Randomized, Open-Label, 2-Way Crossover, 3-Period Study to Evaluate Single Doses of Diazepam Buccal Film Compared With Diazepam Rectal Gel in Adult Males and Females on Concomitant Antiepileptic Drugs for the Treatment of Epilepsy
Phase: PHASE1
Conditions: Epilepsy
Sponsor: Aquestive Therapeutics

180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
24-MAY-2019 
 
 
 
 
 
PROTOCOL 180323 
AMENDMENT III 
 
IND Number: 129068 
 
A RANDOMIZED, OPEN-LABEL, 2-SEQUENCE, 3-TREATMENT, CROSSOVER 
STUDY TO EVALUATE THE PHARMACOKINETICS OF SINGLE DOSES OF 
DIAZEPAM BUCCAL FILM (DBF) (AQUESTIVE THERAPEUTICS) COMPARED 
WITH DIASTAT® RECTAL GEL (VALEANT PHARMACEUTICALS NORTH 
AMERICA) IN ADULT MALE AND FEMALE SUBJECTS ON A CONCOMITANT 
REGIMEN OF ANTIEPILEPTIC DRUGS (AED) FOR THE TREATMENT OF 
EPILEPSY 
 
 
Contract Research Organization: 
inVentiv Health Clinique inc. 
(« inVentiv »), a Syneos Health 
company 
2500, rue Einstein 
Québec (Québec)  
Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA  
Tel.: 908-941-1900 
 
 
 
CONFIDENTIAL 
 
 
This document is strictly confidential. It was developed for Aquestive Therapeutics by inVentiv and must not be 
disclosed to a third party, with the exception of the clinical sites, regulatory agencies and study audit personnel 
without the consent of either inVentiv or the Sponsor. This document is copyrighted in favor of inVentiv and cannot 
be reproduced, modified, or adapted, in part or in total, without prior written approval by inVentiv.  
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Protocol Historical File 
Version 
number 
Brief description/summary of changes 
Date 
Final 
Version submitted to the IEC. 
16-JAN-2019 
Amendment I 
Changes included in Amendment I: 
The following changes were brought to the study protocol as 
required by the Advarra institutional review board (IRB): 
1. Female contraception duration was extended to 51 days 
and male contraception to 111 days following the last 
study drug administration, due to the half-life of the 
study drug. In addition, the sperm donation restriction 
was revised from 105 days to 111 days after the last 
study drug administration. 
2. The exclusion criteria were revised to exclude subjects 
with any clinically significant rectal abnormality or any 
condition for which administration of rectal gel would 
cause a potential risk. 
3. Baseline levels assessment of the concomitant 
antiepileptic drug(s) (AED) was added at screening. The 
AED level(s) must be within an acceptable therapeutic 
range.  
4. The use of any AED of the benzodiazepine class (other 
than diazepam administered as study drug) is prohibited 
during the study.   
For all the pharmacokinetic (PK) blood samples to be 
collected as return visits, it is clarified that subjects may 
have the blood sample collected at home by a home care 
nurse.  
Information was added to section 9.13 Adverse Events in 
order to clarify the adverse events recording, follow up, and 
reporting process. Contact information was added for the 
Sponsor’s safety representative.  
19-FEB-2019 
Amendment II 
Changes included in Amendment II: 
Subjects who complete study periods 1 and 2 may volunteer 
to participate in a third period where they would receive a 
second dose of DBF administered following a high-fat meal.  
Details on clinical sites and biomedical laboratories names 
and locations have been removed from the protocol.  
Any flexibility in the washout duration was excluded since a 
07-MAR-2019 
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washout period of no more than 28 days must be used in this 
study.  
The smoking restriction period of at least 2 hours prior to 
until 4 hours after study drug administration has been 
removed from the protocol. Smoking is allowed on study and 
the restriction period around the dosing procedures will be 
managed by each clinical site.  
In case of a positive result to the urine benzodiazepine (drug) 
screen in periods 2 and 3, continuous subject participation in 
the study will be evaluated by the Principal Investigator.  
In addition, some minor editorial changes and clarifications 
have been made throughout the document, such as sentence 
clarifications, corrections of typographical or punctuation 
errors.  
Amendment III 
See below for a description of changes. 
24-MAY-2019 
Changes included in Amendment III: 
The following changes were brought to the study protocol Amendment II dated 07-MAR-2019: 
The sample size has been increased to a maximum of 32 subjects. Moreover, since only 
exploratory pharmacokinetic data will be gathered from treatment period 3 (DBF administration 
following a high-fat-meal), no more than 50% of the subjects should receive this treatment. This 
involves changes to the following sections: 
• page 9, section 2 Synopsis of Protocol - Study Design and Subjects; 
• 
page 30, section 7 Study Design; 
• 
page 31, section 8.1 Sample Size. 
A discrepancy has been corrected on page 43, under section 9.9.4 DBF Application Site 
Inspection. 
The urobilinogen has been removed from the urinalysis routine tests to be performed at screening 
and at study exit. The change was made on page 43, section 9.9.7.4 Urinalysis.     
 
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Investigator’s Signature Page 
 
I have carefully read this study protocol and agree that it contains all necessary information 
required to conduct this study. I agree to conduct the study according to this protocol (including 
any amendments) and in accordance with ICH Good Clinical Practices (GCP), Good Laboratory 
Practices (GLP), and all other applicable regulations. 
 
 
________________________________________  
______________________ 
Investigator signature 
Date 
 
________________________________________ 
Investigator printed name 
 
________________________________________ 
Name of clinical facility 
 
________________________________________ 
Location of facility 
(City, state, country) 
 
 
 
 
 
 
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1. 
Facilities and Responsible Staff 
1.1 
Clinical Research Organization (CRO)  
inVentiv Health Clinique inc. (« inVentiv »), a Syneos Health company 
2500, rue Einstein 
Québec (Québec)  
Canada, G1P 0A2 
Tel.: 1-418-527-4000 
1.2 
Clinical Research Sites  
This study will be conducted at multiple clinical facilities. Any clinical research sites involved in 
this study will be documented and communicated to the Ethic committee. 
1.3 
Biomedical Laboratory Facilities 
Biomedical laboratories involved in clinical laboratory testing will be documented by the clinical 
research sites. 
1.4 
Clinical Pharmacology 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Pierre-Olivier Tremblay, M.Sc. 
Vice-President, Clinical Pharmacology & Data Services 
France Nadeau, B.Sc. 
Senior Clinical Research Scientist (Protocol Editing) 
1.5 
Bioanalytical Facility 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Clark V. Williard, B.S. 
Executive Director, Mass Spectrometry Operations 
1.6 
Medical Monitor   
Dr. Heidi Mitchell, MD 
Syneos Health 
 
 
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Table of Contents 
1. 
FACILITIES AND RESPONSIBLE STAFF ................................................................................. 6 
1.1 
CLINICAL RESEARCH ORGANIZATION (CRO) .............................................................................................................................................. 6 
1.2 
CLINICAL RESEARCH SITES ......................................................................................................................................................................... 6 
1.3 
BIOMEDICAL LABORATORY FACILITIES ....................................................................................................................................................... 6 
1.4 
CLINICAL PHARMACOLOGY ......................................................................................................................................................................... 6 
1.5 
BIOANALYTICAL FACILITY .......................................................................................................................................................................... 6 
1.6 
MEDICAL MONITOR ..................................................................................................................................................................................... 6 
2. 
SYNOPSIS OF PROTOCOL .......................................................................................................... 9 
3. 
LIST OF ABBREVIATIONS ........................................................................................................ 14 
4. 
SCHEDULE OF EVENTS ............................................................................................................. 16 
5. 
INTRODUCTION .......................................................................................................................... 17 
5.1 
BACKGROUND ON TREATMENT AND MANAGEMENT OF INDIVIDUALS WITH REFRACTORY EPILEPSY ....................................................... 17 
5.2 
DIAZEPAM ................................................................................................................................................................................................. 17 
5.3 
DIASTAT® ACUDIALTM .............................................................................................................................................................................. 19 
5.4 
DIAZEPAM BUCCAL FILM (DBF) ............................................................................................................................................................... 19 
5.5 
BACKGROUND ON DIAZEPAM BUCCAL FILM (DBF) .................................................................................................................................. 20 
5.6 
RATIONALE FOR DOSE LEVELS OF DIAZEPAM BUCCAL FILM .................................................................................................................... 26 
5.7 
RATIONALE FOR STUDY DESIGN ................................................................................................................................................................ 27 
5.8 
CLINICAL RISKS/BENEFITS OF STUDY DRUG ............................................................................................................................................. 28 
5.9 
RATIONALE FOR THE STUDY POPULATION ................................................................................................................................................. 29 
6. 
OBJECTIVES ................................................................................................................................. 30 
7. 
STUDY DESIGN ............................................................................................................................ 30 
8. 
STUDY POPULATION ................................................................................................................. 31 
8.1 
SAMPLE SIZE ............................................................................................................................................................................................. 31 
8.2 
INCLUSION CRITERIA ................................................................................................................................................................................. 31 
8.3 
EXCLUSION CRITERIA ................................................................................................................................................................................ 33 
9. 
CLINICAL PROCEDURES .......................................................................................................... 35 
9.1 
SCREENING PROCEDURES .......................................................................................................................................................................... 35 
9.2 
CONFINEMENTS, VISITS, AND WASHOUT ................................................................................................................................................... 36 
9.3 
RANDOMIZATION AND BLINDING .............................................................................................................................................................. 36 
9.4 
STUDY MEDICATION .................................................................................................................................................................................. 37 
9.5 
DRUG SUPPLIES AND ACCOUNTABILITY .................................................................................................................................................... 37 
9.6 
DRUG ADMINISTRATION ............................................................................................................................................................................ 38 
9.7 
STUDY RESTRICTIONS................................................................................................................................................................................ 39 
9.8 
SAMPLE COLLECTION AND PROCESSING .................................................................................................................................................... 41 
9.9 
SUBJECT MONITORING............................................................................................................................................................................... 42 
9.10 
STUDY EXIT PROCEDURES ......................................................................................................................................................................... 44 
9.11 
DATA COLLECTION AND EVALUATION ...................................................................................................................................................... 44 
9.12 
SUBJECT WITHDRAWAL AND REPLACEMENT ............................................................................................................................................ 44 
9.13 
ADVERSE EVENTS ...................................................................................................................................................................................... 45 
9.14 
REPORTABLE DISEASE ............................................................................................................................................................................... 48 
10. 
STUDY TERMINATION .............................................................................................................. 48 
11. 
ANALYTICAL METHODOLOGY ............................................................................................. 48 
12. 
PHARMACOKINETIC AND STATISTICAL ANALYSES ..................................................... 49 
12.1 
PHARMACOKINETICS ................................................................................................................................................................................. 49 
12.2 
ANALYSIS POPULATIONS ........................................................................................................................................................................... 49 
12.3 
STATISTICAL ANALYSES ............................................................................................................................................................................ 50 
12.4 
SAFETY AND TOLERABILITY PARAMETERS AND ANALYSES ...................................................................................................................... 51 
13. 
FINAL REPORT ............................................................................................................................ 51 
14. 
REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE .................................. 51 
14.1 
INDEPENDENT ETHICS COMMITTEE APPROVAL OF PROTOCOL AND OTHER STUDY DOCUMENTS .............................................................. 51 
14.2 
COMPLIANCE ............................................................................................................................................................................................. 52 
14.3 
AUDITS, INSPECTIONS AND MONITORING .................................................................................................................................................. 52 
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15. 
CONFIDENTIALITY .................................................................................................................... 52 
16. 
REFERENCES ............................................................................................................................... 52 
17. 
APPENDIX I – DIAZEPAM PK STUDY PARTICIPANT QUESTIONS ............................... 54 
18. 
APPENDIX II – STUDY RESTRICTIONS ................................................................................. 57 
19. 
APPENDIX III - PLACEMENT DIAGRAM FOR AQUESTIVE THERAPEUTICS 
BUCCAL FILM ........................................................................................................................................ 59 
20. 
APPENDIX IV - PLACEMENT DIAGRAM FOR DIASTAT® ACUDIAL™ RECTAL 
DELIVERY SYSTEM .............................................................................................................................. 60 
 
