significant AEs will be listed separately. 
 Laboratory Evaluations 
Clinical laboratory (serum chemistry, hematology, and urinalysis) results will be obtained at screening and 
at early termination or follow-up visit. Table 3 provides the list of laboratory assessments. 
Table 3 : Laboratory Assessments 
Type Of Test 
Components 
Hematology 
Hemoglobin  
Hematocrit 
RBC count 
Platelet count 
WBC count and 
differential  
Peripheral blood smear 
Serum chemistry 
Glucose  
Calcium  
Sodium chloride  
Albumin  
Protein  
Bilirubin 
Alkaline phosphatase  
Lactate dehydrogenase 
AST  
ALT  
Potassium  
BUN  
Uric acid  
Creatinine  
Creatine kinase  
Pregnancy (β-hCG)a  
Urinalysis 
Bilirubin  
Blood  
Glucose  
pH  
Ketones  
Leukocytes  
Nitrites  
Protein  
Pregnancya  
Specific gravity  
UBG  
Additional tests  
Breath alcohol test as per EMU/GCRC protocol  
Urine drug tests  
Amphetamines, Phencyclidine, Cocaine, Opiates, Benzodiazepines, THC  
Diazepam and 
Nordiazepam  
Active drug and metabolite in DBF formulation  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = Beta-human chorionic gonadotropin; BUN = blood urea 
nitrogen; DBF = Diazepam Buccal Film; EMU = Epilepsy Monitoring Unit; GCRC = General Clinical Research Center; RBC = red 
blood cells; THC = tetrahydrocannabinol; UBG = urobilinogen; WBC = white blood cells.  
aSerum and urine pregnancy tests for females of child-bearing potential only 
Listings of all clinical laboratory results will be provided with the abnormal values flagged with "L" for low 
and "H" for high for continuous parameters, and “A” for abnormal for categorical parameters.  
Descriptive statistics (sample size, mean, median, SD, Min and Max) for each clinical laboratory test 
(continuous variables) will be presented by age group and overall for screening and follow-up visit. Change 
from screening to follow-up visit will also be presented. For categorical variables (urinalysis), the number of 
subjects (frequency and percentage) will be tabulated by result (e.g, negative, positive, trace). A summary 
table of shifts from screening to follow-up visit will be provided. Results from repeat tests will not be included 
in the summary statistics unless the repeat was required (and documented as such) due to technical 
reasons or an invalid initial result.  
If more than 1 clinical laboratory is used for the study, a formula that takes into consideration the relative 
normal ranges of each test of laboratories used will be applied in order to normalize these data. The 
conversion formula used will depend on the typical distribution of the normal range for each laboratory test; 
the 2 formulae used are presented in the following paragraphs : 


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Hemoglobin, hematocrit, and platelet count test results are considered to have a normal distribution 
(Chuang-Stein, 1992) and the following formula will be used (Karvanen J., 2003): 
𝑠= 𝐿𝑠+ (𝑥−𝐿𝑥) 𝑈𝑠−𝐿𝑠
𝑈𝑥−𝐿𝑥
 
where U= Upper limit; L= Lower limit; s= Primary facility result; and x= Secondary facility results. 
The remaining hematology, serum chemistry, and urinalysis test results are considered to have a non-
normal distribution (Chuang-Stein, 1992) and the following formula will be used (Karvanen J., 2003):  
𝑠= 𝑥𝑈𝑠
𝑈𝑥
 
