Conditions: Epilepsy
Keywords: Interictal Ictal/peri-ictal
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 35
Healthy volunteers: no

Brief summary:
This Phase 2 open-label, two-way study was conducted in adult subjects with epilepsy who were on stable regimens of anti-epileptic drugs (AEDs) and who were admitted to an Epilepsy Monitoring Unit (EMU), General Clinical Research Center (GCRC), or similar facility for evaluation of their seizures. All subjects received a single DBF 12.5 mg dose during the Interictal State and a single DBF 12.5 mg dose during the Ictal/peri-ictal state with at least 14 days washout between the 2 doses.

Detailed description:
This was a Phase 2 multicenter, open-label, two-way study conducted in adult subjects to assess the bioavailability, pharmacokinetics, and safety of DBF during the Interictal Period and during the Ictal/peri-ictal Period, with a minimum of 14 days of washout between periods. Subjects had a clinical diagnosis of epilepsy (with generalized tonic-clonic seizures or focal seizures with impaired awareness) who were on stable regimens of anti-epileptic drugs and were scheduled for admission to an EMU, GCRC, or similar facility for evaluation.

All subjects were to receive a single 12.5-mg dose of study drug, without regard to meals, during both Interictal Period and Ictal/peri-ictal Period. The treatment was identical for both periods. Treatment sequence was not randomized. The interictal period and ictal/peri-ictal could occur in either order as determined by seizure occurrence.

Interictal Period: 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) video 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.

Ictal/peri-ictal Period: For the purposes of this study, the ictal state was defined as an ongoing clinically observable seizure or seizure activity as verified via EEG. The periictal 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 video monitoring, the periictal state was to be defined as less than 5 minutes after cessation of seizure activity as verified via EEG.

Arms:
arm 1: All subjects received 12.5 mg DBF during the interictal state. arm 2: All subjects received 12.5 mg DBF during the ictal/peri-ictal state.

Interventions: intervention 1: Diazepam Buccal Film 12.5 mg
Intervention descriptions: intervention 1: All subjects received a single dose of DBF 12.5 mg during the interictal state and during the ictal/peri-ictal state with at least 14 days washout between the 2 treatment periods

Protocol document:
Prot_000.pdf: 
NCT03179891
A 
Multicenter, 
Open 
Label, 
Cross-Over 
Study 
to 
Assess 
the 
Pharmacokinetics 
and 
Safety 
of 
Diazepam 
Buccal 
Soluble 
Film 
(DBSF) 
in 
Adult 
Subjects 
with 
Epilepsy
Protocol  
Protocol 160326 version 3.3 dated 04 August 2017 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
A Multicenter, Open Label, Cross-Over Study to Assess the Pharmacokinetics and 
Safety of Diazepam Buccal Soluble Film (DBSF) in Adult Subjects with Epilepsy 
 
Amendment 2 
Summary of Changes from Version 2.7 (June 6, 2017) to Version 3.3 (August 4, 2017) 
 
Major changes described in the following table have been made in this document to 
address the following issues: 
• Change in age criteria for eligibility from “18-65” to “17 to 65” to conform to 
FDA classification of pediatric subjects (Section 9.2.1) 
• Addition of date/time of the subject’s last meal before DBSF dose to interview 
questions because of potential effect of food on PK (Section 11.1) 
• Addition of instructions to have subjects lie down on their side for 15 minutes 
after dosing for consistency of dosing conditions (Section 11.2.4) 
• Change in the time of post-dose oral mucosa inspections to omit inspection at 
dissolution, use film placement instead of film disintegration as time zero, and 
change of inspection time at 0.167 hours (10 minutes) to 0.25 hours (15 minutes) 
(Section 11.9) 
• Revision of process for assessing usability to avoid disturbing subjects during the 
15 minutes when they are lying down after dosing (Section 11.10) 
• Clarification of Investigator’s responsibility 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 (Section 
12.1.4). 
• Revision of adverse event recording (Section 12.1) and analysis of safety 
endpoints (Section 14.2.2) to clarify that seizures that occur during treatment 
periods are to be handled as adverse events unrelated to study drug for the 
purposes of analysis  
 
 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
1 
 
 
A Multicenter, Open Label, Cross-Over Study to Assess the Pharmacokinetics and 
Safety of Diazepam Buccal Soluble Film (DBSF) in Adult Subjects with Epilepsy  
 
 
 
 
Protocol Number: 160326 
 
Amendment 2 
Final Protocol Version Number: 3.3 
 
Protocol Version Date: August 4, 2017 
 
Sponsor:  
MonoSol Rx, LLC 
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 MonoSol Rx, LLC (MonoSol Rx) except to the extent that disclosure 
would be required by law and for the purpose of evaluating and/or conducting a clinical 
study for MonoSol Rx. 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 MonoSol Rx and that it may not be 
further disclosed to third parties. 




 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
3 
 
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:  
 
 
 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
4 
2. 
CONTACT INFORMATION AND FACILITIES 
 
Sponsor: 
Dan Barber  
Vice-President Value Creation 
MonoSol Rx, LLC, 
30 Technology Drive, 
Warren, NJ, U.S.A., 07059 
Tel: 908-941-1900 
Fax: 908-561-1209 
Sponsor’s Responsible Study 
Manager: 
T.J. Stalvey, MPH, MBA 
Director of Clinical Operations 
MonoSol Rx, LLC 
30 Technology Drive 
Warren, NJ 07059 USA 
Telephone: 404-663-9659 
Clinical Research Organization 
(CRO): 
inVentiv Health Clinical 
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: 
inVentiv Health Clinique 
2500, rue Einstein  
Québec City, Québec, Canada, G1P 0A2  
Tel.: 1-418-527-4000  
Pharmacokinetic/Statistical 
Facility: 
inVentiv Health Clinique 
2500, rue Einstein  
Québec City, Québec, Canada, G1P 0A2  
Tel.: 1-418-527-4000  


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
5 
CRO Safety 
(Pharmacovigilance) Reporting: 
inVentiv Health Clinical Global Safety & 
Pharmacovigilance 
Facsimile: +1-866-856-1649 
Telephone Hotline No.: 888-750-8020 
E-mail: saereceipt.international@inventivhealth.com 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
6 
3. 
SYNOPSIS 
Title: 
A Multicenter, Open Label, Crossover Study to Assess the 
Pharmacokinetics and Safety of Diazepam Buccal Soluble Film (DBSF) 
in Adult Subjects with Epilepsy 
Objectives: 
The primary objective is to assess the comparative pharmacokinetics of 
DBSF in 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 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 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 include: 
• 
Evaluate the safety/tolerability of DBSF following single-dose 
administration in subjects with epilepsy  
• 
Evaluate the usability of DBSF in Period A and Period B 
Experimental 
Design and Study 
Population: 
Multicenter, open-label cross-over study in adult epilepsy subjects to 
assess the pharmacokinetics and safety of Diazepam Buccal Soluble Film 
(DBSF) during the interictal state (Treatment Period A) and during the 
ictal/peri-ictal states (Treatment Period B). 
 
Male or female adult subjects with a clinical diagnosis of epilepsy being 
admitted to an Epilepsy Monitoring Unit (EMU) setting, General Clinical 
Research Center (GCRC), or similar facility for evaluation of seizures 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
7 
will be eligible for this study. Subjects will be 17 to 65 years of age, 
inclusive, with a body weight of ≥40 kg and ≤111 kg.  
Number of 
Subjects: 
Approximately 40 adult subjects with epilepsy will be enrolled. A 
minimum of 30 subjects are expected to complete the study 
Phase 
2 
Test Drug: 
Diazepam Buccal Soluble Film 12.5  mg (MonoSol Rx, LLC) 
Treatments: 
All subjects will receive one dose of 12.5 mg DBSF in Period A and one 
dose of 12.5 mg DBSF in Period B. 
Study Duration: 
• 
Screening Period: A minimum of 7 and a maximum of 28 days 
prior to admission 
• 
*Treatment Period A (interictal):  Approximately 8 hours in the 
GCRC or EMU facility + 6 additional visits for vital signs, 
adverse events (AEs), and blood samples (either at EMU, GCRC, 
or similar facility, or home visits). 
• 
Washout Period: Minimum of 14 days between treatment periods 
• 
*Treatment Period B: Duration of Treatment Period B will vary, 
depending on seizure occurrence, but the period will last until 
approximately 4 hours after DBSF administration.  
• 
Follow-up Visit: A follow-up visit will be scheduled to obtain 
safety data 14 ± 2 days after the last treatment period.  
*Period A and Period B may occur in either order as determined by seizure 
occurrence; i.e., if a subject experiences a seizure before dosing during the first 
visit to the EMU or GCRC and if it has been determined that the subject meets 
inclusion/exclusion criteria, the Investigator may regard that visit as Treatment 
Period B.  
Dosing Time: 
The treatment periods will begin at a time of day consistent with usual 
EMU/GCRC protocol. In Treatment Period A, DBSF 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 DBSF 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 will start prior to DBSF treatment and will 
continue for 8 hours after dosing in Treatment Period A and 4 hours after 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
8 
dosing in Treatment Period B, 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: 
• 
Columbia Suicide Severity Rating scale (C-SSRS; age-
appropriate version) at Screening, before dosing during Treatment 
Periods A and B, and at Follow-up 
• 
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 during Treatment Periods A and B, and at Follow-up 
• 
12-lead ECG at Screening, for each treatment period before 
DBSF 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 during 
Treatment Periods A and B prior to DBSF administration and 
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); for Treatment 
Period A also at 8 hours (480 minutes) post dose in the EMU, 
GCRC or similar facility, and at 24, 48, 96, 144, 192, and 240 
hours (±4 hours) in an outpatient setting (either at the EMU, 
GCRC or similar facility, or via home visits). 
• 
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: 
- 
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 
DBSF; and  
- 
At Follow-up.  


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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strictly prohibited without written consent from MonoSol Rx LLC. 
9 
Any abnormalities detected after dosing will be followed as 
treatment emergent adverse events (TEAEs) until resolution.  
• 
Type, incidence, and severity of AEs at all visits. 
The Investigator or designee will be present from approximately 
30 minutes prior to dosing until at least 2 hours (120 minutes) post dose 
for each subject for each Treatment Period. The Investigator or designee 
will remain on call throughout the duration of the 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) 
• 
(Period A only) Area under the plasma concentration-time curve 
from time zero until the last measured time (AUC0-t),  
• 
Comparison of Cmax after single-dose administration of DBSF in 
subjects during Period A and Period B, and to that of healthy 
normal subjects from pharmacokinetic data obtained in previous 
studies. 
• 
Comparison of Tmax after single-dose administration of DBSF in 
subjects during Period A and Period B, and to that of healthy 
normal subjects from pharmacokinetic data obtained in previous 
studies. 
• 
Period A only: Comparison of AUC0-24 after single-dose 
administration of DBSF in subjects during Period A to that of 
healthy normal subjects from pharmacokinetic data obtained in 
previous studies. 
PK Blood 
Sampling Time 
points: 
In both treatment periods, plasma samples for diazepam and the active 
metabolite desmethyldiazepam will be obtained before DBSF 
administration and post dose at the following time points (±5 minutes): at 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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strictly prohibited without written consent from MonoSol Rx LLC. 
10 
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). In 
Treatment Period A, a plasma sample will also be taken at 8 hours (480 
minutes) in the EMU, GCRC or similar facility, and additional plasma 
samples will be collected at 24, 48, 96, 144, 192, and 240 hours post 
DBSF administration in an outpatient setting (either at EMU, GCRC or 
similar facility, or via home visits).  
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 151 mL of blood will be taken throughout the 
course of the study for clinical chemistry, hematology, and 
pharmacokinetics: Screening, 12.5 mL; Period A, 84 mL; Period B, 42 
mL; and Follow-up, 12.5 mL.  
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.  
For Period A only, summary statistics will be reported for mean and 
geometric mean values of AUC0-t, AUCinf, Cmax, Cl, Cl/kg, Vd, and Vd/kg, 
as well as mean and median Tmax for diazepam. For Period B, summary 
statistics will be reported for mean and geometric mean Cmax and 
AUC(0-4h) and for mean and median Tmax for diazepam. The 90% 
confidence intervals (CI) for the ratios (period A compared with period B) 
of geometric means for Cmax and AUC(0-4h) will be reported. Tmax will be 
compared (period A and B) with an appropriate non-parametric test.  
A descriptive comparison will also be performed to assess plasma 
concentration data for diazepam and desmethyldiazepam reported in 
subjects having true epileptic events in this study (Period B) compared to 
the data from the non-seizure period (Period A) and to data reported in the 
Phase 1 healthy volunteer studies who are in the DBSF clinical 
development program. 
Summary statistics will also include an evaluation of subjects’ age, 
concomitant medications, and treatment with DBSF for epileptic vs. non-