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2. 
Synopsis of Protocol 
Project No.: 
180323 
Objectives: 
Primary objective: 
• 
Evaluate the pharmacokinetics (PK) of single doses of Diazepam 
Buccal Film (DBF) at the recommended dose regimen (range 10 mg to 
17.5 mg according to body weight) compared with Diastat® (DRG) at 
the labeled dose regimen (range 10 mg to 20 mg according to body 
weight) in adult male and female subjects on a stable concomitant 
regimen of antiepileptic drugs (AED) for the treatment of epilepsy, 
following a moderate-fat meal.  
Secondary objectives: 
• 
Evaluate the PK of single doses of DBF following a high-fat meal 
compared with DRG following a moderate-fat meal at the 
recommended dose regimen in adult male and female subjects on a 
stable concomitant regimen of AED for the treatment of epilepsy. 
• 
Assess the safety-tolerability of single doses of DBF and DRG 
administered to adult male and female subjects on a stable concomitant 
regimen of AEDs under fed conditions. 
Study Design: 
Randomized, multiple centers, single-dose, open-label, three-period, 
three-treatment, two-sequence crossover study under fed conditions.  
Periods 1 and 2: Each subject will receive both DBF and DRG in a randomized 
sequence following a moderate-fat meal administered according to weight 
category. DBF will be administered according to the currently recommended 
dose regimen (derived by Aquestive from population PK modeling in healthy 
volunteers). DRG will be administered depending on weight category according 
to the current product labeling for Diastat®.  
Period 3: Subjects may be asked to participate in period 3. Subjects who 
volunteer to participate in Period 3 will receive a second dose of DBF 
administered in exactly the same manner as the earlier dose of DBF with the 
exception that DBF in Period 3 will be administered following a high-fat meal. 
Subjects: 
No more than 32 male and female volunteers, ≥ 18 and ≤ 65 years of age, 
smoker and/or non-smoker, with body weight between 38 and 134 kg  (83 -294 
lbs.) on a concomitant stable regimen including one or more AED. 
A stable regimen of AED is defined as no change in the prescribed AED regimen 
during the 30-day period prior to the first study drug administration and no 
change anticipated in the prescribed AED regimen over the course of study 
participation until the last PK blood sample collection. 
Eligible subjects will be enrolled in an effort to complete Period 2 with at least 
16 subjects with representation of both genders, representation across the five 
weight categories of subjects taking one or more AED known to induce 
diazepam metabolism, and representation of subjects taking sodium 
divalproex/valproic acid. Subjects who are eligible may be enrolled without 
regard to weight category. Since only exploratory PK data will be gathered 
from treatment period 3, no more than 50% of the subjects who complete 
Period 1 and Period 2 will participate in Period 3.  
Screening Procedures: 
Demographic data, medical and medication histories, physical examination, brief 
neurologic examination, body measurements, oral cavity examination, 
electrocardiogram (ECG), vital signs (blood pressure [BP], heart rate [HR], and 
respiratory rate [RR]), oral temperature, digital oxygen monitoring, hematology, 
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biochemistry, HIV, hepatitis B and C tests, urinalysis, baseline AED levels*, 
alcohol breath test, urine pregnancy test, and urine drug screen.  
*Unless baseline levels of concomitant AED were obtained within one year prior 
to the first dosing and show levels within an acceptable therapeutic range.  
Confinements, Visits, and 
Washout: 
For each period, subjects will be confined from approximately 14 hours before 
dosing until after the 24-hour post-dose blood draw. For subsequent blood draw, 
subjects may come back to the clinical site or have the blood sample collected at 
home by a home care nurse.   
There will be a washout period of 28 days between doses. 
Drug Administration: 
In Period 1 and Period 2, subjects will receive Treatment A and Treatment B 
following a moderate-fat meal, in a randomized sequence. Subjects who 
volunteer to participate in Period 3 will receive DBF following a high-fat meal. 
In each period, subjects will receive a single dose according to body weight, as 
described in the following table: 
Product 
Meal 
Condition 
Weight 
Category 
Weight 
(kg) 
Dose 
Test 
(Treatment A):  
Diazepam 
Buccal Film 
(Aquestive 
Therapeutics, 
USA) 
Moderate-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
Reference 
(Treatment B):  
Diastat® 
AcuDialTM 
rectal gel 
(Valeant 
Pharmaceuticals 
Moderate-Fat 
Meal 
B1 
38-50 
2 mL (10 mg) 
B2 
51-62 
2.5 mL (12.5 
B3 
63-75 
3 mL (15 mg) 
B4 
76-87 
3.5 mL (17.5 
B5 
88-111* 
4 mL (20 mg) 
Test 
(Treatment C):  
Diazepam 
Buccal Film 
(Aquestive 
Therapeutics, 
USA) 
High-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
*Subjects eligible for study with weights in the range of 112 to 134 kg will be 
dosed at the 88-111 kg weight range as shown above. 
After a supervised fast of at least 10 hours, subjects will be served a standardized 
moderate-fat meal (in Periods 1 and 2) or a high-fat high-calorie meal (in 
Period 3). Drug administration will occur approximately 30 minutes after the 
meal has been started.  
No water will be allowed during the DBF administration and for at least 
15 minutes following DBF administration. Water will be allowed ad libitum at 
all other times.  
DBF ease of use will be evaluated by the clinical staff and the subjects following 
the first film administration in Period 1 or Period 2. Questions regarding past 
experience in using DRG or other rescue medication for the treatment of epilepsy 
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will also be asked to subjects, prior to DRG administration. Questions are listed 
in Appendix I – Diazepam PK Study Participant Questions.  
Study Restrictions: 
Subjects will be asked to refrain from using products that may potentially affect 
their safety and/or the pharmacokinetic profile of the study drug. For the 
complete list of restrictions refer to Appendix II – Study Restrictions. Main study 
restrictions include: 
• 
Any benzodiazepines (other than study drug),  phenothiazines, or strong 
inhibitors of cytochrome P450 (CYP) enzymes (e.g. cimetidine, 
fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, itraconazole, diltiazem, and HIV antivirals), from 30 days 
prior to the first dosing until after the last PK blood sample collection of 
the study. Strong inducers of CYP enzymes (e.g. barbiturates, 
carbamazepine, glucocorticoids, phenytoin, phenobarbital, St. John´s 
Wort, rifampicin) and AEDs known to induce CYP enzymes are 
permitted provided that the regimen of such drugs is stable (taken at 
least once a day [q.d]. on a regular basis) within 30 days prior to first 
study drug administration and until at least 10 days after last study drug 
administration; 
• 
Any prescription medication (other than non-systemic topical products) 
within 30 days prior to first study drug administration.  Prescription 
drugs (other than any benzodiazepines, phenothiazines, and strong 
inhibitors of CYP enzymes) that is part of a stable drug regimen (taken 
at least q.d. on a regular basis) are allowed if taken from at least 30 days 
prior to the first study drug administration and if there is no expected 
change in dosage throughout the study.  
• 
Over-the-counter (OTC) medications (other than spermicidal/barrier 
contraceptive products and non-systemic topical products), within 
30 days prior to first study drug administration. OTC drugs that is part 
of a stable drug regimen (taken at least q.d. on a regular basis) is allowed 
if taken from at least 30 days prior to the first study drug administration 
and if there is no expected change in dosage throughout the study. 
• 
Natural health products (including oral multivitamins, herbal and/or 
dietary supplements and/or teas) from 30 days pre-dose until after the 
last PK blood sample collection of each period. 
• 
For females, oral or transdermal hormonal contraceptives within 30 days 
prior to first study drug administration until after the last PK blood 
sample collection of each period. Oral or transdermal hormonal 
contraceptives  with a 28-days treatment cycle taken daily from at least 
30 days prior to the first study drug administration will be allowed if 
there is no expected change in dosage throughout the study; 
• 
For females, implanted, injected, or intravaginal contraceptive within 6 
months prior to first study drug administration until after the last PK 
blood sample collection of each period; 
• 
Monoamine oxidase (MAO) inhibitors from 30 days prior to the first 
dosing until 14 days after the last study drug administration; 
• 
Use of marijuana and THC containing products within 3 months prior to 
screening unless such products are a part of the subject’s stable 
antiepileptic regimen; 
• 
Food containing poppy seeds from 48 hours pre-dose; 
• 
Food or beverages containing caffeine/methylxanthines derivatives or 
energy drinks from 48 hours prior to dosing until after the last PK blood 
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sample collection of each period; 
• 
Food or beverages containing grapefruit, star fruit, and/or pomelo from 
30 days pre-dose until after the last PK blood sample collection of the 
study; 
• 
Alcohol-based products from 48 hours pre-dose until after the last PK 
blood sample collection of each period. 
Diazepam may cause sedation.  Consistent with intended use of DBF and the use 
of DRG subjects should be in a safe comfortable position (sitting or reclining in 
bed) for at least one hour after dosing to allow for an assessment of drug effect 
including sedation. After one hour and depending on the assessment of the 
investigator/clinical staff, the subject may be permitted to ambulate provided that 
ambulation does not interfere with study procedures.  Vital signs should be taken 
in a consistent position (sitting or reclining).  Subject visits to the bathroom or 
washroom will be monitored by clinic staff for 4 hours after each study drug 
administration, and the following information will be recorded: whether the 
subject urinated, defecated, or vomited. Subjects will be instructed not to flush if 
they vomit. Vomitus will be verified and noted in the subject’s file for further 
evaluation if needed.  
Subjects will be advised to avoid performing vigorous physical activities (e.g., 
intense or long-distance running or biking, etc.) at all times during the study 
duration (from at least 5 days prior to admission), including the washout period. 
Sample Collection: 
A total of 19 blood samples will be collected in each period: at pre-dose and 
(± 1 minute) 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, (± 3 minutes) 9, 12, 24, (± 60 minutes) 
48, 72, 96, 120, 144, 192, and 240 hours post-dose. 
Subject Safety: 
Continuous cardiac ECG monitoring: from approximately 1 hour prior to dosing 
until 8 hours post-dose (and beyond if clinically indicated). 
Vital signs and digital oxygen monitoring before dosing and approximately 0.5, 
1, 1.5, 2, 4, and 8 hours post-dose (and beyond if clinically indicated). 
Vital signs will also be recorded at approximately 12 and 24 hours post-dose. 
Serum pregnancy test (for women): before dosing 
Alcohol breath test and urine drug screen: before dosing. 
Medical surveillance: Subjects will be monitored throughout the study by the 
clinical staff for adverse events. In each period, the investigator will be on site 
for drug administration and until 8 hours post-dose, and available on call for the 
remainder of the study. 
DBF Application Site 
Inspection: 
DBF application site will be inspected at screening, prior to DBF administration, 
and approximately 6 and 24 hours after DBF administration to evaluate the oral 
mucosa (normal/abnormal). Assessments will be conducted by the Principal 
Investigator/Sub-Investigator or a trained nurse.  
Study Exit Procedures: 
Physical examination, brief neurologic examination, hematology, biochemistry, 
urinalysis, vital signs (BP, HR, and RR), oral temperature, digital oxygen 
monitoring, ECG, oral temperature, urine pregnancy test, and adverse events 
monitoring. 
Analytical Method: 
The Bioanalytical Division of inVentiv will analyze diazepam and nordiazepam 
in plasma samples using a validated method.   
Pharmacokinetics: 
Parameters: AUC0-t, AUC0-inf, Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, 
Cl/F/kg, and Vd/F/kg. 
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Data from nordiazepam will be reported and presented as supportive data. 
Statistical Analyses: 
Pharmacokinetics: 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be 
performed on untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, 
AUC0-inf, Cmax, Cl/F, Cl/F/kg, Vd/F, and Vd/F/kg at the alpha level of 0.05. 
Factors incorporated in the model will include: Sequence, Subject(Sequence), 
Period, and Treatment. Tmax will be analyzed using an additional non parametric 
test (Wilcoxon signed-rank test). 
Treatment Comparison Following a Moderate-Fat Meal: 
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax  
for the Test product versus the Reference product (A/B) irrespective of weight 
category. The 90% confidence interval for the ratio of geometric means, based on 
least-squares means from the ANOVA of the ln transformed data will also be 
calculated. Intra and inter-subject coefficient of variation will be estimated.  
Treatment Comparison Following Different Meal Conditions:  
An exploratory pair-wise analysis comparing DBF following a high-fat meal 
(Treatment C) with DRG following a moderate-fat meal (Treatment B) will also 
be conducted and reported. 
Additional analyses may be performed.  
Details of the pharmacokinetic and statistical analyses will be provided in the 
statistical analysis plan (SAP). 
Safety and tolerability: 
Treatment-emergent AEs will be tabulated by treatment. Changes from baseline 
values in vital signs, ECG, and clinical laboratory parameters will be evaluated. 
Safety and tolerability data will be reported using descriptive statistics. Details of 
the safety and tolerability analyses will be provided in the SAP. 
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3. 
List of Abbreviations 
AE 
Adverse Event 
AED 
Antiepileptic drug 
ANOVA 
Analysis of variance 
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 to the Last Non-zero Concentration 
BA 
Bioavailability 
BP 
Blood Pressure 
CK 
Creatine Kinase 
Cl/F 
Apparent Total Clearance (L/hr) estimated from 
dose/AUC0-inf 
Cl/F/kg 
Apparent Total Clearance/kg (L/hr) estimated from 
dose/kg/AUC0-inf 
Cmax 
Maximum Observed Concentration 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CYP 
Cytochrome P450 
DBF 
Diazepam Buccal Film 
DRG 
Diastat® rectal gel 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
g 
Grams 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethic Committee 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
lbs. 
pounds 
Kel 
Elimination Rate Constant 
kg 
Kilogram 
kg/m2 
Kilogram/Meter Squared 
MDMA 
Methylene Di-Methamphetamine (Ecstasy) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliters  
msec 
Millisecond 
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mmHg 
Millimeter of Mercury 
MAO 
Monoamine oxidase 
N/A or NA 
Not applicable, Not Available 
NDA 
New drug application 
PCP 
Phencyclidine 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QA 
Quality Assurance 
QC 
Quality Control 
QTcF 
Fridericia’s Corrected QT Interval 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD or STD 
Standard Deviation 
SOC 
System Organ Classification 
SOP 
Standard Operating Procedure 
SARS 
Severe Acute Respiratory Syndrome 
T½ el 
Terminal elimination half-life, estimated as ln(2)/Kel 
THC 
Tetrahydrocannabinol 
Temp 
Temperature 
Tmax 
Time when the maximal plasma concentration is observed 
UBG 
Urobilinogen 
U.S. 
United States 
Vd/F 
Apparent Volume of distribution (L) estimated from 
Cl/Kel (β) 
Vd/F/kg 
Apparent Volume of distribution/kg (L) estimated from 
Cl/Kel (β)/kg 
 