Prior to applying these formulae, if required, units will be adjusted. 
 Vital Signs  
Vital sign measurements (SaO2 measured via pulse oximetry, BP, HR, RR and temperature) will be 
performed at screening, several times during each treatment period and at early termination or follow-up 
visit in each period. During both treatment periods, vital sign measurements (blood pressure, heart rate, 
respiratory rate and temperature) will be measured at pre-dose (±5 minutes) and post-dose at 0.25 h (15 
minutes), 0.5 h (30 minutes), 1 h (60 minutes), 1.5 h (90 minutes), 2 h (120 minutes), 3 h (180 minutes), 
and 4 h (240 minutes). SaO2 will be measured at predose and at 5, 10, 20, 30, 40, and 50 minutes postdose, 
and subsequently at the same times that the other vital signs are recorded.  The subject’s position may be 
seated or supine, but should be consistent throughout. 
Descriptive statistics (sample size, mean, median, SD, Min and Max,) for each vital sign parameter will be 
presented by overall for the screening visit and the follow-up visit. Similar descriptive statistics will also be 
presented by age group, dose level and associated treatment period for on-study measurements. 
Descriptive statistics for change from screening to follow-up visit and changes from baseline for on-study 
measurements will also be presented. Baseline will be defined as the last nonmissing result (scheduled or 
unscheduled) obtained prior to study drug administration in each treatment period. Results from postdose 
repeat tests will not be included in the summary statistics unless the repeat was required (and documented 
as such) due to technical reasons or an invalid initial result.  
A listing of all vital signs results will be provided. 
 ECG 
ECG measurements will be performed at the time of screening, at the beginning of each treatment period, 
and at the end of each treatment period. The quantitative ECG measurements are HR or ventricular rate, 
PR interval, QRS interval, QT interval, QTcB interval (Bazett formula correction), and QTcF interval 
(Fridericia’s formula correction).  
Descriptive statistics (sample size, mean, and median, SD, Min and Max) for each ECG parameter will be 
presented by age group and overall for screening and by age group, dose level and associated treatment 
period for on-study measurements. Descriptive statistics for change from baseline for on-study 
measurements will also be presented. Baseline will be defined as the last nonmissing result (scheduled or 


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unscheduled) obtained prior to study drug administration in each treatment period. Results from postdose 
repeat tests will not be included in the summary statistics unless the repeat was required (and documented 
as such) due to technical reasons or an invalid initial result. 
A listing of all ECG results including screening measurements will be presented. 
 Physical and Neurological Examination 
A physical and neurological examination will be performed at screening, and at the early termination or 
follow-up visit.  
A physical examination includes assessments of head, eyes, ears, nose, throat, respiratory, lymph nodes, 
spine, skin, abdomen, cardiovascular, extremities, general appearance and others, if any. A neurological 
examination includes assessments of cranial nerves, muscle tone and strength, sensory function, 
coordination, gait, cognitive function and others, if any. 
Physical and neurological examination data will be listed separately by age group, dose levels and 
treatment period for each subject.  
Any abnormal findings judged to be clinically significant will be documented as medical history or as an AE, 
depending upon whether noted at screening, prior to dosing or after dosing, as appropriate. Any physical 
examination or neurological examination findings documented as AEs will be included in the AE summaries. 
 Visual Oral Inspection 
A visual inspection assisted by illumination of the DBF application site will be performed at screening and 
during Treatment Periods A and B prior to dosing and at approximately 0.25 h (15 minutes), 0.5 h (30 
minutes), and 1 h (60 minutes) after application of the film (±5 minutes for all time points) to check for any 
mucosal irritation. A further inspection of oral mucosa will be made at follow-up. 
Any abnormal findings judged to be clinically significant will be documented as medical history or as an AE, 
depending upon whether noted at screening, prior to dosing or after dosing, as appropriate. Any oral safety 
findings documented as AEs will be included in the AE summaries.  
A listing of all visual oral inspection results will be provided. 
 Columbia Suicidal Severity Rating Scale 
The C-SSRS, which assesses suicidal behavior and ideation, will be administered at screening, at the check 
-in visit for each treatment period, and at the follow-up visit to subjects aged 7 or older. Qualified, trained 
staff will administer the age-appropriate versions of the C-SSRS: Subjects aged 7-11 will be administered 
the Children’s Baseline-Screening and Children’s Since Last Contact versions. Subjects aged 12-16 years 
will be administered the Baseline-Screening and Since Last Visit versions. 
Subjects with Type 4 (active suicidal ideation with some intent to act, without specific plan) or Type 5 (active 
suicidal ideation with specific plan and intent) suicidal ideation during the study will be discontinued from 
the study and referred to a mental health professional. 
A listing of C-SSRS results will be provided. 


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 Other Safety 
The following usability endpoints will be reported and summarized for each treatment period by age group 
and overall. 
 