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
11 
epileptic events. No efficacy analysis will be performed. 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
12 
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 /BQL 
below the limit of quantitation / below quantitation limit 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CI 
confidence interval 
Clast 
the last measurable concentration 
Cmax 
the maximal observed plasma concentration. 
CRO 
contract research organization 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
CYP 
cytochrome 
DBSF 
Diazepam Buccal Soluble Film 
ECG 
electrocardiogram 
EMU 
Epilepsy Monitoring Unit 
FDA 
Food and Drug Administration 
g 
grams 
GCP 
Good Clinical Practice 
GCRC 
General Clinical Research Center 
GLP 
Good Laboratory Practice 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
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13 
GTC 
generalized tonic-clonic 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
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 
RLD 
Reference Listed Drug 
SAE 
serious adverse event 
SAS® 
Statistical Analysis System 
SD  
standard deviation 
SOC 
System Organ Classification 
SOP 
Standard Operating Procedure 
T1/2 
terminal elimination half-life, estimated as ln(2)/λ 
Tmax 
time of maximal plasma concentration  
THC 
tetrahydrocannabinol 
UBG 
urobilinogen 
WBC 
white blood cell 
 
 
 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from MonoSol Rx LLC. 
14 
 
5. 
TABLE OF CONTENTS 
1. 
PROTOCOL APPROVAL ...........................................................................................2 
2. 
CONTACT INFORMATION AND FACILITIES ......................................................4 
3. 
SYNOPSIS ...................................................................................................................6 
4. 
LIST OF ABBREVIATIONS.....................................................................................12 
5. 
TABLE OF CONTENTS ...........................................................................................14 
6. 
BACKGROUND AND PHARMACOKINETICS .....................................................19 
6.1. 
Treatment and Management of Refractory Patients with Epilepsy ............................19 
6.2. 
Diazepam ....................................................................................................................20 
6.2.1. 
Mechanism of Action .................................................................................................20 
6.2.2. 
Metabolism and Elimination.......................................................................................20 
6.2.3. 
Pharmacokinetics ........................................................................................................21 
6.3. 
Diastat® AcuDial™ Rectal Gel in the Treatment of Seizures ....................................21 
6.4. 
Diazepam Buccal Soluble Film ..................................................................................22 
6.4.1. 
Pilot Studies 1899 and 1900 .......................................................................................23 
6.4.2. 
Study 162013 – Dose Proportionality.........................................................................24 
6.4.3. 
Study 162021 – Pivotal Bioavailability Study............................................................25 
6.4.4. 
Study 162022 – Food Effect Study .............................................................................26 
6.5. 
Rationale for Dose Levels of Diazepam Buccal Soluble Film ...................................26 
6.6. 
Safety ..........................................................................................................................27 
6.6.1. 
Diastat® AcuDial™ Rectal Gel ..................................................................................27 
6.6.2. 
Diazepam Buccal Soluble Film ..................................................................................28 
6.6.3. 
Overdosage .................................................................................................................30 
7. 
STUDY OBJECTIVE .................................................................................................31 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
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15 
8. 
STUDY DESIGN .......................................................................................................31 
8.1. 
Discussion of Study Design ........................................................................................31 
8.1.1. 
Study Design ...............................................................................................................31 
8.1.2. 
Screening Period (Section 9.1) ...................................................................................32 
8.1.3. 
Treatment Periods (Section 11.2) ...............................................................................32 
8.1.4. 
Post-treatment .............................................................................................................34 
8.1.5. 
Follow-up Visit ...........................................................................................................34 
8.1.6. 
PK and Safety Assessments ........................................................................................34 
8.2. 
Study Duration and Washout ......................................................................................35 
8.3. 
Randomization and Blinding ......................................................................................35 
9. 
SUBJECT SELECTION .............................................................................................36 
9.1. 
Screening Procedures ..................................................................................................36 
9.2. 
Inclusion/Exclusion Criteria .......................................................................................37 
9.2.1. 
Inclusion Criteria ........................................................................................................37 
9.2.2. 
Exclusion Criteria .......................................................................................................38 
9.3. 
Permitted and Restricted Items ...................................................................................40 
9.4. 
Sample Size ................................................................................................................41 
9.5. 
Dropout and Withdrawal/Termination .......................................................................41 
10. 
INVESTIGATIONAL PRODUCT ............................................................................42 
10.1. 
Drug Information ........................................................................................................42 
10.2. 
Labeling, Maintenance, and Retention of Study Drugs ..............................................43 
11. 
STUDY PROCEDURES ............................................................................................44 
11.1. 
Schedule of Events .....................................................................................................44 
11.2. 
Treatment Periods A and B.........................................................................................47 
11.2.1. 
Check-in Procedures ...................................................................................................47 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
Diazepam Buccal Soluble Film 
 
 
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16 
11.2.2. 
Treatment Period A .....................................................................................................48 
11.2.3. 
Treatment Period B: ....................................................................................................49 
11.2.4. 
Dosing .........................................................................................................................49 
11.2.5. 
Post-treatment .............................................................................................................50 
11.3. 
Follow-up ....................................................................................................................51 
11.4. 
Blood Sampling Schedule, Sample Collection, Processing, and Storage ...................51 
11.4.1. 
Pharmacokinetic Assessments ....................................................................................51 
11.4.2. 
Clinical Laboratory Assessment .................................................................................52 
11.4.3. 
Number and Volume of Blood Samples .....................................................................53 
11.5. 
Columbia- Suicide Severity Rating Scale (C-SSRS) ..................................................54 
11.6. 
Vital Signs ..................................................................................................................55 
11.7. 
12-Lead Electrocardiogram ........................................................................................55 
11.8. 
Oral Safety Assessment ..............................................................................................55 
11.9. 
Usability ......................................................................................................................56 
11.10. 
Food and Fluid Intake .................................................................................................57 
11.11. 
Physical Activity .........................................................................................................57 
12. 
ADVERSE EVENTS..................................................................................................57 
12.1. 
Adverse Event Recording and Follow-up ...................................................................57 
12.1.1. 
Serious Adverse Events ..............................................................................................57 
12.1.2. 
Evaluation of Severity of AEs ....................................................................................58 
12.1.3. 
Assessing Relationship to Study Drug .......................................................................58 
12.1.4. 
Follow-up of AEs .......................................................................................................59 
12.2. 
Procedures for Reporting Adverse Events ..................................................................60 
13. 
BIOANALYTICAL ANALYSIS ...............................................................................61 
13.1. 
Analytical Procedures .................................................................................................61 


 
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14. 
PHARMACOKINETIC AND STATISTICAL ANALYSIS .....................................62 
14.1. 
Pharmacokinetic Analysis Data Set ............................................................................62 
14.2. 
Data Analyzed ............................................................................................................62 
14.2.1. 
Pharmacokinetic Endpoints ........................................................................................63 
14.2.2. 
Safety Endpoints .........................................................................................................64 
14.2.3. 
Usability Endpoints ....................................................................................................64 
14.3. 
Statistical Analyses .....................................................................................................65 
15. 
ETHICAL CONSIDERATIONS................................................................................67 
15.1. 
Basic Principles ..........................................................................................................67 
15.2. 
Informed Consent .......................................................................................................67 
15.3. 
Revisions and/or Amendments to the Protocol ..........................................................67 
15.4. 
Delegation of Investigator Tasks ................................................................................68 
16. 
REFERENCES ...........................................................................................................69 
APPENDIX A ................................................................................................................................71 
 
 
 


 
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LIST OF TABLES 
 
Table 1. 
Preliminary PK Data from Study 162013 – Dose-Proportionality of DBSF 
at Doses of 5, 10, and 15 mg (N = 25) .............................................................25 
Table 2. 
Dose of DBSF Expected to Provide Cmax Equivalent to Diastat® ...................26 
Table 3. 
Treatment-Emergent Signs and Symptoms That Occurred in >1% of 
Patients Enrolled in Parallel-Group, Placebo-Controlled Trials and were 
Numerically More Common in the Diazepam Rectal Group ..........................28 
Table 4. 
Treatment-Emergent Adverse Events that Occurred in Study 1899 and 
Study 1900 .......................................................................................................29 
Table 5 
Study Restrictions ............................................................................................41 
Table 6 
Study Drug Information ...................................................................................42 
Table 7. 
Schedule of Events ...........................................................................................45 
Table 8 
Clinical Laboratory Assessments .....................................................................53 
Table 9 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject .......................................................................................54 
 
LIST OF FIGURES 
Figure 1. 
Cmax Values by Nominal Dose for DBSF vs. Diastat® ....................................24 
 
 


 
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6. 
BACKGROUND AND PHARMACOKINETICS 
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 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 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 2000; Sankar 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 
this treatment, partly because the rectal route of administration is inappropriate or 
unacceptable (Fisgin 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.  


 
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6.2. 
Diazepam  
Diazepam is a long-acting “classical” benzodiazepine with potent inhibitory activity at 
the 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 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 2008). 
Intravenous diazepam is a first-line treatment for status epilepticus (Riss 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 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 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 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. 
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 December 2016). 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-


 
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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 (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 
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 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 1997). 


 
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6.4. 
Diazepam Buccal Soluble Film 
The new route of diazepam administration is via buccal soluble film. MonoSol Rx 
initiated development of DBSF, specifically intended for buccal delivery for patients who 
require control of intermittent bouts of seizure activity. DBSF 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 DBSF 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 DBSF product is intended for submission as 
a 505(b)(2) NDA using Diastat® AcuDial™ rectal gel as the reference therapy.  
Buccal soluble diazepam may be particularly well-suited for administration in outpatient 
settings. The DBSF 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 position or 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 DBSF will meet the treatment need for a form of diazepam 
that is effective, safe, allows reliable dose administration, and is easier to administer than 
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 clinical studies of DBSF have focused on assessing its bioavailability relative to the 
reference therapy, Diastat® AcuDial™ rectal gel. Overall safety and tolerability are also 
being assessed in all clinical trials conducted with DBSF.  
To date, two human pilot bioavailability studies have been completed with the DBSF 
product (Studies 1899 and 1900). A dose-proportionality study (Study 162013) and a 
food effect study (Study 162022) have been completed, and formal data analysis is 


 
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ongoing at the time of this writing. A pivotal pharmacokinetics study (Study 162021) to 
establish bioavailability compared with Diastat® rectal gel is underway. 
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 
DBSF in comparison to the same nominal dose of Diastat® AcuDial™ rectal gel. Study 
1899 compared DBSF 5 mg to Diastat® AcuDial™ rectal gel 5 mg, with 11 subjects 
completing both treatments. Study 1900 compared DBSF 20 mg to Diastat® AcuDial™ 
rectal gel 20 mg, with 10 subjects completing both treatments.  
Study 1899 compared DBSF 5 mg to Diastat® AcuDial™ rectal gel 5 mg. Among the 11 
subjects who completed both treatments, DBSF 5 mg was bioequivalent to Diastat® 
AcuDial™ rectal gel 5 mg with respect to area under the curve (AUCt and AUCinf), i.e., 
the 90% confidence interval (CI) for the ratio of geometric means was within the 
acceptable range of 80-125%. For Cmax, the ratio of geometric means was 1.07 with the 
90% CI 87.1-131.5%. The median Tmax was 0.67 hours for the DBSF (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 DBSF 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 DBSF 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 DBSF (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 
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 DBSF vs. Diastat® at nominal doses of 5 mg in Study 
1899 and 20 mg in Study 1900. These data suggest that DBSF 5 mg is bioequivalent to 
Diastat® 5 mg. In contrast, because the Cmax after administration of Diastat® 20 mg is 
lower than the Cmax after DBSF 20 mg, DBSF 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 suggest that for DBSF, both Cmax and AUC 
are dose-proportional over the 5 mg to 20 mg dose range, whereas, for Diastat®, although 


 
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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 
DBSF is expected to be lower than the therapeutically equivalent nominal dose of 
Diastat®. 
 
Figure 1. Cmax Values by Nominal Dose for DBSF vs. Diastat® 
 
 Data are Cmax values (geometric means) from Studies 1899 (N=11) and Study 1900 (N=10). As shown in 
the figure, Cmax values for DBSF 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 
DBSF and Diastat® – data not shown.) Analysis of the individual data by linear regression indicated that 
the observed Cmax values for DBSF 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 conducted to assess dose-proportionality of DBSF at doses of 5, 10, 
and 15 mg. Preliminary analysis of the pharmacokinetic data confirms that DBSF is dose-


 
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proportional over the dose range 5 mg to 15 mg (Table 1). These preliminary results are 
consistent with the data from studies 1899 and 1900, which suggest that DBSF is dose 
proportional over the 5 to 20 mg dose range.  
 
Table 1. Preliminary PK Data from Study 162013 – Dose-Proportionality of DBSF 
at Doses of 5, 10, and 15 mg (N = 25) 
Dose 
5mg 
10mg 
Geometric 
Mean Ratio 
90% Confidence Interval 
Cmax (ng/ml)  
177.86 
337.92 
105.27% 
0.988 
1.122 
AUCt (ng.h/ml)  
4201.00 
8104.12 
103.68% 
0.996 
1.08 
AUCinf (ng.h/ml) 
4774.80 
9170.95 
104.13% 
0.997 
1.088 
 
 
 
 
 
 
Dose  
15mg 
10mg 
Geometric 
Mean Ratio 
90% Confidence Interval 
Cmax (ng/ml)  
499.27 
337.92 
98.50% 
0.923 
1.051 
AUCt (ng.h/ml) 
12431.71 
8104.12 
102.27% 
0.980 
1.067 
AUCinf (ng.h/ml)  
14316.04 
9170.95 
104.07%  
0.990 
1.094 
 Preliminary PK data from Study 162013 (n = 25 subjects who completed all three treatments). Values are 
geometric means. Pair-wise comparisons of 5 mg and 15 mg to the 10 mg dose (ratios of the geometric 
means for parameters dose-normalized to the 10 mg dose) meet bioequivalence standards consistent with 
dose-proportionality. 
 