 
 
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4. 
Schedule of Events 
PROCEDURE 
Screening 
Periods 1, 2 & 3 
Study Exit 
D-1 
D1 
D2 
D3-D11 
Demographic Data 
X 
 
 
 
 
 
Medical and Medication Histories 
X 
 
 
 
 
 
Review and Monitoring of AEs 
and Concomitant Medications 
 
X 
X 
X 
X 
X 
Physical Exam and Brief 
Neurologic Exam  
X 
 
 
 
 
X 
Body Measurements 
X 
 
 
 
 
 
Oral Temperature 
X 
 
 
 
 
X 
Vital signs (BP, HR, RR) 
X 
 
X1 
X2 
 
X 
Digital Oxygen Monitoring 
X 
 
X1 
 
 
X 
Continuous Cardiac ECG 
Monitoring 
 
 
X3 
 
 
 
ECG 
X 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
X 
Biochemistry 
X 
 
 
 
 
X 
HIV and Hepatitis 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
Baseline AED Levels Assessment4 
X 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
X 
Confinement 
 
X 
X 
 
 
 
Drug Administration5 
 
 
X 
 
 
 
Visual Inspection of DBF 
Application Site 
X 
 
X6 
X6 
 
 
PK Samples7 
 
 
X 
X 
X 
 
1 Vital signs and digital oxygen monitoring before dosing and approximately 0.5, 1, 1.5, 2, 4, and 8 hours post-dose 
(and beyond if clinically indicated). 
2 Vital signs approximately 12 and 24 hours post-dose.  
3 Continuous cardiac ECG monitoring: from approximately 1 hour pre-dose until 8 h after dosing (and beyond if 
clinically indicated).  
4 Unless baseline levels of concomitant AED was obtained within one year prior to the first dosing and show levels 
within an acceptable therapeutic range. 
5 Questions regarding past experience in using DRG or other rescue medication for the treatment of epilepsy will be 
asked to subjects prior to DRG administration. DBF ease of use will be evaluated by the clinical staff and the 
subjects following the first film administration (in Period 1 or Period 2).  
6 A visual inspection of the application site will be conducted prior to DBF administration and approximately 6 and 
24 hours after DBF administration to evaluate the oral mucosa (normal/abnormal).  
7 Blood samples: pre-dose and (± 1 minute) 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, (± 3 minutes) 9, 12, 24, (± 60 minutes) 48, 
72, 96, 120, 144, 192, and 240 hours post-dose.  
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5. 
Introduction 
5.1 
Background on Treatment and Management of Individuals with Refractory 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. When these seizures occur outside a hospital, the patient is often transported to an acute 
care facility for treatment to prevent prolonged seizures. 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. In these cases, the primary goals of the treatment are seizure cessation 
and prevention of seizure recurrence. 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.1  
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.  
5.2 
Diazepam 
Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant, 
and amnestic effects. Most of these effects are thought to result from a facilitation of the action 
of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous 
system.2 
Diazepam is a Schedule IV controlled substance approved for the treatment of anxiety, acute 
alcohol withdrawal, skeletal muscle spasm, and convulsive disorders. Diazepam is used as 
adjunctive treatment of seizures other than status epilepticus in selected, refractory patients with 
partial seizures or generalized tonic-clonic seizures who require intermittent use of diazepam to 
control bouts of increased seizure activity.2 It is used off-label for numerous other conditions 
including insomnia, restless leg syndrome, and pre-/post-operative sedation. 
Diazepam can be taken by mouth, inserted into the rectum, injected into muscle, or injected 
intravenously. When given intravenously, effects begin in one to five minutes. When diazepam is 
taken orally, effects may be delayed as long as 40 minutes.1  
Intravenous diazepam is a first-line treatment for status epilepticus. Diazepam 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. However, diazepam is effective when used 
intermittently for the prevention of repeated seizures. Like other benzodiazepines, diazepam 
administration may cause sedation, anxiolysis, and amnesia.1  
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5.2.1 
Mechanism of Action 
Diazepam is a benzodiazepine derivative that exhibits anti-anxiety, sedative, hypnotic and 
anticonvulsant properties. 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).3 GABAA receptors mediate the sedative, anterograde amnesic, anticonvulsive, 
anxiolytic, muscle relaxant, and temporal/spatial memory effects of benzodiazepines.1 It is 
believed that diazepam enhances the actions of GABA by causing GABA to more tightly bind to 
the GABAA receptors located within the limbic system, including areas of the thalamus and 
hypothalamus.  
GABA, the major inhibitory neurotransmitter in the central nervous system, acts at these 
receptors to open the membrane channel, and allows chloride ions to flow into neurons. 
Excessive neuronal depolarization is implicated in the generation and spread of seizures.3 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, ultimately leading to membrane 
hyperpolarization and a decrease in neuronal excitability. 
5.2.2 
Metabolism and Elimination 
Diazepam is extensively metabolized to one major active metabolite (N-desmethyldiazepam 
[nordiazepam]) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-
hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, under steady state conditions, 
desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam, while 
oxazepam and temazepam are not usually detectable. Both diazepam and desmethyldiazepam 
bind extensively to plasma proteins (95-98%).3 
The volume of distribution of Diastat rectal gel is calculated to be approximately 1 L/kg. 
Following rectal administration of a 15 mg dose of Diastat, the mean elimination half-life was 
reported to be about 46 hours (CV=43%) for diazepam and 71 hours (CV=37%) for 
desmethyldiazepam.3 After oral administration, the initial distribution phase is followed by a 
prolonged terminal elimination phase, with a half-life up to 48 hours, and the terminal 
elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours.4 
The metabolism of diazepam is primarily hepatic and involves demethylation (involving 
primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), 
followed by glucuronidation. The marked inter-individual variability in the clearance of 
diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is 
known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no 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.3 
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their 
glucuronide conjugates.4 
 