Oral cavity insertion and retention assessment  
 
Oral cavity placement assessment  
The total number of unsuccessful attempts of DBF buccal insertion will be captured in the eCRF. Descriptive 
statistics (n, mean, SD, median, Min, Max) will be provided by treatment period, age group and overall for 
number of unsuccessful attempts to place the DBF. The number and percentage will be provided for 
categories 0, 1, 2, 3 and >3 unsuccessful attempts to place DBF for each treatment period. The categorical 
explanation for each unsuccessful attempt to place DBF will be listed. 
Unsuccessful retention will have occurred if a subject allowed saliva to exit the mouth during DBF 
adherence to the buccal mucosa; if the DBF was swallowed by the subject; or if a subject spit or blew out 
the DBF after adherence to the buccal mucosa or subject chewed, talked, or moved the DBF prior to 
complete disintegration/dissolution. The occurrences of these 3 types of events are recorded in the eCRF 
for each treatment period. The number and percentage of safety subjects with any unsuccessful retention 
will be summarized by age group and treatment period. Also, the number and percentage of safety subjects 
experiencing each type of unsuccessful retention will be summarized by age group and treatment period.  
After DBF administration, visual inspection of film will be conducted every 60 seconds until 
disintegration/dissolution is noted or for a maximum of 5 minutes. All data regarding DBF placement, 
retention and visualization for each treatment period will be listed. Categorical explanation for each type of 
unsuccessful retention will also be included in the listing. 


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 Interim Analyses 
No interim analysis is planned. 


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 Changes from Analysis Planned in Protocol 
The PK profiles for 0 to 2 hours postdose were not initially planned in the protocol. However, as the US 
FDA requested the analysis of the 0 to 2 hours profile along with the 0 to 4 hours profile for the adult study 
(Protocol 160326), the analysis of PK profile for 0 to 2 hours postdose has been included in the SAP for 
this pediatric study to avoid later ad hoc analyses. 
Although AUCs for 0 to 2 hours and 0 to 4 hours postdose were not included in the protocol as endpoints, 
they have been included as PK endpoints in the SAP. 


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 Reference List 
1. 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-center clinical 
trials. Drug Information Journal. 1992; 26:77-84. 
2. 
Karvanen J. The statistical basis of laboratory data normalization. Drug Information Journal. 2003; 
37:101-107. 
3. Diastat® AcuDial™ (diazepam rectal gel) [package insert]. 16 December 2016. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=88e0f275-dd7b-447d-b9d3-316a06da934f 
Accessed 01 Oct 2019. 
 


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 Programming Considerations 
Computer-generated output will adhere to the following specifications. The standard operating procedures 
(SOPs) of Syneos Health Clinical will be followed in the creation and quality control of all tables, listings 
and figures. 
PK analysis will be performed using Phoenix WinNonlin® version 8.0, which is validated for 
bioequivalence/bioavailability studies by Syneos Health. The inferential statistical analyses, the safety data 
tables and listings, as well as PK tables and listings will be created using SAS®, software version 9.2 or a 
higher version. PK figures will be created using R version 3.2.2 (or higher). The PK report text will be created 
using Microsoft® Office Word 2010, or a higher version. 
 General Considerations 
 
One SAS program can create several outputs, or a separate SAS program will be created for each 
output. 
 
One output file can contain several outputs.or  each output will be stored in a separate file. 
 
Output files will be delivered in Word format or portable document format pdf. 
 
Numbering of TFLs will follow ICH E3 guidance. 
 Table, Listing, and Figure Format 
 General 
 
All TFLs will be produced in landscape format on American letter size, unless otherwise specified.  
 
All TFLs will be produced using the Courier New font, size 8  which is the smallest acceptable point 
size for the Regulatory Authorities. 
 
The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
TFLs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used. 
 
Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help display 
math symbols (e.g., μ). Certain subscripts and superscripts (e.g., m2) will be employed on a case-
by-case basis. 


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 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 Headers 
 
All output should have the following header at the top left of each page: 
 
Aquestive Therapeutics Protocol Number: 160325 (Crossover) 
 
Final Run and the system Date 
 
All output should have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number should appear sequentially as page 
n of N, where N is the total number of pages in the table). 
 