6.4.3. 
Study 162021 – Pivotal Bioavailability Study 
The ongoing pivotal relative bioavailability study is designed as a four-period, four-
sequence randomized crossover in 36 healthy adult males and females. The four 
treatments are DBSF 15 mg and three doses of Diastat®: 5 mg, 12.5 mg, and 20 mg. 
These Diastat® doses bracket the full dose range for Diastat®. The objective of this study 
is to gain a thorough and precise understanding of the comparative exposure to diazepam 
and nordiazepam (both AUC and Cmax) after administration of DBSF or Diastat®. 
Overall, the study is expected to provide data that will allow identification of a dose of 


 
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DBSF that will match the Cmax, AUC(0-inf), or AUC(0-t) at any selected time interval for 
any marketed dose of Diastat®.  
6.4.4. 
Study 162022 – Food Effect Study 
Study 162022 (formal analysis ongoing) was designed as a standard open-label, 
randomized, two-period, two-sequence crossover study with DBSF 15 mg administered 
under fasted conditions and following a high-fat meal.  The study was conducted with 16 
healthy male and female subjects aged 18 to 65 years, inclusive.   
6.5. 
Rationale for Dose Levels of Diazepam Buccal Soluble Film 
As described above, the available data indicate that DBSF is dose proportional over the 
studied dose-range, while Diastat® is less than dose proportional with respect to Cmax. 
The data suggest that DBSF and Diastat® are approximately bioequivalent at the 5 mg 
dose, but are not bioequivalent at doses above 5 mg. It is clear from Figure 1 that Cmax 
values for DBSF exceed Cmax from Diastat® as the dose increases beyond 5 mg. 
While it is premature to propose labeling at this point in development, the Sponsor has 
used simple linear modeling of the data from Studies 1899 and 1900 to construct a table 
identifying the dose of DBSF expected to produce Cmax values equivalent to the Cmax 
values expected after a given dose of Diastat® (Table 2). 
 
Table 2. Dose of DBSF Expected to Provide Cmax Equivalent to Diastat® 
Diastat Dose (mg) 
DBSF Equivalent* (mg) 
5 
5 
7.5 
6.5 
10 
8 
12.5 
9 
15 
10.5 
17.5 
11.5 
20 
12.5 
 Table gives the nominal dose of DBSF expected to provide Cmax equivalent to given dose of Diastat®. 
These values are based on linear regression models using the data from Studies 1899 and 1900. Cmax 
following DBSF was linearly related to dose. Cmax following Diastat® was linearly related to Dose to the 
2/3 power.  


 
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In the current adult study, all subjects will receive a single dose of 12.5 mg of DBSF in 
each treatment period. Based on the projections in Table 2, this dose is expected to match 
the Cmax expected from a 20 mg dose of Diastat®, or to exceed that Cmax by no more than 
20%. 
6.6. 
Safety 
It is anticipated that the adverse event (AE) profile from systemic exposure observed with 
DBSF 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 two years of age and older. Clinical studies have not been 
conducted to establish the efficacy and safety of Diazepam rectal gel in children under 
two 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 3 below lists treatment-emergent signs and symptoms 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 3. Treatment-Emergent Signs and Symptoms 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% 
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 Soluble Film 
Diazepam Buccal Soluble Film was administered to 23 healthy male and female adult 
volunteers during the two pilot trials (11 subjects in Study 1899 and 12 subjects in Study 
1900). Table 4 lists the treatment-emergent AEs (TEAEs).  
 


 
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Table 4. Treatment-Emergent Adverse Events that Occurred in Study 1899 and 
Study 1900 
Body System 
Preferred 
Term 
DBSF 
5 mg 
n=11  
n (%) 
DBSF 
20mg 
n=12  
n (%) 
Diastat® 
rectal gel 
5 mg n=11  
n (%) 
Diastat® 
rectal gel 
20 mg n=12 
n (%) 
Nervous 
System 
Disorders 
Somnolence 
7 (63.6) 
12 (100) 
10 (83.3) 
11 (91.7) 
Headache 
 
1 (8.3) 
 
 
Asthenia 
 
1 (8.3) 
 
 
Weak 
 
1 (8.3) 
 
 
Hiccups 
 
1 (8.3) 
 
 
Dizziness 
 
 
 
1 (8.3) 
Cardiovascular 
Disorders 
Hypotension 
 
 
 
2 (16.7) 
Gastrointestinal 
Disorders 
 
 
 
 
 
Musculoskeletal 
System 
Disorders 
Unsteady 
Gait 
 
1 (8.3) 
 
 
 
All AEs in the two pilot studies were mild and transient in nature, and there were no 
Serious Adverse Events (SAEs). Inspections of the oral cavity were conducted before 
application and after disintegration/dissolution of DBSF, without evidence of local 
irritation or AEs related to the application noted. 
The other studies mentioned above have not been completed as of the time of this 
writing. However, it should be noted that a serious adverse event (SAE) was reported in 
the pivotal pharmacokinetics study (Study 162021). A healthy 28-year-old male subject 
with no significant medical history experienced decreased heart rate (37 bpm), decreased 
respiratory rate, and drowsiness after administration of 15 mg of DBSF. Telemetry 
showed sinus bradycardia. The investigator administered multiple doses of flumazenil as 
well as a single dose of atropine in the clinical research unit. The patient was hospitalized 


 
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overnight for observation and bradycardia resolved with no further treatment. The onset 
of symptoms occurred near the expected time of peak concentration of the study drug, 
and symptoms were consistent with known effects of diazepam. Plasma concentrations of 
diazepam were available until 2 hours after dosing and again at 48 hours. The maximum 
concentration (Cmax) for diazepam in this subject (Tmax 1.5 h) was 482.37 ng/mL. This 
value is in line with the mean Cmax observed following 15 mg DBSF in the dose-
proportionality study (Study162013): mean Cmax 492.21, median Tmax 1.268 h (N = 30). 
Similarly, the diazepam plasma concentration at 48 hours (112.68 ng/mL) was also in the 
expected range. Based on this information, the principal investigator judged that the event 
was attributable to an unusual sensitivity to diazepam and not specific to DBSF. The 
reason for this subject’s unusual sensitivity to diazepam is unknown.  
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. 
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 resedation, 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 OBJECTIVE  
The primary objective is to assess the pharmacokinetics of DBSF in adult 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 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 include: 
• Evaluate the safety/tolerability of DBSF following single-dose administration in 
subjects with epilepsy  
• Evaluate the usability of DBSF in Period A and Period B 
Data from this study are intended to support a 505(b)(2) New Drug Application for the 
test product. 
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, Treatment Period A (interictal DBSF dosing and pharmacokinetic evaluation), 
minimum washout period of 14 days, Treatment Period B (ictal/peri-ictal DBSF dosing 
and pharmacokinetic evaluation), 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 


 
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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.  
8.1.2. 
Screening Period (Section 9.1)  
The Screening Period will occur 7 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. Subjects under the age of 18 
must provide oral assent as required by the 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 (Section 11.2)  
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.  
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, 12-lead ECG, and the Columbia Suicide Severity Rating 
scale (C SSRS). Urine drug tests and a breath alcohol test will be performed on all 
subjects. Urine pregnancy tests will also be performed for women of child bearing 
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 (respiratory 
rate [RR], heart rate [HR], blood pressure [BP], temperature), 12-lead ECG, clinical 
laboratory tests, and AEs. The subject’s informed consent, 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. If enrolled subjects who have completed 
a previous treatment visit no longer meet inclusion and exclusion criteria, they will be 
discontinued from the study.  


 
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A study drug kit will be assigned by the Interactive Web Response System (IWRS). All 
subjects will receive one dose of 12.5 mg DBSF in Period A and one dose of 12.5 mg 
DBSF in Period B.  
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.  
Treatment Period A. Subjects will enter Treatment Period A as scheduled if an interval 
of at least 3 hours 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 12.5 mg DBSF (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 (8 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 Period 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: 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 (DBSF) will receive a 
single-dose of 12.5 mg DBSF  
• 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.  


 
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If the subject’s seizure persists after the single dose of DBSF, an alternative AED 
medication (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 will be 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 medication, 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.  
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 medication, vital signs, clinical laboratory tests, AEs, 
comprehensive 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. 
PK and Safety Assessments 
The following assessments will be performed (see Section 11.4 for details):  
Diazepam PK (Section 11.4.1). In both treatment periods, plasma samples for diazepam 
and the active metabolite desmethyldiazepam PK will be obtained before DBSF 
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). In Treatment Period A, a plasma sample will 
also be taken at 8 hours (480 minutes) in the EMU, GCRC or similar facility, and 
additional plasma samples will be collected at 24, 48, 96, 144, 192, and 240 hours after 
DBSF administration in an outpatient setting (either at the EMU, GCRC or similar 


 
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facility, or via home visits). Collection of plasma samples will continue regardless of 
whether another AED is administered for rescue. 
Vital Signs. The subject’s BP, HR, RR, and temperature will be recorded at Screening, 
during the treatment visits predose 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 DBSF 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.  
Usability.  The usability of DBSF 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 7 to 28 days before Day 1; Treatment Period A 
(interictal) 1 day; a minimum washout period of 14 days; Treatment Period B (ictal/peri-
ictal) 1 day; and Follow-up 14 days (±2 days) after the second treatment period. Thus, the 
minimum study duration will be approximately 35 days, and the maximum will be 
approximately 58 days. 
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 
9.1. 
Screening Procedures 
Screening procedures will be conducted within 7 to 28 days prior to the first treatment 
period. Screening procedures can be performed after signing of the Study Informed 
Consent Form (ICF).  
The following screening procedures will be conducted for each potential subject: 
• Obtain written informed consent for screening as evidenced by potential subject 
or subject’s legally authorized representative (or parent[s], if the subject is under 
the age of 18) signing an ICF. Obtain oral assent from subjects under the age of 
18 as required by the IRB. Subjects and legally authorized representatives (or 
parents, if applicable) will be given an opportunity to ask questions about the 
study before giving consent.  
• 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 the Columbia-Suicide Severity Rating Scale (see Section 11.5).  
• Collect urine samples for urinalysis and drug screening (see Section 11.4.2).  
• If the subject reports having received any dosage form of diazepam within the 
past 2 weeks, then the clinic admission for the first treatment should be deferred 
for at least 2 weeks. If the subject reports taking 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. Use of a benzodiazepine other than diazepam in the past two 
weeks and/or a positive urine test for benzodiazepines is not a basis for 
rescheduling admission to the clinic.  
• Obtain height and body weight. 
• Obtain vital signs (temperature, respiratory rate (RR), heart rate (HR), blood 
pressure (BP), and electrocardiogram (ECG). 
• Collect blood samples for hematology, chemistry, and pregnancy testing (for 
women of childbearing potential). For a complete listing of all tests to be 
performed, please refer to Section 11.4.2. 
• Perform breath alcohol test in subjects as per EMU/GCRC protocol.  


 
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• Perform a physical and neurological examination. 
• Dispense seizure diaries, with instructions to subjects 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 EMU, GCRC, or 
similar facility for evaluation. 
2. Male and female subjects between 17 and 65 years of age, inclusive. 
3. Subjects have a body weight of ≥40 kg and ≤111 kg. 
4. Subjects have an average frequency of ≥1 seizure every 3 days or ≥10 seizures / 
month 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 not surgically sterile or are 2 
years postmenopausal) 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. Subjects are currently receiving at least one antiepileptic medication. 
7. Subjects or subject’s legally authorized representative must be willing and able to 
complete informed consent/assent and HIPAA authorization. 


 
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8. Subject must agree to be available or subject’s 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. 
9. Subject or subject’s 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: 
1. Subjects with a progressive neurological disorder such as brain tumor, 
demyelinating disease, or degenerative central nervous system (CNS) disease that 
is likely to progress in the next 12 months. 
2. Subjects with 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 (including Type 4 or Type 5 suicidal ideation on 
the C-SSRS) that in the Investigator's judgment would prevent the subject’s 
successful completion of the study. 
5. 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 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. 
6. Subjects with any clinically significant illness other than epilepsy within 30 days 
prior to first dosing, as determined by the Investigator. 
7. 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. 