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5.2.3 
Pharmacokinetics 
Following rectal administration, diazepam is well absorbed, reaching peak plasma concentrations 
in 1.5 hours,3 and the absolute bioavailability of Diastat rectal gel relative to Valium injectable is 
90%.  
After Valium oral administration, the average time to achieve peak plasma concentrations is 1–
1.5 hours, with a range of 0.25 to 2.5 hours, and more than 90% of diazepam is absorbed. Valium 
absorption is delayed and decreased when diazepam is administered with a moderate-fat meal. In 
the presence of food, mean lag times are approximately 45 minutes as compared with 15 minutes 
when fasting. There is also an increase in the average time to achieve peak concentrations to 
about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in 
an average decrease in Cmax of 20% in addition to a 27% decrease in area under the plasma 
concentration-time curve (AUC; range 15% to 50%) when administered with food.4 
5.3 
Diastat® AcuDialTM  
Diazepam rectal gel administered after the onset of acute repetitive and prolonged seizures has 
been shown to significantly reduce seizure recurrence and emergency department admissions. 
Nonetheless, social objections to and legal concerns about rectal administration have limited its 
use.1  
The rectal route of administration of diazepam is not ideal. First, it entails the need to expose and 
appropriately position a patient in order to administer drug, both of which can be time 
consuming, with a potential delay of time to treatment. Successful use of a rectal product also is 
dependent upon the competence of the caregiver and requires training in the correct 
administration of the gel. Improper technique could lead to patient injury and leakage of gel from 
the rectum can result in incomplete dosing. Additionally, the attitude of many patients toward a 
rectal route of drug administration is unfavorable, which may impact compliance to treatment. 
Each of these factors has a potential impact on usability and morbidity. Persistent seizure activity 
is associated with worse outcomes across a spectrum of precipitating conditions. In addition, 
experimental models of status epilepticus have demonstrated that the effectiveness of 
anticonvulsant medication to terminate seizures rapidly decreases as the time between the start of 
convulsions and drug administration lengthens. 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.1 
A need for better, more patient-friendly therapies for seizure emergencies such as prolonged 
seizures, acute repetitive seizures, or status epilepticus has resulted in development of innovative 
benzodiazepine formulations using non-rectal routes.1  
5.4 
Diazepam Buccal Film (DBF) 
One new route of diazepam administration is via buccal soluble film. Buccal soluble diazepam 
(DBF) may be particularly well-suited for administration in outpatient settings. The study drug is 
administered by placing the film against the inner aspect of the cheek, where it adheres, and 
allows for transbuccal absorption of diazepam. There is no need to position or disrobe the 
subject. Additionally, there is less potential for delay in initial treatment and greater subject and 
caregiver acceptance with improved compliance may also be expected.  
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The development of DBF will meet the treatment need for a form of diazepam that is effective, 
safe, allows for reliable dose administration, and is easier to administer than the rectal gel in a 
subset of epileptic subjects. Subjects, 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 trials with DBF have focused on assessing its relative bioavailability to the 
reference therapy, Diastat® AcuDial™ rectal gel, dose proportionality, assessment of food 
effect, and the pharmacokinetics in subjects with epilepsy. Overall safety and tolerability have 
been assessed in clinical trials conducted with DBF.  
Aquestive Therapeutics initiated development of DBF, specifically intended for buccal delivery 
for subjects who require control of intermittent bouts of seizure activity. DBF contains the Food 
and Drug Administration (FDA) approved active ingredient diazepam, a benzodiazepine, as a 
treatment for the management of selected, refractory subjects with epilepsy, on stable regimens 
of antiepileptic drugs who require intermittent use of diazepam to control bouts of increased 
seizure activity. The study drug, with a planned dose range of 5 mg to 17.5 mg, is expected to 
achieve peak plasma concentrations of diazepam equivalent to the reference therapy, Diastat® 
AcuDial™ rectal gel. The DBF product is intended for submission as a 505(b)(2) New Drug 
Application (NDA) using Diastat® AcuDial™ rectal gel as the reference therapy.  
5.5 
Background on Diazepam Buccal Film (DBF) 
Diastat® AcuDial™ rectal gel is prescribed for increased seizure activity as defined by a marked 
increase in seizure activity, sometimes heralded by non-convulsive symptoms that are 
characteristic for each subject and deemed by the prescriber to be the kind of seizure for which a 
benzodiazepine would be administered.3 Diastat® AcuDial™ rectal gel has been marketed in the 
US since 1997 and currently is the only FDA approved drug in the US for this indication.  
Though the Diastat® AcuDial™ rectal gel formulation is considered 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 subject and care-givers alike. For 
example, the subject or caregiver must first remove articles of clothing and then place the subject 
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 subject injury, and leakage of gel from the rectum can result in incomplete 
dosing. Additionally, some subjects have a negative view of the rectal route of administration, 
and this may reduce compliance to treatment. Each of these factors has a potential influence on 
subject morbidity. Persistent seizure activity is associated with less favorable outcomes across a 
spectrum of precipitating conditions. 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.  
The DBF is intended for application to the inner aspect of the cheek where it adheres, dissolves, 
and releases the drug into the buccal mucosa. Though buccal absorption is expected as the 
primary route of absorption of the drug, some absorption through the gastrointestinal (GI) tract 
may be possible due to swallowing of some dissolved drug substance in the saliva. It is expected 
that that timing of use of the buccal film will be similar to the use of Diastat® AcuDial™ rectal 
gel, i.e., the film would be administered after a seizure with characteristics for which the 
Reference Listed Drug (RLD) would be indicated. 
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5.5.1 
Nonclinical Studies 
Mechanism of Action: Diazepam is a benzodiazepine derivative that exhibits anti-anxiety, 
sedative, hypnotic and anticonvulsant properties. 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).3 GABAA receptors mediate the sedative, anterograde amnesic, 
anticonvulsive, anxiolytic, muscle relaxant, and temporal/spatial memory effects of 
benzodiazepines.1 It is believed that diazepam enhances the actions of GABA by causing GABA 
to more tightly bind to the GABAA receptors located within the limbic system, including areas of 
the thalamus and hypothalamus.  
GABA, the major inhibitory neurotransmitter in the central nervous system, acts at these 
receptors to open the membrane channel, and allows chloride ions to flow into neurons. 
Excessive neuronal depolarization is implicated in the generation and spread of seizures.3 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, ultimately leading to membrane 
hyperpolarization and a decrease in neuronal excitability. 
Metabolism and Elimination: It has been reported in the literature that diazepam is extensively 
metabolized to one major active metabolite (desmethyldiazepam) and two minor active 
metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam). With 
steady state dosing, desmethyldiazepam is found in plasma at concentrations equivalent to those 
of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of 
diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and 
CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The 
marked inter-individual variability in the clearance of diazepam reported in the literature is 
probably attributable to variability of CYP2C19 (which is known to exhibit genetic 
polymorphism; about 3-5% of Caucasians have little or no CYP2C19 activity and are “poor 
metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of inhibitors 
selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes 
are not significantly involved in metabolism of diazepam.3  
5.5.2 
Clinical Studies 
As of December, 2018, six clinical studies in healthy adult volunteers have been completed with 
the DBF product. These comprise two bioavailability pilot studies in comparison with Diastat 
gel® (1899 and 1900), a dose-proportionality study (162013), a bioavailability study in 
comparison with Diastat® gel (162021), and two food effect studies. A two-arm food effect study 
investigated the effect of a high fat meal (Study 162022). A four-arm food effect study compared 
the pharmacokinetics of diazepam (A) fasting in an upright position after dosing (B) fasting in a 
reclining position after dosing (C) Following a high fat meal in a reclining position after 
dosing (D) Following a moderate fat meal in a reclining position after dosing (Study172018).1 
5.5.2.1 
Safety in Clinical Studies 
It is anticipated that the adverse event (AE) profile from systemic exposure observed with study 
drug will resemble the already well-known profile for diazepam in general and the reference 
therapy, Diastat® AcuDial™ rectal gel, in particular. Diazepam rectal gel AE data were collected 
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from double-blind, placebo-controlled studies and open label studies with 573 subjects exposed 
to diazepam rectal gel. The majority of AEs were mild to moderate in severity and transient. The 
most frequent AE reported with diazepam rectal gel in the two double-blind, placebo-controlled 
studies was somnolence (23%). Less frequent AEs were headache (≤5%), diarrhea (≤4%), ataxia 
(≤3%), dizziness (≤3%), euphoria (≤3%), incoordination (≤3%), rash (≤3%), vasodilatation 
(≤2%), and asthma (≤2%).3  
In the 6 completed DBF studies, there have been a total of 154 subjects enrolled, with 132 
subjects (65.9% male, 34.1% female; age range 19-64) having received at least one dose of study 
drug.  A total of 268 doses of DBF and 119 doses of Diastat® AcuDial™ were administered.1 
Sixty-five percent of all administrations of DBF (n = 175) and 63.9% (n=78) of Diastat 
administrations were followed by one or more Treatment Emergent Adverse Events (TEAE). A 
total of 252 TEAEs were reported following administrations of DBSF; the majority were mild 
(90.9%) or moderate (8.3%) in severity.  80.1% were deemed to be possibly or probably related 
to study drug. Of 103 TEAEs reported following Diastat doses, 98%were mild and 2% were 
moderate. 75.7% were possibly or probably related.1   
There was 1 serious adverse event (SAE) reported and 2 TEAEs leading to discontinuation. 
There were no adverse events resulting in persistent impairment and there were no deaths 
reported.1 
In all studies to date, somnolence followed by dizziness was the most frequently reported TEAE, 
consistent with the known pharmacologic action of diazepam. Somnolence has also been the 
most frequent AE reported for Diastat.1 
The frequency of AEs increased in a dose-related manner with DBSF. An analysis of 
138 administrations of 15 or 20 mg in a fasted state showed no particular pattern of TEAEs 
according to Cmax or increase in frequency with an increase in Cmax.1    
A decreased frequency of AEs following dosing in a fed state was observed in the two food 
effect studies.1  
Overall, the administration of DBF was safe and well tolerated in healthy subjects following a 
single oral dose of 5 mg through 20 mg under both fast and fed conditions. Adverse events were 
primarily mild to moderate in severity, short-lasting and consistent with the known 
pharmacologic effects of diazepam. There were few SAEs reported and no events associated 
with death or lasting impairment were observed.1 
5.5.2.2 
Pharmacokinetics in Clinical Studies 
Pharmacokinetics: A 15 mg dose of Diastat® AcuDial™ rectal gel following rectal 
administration 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 (CV=43%) and 71 hours (CV=37%), respectively. Both diazepam and its 
major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).3 
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5.5.2.2.1 
Pilot Studies 1899 and 1900 
The Sponsor conducted two randomized, open label, single-dose, fasting condition, crossover 
pilot studies in healthy male and female volunteers to assess the bioavailability of study drug in 
comparison to the same nominal dose of Diastat® AcuDial™ rectal gel. The planned enrollment 
was 12 subjects in both studies. 
Study 1899 compared study drug 5 mg to Diastat® AcuDial™ rectal gel 5 mg. Among the 11 
subjects who completed both treatments, DBF 5 mg was bioequivalent to Diastat 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 DBF (range 0.33-1.50 hours) and 0.25 hours for the Diastat rectal gel (range 0.15-
1.00 hours). The difference in Tmax values was not statistically significant.1 
Study 1900 compared DBF 20 mg to Diastat® AcuDial™ rectal gel 20 mg. Evaluable data from 
10 subjects who completed both treatments showed that the extent of the absorption of DBF 
20 mg was comparable to Diastat® AcuDial™ 20 mg rectal gel, with the ratio of geometric 
means for AUCt and AUC∞ within the acceptable range of 80-125%. For Cmax, the ratio of 
geometric means was 158.72% (90% CI 122.81-205.14). The median Tmax was 1.25 hours for the 
DBF (range 0.36-2.05 hours) and 1.00 hours for the Diastat® AcuDial™ rectal gel (range 0.25-
2.00 hours). The difference in Tmax values was not statistically significant. Examination of the 
mean plasma curves for DBF and Diastat® AcuDial™ showed that although the Cmax was higher 
for the DBF relative to Diastat® AcuDial™, the pharmacokinetics were comparable in terms of 
rapid rate of absorption, duration of plateau, and the rate of elimination.1 
5.5.2.2.2 
Study 162013 – Dose-Proportionality 
Study 162013 was a single-dose, randomized, open-label, three-period, six-sequence, crossover 
study conducted to assess dose-proportionality of DBSF at doses of 5, 10, and 15 mg. A total of 
30 subjects were randomized and dosed in the study. Analysis of the pharmacokinetic data 
confirmed that DBSF is dose-proportional over the dose range 5 mg to 15 mg (Table 1). The 
criteria for dose proportionality were met for diazepam since for both comparisons (A/B: DBSF 
5 mg/DBSF 10 mg and C/B: DBSF 15 mg/DBSF 10 mg), the geometric mean 90% CI of the 
ratios of Least-Squares means from the analysis of variance (ANOVA) of the ln-transformed 
AUCt, AUC∞, and Cmax were within the acceptable range 80-125%.1  
 