The date output was generated should appear along with the program name as a footer on each 
page. 
Sponsor Name: Aquestive Therapeutics 
Protocol: 160325 (Crossover) 
Confidential 
Page n of N 
Dry Run/Final Run Outputs 
 Display Titles 
 Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
  Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
(Safety Set) 
 Column Headers 
 Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
 In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed by 
the treatment group columns and total column (if applicable). P-values may be presented under the 
total column or in separate p-value column (if applicable). Within-treatment comparisons may have 
p-values presented in a row beneath the summary statistics for that treatment. 
 For numeric variables, include “unit” in column or row heading when appropriate. 
 Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or in 
the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 


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 The order of treatments in the tables and listings will be Placebo first in the case of placebo controlled 
studies and Active comparators first in the case of active comparator trials, followed by a total column 
(if applicable). 
 Body of the Data Display 
14.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values are left-justified; 
 Whole numbers (e.g., counts) are right-justified; and 
 Numbers containing fractional portions are decimal aligned. 
14.2.5.2. 
Table Conventions 
 Units will be included where available 
 If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category are presented in the table, even if n=0 for all treatment groups in a given category that is 
between the minimum and maximum level for that parameter. For example, the frequency distribution 
for symptom severity would appear as: 
Severity Rating N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
 If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented in 1 or more groups 
are included. 
 An Unknown or Missing category are added to each parameter for which information is not available 
for 1 or more subjects.  
 Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
n 
XX 
Mean 
XXX.X 
SD 
X.XX 
Median 
XXX.X 
Min 
XXX 
Max 
XXX 


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 P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Everyp-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 Percentage values are printed to one decimal place, in parentheses with no spaces, one space after 
the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down to 0.0.  
A common convention is to display as '<0.1', or as appropriate with additional decimal places. Unless 
otherwise noted, for all percentages, the number of subjects in the analysis set for the treatment 
group who have an observation will be the denominator. Percentages after zero counts should not 
be displayed and percentages equating to 100% are presented as 100%, without decimal places.  
 Tabular display of data for medical history, prior/concomitant medications, and all tabular displays of 
adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more than 
1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or p-values 
which cannot be estimated are reported as “-”. 
 The percentage of subjects is normally calculated as a proportion of the number of subjects assessed 
in the relevant treatment group (or overall) for the analysis set presented. However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
 For categorical summaries (number and percentage of subjects) where a subject can be included in 
more than one category, describe in a footnote or programming note if the subject are included in 
the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
 Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent page.  The 
overall summary statistics for the subheading should only be output on the first relevant page. 
14.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
 Dates are printed in SAS ISO8601DT.format (“yyyy-mm-dd”: 2000-06-01). Missing portions of dates 
are represented on subject listings as dashes (2000-06). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 


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 All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 Units will be included where available 
14.2.5.4. 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes.  
 All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
 Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote should start on a new line, where possible. 
 Subject specific footnotes are avoided, where possible. 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines of 
footnotes are planned, then a cover page is strongly recommended to be used to display footnotes, 
and only those essential to comprehension of the data will be repeated on each page.  
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (i.e., 
‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


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 Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907)  . 
Syneos Health SOPs Developing Statistical Programs (3907) and  Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output. 


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 Index of Tables 
Header 
Table 
Number 
Name 
Analysis 
Population 
14. 
 
Tables, Figures, and Graphs Referred to but not Included 
in the Text 
 
14.1 
 
Demographic Data Summary Tables 
 
14.1.1 
 
Subject Disposition 
 
* 
14.1.1.1 
Subject Disposition 
All Screened 
14.1.2 
 
 
 
* 
14.1.2.1 
PK population by period and profile 
PK 
* 
14.1.2.2 
Dose-Age-Weight distribution 
Safety 
* 
14.1.2.3 
Dose-Age-Weight distribution by period 
PK 
14.1.3 
 
Demographic and Baseline Characteristics 
 
* 
14.1.3.1 
Subject Demographic and Baseline Characteristics 
Safety 
* 
14.1.3.2 
Subject Demographic and Baseline Characteristics 
PK 
14.1.4 
 