 
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8. Subjects with any significant lesion of the oral cavity or having oral prophylactic 
or dental procedures within 30 days prior to study drug administration. 
9. Subjects with a QTc interval QTcF>450 msec for males and QTcF>470 msec for 
females on screening ECG, unless determined as not clinically significant by the 
Investigator. 
10. Subjects with a positive test result for any of the following: drugs of abuse: 
amphetamines, cocaine, opiates, phencyclidine, or tetrahydrocannabinol [THC] 
(unless legal in state where subject resides and obtained with a prescription); or a 
positive breath alcohol test. 
11. 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 
12. Subjects who have participated in another clinical trial or who received an 
investigational drug within 30 days prior to first study drug administration or 5 
half-lives of the investigational drug—whichever is the longer period.  
13. Subjects with presence of mouth jewelry, dentures, oral implants, braces, or 
piercings in the mouth or tongue that, in the opinion of the Investigator, would be 
likely to interfere with successful completion of the dosing procedure. 
14. Subjects with a blood or plasma donation within 30 days prior to Screening 
15. Subjects not willing or unable to tolerate blood draws. 
16. 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 first study drug administration. 
17. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome 
(CYP) P450 enzymes (e.g. cimetidine, fluoxetine, quinidine, erythromycin, 
ciprofloxacin, fluconazole, ketoconazole, diltiazem, or HIV antivirals) and strong 
inducers of CYP enzymes (e.g. glucocorticoids, St. John´s Wort, or rifampicin) in 
the previous 30 days before first study drug administration. (Barbiturates, 


 
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carbamazepine, phenytoin, and other enzyme-modifying AEDs that are medically 
needed are permitted.). 
18. Use of any monoamine oxidase (MAO) inhibitors (e.g., phenelzine, 
tranylcypromine), phenothiazines (chlorpromazine) within 30 days prior to first 
study drug administration. 
19. Employee or immediate relative of an employee of the Investigator, MonoSol Rx 
LLC, any of its affiliates or partners, or inVentiv Health. 
9.3. 
Permitted and Restricted Items 
Study restrictions are summarized in Table 5. 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 treatment 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. 
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 5 Study Restrictions 
Restriction Period 
Item Restricted 
Examples 
30 days prior to first drug 
administration until 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. 
barbiturates, carbamazepine, 
glucocorticoids, phenytoin, 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 first drug 
administration until 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 
Approximately forty (40) subjects with epilepsy will be recruited to attain a sample size 
of at least 30 completed.  
9.5. 
Dropout and Withdrawal/Termination 
Subjects whose participation in the study is discontinued (for any reason) will not be 
replaced. 


 
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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 the subject’s 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 termination visit at which clinical seizure assessment will be done, vital 
signs will be recorded, clinical laboratory tests will be performed, an oral mucosal 
inspection will be performed, and any concomitant medications, including AEDs, will be 
recorded.  
10. 
INVESTIGATIONAL PRODUCT 
10.1. 
Drug Information 
Information on the study drug is given in Table 6. 
 
Table 6 Study Drug Information 
Drug Name: 
Diazepam 
Strength: 
12.5 mg 
Dosage form: 
Buccal Soluble Film 
Manufacturer: 
MonoSol Rx LLC 
Dose: 
1 x 12.5 mg (fasting or fed condition) 
 


 
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Diazepam Buccal Soluble Film 
 
 
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10.1.1. 
Controlled Substance Documentation 
Diazepam Buccal Soluble 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 Soluble Film (DBSF) contains the active ingredient diazepam 
incorporated into a polymer-based film matrix utilizing MonoSol Rx’s 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, and 12.5 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 DBSF doses up to 20 mg were tested in a pilot clinical 
study. The inactive ingredient composition, the film dimensions, and the manufacturing 
process selected for this drug product are based on the information gained from the 
development of the DBSF and other film products produced by MonoSol Rx 
(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 DBSF product is a green rectangular film.  
The primary package used for DBSF 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 DBSF. 
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 


 
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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 minimum the 
Investigation site, Investigator, Protocol Number, Subject Number, Drug Name, Strength 
and Treatment Code/Kit Identification Number, Route of Administration, Quantity of 
Dosage Units, Sponsor’s Name, Address, and Phone Number, 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.  
An inventory record of the drugs received and dispensed will be maintained by the 
Investigator. 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.  
In Period B, the study drug kit assigned by the study IWR system will be secured in close 
proximity to the subject’s room when the subject is admitted to the EMU, GCRC or 
similar facility so that the medication can be administered within 5 minutes of clinical 
confirmed seizure activity.  
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. 
11. 
STUDY PROCEDURES 
11.1. 
Schedule of Events 
The schedule of study events is given in Table 7. 
 


 
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Table 7. Schedule of Events 
Procedure/Activity 
Screening  
(-28 days to -7 
days to Period 
A/B, Day1) 
Period A/Ba 
Check-in 
(Predose) 
Period A/Ba  
Dosing /  
Postdose  
Follow-up 
(14 ±2 d 
post dose) 
ICF 
X 
 
 
 
Register subject status 
in IWRS/ update status 
X 
X 
 
X 
Medical history/ 
demographics 
X 
X 
 
 
Concomitant 
medication review 
X 
X 
X 
X 
Date/time of the 
subject’s last meal 
before DBSF dose 
 
X 
 
 
Review of restrictions  
X 
Xb 
Xb 
 
Columbia-Suicide 
Severity Rating Scale 
X 
X 
 
X 
Height and body weight 
Xc 
X 
 
 
Blood pressure 
X 
Xd 
Xd 
X 
Heart rate 
X 
Xd 
Xd 
X 
Respiratory rate 
X 
Xd 
Xd 
X 
Temperature 
X 
Xd 
Xd 
X 
Physical/neurological 
examination 
Xe 
 
 
Xe 
ECG 
X 
Xf 
Xf 
 
Pregnancy test 
Xg 
Xg 
 
Xg 
Clinical laboratory tests  
X 
 
 
X 
Drug screen (urine) 
Xh 
Xh 
 
 


 
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Procedure/Activity 
Screening  
(-28 days to -7 
days to Period 
A/B, Day1) 
Period A/Ba 
Check-in 
(Predose) 
Period A/Ba  
Dosing /  
Postdose  
Follow-up 
(14 ±2 d 
post dose) 
Breath alcohol test 
X 
X 
 
 
Oral mucosal inspection 
Xi 
Xi 
Xi 
Xi 
Inclusion/exclusion 
assessment 
X 
X 
 
 
Dispense/collect seizure 
diaries 
X 
X 
 
 
Continuous video EEG 
 
Xj 
Xj 
 
Study drug dosing 
 
 
X 
 
PK sampling 
 
Xk 
Xk 
 
Assessment of usability 
 
 
Xl 
 
Adverse event reporting 
 
Xm 
Xm 
Xm 
C-SSRS = Columbia-Suicide Severity Rating Scale; DBSF = Diazepam Buccal Soluble Film; ECG = 
electrocardiogram; EEG = electroencephalogram; ICF = informed consent form; PK = pharmacokinetics.  
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. Confirmed at each follow-up visit blood draw, if applicable. 
c. 
Height collected at Screening only. 
d. At both treatment visits, vital signs (BP, HR, RR, and temperature) will be recorded 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), 3 hours (180 
minutes), and 4 hours (240 minutes). In Treatment Period A, vital signs will also be measured at 8 
hours (480 minutes) in the EMU, GCRC or similar facility, and additional vital sign measurements 
will be made at 24, 48, 96, 144, 192, and 240 hours (± 2 hours) after DBSF administration in an 
outpatient setting (either at EMU, GCRC or similar facility, or via home visits). The subject’s 
position may be seated or supine, but should be consistent throughout. 
e. 
Physical/neurological examination will be performed at Screening and at Follow-up or at an early 
discontinuation visit. 
f. 
A 12-lead ECG will be obtained at Screening, at the beginning of each Treatment Period, and at 4 
hours after dose administration.  


 
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g. Serum pregnancy test will be performed for females of childbearing potential at Screening; urine 
pregnancy test will be performed at Check-in for both treatment periods and at Follow-up. 
h. Screening: If the subject reports taking any dosage form of diazepam within the 2 weeks before 
screening, the clinic admission for the first treatment should be deferred for at least 2 weeks. If the 
subject reports taking 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.  
Treatment periods: If the subject reports having received any dosage form of diazepam within the 
2 weeks before a treatment visit, then the visit should be deferred for at least 2 weeks. If the 
subject reports taking no diazepam and the urine test is positive for benzodiazepines, then the 
Investigator will make a judgment as to whether to reschedule the visit. 
i. 
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 placement of the film. A further 
inspection of oral mucosa will be made at Follow-up. 
j. 
If indicated by EMU or GCRC protocol, continuous video EEG monitoring for seizure detection 
will be performed throughout each Treatment Period. Sites will maintain the EEG recordings with 
the study documents, but data from the EEG recordings will not be collected for the study dataset.  
k. For both treatment periods, plasma samples for determination of diazepam and 
desmethyldiazepam PK will be obtained 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). In Treatment Period A, a plasma 
sample will also be taken at 8 hours (480 minutes) in the EMU, GCRC or similar facility, and 
additional plasma samples will be collected post DBSF administration at 24, 48, 96, 144, 192, and 
240 hours (±2 hours) in an outpatient setting (either at EMU, GCRC or similar facility, or via 
home visits). Collection of plasma samples will continue even if the administration of another 
AED is needed for rescue. 
l. 
The study staff will evaluate the insertion process to determine usability of the film as described in 
Section 11.10.  
m. AEs are to be collected from time of consent throughout the study.  
 
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 DBSF dose, vital signs, urine pregnancy and drug tests, breath tests, 12-lead 
ECG, and the Columbia Suicide Severity Rating scale (C SSRS), as age appropriate.  
Subjects or their legally authorized representatives will be questioned about whether they 
have complied with the study restrictions. If a restricted drug or non-drug therapy 


 
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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 reports having received any dosage form of diazepam within the past 2 
weeks, then the visit should be deferred for at least two weeks. If the subject reports 
taking no diazepam, and the urine test is positive for benzodiazepines, then the 
Investigator will make a judgment as to whether to reschedule the visit. 
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 (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). All 
subjects will receive one dose of 12.5 mg DBSF in Period A and one dose of 12.5 mg 
DBSF in Period B.  
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 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 
12.5 mg DBSF (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 (8 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 


 
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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:  
Monitoring for the occurrence of seizures will continue until the subject experiences a 
GTC seizure or focal seizure with impaired awareness. 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 (DBSF) will receive a 
single-dose of 12.5 mg DBSF 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 DBSF, an alternative AED 
medication (rescue medication) can be administered as medically required and according 
to the standard-of-care EMU or GCRC treatment protocol. 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 
Before administration of the DBSF, 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 DBSF in that area.  


 
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• 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.  
• The subject will be instructed to close his/her mouth in a natural way, without 
swallowing, chewing, biting, or breaking the DBSF. 
• As soon as the film has been placed on the buccal mucosa, the subject should be 
instructed to lie on his or her side. The subject should lie on the right side (right 
side down) if the DBSF has been placed on the right buccal surface, or on the left 
side (left side down) if the DBSF has been placed on the left buccal surface. It is 
recommended that the subject should remain in position (lying on the appropriate 
side) for 15 minutes. Subjects should be instructed that during this time they 
should not chew, bite, or manipulate the side of the oral cavity to which the DBSF 
was applied.  
• 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. 
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.  


 
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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, comprehensive 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), 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 
Designate. 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 diazepam and the active metabolite 
desmethyldiazepam PK will be obtained before DBSF 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). In Treatment Period A, a plasma sample will also be taken at 8 hours (480 
minutes) in the EMU, GCRC, or similar facility, and additional plasma samples will be 
collected (±2 hours), at 24, 48, 96, 144, 192, and 240 hours after DBSF administration in 
an outpatient setting (either at the EMU, GCRC or similar facility, or via home visits). 
Collection of plasma samples will continue regardless of the administration or whether 
another AED is administered for rescue. 
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 


 
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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 termination.  
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 8. 
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 8 Clinical Laboratory Assessments 
TYPE OF 
TEST 
COMPONENTS 
Hematology 
• Hemoglobin 
• Hematocrit 
• RBC 
• Platelet count 
• RBC morphology and MCV  
• WBC and differential  
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 
 
Urine Tests 
for Drugs of 
Abuse  
Amphetamines, Phencyclidine, Cocaine, Opiates, Benzodiazepines, THC  
Diazepam & 
desmethyl-
diazepam 
Active drug and metabolite in DBSF formulation 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
RBC = red blood cells; 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 is shown for the individual study visits and 
total volumes over the course of the study in Table 9. 


 
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Table 9 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 
8.5 
1 
- 
- 
1 
17 
Hematology a 
4 
1 
- 
- 
1 
8 
PK b, c 
6 
14 b 
7 b 
 
126 
 
 
Maximum Blood Volume (mL) 
 
TOTAL (mL) 
  
12.5 
84 
42 
12.5 
151 
 
 
 
 
 
 
 
Type of Vacutainer® 
PK – pre-chilled K2EDTA Vacutainer®, 6 mL 
Chemistry – Vacutainer®, 8.5 mL 
Hematology – Vacutainer®, 4 mL 
Blood sampling time points 
a. Samples for the clinical laboratory tests will be obtained at Screening and at 
Follow-up (or at early termination). 
b. Plasma samples for diazepam and desmethyldiazepam PK will be obtained 
during both Treatment Periods at predose 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 (total of 7 samples per period). In Treatment Period A, 
a plasma sample will be taken at 8 hours (480 minutes) in the EMU, GCRC 
or similar facility, and additional plasma samples will be collected at 24, 48, 
96, 144, 192, and 240 hours post dose (7 additional samples). 
c. The actual time of blood sample collection will be used for PK and 
statistical analysis. 
 