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Table 1: 
Study 162013 - Dose-Proportionality of DBSF at Doses of 5, 10, and 15 mg 
Parameter1 
Treatment Comparisons 
Geometric Mean 
Ratio2 
90% CI3 
Lower 
Upper 
AUCt 
DBSF 5 mg (A) – DBSF 10 mg (B) 
103.53% 
99.51% 
107.72% 
AUC∞ 
DBSF 5 mg (A) – DBSF 10 mg (B) 
104.08% 
99.43% 
108.96% 
Cmax 
DBSF 5 mg (A) – DBSF 10 mg (B) 
104.57% 
97.92% 
111.67% 
 
 
 
 
 
AUCt 
DBSF 15 mg (C) – DBSF 10 mg (B) 
101.94% 
97.62% 
106.44% 
AUC∞ 
DBSF 15 mg (C) – DBSF 10 mg (B) 
103.64% 
98.52% 
109.02% 
Cmax 
DBSF 15 mg (C) – DBSF 10 mg (B) 
98.84% 
92.36% 
105.78% 
AUC∞ = area under the concentration-time curve from time zero to infinity; AUCt = area under the concentration-
time curve from time zero until the last measurable concentration or last sampling time t; CI = confidence interval; 
Cmax= the maximal observed plasma concentration; DBSF= Diazepam Buccal Soluble Film (equivalent to DBF). 
1 Dose normalized to 10 mg 
2 Calculated using least-squares means according to the formula eDIFFERENCE X 100 
90% Geometric Mean Confidence Interval using ln-transformed data. 
5.5.2.2.3 
Study 162021 – Pivotal Bioavailability Study 
This pivotal relative bioavailability study was a four-period, four-sequence randomized 
crossover in 36 healthy adult males and females. The four treatments were DBSF 15 mg and 
three doses of Diastat® AcuDial™ rectal gel: 5 mg, 12.5 mg, and 20 mg. These Diastat® 
AcuDial™ doses span the approved dose range for the rectal gel. The objective of this study was 
to gain a thorough and precise understanding of the comparative exposure to diazepam and 
nordiazepam (both AUC and Cmax) after administration of DBF or Diastat® AcuDial™. A 
secondary objective was to evaluate the dose proportionality of the three doses of Diastat rectal 
gel.1 
Pharmacokinetic parameters (Cmax, AUCt, and AUC∞) were compared pairwise; DBF 15 mg with 
each of the three doses of the rectal gel (Table 2). Results demonstrate that AUC (both AUCt and 
AUC∞) are dose proportional following single doses for both DBF and for Diastat® AcuDial™ 
gel over the studied dose. These results, normalized for dose in mg, suggest that the relative 
bioavailability of diazepam administered as DMF compared with Diastat® AcuDial™ gel is 
118% to 128%.1  
 
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Table 2: 
Study 162021: Ratios (DBSF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUCt, AUC∞, and Cmax - 
PK Population 
Treatment  
 
 
Geometric 
Geometric 
 
90% Geometric CI2 
Comparison 
N 
Parameter 
LSM A 
LSM B 
Ratio1 
Lower 
Upper 
DBSF 15 mg (A) 
24 
AUCt 
11310.33 
3181.98 
355.45% 
292.89% 
431.37% 
Diastat  
24 
AUC∞ 
13204.10 
3730.87 
353.91% 
295.32% 
424.14% 
rectal gel 5 mg (B) 
24 
Cmax 
461.88 
116.88 
395.18% 
291.06% 
536.54% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM C 
 
 
 
DBSF 15 mg (A) 
23 
AUCt 
11381.05 
7314.63. 
155.59% 
127.26% 
190.24% 
Diastat  
23 
AUC∞ 
12871.61 
8370.26 
153.78% 
126.56% 
186.86% 
rectal gel 12.5 mg (C) 
23 
Cmax 
490.93 
206.30 
237.97% 
176.72% 
320.45% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM D 
 
 
 
DBSF 15 mg (A) 
21 
AUCt 
11186.57 
12392.66 
90.27% 
42.23% 
112.80% 
Diastat  
20 
AUC∞ 
13191.81 
14824.85 
88.98% 
69.28% 
114.29% 
rectal gel 12.5 mg (D) 
21 
Cmax 
458.51 
327.86 
139.85% 
140.92% 
186.42% 
AUC∞ = area under the concentration-time curve from time zero to infinity; AUCt = area under the concentration-
time curve from time zero until the last measurable concentration or last sampling time t; CI = confidence interval; 
Cmax= the maximal observed plasma concentration; DBSF= Diazepam Buccal Soluble Film (equivalent to DBF); 
LSM = Least-Squares Mean 
1 Calculated least-squares means according to the formula: e(Difference) x 100 
2 90% Geometric Mean Confidence Interval using ln-transformed data 
5.5.2.2.4 
Food Effect Studies 
Aquestive Therapeutics conducted two food effect studies (Study 162022 in Section 5.5.2.2.5 
and Study 172018 in Section 5.5.2.2.6 ). Results for a high fat meal were consistent across the 
two studies.1  
The food effect studies indicate that a high fat or moderate fat meal within 30 minutes prior to 
dosing of DBF has no effect on diazepam AUC but reduces diazepam Cmax on average of 45% 
and 33%, respectively. Bimodal peaks were observed under fed conditions due to the 
combination of oral transmucosal absorption and intestinal absorption of DBF. The first peak 
(mean concentration curves) for both high fat and moderate fat meals is observed at 45 minutes 
(mean of 199.04 ng/mL and 222.37 ng/mL, respectively) and the second peak of the mean 
concentration curves is observed at 3 hours (mean of 196.22 ng/mL and 261.79 ng/mL, 
respectively).1 
5.5.2.2.5 
Study 162022 
Study 162022 was a single-dose, open-label, two-period, randomized two-sequence crossover 
study with DBF 15 mg administered under fasted conditions and within 30 minutes following a 
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high-fat meal. The washout period between doses was 28 days. The study was conducted with 
18 healthy male and female subjects aged 18 to 62 years, inclusive. AUCt and AUC∞ were not 
affected by food; however, Cmax after a high fat meal was approximately 55% of the fasting 
value, 90% CI 48.6% – 62.7% (ratio of geometric means). Median Tmax fasting was 
approximately 0.75 hour with range of 0.25 hour to 2 hours whereas median Tmax after a high fat 
meal was 3.0 hours with range 0.5 hour to 6.0 hours, p = 0.0008.1  
5.5.2.2.6 
Study 172018 
Study 172018 was a four-period, randomized four-sequence crossover study in 24 male and 
female adults with four treatments: (A) DBF 15 mg fasted, administered upright; (B) DBF 15 mg 
fasted, administered reclining; DBF 15 mg within 30 minutes following a standardized high-fat 
meal, administered reclining; and DBF 15 mg within 30 minutes of a standardized moderate-fat 
meal, administered reclining.1 
The primary objective was to assess the effect of a moderate-fat meal on the diazepam PK 
profile. A secondary objective was to assess the effect of administration of DBF with the subject 
reclining on his/her side (application site downward) for 15 minutes after application. This was 
based on aligning treatment administration with the typical posture assumed by subjects in a 
postictal state and the Sponsor’s interest in investigating whether position affected diazepam PK 
following administration of DBF.1  
Analysis comprised pairwise comparisons of Treatment C (high-fat meal, reclining) and 
Treatment D (moderate-fat meal, reclining) with Treatment B (fasting, reclining) as well as a 
comparison between Treatment B (fasting, reclining) with Treatment A (fasting, upright).1 
Overall, AUCt and AUC∞ were not affected by either food or position. Cmax after the high fat 
meal (reclining) was approximately 53% of the fasting value (reclining), 90% CI: 41.1% - 59.5% 
(ratio of geometric means). Cmax after the moderate fat meal (reclining) was approximately 67% 
of the fasting value (reclining), 90% CI 59.8% - 74.6% (ratio of geometric means). Comparison 
of Treatment B with Treatment A demonstrated that position in the fasting condition (reclining 
versus upright) had no meaningful effect on either Cmax or AUC. Diazepam profiles (reclining 
versus upright) met bioequivalence criteria for the upright and fasting condition. There was no 
difference in Tmax, p = 0.4979.1 
Median Tmax fasting, upright was 1.00 hour with range 0.28 hour to 2.03 hours. Median Tmax 
fasting, reclining was 0.80 hour with range 0.50 hour to 2.03 hours whereas median Tmax after a 
high fat meal, reclining was 2.01 hours with range 0.50 hour to 4.06 hours (p = 0.0147 versus 
fasting, reclining). and median Tmax after a moderate fat meal, reclining was 3.00 hours with 
range 0.50 hour to 4.02 hours (p = 0.0005 versus fasting, reclining).1  
5.6 
Rationale for Dose Levels of Diazepam Buccal Film 
As described above, the data from Study 162013 and Study 162021 demonstrate that DBF is 
dose-proportional over the studied dose-range, while Diastat rectal gel is less than dose-
proportional with respect to Cmax. Also, as described above, the data from Study 162022 and 
Study 172018 demonstrate that food taken within 30 minutes prior to dosing affects the rate (but 
not the extent) of absorption of diazepam administered as DBF. Accordingly, Aquestive used 
population PK modeling to select a dosing regimen to compensate for the differences in PK 
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between DBF and DRG. The recommendation for adults derived from Population PK modelling 
is a weight-based dosing regimen with doses of 10.0 mg, 12.5 mg, 15.0 mg, 15.0 mg, and 17.5 
mg for the five weight bins (weight range 38 to 111 kg) corresponding to the labeled Diastat 
doses of 10.0 mg, 12.5 mg, 15.0 mg, 17.5 mg, and 20.0 mg (Table 3).1  
Table 3:  
Table 3Calculated Prescribed Dose of Study Drug 
Weight (Kg) 
DRG (mg) 
DBF Weight – Adjusted (mg) 
38 to 50 
10 
10 
51 to 62 
12.5 
12.5 
63 to 75 
15 
15 
76 to 87 
17.5 
15 
88 to 111 
20 
17.5 
 