Medications 
 
* 
14.1.4.1 
Prior Medications 
Safety 
* 
14.1.4.2 
Concomitant Medications 
Safety 
14.2 
 
Efficacy Data Summary Tables 
 
14.2.3 
 
Pharmacokinetic Endpoints 
 
14.2.3.1 
 
PharmacokineticConcentrations 
 
* 
14.2.3.1.1 
Listing and Descriptive Statistics for Diazepam Plasma 
Concentrations (ng/mL) over Nominal Time 
PK 
* 
14.2.3.1.2 
Listing and Descriptive Statistics for Nordiazepam Plasma 
Concentrations (ng/mL) over Nominal Time 
PK 
14.2.3.2 
 
Pharmacokinetic Parameters 
 
* 
14.2.3.2.1 
Listing and Descriptive Statistics for Diazepam 
Pharmacokinetic Parameters 
PK 
* 
14.2.3.2.2 
Listing and Descriptive Statistics for Noriazepam 
Pharmacokinetic Parameters 
PK 
* 
14.2.3.2.3 
Summary of Pharmacokinetic Parameters for Diazepam - 
Comparison between Periods A and B 
PK 
* 
14.2.3.2.4 
Comparisons of Least Square Means between Periods - 
Pharmacokinetic Parameters for Diazepam 
PK 
* 
14.2.3.2.5 
Comparing PK Profiles (0-2 hours) for Period A vs Period 
B – ANCOVA on ln-Transformed PK Parameters for 
Diazepam 
PK 
* 
14.2.3.2.6 
Comparing PK Profiles (0-4 hours) for Period A vs Period 
B – ANCOVA on ln-Transformed PK Parameters for 
Diazepam 
PK 
* 
14.2.3.2.7 
Comparing PK Profiles for Period A to Period B - Wilcoxon 
Signed-rank Test for Untransformed Tmax for Diazepam 
PK 
14.3 
 
Safety Data Summary Tables 
 
14.3.1 
 
Adverse Events 
 
* 
14.3.1.1 
Treatment-Emergent Adverse Events – Overall Summary 
– by age group and overall 
Safety 
* 
14.3.1.2 
Treatment-Emergent Adverse Events – Overall Summary 
– by dose and overall 
Safety 
* 
14.3.1.3 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – by age group and overall 
Safety 


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Header 
Table 
Number 
Name 
Analysis 
Population 
* 
14.3.1.4 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – by dose and overall 
Safety 
* 
14.3.1.5 
Treatment-Emergent Adverse Events by Severity, System 
Organ Class and Preferred Term – by age group and 
overall 
Safety 
* 
14.3.1.6 
Treatment-Emergent Adverse Events by Severity, System 
Organ Class and Preferred Term – by dose and overall 
Safety 
* 
14.3.1.7 
Treatment-Emergent Adverse Events by Relationship, 
System Organ Class and Preferred Term – by age group 
and overall 
Safety 
* 
14.3.1.8 
Treatment-Emergent Adverse Events by Relationship, 
System Organ Class and Preferred Term – by dose and 
overall 
Safety 
14.3.4 
 
Laboratory Data, Vital Signs, and Other Safety Results 
 
14.3.4.1 
 
Clinical Laboratory Data 
 
14.3.4.1.1 
 
Hematology Data 
 
* 
14.3.4.1.1.1 
Hematology: Summary by Visit and Change from 
Screening 
Safety 
* 
14.3.4.1.1.2 
Hematology: Shifts by Visit 
Safety 
14.3.4.1.2 
 
Serum Chemistry Data 
 
* 
14.3.4.1.2.1 
Serum Chemistry: Summary by Visit and Change from 
Screening 
Safety 
* 
14.3.4.1.2.2 
Serum Chemistry: Shifts by Visit 
Safety 
14.3.4.1.3 
 