11.5. 
Columbia- Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS, which assesses suicidal behavior and ideation, will be administered at each 
study visit. Qualified, trained staff will administer the C-SSRS, Baseline-Screening 
version at Screening, and the C-SSRS, Since Last Visit version will be administered at 
Treatment Period A and B check-in, and at Follow-up. 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. 


 
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11.6. 
Vital Signs  
The subject’s vital signs (BP, HR, RR, and temperature) will be recorded at Screening 
and during both treatment periods pre-dose 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), 3 hours (180 minutes), and 4 hours (240 minutes). 
The subject’s position may be seated or supine, but should be consistent throughout. In 
Treatment Period A, vital signs will also be measured at 8 hours (480 minutes) in the 
EMU, GCRC or similar facility, and additional vital sign measurements will be made at 
24, 48, 96, 144, 192, and 240 hours after DBSF administration in an outpatient setting 
(either at EMU, GCRC or similar facility, or via home visits). Vital signs will also be 
recorded at Follow-up. 
For subjects with pre- or post-dose vital signs outside of the acceptable range of systolic 
blood pressure between 90-140 mmHg, inclusive; diastolic blood pressure between 50-
90 mmHg, inclusive; or heart rate between 50-100 bpm, inclusive, the measurement will 
be repeated up to two times. If vital signs are still outside of the acceptable range, the 
Investigator will determine the appropriate course of action. 
Additional vital signs measurements will be taken if deemed necessary by the 
Investigator. Should a timing conflict arise, blood draws will take precedence over vital 
signs measurements and other scheduled activities, unless deemed otherwise by the 
Investigator. 
11.7. 
12-Lead Electrocardiogram 
A 12-lead ECG will be obtained at Screening, and at each treatment period both predose 
and 4 hours after dosing. 
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 Assessment 
The Investigator will make an illumination-assisted visual inspection of the oral mucosa, 
including the DBSF application site, at the following times: 
• At Screening;  


 
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• 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 12.1.2. 
11.10. 
Usability 
To assess usability of DBSF, 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.) 
• 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). 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
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11.11. 
Food and Fluid Intake 
The date/time of the patient’s last meal before DBSF 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.  
12. 
ADVERSE EVENTS 
The CRO, inVentiv 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. Seizures will be recorded as 
AEs. 
At the treatment periods and follow-up visit, subjects will be questioned concerning 
symptoms that may have occurred after the previous administration of the study drug. 
The incidence, seriousness, severity, duration, and relationship to study drug of all AEs 
will be recorded. 
12.1.1. 
Serious Adverse Events 
An SAE is an AE 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 
• Is a congenital anomaly or birth defect (in the child of a subject who was exposed 
to the study drug) 


 
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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. 
12.1.2. 
Evaluation of Severity of AEs 
Severity will be evaluated according to the following scale: 
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.  
 
Adverse Event monitoring and reporting will be followed-up until resolution or for up to 2 
weeks following completion of the study, after which the Investigator will decide the course 
of action. 
12.1.3. 
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. 
12.1.4. 
Investigator Presence 
The Investigator or designee will be present from approximately 30 minutes prior to 
dosing until at least 2 hours post dose for each subject. The Investigator or 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.  
12.1.5. 
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. 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
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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 course of 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 the 
current version of 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 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, inVentiv 
Health within twenty-four hours (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:  
Fax No. +1 866 856 1649 


 
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Email. In case of emergency or fax failure the report can also be submitted by 
email to saereceipt.international@inventivhealth.com 
If notification cannot be made via these means due to technical delivery problems, initial 
notification may be made by phone, using the inVentiv 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 inVentiv Health SAEs reported 
via the Hotline number must be followed with the SAE report the same day.  
Hotline No.: 888-750-8020 
In the event of any fatal or life-threatening SAE, the Investigator must also inform a 
Medical Monitor at inVentiv Health by telephone or email:   
 
Dr. Nermina Nakas 
Sr. Medical Director 
Tel: 804-270-6074 
Cellular: 804-837-6101 
Email:  
nermina.nakas@inventivhealth.com 
Dr. Marcel Reichert 
Medical Director 
Tel: 650-554-1706 
Cellular: 650-550-1706 
Email: 
marcel.reichert@inventivhealth.com 
 
The Investigator will be responsible for notifying the IRB. The Sponsor will be 
responsible for notifying the regulatory agencies, as appropriate. 
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: 
inVentiv Health 
2500, rue Einstein 
Québec City, Québec G1P 0A2 Canada 
Tel.: 1-418-527-4000 
 


 
Protocol Number: 160326  
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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.  
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 study 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 Medical Monitor and/or the Sponsor 
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 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 PK data set will be defined prior to sample analysis. 
14.2. 
Data Analyzed 
Pharmacokinetic and statistical analysis will be performed by inVentiv Health. Summary 
statistics will be reported for pharmacokinetic, safety, and usability endpoints. 
Pharmacokinetic and statistical analysis will be performed on all data from all subjects in 
the final PK data set (Intent-to-Treat population). The actual time of blood samples 
collection will be used for PK and statistical analysis. 


 
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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 Endpoints 
For Treatment Period A, 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: 
Cmax 
The maximal observed plasma concentration. 
Tmax 
Time when the maximal plasma concentration is observed. 
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. 
λ 
Terminal elimination rate constant, estimated by linear regression analysis of 
the terminal portion of the ln-concentration vs. time plot. 
T1/2 
Terminal elimination half-life, estimated as ln(2)/λ. 
Cl 
Clearance (L/hr) estimated from Dose/AUCinf 
Cl/kg 
Clearance/kg (L/hr/kg) estimated from Dose/kg/AUCinf 
Vdβ 
Volume of distribution (L) estimated from Cl/ λ(β) 
 
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. 
The λ, T1/2, and AUCinf parameters will not be estimated for plasma concentration-time 
profiles where the terminal linear phase is not clearly defined. 


 
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For subjects with missing or non-reportable diazepam concentrations for three or more of 
the last samples, only the Cmax and Tmax will be presented and included in the statistical 
analysis. Other PK parameters will not be reported. 
For Period B, Cmax, Tmax, and AUC(0-4h) will be estimated. 
Descriptive statistics (min, max, median, mean, standard deviation and coefficient of 
variability) will be provided for all PK parameters. 
 
14.2.2. 
Safety Endpoints 
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) 
• Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• Physical and neurological examinations 
• Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) 
• 12-lead ECG 
• Clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
For purposes of the analysis, seizures that occur during Period A (within 8 hours after 
dosing) or during Period B (within 4 hours after dosing) will be handled as AEs unrelated 
to the study drug.  
14.2.3. 
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 


 
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- 
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 DBSF 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).  
14.3. 
Statistical Analyses 
No formal statistical tests will be performed to compare Period A vs. Period B on 
pharmacokinetic, safety, or usability endpoints.  
For Period A only, summary statistics will be reported for mean and geometric mean 
values of AUC0-t, AUCinf, Cmax, Cl, Cl/kg, Vd, and Vd/kg, as well as mean and median 
Tmax for diazepam. For Period B, summary statistics will be reported for mean and 
geometric mean Cmax and AUC(0-4h), and for mean and median Tmax for diazepam. The 
90% confidence intervals (CI) for the ratios (period A compared with period B) of 
geometric means for Cmax and AUC(0-4h) will be reported. Tmax will be compared (period 
A and B) with an appropriate non-parametric test.  
Summary statistics for desmethyldiazepam shall be limited to Cmax and AUCt for Period 
A and to Cmax and AUC(0-4h) for Period B.  
A descriptive comparison will also be performed to assess plasma concentration data for 
diazepam and desmethyldiazepam reported in subjects having true epileptic events in this 
study (Period B) compared to the data from the non-seizure period (Period A) and to data 
reported in the Phase 1 healthy volunteer studies who are in the DBSF clinical 
development program. 


 
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Summary statistics will also include an evaluation of subjects’ age, concomitant 
medications, and treatment with DBSF for epileptic vs non-epileptic events. No efficacy 
analysis will be performed. 
Additional statistical and alternate tests will be performed if necessary. The PK and 
statistical analysis will be performed using an appropriate 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 obtained 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 
each potential subject or their legally authorized representative, or parent(s) if the subject 
is under the age of 18, before any study-specific procedures or assessments are performed 
and after the aims, methods, anticipated benefits, and potential hazards are explained. 
Willingness to participate in the study will be documented in writing in a consent form, 
approved by the IRB, which will be signed by the subject or their legally authorized 
representative, or parent(s), as applicable, and by the Investigator or designee, with the 
date of signature indicated. Subjects under the age of 18 must provide oral assent as 
required by the IRB. The Investigator will keep the original consent forms and copies 
will be given to the subject or their legally authorized representative or parent(s). It will 
also be explained to the subject or their legally authorized representative or parent(s) that 
the subject is 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 all subjects and legally authorized representatives or parent(s). 
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 
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. 


 
Protocol Number: 160326  
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For revisions or amendments to the protocol that substantially alter the study design after 
initiation of the study, the Investigator and Sponsor will decide whether a revised 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.  
 
 


 
Protocol Number: 160326  
Adult EMU Protocol Version Number: 3.3, August 4, 2017 
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16. 
REFERENCES 
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/ 
 
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. 
 
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. 
 


 
Protocol Number: 160326  
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CONFIDENTIAL INFORMATION 
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Page 70 
 
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. 
 
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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Page 71 
 
Appendix A  
Placement Diagram for MonoSol Rx Buccal Soluble Film 
 
 
 
As soon as the film has been placed on the buccal mucosa, the subject should be instructed to lie on his or 
her side. The subject should lie on the right side (right side down) if the DBSF has been placed on the right 
buccal surface, or on the left side (left side down) if the DBSF has been placed on the left buccal surface. It 
is recommended that the subject should remain in position (lying on the appropriate side) for 15 minutes. 
Subjects should be instructed that during this time they should not chew, bite, or manipulate the side of the 
oral cavity to which the DBSF was applied. 
Test Drug: Placement against the buccal mucosa (either side of film can be placed 
against the buccal mucosa): 
MonoSol Rx film is to be centered against the inner aspect of the right or left cheek, as 
illustrated by the Figure below. The 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. 

SAP_001.pdf: 
NCT03179891
A Multicenter, Open Label, Cross-Over Study to Assess the Pharmacokinetics and Safety 
of Diazepam Buccal Soluble Film (DBSF) in Adult Subjects with Epilepsy
STATISTICAL ANALYSIS PLAN FINAL VERSION 1.1 DATED 14 SEPTEMBER 2018 


STATISTICAL ANALYSIS PLAN 
MonoSol Rx, LLC 
Protocol 160326, Amendment I 
Version: 1.1, 14Sep2018 
Confidential 
SOP-STAT-005-AD-01-01 
1 of 27     STATISTICAL ANALYSIS PLAN 
STATISTICAL ANALYSIS PLAN 
Sponsor: 
MonoSol Rx, LLC 
30 Technology Drive 
Warren, NJ 07059 
USA 
 A Multicenter, Open Label, Cross-Over Study to Assess the 
Pharmacokinetics and Safety of Diazepam Buccal Soluble  
Film (DBSF) in Adult Subjects with Epilepsy 
Protocol No: 160326 
Final Version: 1.1 
Date: 14-Sep-2018 
Prepared by: 
Yogesh Pokharkar / Priya Diana D’silva 
Syneos Health  
This document contains confidential information of MonoSol Rx. LLC.  Any viewing or disclosure of such 
information that is not authorized in writing by MonoSol Rx. LLC is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.  