Using data from Study 162013, Study 162021, and Study 172018, population pharmacokinetic 
modeling was used to model the pharmacokinetic profiles for DBF and Diastat rectal gel under 
fasted and fed conditions. In brief, the recommended DBF dose for each weight class as defined 
in the Diastat rectal gel label was selected (1) to provide a dose sufficiently high to ensure that 
the predicted median of the resulting diazepam Cmax following a moderate fat meal was similar to 
the median Cmax following the labeled dose of Diastat rectal gel, and (2) to provide a dose for 
which the predicted median of the resulting diazepam Cmax under fasting conditions would not 
exceed the median Cmax values observed and demonstrated as safe in Phase 1 studies with DBF. 
It was demonstrated that the predicted median diazepam Cmax values with the proposed regimen 
administered under fasting conditions did not meaningfully exceed the median Cmax values 
observed in the 115 healthy volunteers (adult men and women) who received DBF 15 or 20 mg 
under fasting conditions in Phase 1 studies conducted by Aquestive. The median Cmax among 
these 115 healthy subjects (138 DBF administrations) was 486 ng/mL. Under conditions of a 
moderate fat meal, the proposed DBF dosing regimen produces a Cmax similar to the Cmax 
expected following the labeled dose of Diastat rectal gel.1 
5.7 
Rationale for Study Design 
A prior study to investigate the PK of DBF in patients with epilepsy on a regimen of AEDs 
(Aquestive Study 160326) indicated that diazepam plasma concentrations observed in patients 
were on average lower than the concentrations predicted from healthy volunteer data.  Lower 
diazepam concentrations in patients could result from drug interactions with concomitant AEDs 
by means of induction of enzymes involved in diazepam metabolism and/or displacement of 
diazepam from binding sites on albumin (as described for valproic acid and sodium divalproex).   
If the lower plasma diazepam concentrations observed in patients vs. healthy volunteers 
following DBF is a consequence of enzyme induction and/or protein binding displacement from 
concomitant AEDs, the same effect of concomitant AEDs would be expected following 
administration of DRG, and the relative bioavailability of diazepam administered as DBF 
compared with DRG should be the same in patients as in healthy volunteers.  
In the current study, the PK of diazepam will be compared in patients already receiving a stable 
concomitant AED treatment following single doses of DBF or Diastat® AcuDial™ according to 
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body weight as described in Table 3. Moreover, the DBF regimen was demonstrated in healthy 
male and female volunteer simulations to produce within each weight group a median Cmax value 
following a moderate-fat meal comparable to the median Cmax value following DRG 
administration. Therefore Period 1 and Period 2 of this study will be conducted under fed 
conditions where DBF and Diastat® AcuDial™ will be administered following intake of a 
moderate-fat meal. In addition, subjects who volunteer to participate in a third period will receive 
DBF in Period 3 following a high-fat meal. This third period will allow for the PK evaluation of 
DBF following a single dose administration under conditions of a high-fat meal.  
The study will also aim to obtain PK data for Diastat® AcuDial™ under conditions of use in 
patient population and to address whether lower concentrations observed in patients versus 
healthy volunteers following DBF administration are also observed following Diastat® 
AcuDial™ administration. The study will also determine whether the DBF recommended dose 
regimen (mapping between DBF and Diastat® AcuDial™) developed from healthy volunteer 
data is applicable to patients under conditions of use.  
The weight-based DBF dose regimen was designed to elicit within each weight group a median 
Cmax value following a moderate fat meal comparable to the median Cmax value following DRG 
administered according to the current weight-based product labeling for Diastat® AcuDial™. 
Because of the crossover design, the effect of drug-drug interactions can be expected to be 
similar for both treatments.  Therefore, to the extent that population PK modeling in healthy 
volunteers is predictive for patients under conditions of use, it can be expected that diazepam 
Cmax values observed in this study following a moderate-fat meal will be similar under both 
treatments.  In the event that this is not the case, Aquestive anticipates that results from this study 
will be used to refine the recommended dose regimen in consultation and collaboration with the 
Agency. 
5.8 
Clinical Risks/Benefits of Study Drug 
5.8.1 
Managing Clinical Risks/Benefits in the Current Study 
The available data indicate that study drug is dose proportional over the studied dose-range, 
while Diastat® AcuDial™ is less than dose proportional with respect to Cmax.  
In this study, dose is based on weight category (Table 3). Subjects will be weighed at screening 
visit and dose dispensed will be adjusted depending on weight category at that visit. The 
rationale for the dose regimen for DBF is explained in Section 5.6. Trained study site staff will 
administer the study drug. The study design includes several study site visits in each period to 
monitor safety and tolerability.  
5.8.2 
Overdosage Information Derived from Diastat® AcuDialTM Prescribing 
Information 
According to the prescribing information for Diastat® AcuDial™ rectal gel, 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, 
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and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or 
metaraminol. Dialysis is of limited value.3 
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.3 
5.9 
Rationale for the Study Population 
The study employs a 3-period, 2-sequence crossover design enrolling male and female 
volunteers on a concomitant stable regimen including one or more AED for the treatment of 
epilepsy. Eligible subjects will be enrolled in an effort to complete Period 2 with at least 
16 subjects with representation of both genders, representation of subjects taking/not taking one 
or more AED known to induce diazepam metabolism, and representation of subjects taking/not 
taking Sodium divalproex/valproic acid.   
No clinical studies have been conducted with diazepam rectal gel in pregnant women. However, 
an increased risk of congenital malformations associated with the use of benzodiazepine drugs 
has been suggested by several studies. There have been reports of neonatal flaccidity, respiratory 
and feeding difficulties, and hypothermia in children born to mothers who have been receiving 
benzodiazepines late in pregnancy. Children born to mothers receiving benzodiazepines on a 
regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during 
the postnatal period. During labor and delivery, measurable amounts of diazepam have been 
found in maternal and cord blood, indicating placental transfer of the drug. Additionally, 
diazepam and its metabolites may be present in human breast milk for prolonged periods of time 
after acute use. A recent study suggested that paternal exposure may be associated with fetal 
abnormalities.1 In humans, measurable amounts of diazepam have been found in maternal and 
cord blood, indicating placental transfer of the drug.3  
Since there have been no studies conducted in pregnant women, it is uncertain whether there is 
human fetal risk associated with the use of diazepam. Therefore, non-pregnant, non-lactating 
females will be included in the study. Any females of childbearing potential will be included if 
they use appropriate methods of contraception. In addition, non-surgically-sterile male subjects 
who are sexually active with non-sterile female partners will be required to use effective 
contraceptive methods for the duration of the study and for 111 days following administration of 
the study medication.  
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6. 
Objectives 
Primary objective: 
• Evaluate the PK of single doses of DBF at the recommended dose regimen (range 10 mg 
to 17.5 mg according to body weight) compared with DRG at the labeled dose regimen 
(range 10 mg to 20 mg according to body weight) in adult male and female subjects on a 
stable concomitant regimen of AED for the treatment of epilepsy, following a 
moderate-fat meal.  
Secondary objectives: 
• Evaluate the PK of single doses of DBF following a high-fat meal compared with DRG 
following a moderate-fat meal at the recommended dose regimen in adult male and 
female subjects on a stable concomitant regimen of AED for the treatment of epilepsy. 
• Assess the safety-tolerability of single doses of DBF and DRG administered to adult male 
and female subjects on a stable concomitant regimen of AEDs under fed conditions. 
7. 
Study Design 
This will be a randomized, multiple centers, single-dose, open-label, three-period, 
three-treatment, two-sequence crossover study under fed conditions.  
The study will evaluate single doses of DBF compared with DRG administered according to 
weight category in adult male and female subjects on a stable concomitant regimen of AED for 
the treatment of epilepsy. A stable regimen of AED is defined as no change in the prescribed 
AED regimen during the 30-day period prior to the first study drug administration and no change 
anticipated in the prescribed AED regimen over the course of study participation until the last 
PK blood sample collection.  
Subjects will receive Treatment A and Treatment B (DBF and DRG following a moderate-fat 
meal) in Period 1 and Period 2 in a randomized sequence, and at a dosage specific to body 
weight, as described in Table 4. DBF will be administered according to the currently 
recommended dose regimen (derived by Aquestive from population PK modeling in healthy 
volunteers). DRG will be administered depending on weight category according to the current 
product labeling for Diastat®. Subjects may be asked to participate in a third period, on a 
voluntary basis. Subjects who volunteer to participate in a third period will receive a second 
dose of DBF administered in exactly the same manner as the earlier dose of DBF with the 
exception that DBF in Period 3 will be administered following a high-fat meal. 
A maximum of 32 eligible subjects will be enrolled in an effort to complete Period 2 with at 
least 16 subjects with representation of both genders, representation across the five weight 
categories of subjects taking one or more AEDs known to induce diazepam metabolism, and 
representation of subjects taking sodium divalproex/valproic acid.  Subjects who are eligible may 
be enrolled without regard to weight category. Since only exploratory PK data will be 
gathered from treatment period 3, no more than 50% of the subjects who complete Period 1 
and Period 2 will participate in Period 3.  
This study is intended for filing under FDA regulations. 
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Table 4: 
Table 4 Study Treatment Administration According to Weight Category 
Product 
Meal 
Condition 
Weight 
Category 
Weight (kg) 
Dose 
Test (Treatment A):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
Moderate-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
Reference (Treatment B):   
Diastat® AcuDialTM rectal gel 
(Valeant Pharmaceuticals, 
USA) 
Moderate-Fat 
Meal 
B1 
38-50 
2 mL (10 mg) 
B2 
51-62 
2.5 mL (12.5 mg) 
B3 
63-75 
3 mL (15 mg) 
B4 
76-87 
3.5 mL (17.5 mg) 
B5 
88-111* 
4 mL (20 mg) 
Test (Treatment C):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
High-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
*Subjects eligible for study with weights in the range of 112 to 134 kg will be dosed at the 88-111 kg weight range 
as shown above. 
8. 
Study Population 
8.1 
Sample Size 
Subjects will be enrolled to attain a sample size of no more than 32 subjects (and a minimum of 
16 completed subjects in Period 2). Because this is not a formal hypothesis testing study, the 
sample size is proposed based on the desired level of precision for estimating pharmacokinetic 
parameters and the relationship between pharmacokinetic parameters. In principle, the expected 
precision of the estimates of the ratios of geometric means of interest can be estimated from the 
intra-subject variability observed in Aquestive Study 162021 (pharmacokinetic crossover of DBF 
15 mg with DRG 5, 12.5, and 20 mg in healthy volunteers). Aquestive has not undertaken a 
formal analysis to predict the expected precision. 
8.2 
Inclusion Criteria 
Subjects enrolled in this study will be members of the community at large. The recruitment 
advertisements may use various media types (e.g. radio, newspaper, Web site, volunteer 
database). Subjects must meet all of the following criteria to be included in the study: 
1) Male or female, smoker (no more than 25 cigarettes or equivalent daily) or non-smoker, ≥ 18 
and ≤ 65 years of age, with body weight between 38 and 111 kg, inclusive. Potential subjects 
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with weights in the range of 112 to 134 kg (247 – 249 pounds) may be allowed to participate 
in the study at the discretion of the Principal Investigator. 
 