Urinalysis Data 
 
* 
14.3.4.1.3.1 
Urinalysis: Numerical Data: Summary by Visit and Change 
from Screening 
Safety 
* 
14.3.4.1.3.2 
Urinalysis: Categorical Data: Summary by Visit 
Safety 
* 
14.3.4.1.3.3 
Urinalysis: Numerical Data: Shifts by Visit 
Safety 
* 
14.3.4.1.3.4 
Urinalysis:  Categorical Data: Shifts by Visit 
Safety 
14.3.4.2 
 
Vital Signs 
 
* 
14.3.4.2.1 
Summary of Vital Signs by Visit and Change from 
Baseline – by age group and overall 
Safety 
* 
14.3.4.2.2 
Summary of Vital Signs by Visit and Change from 
Baseline – by dose and overall 
Safety 
* 
14.3.4.2.3 
Summary of Vital Signs - Change from Screening to 
Follow-up 
Safety 
14.3.4.3 
 
Electrocardiogram (ECG) Data 
 
* 
14.3.4.3.1 
Summary of ECG by Visit and Change from Baseline – by 
age group and overall 
Safety 
* 
14.3.4.3.2 
Summary of ECG by Visit and Change from Baseline – by 
dose and overall 
Safety 
* 
14.3.4.3.3 
Summary of ECG Interpretation by Visit and Shift from 
Baseline – by age group and overall 
Safety 
* 
14.3.4.3.4 
Summary of ECG Interpretation by Visit and Shift from 
Baseline – by dose and overall 
Safety 
14.3.4.4 
 
Usability Endpoints 
 


Statistical Analysis Plan 
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Header 
Table 
Number 
Name 
Analysis 
Population 
* 
14.3.4.4.1 
Summary of Usability Endpoints 
Safety 
 


Statistical Analysis Plan 
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 Index of Figures 
Header 
Table 
Number 
Name 
Analysis 
Population 
14. 
 
Tables, Figures, and Graphs Referred to but not Included in 
the Text 
 
14.2 
 
Efficacy Data Summary Figures 
 
14.2.3 
 
Pharmacokinetic Endpoints 
 
14.2.3.1 
 
PharmacokineticConcentrations 
 
* 
14.2.3.1.1 
Plasma Concentrations(Diazepam) - Linear Scale 
PK 
* 
14.2.3.1.2 
Plasma Concentrations(Diazepam) - Semi-Log Scale 
PK 
* 
14.2.3.1.3 
Mean(± SD) Plasma Concentrations(Diazepam) - Linear 
Scale 
PK 
* 
14.2.3.1.4 
Mean(± SD) Plasma Concentrations(Diazepam) - Semi-Log 
Scale 
PK 
* 
14.2.3.1.5 
Overlay of Individual and Mean Plasma 
Concentrations(Diazepam) by Treatment Period - Linear 
Scale 
PK 
* 
14.2.3.1.6 
Overlay of Individual and Mean Plasma 
Concentrations(Diazepam) by Treatment Period - Semi-Log 
Scale 
PK 
* 
14.2.3.1.7 
Overlay of Individual and Geometric Mean Plasma 
Concentrations(Diazepam) by Treatment Period - Semi-Log 
Scale 
PK 
* 
14.2.3.1.8 
Plasma Concentrations(Nordiazepam) - Linear Scale 
PK 
* 
14.2.3.1.9 
Plasma Concentrations(Nordiazepam) - Semi-Log Scale 
PK 
* 
14.2.3.1.10 
Mean(± SD) Plasma Concentrations(Nordiazepam) - Linear 
Scale 
PK 
* 
14.2.3.1.11 
Mean(± SD) Plasma Concentrations(Nordiazepam) - Semi-
Log Scale 
PK 
* 
14.2.3.1.12 
Overlay of Individual and Mean Plasma 
Concentrations(Nordiazepam) by Treatment Period - Linear 
Scale 
PK 
* 
14.2.3.1.13 
Overlay of Individual and Mean Plasma 
Concentrations(Nordiazepam) by Treatment Period - Semi-
Log Scale 
PK 
* 
14.2.3.1.14 
Overlay of Individual and Geometric Mean Plasma 
Concentrations (Nordiazepam) by Treatment Period - Semi-
Log Scale 
PK 
14.2.3.2 
 