 
 
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 Page 2 of 27 Approval 
Approval 
 
Sponsor: 
MonoSol Rx, LLC 
30 Technology Drive 
Warren, NJ 07059 
USA 
 
 
 A Multicenter, Open Label, Cross-Over Study to Assess the 
Pharmacokinetics and Safety of Diazepam Buccal Soluble  
Film (DBSF) in Adult Subjects with Epilepsy 
 
 
 
 
Protocol No:  160326, Amendment I 
 
 
Frances Ekweonu, Clinical Operations Manager 
Aquestive Therapeutics 
Approval Date 
 
 
 
Allen H Heller MD MPH,  
Principal, Pharma Study Design 
Consultant to Aquestive Therapeutics 
Approval Date 
 
 
 
Priya Diana D’silva, Senior Statistician 
Syneos Health  
Approval Date 
 
 
 
Yogesh Sable, Principal Statistician 
 
Syneos Health  
Approval Date 
 
 
 
 
 




 
 
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TABLE OF CONTENTS  
 
TABLE OF CONTENTS ................................................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 4 
1. 
INTRODUCTION ............................................................................................................................. 7 
2. 
STUDY OBJECTIVES ..................................................................................................................... 8 
2.1 
Primary Objective ............................................................................................................................ 8 
2.2 
Secondary Objectives ...................................................................................................................... 8 
3. 
STUDY DESIGN .............................................................................................................................. 9 
3.1 
General Design ................................................................................................................................ 9 
3.2 
Study Period Definitions .................................................................................................................. 9 
3.3 
Treatment description .................................................................................................................... 10 
4. 
SCHEDULE OF ASSESSMENTS ................................................................................................. 11 
5. 
ANALYSIS POPULATIONS ......................................................................................................... 13 
5.1 
Safety Population ........................................................................................................................... 13 
5.2 
Pharmacokinetic Population and Pharmacokinetic Analysis Data Set .......................................... 13 
6. 
STATISTICAL METHODOLOGY ................................................................................................ 14 
6.1 
Statistical and Analytical Issues .................................................................................................... 14 
6.1.1 
Statistical Methods ............................................................................................................. 14 
6.1.2 
Handling of Dropouts and Missing Data ........................................................................... 14 
6.1.3 
Pooling of Investigative Sites ............................................................................................ 15 
6.2 
Determination of Sample Size ....................................................................................................... 15 
6.3 
Subject Characteristics ................................................................................................................... 15 
6.3.1 
Subject Disposition ............................................................................................................ 15 
6.3.2 
Protocol Deviations ............................................................................................................ 15 
6.3.3 
Background and Demographic Characteristics .................................................................. 15 
6.3.4 
Study Drug Administration ................................................................................................ 16 
6.3.5 
Prior and Concomitant Medications and Therapies ........................................................... 16 
6.3.6 
Medical Histories ............................................................................................................... 16 
6.4 
Efficacy Analysis ........................................................................................................................... 17 
6.5 
Safety Analysis .............................................................................................................................. 17 
6.5.1 
Adverse Events .................................................................................................................. 17 
6.5.2 
Physical and Neurological Examination ............................................................................ 18 
6.5.3 
Vital Signs ......................................................................................................................... 18 
6.5.4 
Electrocardiogram .............................................................................................................. 19 
6.5.5 
Laboratory Parameters ....................................................................................................... 19 
6.5.6 
Visual Oral Inspection ....................................................................................................... 20 
6.5.7 
Columbia Suicidal Severity Rating Scale .......................................................................... 20 
6.6 
Pharmacokinetics Analysis ............................................................................................................ 21 
6.6.1 
Handling of the BLQ and the No Reportable Concentration Values ................................. 21 
6.6.2 
Handling of the Difference Between the Scheduled and the Actual Sampling Times ....... 21 
6.6.3 
Pharmacokinetic Parameters .............................................................................................. 21 
6.6.4 
Statistical Analyses ............................................................................................................ 23 
6.7 
Analysis of Other Assessments ...................................................................................................... 25 
6.8 
Interim Analysis............................................................................................................................. 26 
6.9 
Changes to Methods Planned in the Protocol ................................................................................ 26 
7. 
REFERENCES ................................................................................................................................ 27 
 
 
 
 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
AUC 
Area under the concentration-time curve  
AUC0-inf 
Area under the concentration-time curve from time zero to infinity (extrapolated) 
AUC0-t 
Area under the concentration-time curve from time zero until the last measurable 
concentration or last sampling time t, whichever occurs first. 
AUC0-4h 
Area under the concentration-time curve from time zero to 4 hour 
AUC0-2h 
Area under the concentration-time curve from time zero to 2 hour 
BLQ 
Below the lower limit of quantitation 
BMI 
Body mass index 
CI 
Confidence interval 
Cl 
Clearance 
Cl/kg 
Clearance normalized for the subject body weight in kg 
Ct 
The last measurable concentration 
Cmax 
Maximal observed plasma concentration 
Corr 
Correlation coefficient 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicidal Severity Rating Scale 
CV 
Coefficient of variation (equivalent to C.V.) 
Df 
Degree of freedom 
DIFF 
Difference 
DBSF 
Diazepam Buccal Soluble Film 
E 
Base for natural logarithm 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram  
EMU 
Epilepsy Monitoring Units 
Err 
Error 
F 
F statistic for F test 
G 
Gram 
GCRC 
General Clinical Research Centers 
Geom 
Geometric 
GTC 
Generalized Tonic-Clonic 
Hr 
Hour (equivalent to h) 
H 
Above normal range 
H0 
Null hypothesis 
ICF 
Informed consent form 


 
 
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Inc. 
Incorporated 
IWRS 
Interactive Web Response System 
Kel  
Terminal elimination rate constant (equivalent to λ) 
Kel Lower 
The actual sampling time where Kel calculation begins 
Kel Upper 
The actual sampling time of the last measurable concentration used to estimate the 
Kel 
Kg 
Kilogram 
/L 
Per liter 
L 
Below normal range (conflicting with Liter) 
Ln 
Natural logarithm (equivalent to ln) 
LS 
Least-squares 
Max 
Maximum (equivalent to max.) 
MedDRA® Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
Min 
Minimum (equivalent to min.) 
mL 
Milliliter 
MS 
Mean squares 
MSE 
Mean squares error 
N 
Number of observations 
Ng 
Nanogram 
Pg 
Picogram 
PK 
Pharmacokinetic 
PR 
Probability (equivalent to Pr and p) 
PT 
MedDRA® Preferred Term 
QI 
Qualified Investigator 
QRS 
The QRS complex is 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 
QTcF 
QT corrected with Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical analysis system 
SD 
Standard deviation 
SE 
Standard error 
SEQ 
Sequence 
SOC 
MedDRA® System Organ Class 


 
 
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SOP 
Standard Operating Procedure 
SQRT 
Square root 
SS 
Sum of squares 
STD 
Standard 
T 
t statistic for t-test (equivalent to T) 
TEAE 
Treatment-emergent adverse event 
T½ el 
Terminal elimination half-life 
Tmax 
Time of maximal observed plasma concentration 
TRT 
Treatment 
Vs 
Versus 
Vd 
Volume of distribution 
Vd/kg 
Volume of distribution normalized for the subject body weight in kg 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 


 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is intended to give a detailed description of the summaries 
and the analyses that will be generated for the present study by inVentiv Health Clinical. 
Analyses specified in this plan are based on Protocol 160326 Version 2.7, Amendment I, dated 
06 June 2017. Safety, tolerability, and pharmacokinetic (PK) analyses will all be described.  
 
The plan may change due to unforeseen circumstances and any changes made after the plan has 
been finalized will be documented. If additional analyses are required to supplement the planned 
analyses described in the SAP, the changes and justification for the changes will be outlined in 
the clinical study report (CSR). No change will be made without prior approval of the study 
sponsor. No revision to the SAP is required for changes which do not affect the statistical 
analysis methods, definitions, or rules defined in this document.  
 
When applicable, all methodology and related processes will be conducted according to Standard 
Operating Procedures (SOPs) of InVentiv Health Clinical.  
 
 


 
 
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2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to assess the comparative pharmacokinetics (PK) of Diazepam Buccal 
Soluble Film (DBSF) in 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 patient has been seizure free over this period. Patients on 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 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.  
 
2.2 Secondary Objectives 
Secondary objectives include:  
 Evaluate the safety/tolerability of DBSF following single-dose administration in subjects 
with epilepsy  
 Evaluate the usability of DBSF in Period A and Period B  
 
Data from this study is intended to support a 505(b)(2) New Drug Application for the test 
product. 
 
 


 
 
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3. STUDY DESIGN  
3.1 General Design 
This is a multicenter, open label, single-dose, cross-over study in adult epilepsy subjects to 
assess the bioavailability of DBSF during the interictal and ictal/peri-ictal periods. It consists of 
following periods: Screening Period, Treatment Period A (interictal pharmacokinetic evaluation), 
Treatment Period B (ictal/peri-ictal DBSF dosing and pharmacokinetic evaluation), and Follow-
up visit (14 ± 2 days after last treatment). Definitions of the interictal and ictal/peri-ictal states are 
given in Section 2.1. Approximately 40 adult (male or female) subjects with a clinical diagnosis 
of epilepsy being admitted to an Epilepsy Monitoring Units setting (EMUs), General Clinical 
Research Centers (GCRCs), or similar facility for evaluation of seizures will be enrolled for this 
study. A minimum of 30 subjects are expected to complete the study. All subjects will receive a 
12.5 mg DBSF dose in both periods. There will be a washout period of at least 2 weeks between 
DBSF doses of Treatment Period A and Treatment Period B.  
 
3.2 Study Period Definitions  
Study periods will be conducted as follows: 
Screening Period: The screening period will be from day of informed consent signed to one day 
prior to first visit (admission) in Treatment Period A or Treatment Period B, whichever occurs 
first. The screening period will occur minimum of 7 and maximum of 28 days prior to admission 
in GCRC or EMU facility.  
Treatment Period A : Upon admission and until 8 hours (approximately) in GCRC or EMU 
facility + 6 additional visits for vital signs, adverse events (AEs), and blood samples (either at 
EMU, GCRC or similar facility, or Home Visits).  
Washout Period: Minimum of 14 days between Treatment Period A and Treatment Period B 
doses.  
Treatment Period B: Upon admission in Treatment Period B and until 4 hours (approximately) 
following DBSF administration. Duration of Treatment Period B will vary depending on seizure 
occurrence. 
Period A and Period B may occur in either order as determined by seizure occurrence, e.g. if a 
subject experiences a seizure before dosing during first visit to EMU, GCRC or similar facility 
and if it has been determined that the subject meets inclusion/exclusion criteria, the investigator 
may regard that visit as Treatment Period B.  
Post-Treatment Period: If the subject remains in the EMU, GCRC, or similar facility following 
the end of a treatment period, that time will be regarded as post-treatment period.  
 
 


 
 
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3.3 Treatment description 
A subject will be administered a single dose of 12.5 mg DBSF, under fasting or fed conditions. 
The treatments administered in this study are presented in Table 3-1 
Table 3-1 Treatment Description  
Treatment 
Description 
A 
1 x 12.5 mg Diazepam Buccal Soluble Film under fed or fasting conditions 
The same treatment and dose will be used within-subject for Treatment Period A and Treatment 
Period B. This is an open-label study and subjects as well as clinic staff will not be blinded. 
Treatment assignment will not be randomized. 
 
 


 
 
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4. SCHEDULE OF ASSESSMENTS 
Procedure/Activity  
Screening (-28 
days to -7 days to 
Period A/B, Day1)  
Period A/Ba 
Check-in 
(Predose)  
Period A/Ba 
Dosing / 
Postdose  
Follow-up (14 
±2 d postdose)  
ICF  
X 
 
 
 
Register subject status in 
IWRS/ update status  
X 
X 
 
X 
Medical history/ 
demographics  
X 
X 
 
 
Concomitant medication 
review  
X 
X 
X 
X 
Review of restrictions  
X 
Xb 
Xb 
 
Columbia-Suicide Severity 
Rating Scale  
X 
X 
 
X 
Height and body weight  
Xc 
X 
 
 
Blood pressure  
X 
Xd 
Xd 
X 
Heart rate  
X 
Xd 
Xd 
X 
Respiration rate  
X 
Xd 
Xd 
X 
Temperature  
X 
Xd 
Xd 
X 
Physical exam  
X 
 
 
X 
Neurological exam  
X 
 
 
X 
ECG  
X 
X 
Xe 
 
Pregnancy test  
Xf 
Xf 
 
Xf 
Clinical laboratory tests  
X 
 
 
X 
Drug screen (urine)  
Xg 
Xg 
 
 
Breath alcohol test  
X 
X 
 
 
Oral mucosal inspection  
Xh 
Xh 
Xh 
Xh 
Inclusion/exclusion 
assessment  
X 
X 
 
 
Dispense/collect seizure 
diaries  
X 
X 
 
 
Continuous video EEG  
 
Xi 
Xi 
 
Study drug dosing  
 
 
X 
 
PK sampling  
 
Xj 
Xj 
 
Assessment of usability  
 
 
Xk 
 
Adverse event reporting  
 
Xl 
Xl 
Xl 
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. Confirmed at each follow-up visit blood draw, if applicable.  
c. 
Height collected at screen only.  
d. Vital signs (BP, HR, RR, and temperature) will be recorded 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), 3 hours (180 minutes), and 4 hours (240 minutes). In Treatment Period A, 
vital signs will also be measured at 8 hours (480 minutes) in the EMU, GCRC or similar facility, and 
additional vital sign measurements will be made at 24, 48, 96, 144, 192, and 240 hours (± 2 hours) after 
DBSF administration in an outpatient setting (either at EMU, GCRC or similar facility, or via home visits). 
The subject’s position may be seated or supine, but should be consistent throughout.  