2) On a stable and ongoing regimen of at least one AED for treatment of epilepsy.  Stable 
regimen is defined as no change in AED regimen for at least 30 days before the first study 
drug administration and no change anticipated in the prescribed AED regimen over the 
course of study participation. 
3) Subjects must have a diagnosis of seizure disorder (any seizure type or frequency) under 
treatment with at least one AED.  
4) Healthy (except for seizure disorder), according to the medical history, ECG, vital signs, 
laboratory results and physical examination as determined by the Principal Investigator/Sub-
Investigator. 
5) Clinical laboratory values within local laboratories acceptable ranges, unless values are 
deemed by the Principal Investigator/Sub-Investigator as “Not Clinically Significant”. 
6) Ability to comprehend and be informed of the nature of the study, as assessed by clinic staff.  
7) Availability to volunteer for the entire study duration and willing to adhere to all protocol 
requirements. 
8) Agree not to have a tattoo or tongue or body piercing until the end of the study. 
9) Agree not to drive or operate heavy machinery if feeling dizzy or drowsy following drug 
administration until full mental alertness is regained. 
10) Subjects must be able and willing to remove denture or bracing at the time of dosing. 
11) Non-vasectomized male subjects must use two forms of medically accepted method of 
contraception with all sexual partners of childbearing potential during the study and for 
111 days following the last dose of study drug. Medically accepted effective forms of 
contraception include:  
a) simultaneous use of a male condom and  
b) for the female partner, hormonal contraceptives (used since at least 4 weeks) or intra-
uterine contraceptive device (placed since at least 4 weeks) or diaphragm or cervical cap 
with intravaginally applied spermicide. 
12) Male subjects must be willing not to donate sperm until 111 days following the last study 
drug administration. 
13) Female subjects who are sexually active with a non-sterile male partner (sterile male partners 
are defined as men vasectomized since at least 6 months) must fulfill at least one of the 
following: 
a) Be surgically sterile for a minimum of 6 months; 
b) Post-menopausal for a minimum of 1 year; 
c) Agree to avoid pregnancy and use medically acceptable method of contraception as 
described below until at least 51 days after the last PK blood sample collection of the 
study. Medically acceptable methods of contraception include: 
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• Intrauterine device (hormonal and non-hormonal) placed at least 4 weeks prior to 
first study drug administration,  
• Oral or transdermal hormonal contraceptives with a 28-days treatment cycle taken 
daily from at least 30 days prior to first study drug administration and with no 
expected change in dosage throughout the study, or  
• Double barrier method (male condom and intravaginally applied spermicide used 
simultaneously with diaphragm or cervical cap) starting at least 21 days prior to 
first study drug administration;  
d) agree to complete abstinence. 
8.3 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1) Clinically significant abnormal laboratory test results found during medical screening.  
2) Positive pregnancy test at screening. 
3) Known presence of any clinically significant: hepatic (e.g. hepatic impairment), 
renal/genitourinary (renal impairment, kidney stones), gastrointestinal (e.g. ulcerative colitis, 
ileus, partial or complete intestinal blockage, appendicitis), cardiovascular (e.g. uncontrolled 
hypertension), cerebrovascular, pulmonary, endocrine (controlled diabetes is acceptable), 
immunological, musculoskeletal, neurological (other than known seizure disorder), 
psychiatric, dermatological or hematological disease or condition unless determined as not 
clinically significant by the Principal Investigator/Sub-Investigator and confirmed by 
Sponsor via written communication prior to subject enrollment. 
4) Presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, 
inflammatory bowel disease), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), 
or other conditions known to interfere with the absorption, distribution, metabolism or 
excretion of the study drug experienced within 7 days prior to first study drug administration, 
as determined by the Principal Investigator/Sub-Investigator.  
5) Any clinically significant rectal abnormality suspected by medical history or general physical 
examination, or any condition, for which, in the judgment of the Principal Investigator/Sub-
Investigator, administration of rectal gel would cause a potential risk to the subject. 
6) Baseline levels of concomitant AED outside of an acceptable therapeutic range at screening. 
7) Presence of any clinically significant illness within 30 days prior to first study drug 
administration, as determined by the Principal Investigator/Sub-Investigator. 
8) Presence of any clinically significant physical or organ abnormality as determined by the 
Principal Investigator/Sub-Investigator. 
9) Presence of any clinically significant lesion of the oral cavity. 
10) Clinically significant ECG abnormalities (QTcF interval > 450 msec for males or QTcF 
interval > 470 msec for females) or vital sign abnormalities (systolic blood pressure lower 
than 90 or over 160 mmHg, diastolic blood pressure lower than 50 or over 100 mmHg, or 
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heart rate less than 50 or over 100 bpm) at screening, unless deemed otherwise by the 
Principal Investigator/Sub-Investigator. 
11) A positive test result for HIV, Hepatitis B surface antigen, Hepatitis C.  
12) A positive test result for any of the following: drugs of abuse (amphetamines, 
methamphetamines, barbiturates, cocaine, opiates, phencyclidine, tetrahydrocannabinol, 
MDMA, methadone, and benzodiazepines, except where a positive test is consistent with a 
stable regimen of a prescribed medication) and alcohol breath test. 
13) Known history or presence of: 
a) Alcohol abuse or dependence within one year prior to screening; 
b) Drug abuse or dependence; 
c) Hypersensitivity or idiosyncratic reaction to diazepam, DBF excipients, DRG excipients; 
d) Glaucoma (open or acute narrow angle); 
e) Food allergies and/or presence of any dietary restrictions that, in the judgment of the 
investigator or the Sponsor, would interfere with study procedures or the subject’s safe 
participation in the study. 
f) Severe allergic reactions (e.g. anaphylactic reactions, angioedema). 
14) Intolerance to and/or difficulty with blood sampling through venipuncture. 
15) Individuals who have donated, in the days prior to first study drug administration: 
• 50-499 mL of blood in the previous 30 days; 
• 500 mL or more in the previous 56 days. 
16) Donation of plasma by plasmapheresis within 7 days prior to first study drug administration. 
17) Individuals who have participated in another clinical research study involving the 
administration of an investigational or marketed drug or device within 30 days prior to the 
first dosing, administration of a biological product in the context of a clinical research study 
within 90 days prior to the first dosing, or concomitant participation in an investigational 
study including an investigational study involving no drug or device administration.  
18) Use of diazepam within 30 days prior to first study drug administration.   
19) Use of strong inhibitors of CYP enzymes (e.g. cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) in the 
previous 30 days before first study drug administration. Use of strong inducers of CYP 
enzymes (e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, St. John´s Wort, and 
rifampicin) and AEDs known to induce CYP enzymes are permitted provided that the 
regimen of such drugs is stable (taken at least q.d. on a regular basis) within 30 days prior to 
first study drug administration and until 10 days after last study drug administration.        
20) Use of any prescription medication (other than non-systemic topical products) within 30 days 
prior to first study drug administration. A prescription drug (other than any benzodiazepines, 
phenothiazines, and strong inhibitors of CYP enzymes) that is part of a stable drug regimen 
(taken at least q.d. on a regular basis) is allowed if taken from at least 30 days prior to the 
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first study drug administration and if there is no expected change in dosage throughout the 
study.  
21) Use of any OTC medications (other than spermicidal/barrier contraceptive products and non-
systemic topical products), within 30 days prior to first study drug administration. OTC drugs 
that is part of a stable drug regimen (taken at least q.d. on a regular basis) is allowed if taken 
from at least 30 days prior to the first study drug administration and if there is no expected 
change in dosage throughout the study. 
22) Natural health products (including oral multivitamins, herbal and/or dietary supplements 
and/or teas) from 30 days pre-dose until after the last PK blood sample collection of each 
period. 
23) Use of marijuana and THC containing products within 3 months prior to screening unless 
such products are a part of the subject’s stable antiepileptic regimen.  
24) Use of any monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine), 
phenothiazines (e.g. chlorpromazine) within 30 days prior to first study drug administration. 
25) Female subjects who have taken oral or transdermal hormonal contraceptives (other than 
28-days treatment cycle contraceptive products) within 30 days prior to first drug 
administration, or have used an implanted, injected, or intravaginal contraceptive within 6 
months prior to first drug administration. 
26) Individuals having undergone any major surgery within 6 months prior to the start of the 
study, unless deemed otherwise by Principal Investigator/Sub-Investigator. 
27) Presence of mouth jewellery, dentures, braces, or piercings in the mouth or tongue that, in the 
opinion of the Principal Investigator, would be likely to interfere with successful completion 
of the dosing procedure 
28) Dental procedures performed within 14 days of dosing or dental procedures scheduled to 
occur during study duration. 
29) Unable or unwilling to provide informed consent. 
30) Have had a tattoo or body/mouth piercing within 30 days prior to first study drug 
administration. 
31) Employee or immediate relative of an employee of Aquestive Therapeutics, any of its 
affiliates or partners, of the CRO, or the clinical site. 
32) Breast-feeding subject. 
9. 
Clinical Procedures 
The clinical portion of the study will be conducted at multiple clinical research facilities, as listed 
in Section 1.2. Unless otherwise specified, procedures, data collection and evaluation will be 
conducted as per involved clinical facilities SOPs. Subjects' personal information will be stored 
in electronic data capture (EDC) system or raw data sheets. 
9.1 
Screening Procedures 
Subject screening procedures will be performed within 30 days preceding administration of study 
medication. Subjects must provide written informed consent prior to initiation of any screening 
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procedures. The consent to perform some general screening procedures may be obtained on a 
consent document other than the Informed Consent Form (ICF) specific to this study, and 
therefore, some screening test results could be obtained before signature of the ICF specific to 
this study. The study-specific ICF must be signed and dated by the subject before participation to 
study-specific procedures. 
Screening procedures will include: demographic data, medical and medication histories, physical 
examination, brief neurologic examination, visual inspection of DBF application site, body 
measurements, ECG (12-lead), vital signs (BP, HR, and RR), oral temperature, digital oxygen 
monitoring, hematology, biochemistry, HIV, hepatitis B and C tests, urinalysis, baseline AED 
levels if applicable*, alcohol breath test, urine pregnancy test, and urine drug screen.     
* The Investigator should confirm and document, for those AEDs medications that the patient is 
receiving at baseline screening, that AED drug level testing has been conducted within one year 
prior to the first dosing, and determine, in consultation with patient’s referring neurologist (if not 
the study Investigator), that AEDs are at acceptable therapeutic levels.  
For any AED medication where testing was not conducted within one year before the first dosing 
or was determined in the past not to be therapeutic, the Investigator should obtain and confirm a 
blood test result demonstrating a current therapeutic level for that AED medication.  If the 
Investigator determines that a dose adjustment for that AED medication is needed, then the 
patient will be considered not to be stable on their AED medication regimen, and ineligible for 
study enrollment.  
For eligibility purposes, abnormal laboratory or vital signs results may be repeated once if 
abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG may 
need to be confirmed by repeated measurements. In the event that the participation of a subject in 
the study is delayed and some screening procedures had been performed outside the prescribed 
screening window, outdated screening procedures can be repeated. 
9.2 
Confinements, Visits, and Washout 
For each period, subjects will be confined from approximately 14 hours before dosing until after 
the 24-hour post-dose blood draw. For subsequent blood draw, subjects may come back to the 
clinical site or have the blood sample collected at home by a home care nurse. 
There will be a washout of 28 days between doses. Participation of each subject in this study 
should last approximately 10 weeks (6 weeks for subjects participating in Period 1 and Period 2 
only), excluding the 30 days screening window. 
9.3 
Randomization and Blinding 
Subjects will be administered each treatment according to the 3-period, 2-sequence, block 
randomization scheme produced by inVentiv. At admission to the clinic, subjects who meet the 
inclusion/exclusion criteria will be assigned between the 2-sequence arms (ABC or BAC) 
according to the randomization schedule. inVentiv will inform the site about the medication to be 
dispensed to each particular subject at the time of subject’s randomization and at the prospective 
protocol visits. The clinic will administer the study treatment as described in Table 4, according 
to the subject’s weight obtained at screening visit.  
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The randomization code will not be available to the Bioanalytical Division until the clinical and 
analytical phases of the study have been completed.  
9.4 
Study Medication 
Test product 
(Treatment A): 
Diazepam Buccal Film (DBF) (Aquestive Therapeutics, USA), under 
fed conditions (breakfast with moderate fat content) 
Strengths: 
10 mg, 12.5 mg, 15 mg, and 17.5 mg 
Doses: 
1 x 10 mg, 1 x 12.5 mg, 1 x 15 mg, or 1 x 17.5 mg 
Reference product 
(Treatment B): 
Diastat® AcuDialTM  rectal gel (Valeant Pharmaceuticals, USA), 
under fed conditions (breakfast with moderate fat content) 
Strengths: 
10 mg/2 mL (5 mg/mL), 20 mg/4 mL (5 mg/mL) 
Doses: 
2 mL (10 mg), 2.5 mL (12.5 mg), 3 mL (15 mg), or 3.5 mL (17.5 mg) 
Test product 
(Treatment C,     
Period 3): 
Diazepam Buccal Film (DBF) (Aquestive Therapeutics, USA), under 
fed conditions (breakfast with high fat content) 
Strengths: 
10 mg, 12.5 mg, 15 mg, and 17.5 mg 
Doses: 
1 x 10 mg, 1 x 12.5 mg, 1 x 15 mg, or 1 x 17.5 mg 
 