Pharmacokinetic Parameters 
 
* 
14.2.3.2.1 
Individual plot of Cmax, 0-2h/D(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.2 
Individual plot of Cmax, 0-4h/D(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.3 
Individual plot of AUC0-2h/D(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.4 
Individual plot of AUC0-4h/D(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.5 
Individual plot of Cmax, 0-2h(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
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Header 
Table 
Number 
Name 
Analysis 
Population 
* 
14.2.3.2.6 
Individual plot of Cmax, 0-4h(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.7 
Individual plot of AUC0-2h(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
* 
14.2.3.2.8 
Individual plot of AUC0-4h(Diazepam)  vs Age-group and 
Weight-category by Treatment Period - Linear Scale 
PK 
 


Statistical Analysis Plan 
Sponsor: Aquestive Therapeutics; Protocol No.: 160325 (Crossover) 
 
 
 
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 Index of Listings 
Header 
Table 
Number 
Name 
Analysis 
Population 
16.2 
 
Subject Data Listings 
 
16.2.1 
 
Discontinued Subjects 
 
* 
16.2.1.1 
Subject Disposition 
All Screened 
16.2.2 
 
Protocol Deviations 
 
* 
16.2.2.1 
Protocol Deviations 
All Screened 
16.2.3 
 
Subjects Excluded from the Efficacy Analysis 
 
* 
16.2.3.1 
Exclusions from Analysis Sets 
All Screened 
16.2.4 
 
Demographic Data 
 
* 
16.2.4.1 
Demographics 
Safety 
* 
16.2.4.2 
Medical/Surgical History 
Safety 
* 
16.2.4.3 
Prior and Concomitant Medications 
Safety 
* 
16.2.4.4 
Concomitant Medications – Comparison by Treatment 
Period 
Safety 
16.2.5 
 
Compliance and Drug Concentration Data 
 
16.2.5.1 
 
Exposure and Treated Seizures and Usability Data 
 
* 
16.2.5.1.1 
Study Drug Administration 
Safety 
* 
16.2.5.1.2 
Seizure Diary 
Safety 
* 
16.2.5.1.3 
Treated Seizure Information 
Safety 
* 
16.2.5.1.4 
Usability Data 
Safety 
16.2.5.2 
 
Concentration Data 
 
* 
16.2.5.2.1 
Pharmacokinetic Concentrations for Diazepam 
PK 
* 
16.2.5.2.2 
Pharmacokinetic Concentrations for Nordiazepam 
PK 
* 
16.2.5.2.3 
Pharmacokinetic Parameters for Diazepam 
PK 
* 
16.2.5.2.3 
Pharmacokinetic Parameters for Nordiazepam 
PK 
16.2.7 
 
Adverse Event Listings 
 
* 
16.2.7.1 
Non-Treatment Emergent Adverse Events 
Safety 
* 
16.2.7.2 
Treatment Emergent Adverse Events 
Safety 
* 
16.2.7.3 
Serious Adverse Events 
Safety 
* 
16.2.7.4 
Significant Adverse Events 
Safety 
16.2.8 
 
Listing of Individual Laboratory Measurements by Subject 
 
16.2.8.1 
 
Clinical Laboratory Data 
 
* 
16.2.8.1.1 
Hematology 
Safety 
* 
16.2.8.1.2 
Serum Chemistry 
Safety 
* 
16.2.8.1.3 
Urinalysis 
Safety 
* 
16.2.8.1.4 
Breathe Alchohol Test 
Safety 
* 
16.2.8.1.5 
Drug Screen 
Safety 
16.2.8.2 
 
Other Safety Data 
 
* 
16.2.8.2.1 
Vital Signs 
Safety 
* 
16.2.8.2.2 
Pulse Oximetry 
Safety 
* 
16.2.8.2.3 
Electrocardiogram (ECG) 
Safety 
* 
16.2.8.2.4 
Physical Examinations 
Safety 
* 
16.2.8.2.5 
Neurological Examinations 
Safety 
* 
16.2.8.2.6 
Oral Cavity Visual Inspection 
Safety 
* 
16.2.8.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Safety 
 


Statistical Analysis Plan 
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 Shells 
Shells are provided in a separate document.