 
 
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e. 
A 12-lead ECG will be obtained at Screening, at the beginning of each Treatment Period, and at 4 hours 
after dose administration.  
f. 
 Serum pregnancy test will be performed for females of childbearing potential at screening; urine pregnancy 
test will be performed at Check-in for both treatment periods and at the follow-up visit.  
g. If the subject reports taking any dosage form of diazepam or other benzodiazepines within the past 2 weeks, 
the visit will be rescheduled for 2 weeks later at the Investigator’s discretion. If the subject reports taking no 
diazepam or other benzodiazepines, but the urine test is positive for benzodiazepines, then the Investigator 
will make a judgment as to whether to reschedule the visit.  
h. The Investigator will make an illumination-assisted visual inspection of the oral mucosa during Screening 
and on Day 1 prior to study drug administration. After the study staff assesses the timing of 
disintegration/dissolution of the buccal film, the Investigator will again make an illumination-assisted visual 
inspection of the oral mucosa, including the DBSF application site, at approximately 10 minutes, 30 
minutes, and 60 minutes after complete disintegration/dissolution of the film. A further inspection of oral 
mucosa will be made at the Follow-up Visit. 
i. 
If indicated by EMU or GCRC protocol, continuous video EEG monitoring for seizure detection will be 
performed throughout each Treatment Period. Sites will maintain the EEG recordings with the study 
documents, but data from the EEG recordings will not be collected for the study dataset.  
j. 
For both treatment periods, plasma samples for diazepam and desmethyldiazepam PK will be obtained 
predose and post dose 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). In Treatment Period A, a plasma sample will also be taken at 8 hours (480 minutes) in the EMU, 
GCRC or similar facility, and additional plasma samples will be collected post DBSF administration at 24, 
48, 96, 144, 192, and 240 hours (±2 hours) in an outpatient setting (either at EMU, GCRC or similar facility, 
or via home visits).  
k. To assess usability of DBSF, oral cavity insertion, retention, and placement will be evaluated for each study 
drug administration.  
l. 
Adverse events are to be collected from time of consent throughout study. Seizures that occur after dosing 
during Treatment Period A or B, including after DBSF administration in Period A at 24, 48, 96, 144, 192, 
and 240 hours (±2 hours) in an outpatient setting, should be captured as adverse events unrelated to study 
drug.  
m. 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).  
 
 


 
 
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5. ANALYSIS POPULATIONS 
The analysis of safety or usability parameters will be based on the safety population detailed in 
Section 5.1 below. The analysis of PK parameters will be based on the PK population detailed in 
Section 5.2 below. Treatment assignment will be according to the actual treatment received. 
 
5.1 Safety Population  
The safety population is defined as the group of subjects who receive at least one dose of the 
study medication. 
 
5.2 Pharmacokinetic Population and Pharmacokinetic Analysis Data Set  
The pharmacokinetic population will include all subjects who:  
 Do not have a major protocol deviation that would impact the reliability of PK parameter 
estimation,  
 Have completed at least one treatment period (Period A or Period B), and  
 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.  
 
Data from subjects who were dismissed/withdrawn (for any reason other than non-compliance) 
or who withdrew will be evaluated by Medical Monitor and/or the Sponsor 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 
pharmacokinetic 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 all statistical analyses.  
 
Here are some aspects to be considered (but not to be limited to) when determining data 
availability for 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 principal investigator and/or the sponsor. The data from the subject 
included in the PK population will be included in the final PK analysis data set. All PK 
summaries and analyses will be performed using the final PK analysis data set. The final data set 
will be defined prior to bio-analysis. 


 
 
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6. STATISTICAL METHODOLOGY 
6.1 Statistical and Analytical Issues 
6.1.1 Statistical 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 point. 
 Percentages equal to 0 or 100 will be presented as such without a decimal point. 
 Minimum and maximum will be presented with the same precision as the original values 
and, mean, standard deviation, and median will be presented with one more decimal place 
than the original values. 
 
All digits will be used for pharmacokinetic and statistical PK calculations. For PK tables and 
listing, the final reportable results or data will be presented by rounding off to two decimal digits, 
except for the following situations (this applies to individual data and descriptive statistics): 
 Kel and correlation (Corr) data: rounded off to four decimal digits. 
 Pharmacokinetic parameters related to time such as Tmax, Kel Lower, Kel Upper, Tlag, Tlast, and 
Tmin must be reported with the same precision as the actual sampling time: rounded off to 
3 decimal digits. 
 Concentration versus time data: reported as they appear in the final summary 
concentration table provided by the bioanalytical laboratory. 
 Ratios and 90% confidence intervals are presented to 2 decimal places. 
 
Analysis 
Unless specified, all the analyses will be performed overall or by associated current or more 
recent treatment period, 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 subject received treatment prior to discontinuation. 
 
 
Software to be used for Analysis 
PK analysis will be performed using Phoenix WinNonlin® version 6.4, which is validated for 
bioequivalence/bioavailability studies by inVentiv Health Clinical. 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. 
 
6.1.2 Handling of Dropouts and 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. The shifts required for the shift tables should already 
be included in the ADaM dataset. 


 
 
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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 6.6.1. 
 
6.1.3 Pooling of Investigative Sites 
Pooling of investigative sites is not applicable for this study. 
 
6.2 Determination of Sample Size 
Approximately forty (40) subjects with epilepsy will be recruited to attain a sample size of at 
least 30 completed. 
 
6.3 Subject Characteristics 
6.3.1 Subject Disposition 
Subject disposition will be summarized by treatment period and overall as indicated below. The 
following categories will be summarized by number and percentage. 
 Screened and screen failures subjects (only overall) 
 Enrolled and not enrolled subjects (only overall) 
 Subject who are dosed in Treatment Period A, Treatment Period B, and overall 
 Subject who are not dosed in Treatment Period A, Treatment Period B, and overall 
 Subject who are included in PK population for each treatment period and overall 
 Subject who have completed treatment Period A, Treatment Period B and overall 
 Subjects who were dismissed or did not complete the treatment period.  
 Reason for absence/early termination 
 
Subject disposition information will be listed. In addition, subjects who were dismissed 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. For overall, percentages based on the overall 
number of subjects dosed (safety population). 
 
6.3.2 Protocol Deviations 
All protocol deviations will be collected on CRF and will be 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. 
 
6.3.3 Background and Demographic Characteristics 
Descriptive statistics (sample size, mean, median, standard deviation [SD], minimum [Min] and 
maximum [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 (<18, 18-40, 41-65, and > 65 years), gender, ethnicity, and race.  


 
 
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Results will be presented overall for the safety population and by treatment period for PK 
population. No statistical tests for comparison of demographic and baseline data between 
treatment periods will be performed  
 
All demographic characteristics will be listed by subject. 
 
6.3.4 Study Drug Administration 
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. 
 
6.3.5 Prior and Concomitant Medications and Therapies 
The World Health Organization Drug Enhanced (WHO DDE) Version Jun2016, format B2 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. 
 
Prior is all medication/therapy stopped prior to the first drug administration, regardless of 
medication start date. Concomitant is any medication started and not stopped before the first 
drug administration in Treatment Period A or Treatment Period B, whichever occurs first. 
 
Medications will be summarized overall and separately for prior and concomitant medications by 
Anatomical Therapeutic Chemical (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. 
 
6.3.6 Medical Histories 
Medical history will be collected at screening and reviewed at the check-in visit for each 
treatment period. The Medical Dictionary for Regulatory Activities (MedDRA®) Version 20.0 
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 
 
 
 


 
 
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6.4 Efficacy Analysis 
No efficacy analysis is planned as per the protocol. 
 
6.5 Safety Analysis 
Safety data will be evaluated through the assessment of adverse events (AEs), laboratory 
parameters (serum chemistry, hematology, and urinalysis), 12-lead electrocardiogram (ECG), 
clinical signs and symptoms from physical and neurological examination, Columbia-Suicide 
Severity Rating Scale (C-SSRS) and vital signs assessments. Treatment-Emergent Adverse 
Events (TEAEs), laboratory values, and vital signs, will be summarized 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 listing referred to in this section are displayed in separate document. 
 
6.5.1 Adverse Events 
Treatment-emergent AEs (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. The MedDRA® 
dictionary version 20.0 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 treatment period and overall, 
for 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 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 treatment, or significant additional concomitant therapy. 
Serious and significant AEs will be listed separately. 
6.5.2 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 (HEENT), 
respiratory, lymph nodes, spine, skin, abdomen, cardiovascular, extremities, general appearance 
and others, if any. A neurological examination includes assessments of cranial nerves, muscle 
tone & strength, sensory function, coordination, gait, cognitive function and others, if any. 
 
Physical and neurological examination data will be listed separately by 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. 
 
6.5.3 Vital Signs 
Vital sign measurements (blood pressure, heart rate, respiratory rate and temperature) will be 
performed at screening, several times during each treatment period and at early termination or 
follow-up visit in each period.  
 
 
In Treatment Period A, vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature) will be measured at pre-dose (within 1 hour prior to drug administration) and at 
0.25, 0.5, 1, 2, 3, 4 and 8 hours post-dose, +/- 5 minutes for all timepoints; in addition, vital signs 
are also to be collected at 24, 48, 96, 144, 192, and 240 hours (+/- 2 hours) post DBSF 
administration in an outpatient setting. In Treatment Period B, vital sign measurements (blood 
pressure and heart rate) will be measured at pre-dose (within 1 hour prior to drug administration) 
and at 0.25, 0.5 and 2 hours post-dose, +/- 5 minutes for all timepoints. 
 
Descriptive statistics (sample size, mean, median, SD, Min and Max,) for each vital sign 
parameter will be presented overall for screening and follow-up visit and by the 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 non-missing result (scheduled or unscheduled) obtained prior 
to study drug administration in each treatment period. Results from post-dose 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. 


 
 
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6.5.4 Electrocardiogram 
ECG measurements will be performed at the time of screening. During Treatment Periods A and 
B, ECG measurements will be obtained pre-dose and post dose administration at the end of the 
treatment period. The quantitative ECG measurements are heart rate (HR) or ventricular rate 
(VR), PR interval, QRS interval, QT interval, QTcB interval (Bazett formula correction), and 
QTcF interval (Fridericia’s formula correction).  
 
Descriptive statistics (sample size, mean, median, SD, Min and Max) for each ECG parameter 
will be presented overall for screening and by 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 non-missing result (scheduled or 
unscheduled) obtained prior to study drug administration in each treatment period. Results from 
post-dose 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. 
 
6.5.5 Laboratory Parameters 
Clinical laboratory (serum chemistry, hematology, and urinalysis) results will be obtained at 
screening and at early termination or follow-up visit. In addition, clinical laboratory results will 
be obtained post-dose administration at the end of each treatment period.  
 
 
Serum chemistry parameters include the following: alanine aminotransferase, albumin, alkaline 
phosphatase, aspartate aminotransferase, urea, calcium, chloride, creatinine, creatinine kinase, 
lactate dehydrogenase, glucose, potassium, sodium, bilirubin, protein, uric acid and serum 
pregnancy test. 
 
Hematology parameters include the following: hematocrit, hemoglobin, platelet count, red blood 
cell count, red blood cell indices (mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC]), and white blood 
cell count with differential.  
 
Urinalysis parameters include the following: pH, specific gravity, protein, glucose, ketones, 
bilirubin, occult blood, nitrite, urobilinogen, leukocytes, and urine pregnancy test. Unless 
otherwise specified, microscopic examination will be performed on abnormal finding.  
 
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 overall for screening and follow-up visit. Change 
from screening to follow-up visit will also be presented. For categorical variable (urinalysis), the 
number of subjects (frequency and percentage) will be tabulated by result (e.g. negative, 


 
 
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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 one 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 two formulae used are presented below: 
 
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= x Us
Ux  
Prior to applying these formulae, if required, units will be adjusted.  
 
6.5.6 Visual Oral Inspection 
A visual inspection assisted by illumination of the DBSF application site will be performed at 
screening and on day 1 prior to study drug administration and approximately 0.167(10 minutes), 
0.5 (30 minutes), and 1 hour (60 minutes) +/- 5 minutes for all timepoints, after complete 
disintegration/dissolution of the buccal soluble film in both treatment periods to check for any 
mucosal irritation.  
 
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. 
6.5.7 Columbia Suicidal Severity Rating Scale 
The Columbia Suicidal Severity Rating Scale (C-SSRS), which assesses suicidal behavior and 
ideation, will be administered at each study visit. Qualified, trained staff will administer the C-
SSRS, Baseline-Screening version at screening, and the C-SSRS, Since Last Visit version at the 
Treatment Period A and Treatment period B check-in. Subjects with Type 4 (active suicidal 
ideation with some intent to act, without specific plan) or Type 5 (active suicidal ideation with 


 
 
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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. 
6.6 Pharmacokinetics Analysis 
Shells for all summary descriptive statistic tables and listings referred to in this section are 
displayed in 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. 
 
6.6.1 Handling of the BLQ and the No Reportable Concentration Values 
During pharmacokinetic and statistical analyses, drug concentration values 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 for pharmacokinetic 
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. 
 
6.6.2 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 post-dose sampling times expressed in hours 
and rounded off to three decimal digits will be used to calculate the PK parameters, except for 
pre-dose samples occurring prior to dosing, which will always be reported as zero (0.000), 
regardless of the time difference. In the PK section of the report, scheduled sampling times will 
be presented in concentration tables and mean graphs while actual times are presented for the 
individual graphs. A listing of the actual times for PKs will be provided for PK samples. 
 
6.6.3 Pharmacokinetic Parameters 
Epilepsy Study 
For both treatment periods, plasma samples for diazepam and the active metabolite 
desmethyldiazepam will be obtained pre-dose and post dose 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).  
 
To facilitate comparison between Treatment Period A and Treatment Period B, plasma 
concentrations from diazepam and desmethyldiazepam will be used to calculate the following 
PK parameters based on truncated PK profile (0 to 4 hours) by standard non-compartmental 
methods: 
AUC0-4h 
Area under the concentration-time curve from time zero to 4 hour. AUC0-4h is 


 
 
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calculated using the trapezoidal method. For a subject with a missing 
concentration data at the sampling time 4 hours post-dose, the calculation of 
AUC0-4h must not be done for the concerned treatment period. 
Cmax 
Maximal 
observed 
plasma 
concentration, 
taken 
from 
the 
plasma 
concentration-time profile. 
Tmax 
Time when the maximal plasma concentration is observed, taken from the 
concentration-time profile. 
AUC0-2h 
Area under the concentration-time curve from time zero to 2 hour. AUC0-2h is 
calculated using the trapezoidal method. For a subject with a missing 
concentration data at the sampling time 2 hours post-dose, the calculation of 
AUC0-2h must not be done for the concerned treatment period. 
 
In addition, plasma samples in Treatment Period A will also be taken at 8 hours (480 minutes) in 
the EMU, GCRC or similar facility, and additional plasma samples will be collected post DBSF 
administration at 24, 48, 96, 144, 192, and 240 hours (±2 hours) in an outpatient setting (either at 
EMU, GCRC or similar facility, or via home visits).  
 
For diazepam and desmethyldiazepam, plasma samples based on full PK profile (0 to 240 hours) 
will be used to calculate the following PK parameters in Treatment Period A by standard non-
compartmental methods: 
AUC0-t 
Area under the concentration-time curve from time zero until the last 
measurable concentration or last sampling time t, whichever occurs first. 
AUC0-t is calculated using the trapezoidal method. 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
(extrapolated), calculated as AUC0-t + Clast / Kel, where Clast is the last 
observed non-zero concentration. 
Residual Area Residual area, calculated as 100*(1- AUC0-t / AUC0-inf).  
Cmax 
Maximal 
observed 
plasma 
concentration, 
taken 
from 
the 
plasma 
concentration-time profile 
Tmax 
Time when the maximal plasma concentration is observed, taken from the 
concentration-time profile 
Kel or λ 
 
Terminal elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed concentration 
versus time profile in the elimination phase. Four non-zero observations 
during the elimination phase (excluding the Cmax) will be used to calculate 
Kel, or a minimum of 3 concentration points will be used if fewer than four 
observations are available. The time point where ln-linear Kel calculation 
begins (Kel Lower), and the actual sampling time of the last quantifiable 
concentration used to estimate the Kel (Kel Upper) will be reported with the 
correlation coefficient from the linear regression to calculate Kel (Corr). 


 
 
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T½ el 
Terminal elimination half-life, calculated as ln(2) / Kel. 
Cl 
Clearance, calculated as Dose / AUC0-inf. 
Cl/kg 
Clearance normalized for the subject body weight in kg, calculated as 
(Dose / AUC0-inf) / weight. 
Vd 
Volume of distribution, calculated as Cl/ Kel. 
Vd/kg 
Volume of distribution normalized for the subject body weight in kg, 
calculated as (Cl/ Kel) / weight. 
 
The Kel, T½ el, AUC0-inf, Cl, Cl/kg, Vd, and Vd/kg parameters will not be estimated for plasma 
concentration-time profiles where the terminal linear phase is not clearly defined.  
 
For subjects with missing or non-reportable diazepam/desmethyldiazepam concentrations for 
three or more of the last samples (e.g. timepoints pass Tmax), the data will be reviewed on a case-
by-case basis by pharmacokinetic scientist and/or sponsor to determine if the data are reliable for 
Cmax and Tmax. If so, only the Cmax and Tmax will be presented and included in the statistical 
analysis. Other PK parameters will not be reported. Explanations for PK parameters that could 
not be estimated will be provided in the CSR. 
 
Phase 1 Healthy Volunteers Data 
For diazepam and desmethyldiazepam, the plasma concentration data for treatment Diazepam 15 
mg buccal soluble film will be selected from ongoing pivotal study (MonoSol 162021).     
 
In this pivotal study, a total of 20 blood samples will be collected from each subject (N=36) at 
pre-dose (0.000), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 192, and 240 
hours post-dose in each study period. For the 48, 72, 96, 144, 192, and 240-hour post-dose 
timepoints, a window of ±60 minutes will be allowed for blood collection. 
For diazepam and desmethyldiazepam, plasma samples based on full PK profile (0 to 240 hours) 
will be used to calculate PK parameters (as mentioned for epilepsy study) in healthy volunteer’s 
data by standard non-compartmental methods. To facilitate comparison between epilepsy study 
with healthy volunteer study, PK parameters (AUC0-4h, Cmax and Tmax) will also be calculated 
based on truncated PK profile (0 to 4 hours). 
As PK profile in healthy volunteers is richer (more frequent timepoints) than the PK profile in 
EMU study. It might be possible that the PK parameter comparisons between epilepsy study and 
healthy volunteer data will be biased. Hence, to avoid this bias, PK parameter calculation for 
healthy volunteers mentioned above will be performed on both full data (with all available 
timepoints) and more sparse data (excluding timepoints which are not there in the epilepsy 
study).  
6.6.4 Statistical Analyses 
All inferential statistical analyses comparing Period A, Period B and healthy volunteers will be 
interpreted in an exploratory sense only at an alpha level of 5% for statistical significance. 


 
 
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For both epilepsy and healthy volunteer’s studies, individual and mean plasma concentration 
versus time curves will be presented using linear and semi-log scales for diazepam and 
desmethyldiazepam. Listings and descriptive statistics (number of observations, arithmetic mean, 
SD, coefficient of variation [CV%], median, Min, Max, and geometric mean) of the 
concentrations versus time will be provided.  
 
For diazepam and desmethyldiazepam, plasma PK parameters based on both full and truncated 
PK profiles in epilepsy and healthy volunteers (full and sparse data) studies will be listed and 
summarized descriptively for each treatment period (Period A and Period B) for subjects with 
epilepsy, and for the DBSF 15 mg treatment for healthy volunteers. Arithmetic means, standard 
deviations, minimum, maximum, median, and coefficients of variation will be calculated for PK 
parameters. Additionally, geometric means will be calculated for AUC0-t, AUC0-2h, AUC0-4h, 
AUC0-inf, Cmax, Cl, Cl/kg, Vd, and Vd/kg.  
 
Analysis for Epilepsy Study 
For comparison (Period A vs. Period B), additional tables presenting the individual ratios for 
AUC0-2h, AUC0-4h and Cmax (based on truncated PK profile (0 to 2 hours and 0 to 4 hours)) as well 
as individual differences for Tmax (based on truncated PK profile (0 to 4 hours)) will be provided. 
 
Using GLM procedure in SAS®, analysis of variance (ANOVA) will be performed on ln-
transformed AUC0-2h, AUC0-4h and Cmax (based on truncated PK profile (0 to 2 hours and 0 to 4 
hours)) for diazepam only. Factors incorporated in the statistical model will include Period as a 
fixed factor and Subject as a random factor. The Period effect will be tested against residual 
mean square. ANOVA, for each parameter, will include calculations of least-squares (LS-) 
means for each period, the LS-mean for period differences using the ESTIMATE statement, and 
the standard error associated with this difference. Tmax (based on truncated PK profile (0 to 2 
hours and 0 to 4 hours)) will be analyzed using a non-parametric test (Wilcoxon signed-rank 
test). 
 
The ratios of geometric means (Period A/ Period B) and corresponding 90% confidence interval, 
based on least-squares means from the ANOVA of the ln-transformed data, will be calculated for 
AUC0-2h, AUC0-4h and Cmax (based on truncated PK profile (0 to 2 hours and 0 to 4 hours)). Inter 
and intra-subject coefficients of variation will be estimated. 
 
Note: There were few subjects who were in Tretament B administered the film incorrectly for 
one of the site. Hence an ad-hoc analysis will be done for the B Vs A comparison tables, by 
excluding these subjects. The subjects are 104007, 104008, 104015, 104029 and 104030. 
 
 
Comparison with Phase 1 Healthy Volunteers Data 
For all comparisons with healthy volunteers, the PK parameters calculated from sparse data 
(considering only common timepoints with epilepsy study) of healthy volunteers will be used. 
PK parameters calculated based on full data (including all timepoints) of healthy volunteers will 
be summarized separately by descriptive statistics only. 


 
 
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For diazepam and desmethyldiazepam, PK parameters AUC0-4h and Cmax (based on truncated PK 
profile (0 to 4 hours)), and AUC0-t, AUC0-inf and Cmax (based on full PK profile (0 to 240 hours)) 
for the healthy volunteers will also be dose-normalized to 12.5 mg (the dose in epilepsy study) 
for comparison purpose. The descriptive statistics for the parameters dose-normalized to 12.5 mg 
will also be presented. 
 
For each group comparison separately (i.e. Subject with Epilepsy (Period A) vs Healthy 
Volunteers, and Subject with Epilepsy (Period B) vs Healthy Volunteers), using GLM procedure 
in SAS®, ANOVA will be performed on ln-transformed dose normalized (to 12.5 mg) AUC0-4h 
and Cmax (based on truncated PK profile (0 to 4 hours)) for diazepam only. Factors incorporated 
in the model will include Group as a fixed factor. The Group effect will be tested against residual 
mean square. ANOVA, for each parameter, will include calculations of least-squares (LS-) 
means for each period, the LS-mean for group difference using the ESTIMATE statement, and 
the standard error associated with this difference. Tmax (based on truncated PK profile (0 to 4 
hours)) will be analyzed using a non-parametric test (Wilcoxon rank-sum test). 
 
The dose-normalized ratios of geometric means (Subject with Epilepsy (Period A)/Healthy 
Volunteers, and Subject with Epilepsy (Period B)/Healthy Volunteers) and corresponding 90% 
confidence intervals, based on least-squares means from these separate ANOVAs of the ln-
transformed dose-normalized data, will be calculated for AUC0-4h and Cmax (based on truncated 
PK profile (0 to 4 hours)). 
 
In addition, similar ANOVA will also be performed on ln-transformed dose normalized (to 12.5 
mg) PK parameters AUC0-t, AUC0-inf, and Cmax for diazepam only.  The Group (Subjects with 
Epilepsy (Period A) and Healthy Volunteers) will be considered as a fixed factor. Tmax (based on 
full PK profile (0 to 240 hours)) will be analyzed using a non-parametric test (Wilcoxon rank-
sum test). The dose-normalized ratio of geometric means (Subject with Epilepsy (Period 
A)/Healthy Volunteers) and corresponding 90% confidence interval, based on least-squares 
means from the ANOVA of the ln-transformed dose-normalized data, will be calculated for 
AUC0-t, AUC0-inf and Cmax. 
 
6.7 Analysis of Other Assessments 
The following usability endpoints will be reported and summarized by treatment period 
 Oral cavity insertion and retention assessment  
 Oral cavity placement assessment  
 
The total number of unsuccessful attempts of DBSF buccal insertion will be captured on CRF. 
Descriptive statistics (n, mean, SD, median, min, max) will be provided by treatment period for 
number of unsuccessful attempts to place DBSF. The number and percentage will be provided 
for categories 0, 1, 2, 3 and >3 unsuccessful attempts to place DBSF for each treatment period. 
The categorical explanation for each unsuccessful attempt to place DBSF will be listed. 
 


 
 
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Unsuccessful retention will have occurred if a subject allowed saliva to exit the mouth during 
DBSF adherence to the buccal mucosa; if the DBSF was swallowed by the subject; or if a subject 
spit or blew out the DBSF after adherence to the buccal mucosa or subject chewed, talked, or 
moved the DBSF prior to complete disintegration/dissolution.  The occurrences of these three 
types of events are recorded on the CRF for each treatment period.  The number and percentage 
of safety subjects with any unsuccessful retention will be summarized by treatment period, and 
the number and percentage of safety subjects experiencing each type of unsuccessful retention 
will be summarized by treatment period.  
 
After DBSF administration, visual inspection of film will be conducted every 60 second until 
disintegration/dissolution is noted or for a maximum of 5 minutes. All data regarding DBSF 
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.  
 
 
6.8 Interim Analysis 
No interim analysis is planned. 
 
6.9 Changes to Methods Planned in the Protocol  
 In protocol Section 14.2.2. it is written:  
“Summary statistics for desmethyldiazepam shall be limited to Cmax and AUCt (Period A) 
and to Cmax and AUC(0-4h) (Period B)”.  
 
However, summary statistics will be calculated for each PK parameter. 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
MonoSol Rx, LLC 
Protocol 160326, Amendment I 
Version: 1.1, 14Sep2018 
 
 
Confidential 
 
SOP-STAT-005-AD-01-01 
 
 Page 27 of 27 
 
 
7. REFERENCES 
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.