9.5 
Drug Supplies and Accountability 
It is the responsibility of the Sponsor to ensure that study medication provided for this study are 
manufactured under Good Manufacturing Practices (GMP) and are suitable for human use. It is 
the responsibility of the Sponsor to ship a sufficient amount of dosage units to allow the clinical 
sites to maintain an appropriate sampling for the study. Study medication will be stored by the 
clinical sites as per applicable requirements. 
The medications will be stored in a locked, environmentally-controlled medication room with 
restricted access. Container(s) will bear a label containing at least the name of the study drug, lot 
and/or batch number, and manufacturing and/or expiry/retest date. Individual subject doses will 
be dispensed according to the randomization schedule. The medications will be dispensed 
according to study specific procedure. 
All study drug received at each site will be inventoried and accounted for throughout the study 
by the pharmacy staff.   
Further details regarding the proper shipment, storage conditions, dispensing, or responsibilities 
will be provided by inVentiv in the pharmacy manual. 
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9.6 
Drug Administration 
In each period, subjects will undergo a 10-hour overnight fast before the dosing procedure. 
Subjects will receive a single dose according to their body weight (as described in Table 4). The 
body weight of each subject will be measured at screening and this value will be used to 
calculate the exact individual dose of diazepam required. 
Following each study drug administration, subjects will remain in a safe comfortable position 
(sitting or reclining in bed) for at least one hour after dosing to allow for an assessment of drug 
effect including sedation. After one hour and depending on the assessment of the 
investigator/clinical staff, the subject may be permitted to ambulate provided that ambulation 
does not interfere with study procedures.   
DBF ease of use will be evaluated by the clinical staff and by the subjects following the first film 
administration in Period 1 or Period 2. Questions regarding past experience in using DRG or 
other rescue medication for the treatment of epilepsy will also be asked to subjects prior to DRG 
administration. Questions are listed in Appendix I – Diazepam PK Study Participant Questions. 
Test (Treatment A and Treatment C): 
After the overnight fast, subjects will be served a standardized moderate-fat meal (Treatment A, 
Period 1 or Period 2) or a high-fat, high-calorie meal (Treatment C, Period 3). Subjects will have 
20 ± 1 minutes to finish the meal. The study drug will be administered 30 ± 1 minutes after the 
start of the meal. A single dose of DBF will be administered by placement of the film against the 
buccal mucosa.   
When opening the foil pouch containing the study drug film, the clinical staff will 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. 
Prior to dosing, the subject will be asked to move his/her tongue around the mouth (front and 
back part of gums, teeth and palate) two times to note any signs of oral irritation and/or any 
mouth, tongue or gum ulcer(s). Study staff will check the subjects’ mouth to ensure the mouth is 
clean and free of food before study drug administration. Subsequently, staff will center the DBF 
against the inner aspect of the right or left buccal mucosa (inside the cheek) and ask the subject 
to close his/her mouth in a natural way, without swallowing, chewing, biting or breaking the 
DBF (refer to Appendix III - Placement Diagram for Aquestive Therapeutics Buccal Film). If the 
subject chews, talks, or moves the study drug within 10 minutes of administration, it is to be 
noted. Dosing time will be set to the time the film is placed on the buccal mucosa.  
The study staff will record the actual time of film placement. Subjects will be instructed to notify 
study staff if the DBF is accidentally swallowed within 5 minutes of dosing. Study staff will 
record the time the film was swallowed.  
Following the administration of the DBF, hands and mouth will be checked in order to confirm 
the consumption. 
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Reference (Treatment B): 
Subjects will consume a standardized moderate-fat meal after the overnight fast. Subjects will 
have 20 ± 1 minutes to finish the meal. The study drug will be administered 30 ± 1 minutes after 
the start of the meal.  
A single dose of DIASTAT® rectal gel will be administered, with subjects lying down on their 
right side. The tip of the syringe containing the DIASTAT® gel will be inserted gently in the 
rectum and the gel will be inserted inside the rectum according to the dosing procedure (refer to 
Appendix IV - Placement Diagram for DIASTAT® AcuDial™ Rectal Delivery System).  
9.7 
Study Restrictions 
If any subject does not comply with the study restrictions, at any time prior to or during the 
study, continued participation will be re-assessed by the Principal Investigator/Sub-Investigator, 
CRO PK Scientist and the Sponsor. 
If drug therapy other than that specified in the protocol, including any change in the subject’s 
stable AED regimen, is required during the study, the decision whether to continue or 
discontinue the subject’s participation in the study will be made by the Principal 
Investigator/Sub-Investigator and/or by the CRO PK Scientist in consultation with the Sponsor.   
Concomitant drug or non-drug treatment (e.g. prune juice, ginger ale) administered to subjects as 
per instructions from clinical sites physicians for treatment of any Adverse Events [AEs] (as 
required) will be permitted. Clinic staff will provide the subjects with the treatment (e.g. 
medication, fluids) and will document all substances given outside of the protocol specified 
requirements. All cases of concomitant medication or herbal/dietary supplement administration 
will be reported as soon as possible to the CRO PK Scientist and/or the Sponsor and will be 
reviewed on a case by case basis to determine the subject’s further participation in the study. 
9.7.1 
Food and Fluids 
After a supervised fast of at least 10 hours, subjects will be served either a standardized 
moderate-fat meal or a high-fat, high-calorie meal. The standardized moderate-fat meal will 
contain approximately 625 calories. Approximately 14% of total calories will be derived from 
protein, 54% from carbohydrates, and 32% from fat.5 The high-fat, high-calorie meal will 
contain approximately 800 to 1000 calories (approximately 50% of total caloric content of the 
meal will be derived from fat). This meal should derive approximately 150, 250, and 500-600 
calories from protein, carbohydrate, and fat, respectively.7 Subjects will be required to start their 
meal as soon as it is served and to complete it within 20 ± 1 minutes. Drug administration will 
occur 30 ± 1 minutes after the meal has been started. Subjects will fast for not less than 4 hours 
after drug administration. Meals will be standardized and similar in composition between 
periods. 
No water will be allowed during the DBF administration and for at least 15 minutes following 
DBF administration. Water will be allowed ad libitum at all other times.  
In addition, subjects will be required to abstain from (refer to Appendix II – Study Restrictions 
for detailed study restrictions): 
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• food containing poppy seeds within 48 hours prior to dosing in each period; 
• food or beverages containing caffeine/methylxanthines derivatives or energy drinks 
from 48 hours prior to dosing until after the last PK blood sample collection of each 
period; 
• natural health products (dietary and/or herbal supplements and/or teas) from 30 days 
pre-dose until after the last PK blood sample collection of each period; 
• Food or beverages containing grapefruit, star fruit, and/or pomelo from 30 days prior 
to the first dosing until the last PK blood sample collection of the study. 
9.7.2 
Tobacco, Alcohol, and Illicit Drugs 
Subjects will be required to abstain from using soft or hard drugs from screening and throughout 
the study. Subjects will not be allowed to smoke more than 25 cigarettes or equivalent per day. 
Marijuana and THC containing products may be allowed if prescribed and part of the subject’s 
stable antiepileptic regimen.  
Consumption of alcohol-based products will be prohibited from 48 hours prior to dosing until 
after the last PK blood sample collection of each period. 
9.7.3 
Medications 
Prescription and OTC medications will be prohibited throughout the study except for 
prescription and OTC drugs that are administered as a stable regimen (taken at least q.d. on a 
regular basis). Any stable prescription drug and OTC treatment (except any benzodiazepines, 
phenothiazines, and strong inhibitors of CYP enzymes) will be allowed if taken from at least 
30 days prior to the first study drug administration and with no changes expected in dosage 
regimen through the study (until the last PK sample).  
No other concomitant drug therapy will be allowed during the study except one(s) required for 
the medical management of an AE. In this case, any concomitant medication use will be 
evaluated on a case-by-case basis by the Principal Investigator or a physician. Concomitant drug 
or non-drug treatment (e.g. acetaminophen, ibuprofen (or other NSAIDs), prune juice, ginger 
ale) for the treatment of an AE will be administered as per instructions from clinic physicians. 
Clinic staff will provide the subjects with the treatment (e.g. medication, fluids) and will 
document all substances given outside of the protocol specified requirements. All cases of 
concomitant medication or herbal/dietary supplement administration will be reported as soon as 
possible to the Sponsor and will be reviewed on a case by case basis to determine the subject’s 
further participation in the study. 
Any benzodiazepines (other than study drug), phenothiazines, and strong inhibitors of CYP 
enzymes (e.g. cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, itraconazole, diltiazem, and HIV antivirals) will be prohibited from 30 days prior 
to the first dosing until after the last PK blood sample collection of the study. Strong inducers of 
CYP enzymes (e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, phenobarbital, St. 
John´s Wort, rifampicin) and AEDs known to induce CYP enzymes are permitted provided that 
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the regimen of such drugs is stable (taken at least q.d. on a regular basis) within 30 days prior to 
first study drug administration and until at least 10 days after last study drug administration.     
Subjects will be advised that they are not allowed to take MAO inhibitors for 30 days before 
dosing and until 14 days after the last study drug administration. 
For females, oral or transdermal hormonal contraceptives other than 28-days treatment cycle 
contraceptives are prohibited within 30 days prior to first study drug administration and 
implanted, injected, or intravaginal hormonal contraceptive are prohibited within 6 months prior 
to first study drug administration and through the study. 
9.7.4 
Posture and Physical Activity 
Diazepam may cause sedation.  Consistent with intended use of DBF and the use of DRG 
subjects should be in a safe comfortable position (sitting or reclining in bed) for at least one hour 
after dosing to allow for an assessment of drug effect including sedation. After one hour and 
depending on the assessment of the investigator/clinical staff, the subject may be permitted to 
ambulate provided that ambulation does not interfere with study procedures.  Vital signs should 
be taken in a consistent position (sitting or reclining).  Subject visits to the bathroom or 
washroom will be monitored by clinic staff for 4 hours after each study drug administration, and 
the following information will be recorded: whether the subject urinated, defecated, or vomited. 
Subjects will be instructed not to flush if they vomit. Vomitus will be verified and noted in the 
subject’s file for further evaluation if needed.  
Because excessive physical activity may increase the level of CK above the upper normal limit 
value, subjects will be advised to avoid performing vigorous physical activities (e.g., intense or 
long-distance running or biking, etc.) at all times during the study duration (from at least 5 days 
prior to admission), including the washout period.  
9.8 
Sample Collection and Processing 
In each period, a total of 19 blood samples will be drawn from each subject for pharmacokinetic 
analyses. Blood samples will be collected prior to study drug administration and 0.5, 0.75, 1, 1.5, 
2, 3, 4, 6, 9, 12, 24, 48, 72, 96, 120, 144, 192, and 240 hours post-dose (3 mL for each sampling 
time). The time tolerance window for blood samples collected during the confinement period 
will be ±1 minute for all samples collected before 8 hours post-dose and ±3 minutes for 
subsequent samples. The time tolerance window for return visit samples will be ±60 minutes. 
Blood samples will be collected as close as possible to nominal times; exact sample collection 
times will be recorded on the appropriate source documents and reported for each subject. The 
actual time of blood sample collection will be used for PK and statistical analysis. Unless 
otherwise specified or for subject safety, when blood draws and other procedures coincide, blood 
draws will have precedence. A saline intravenous catheter will be used for blood collection to 
avoid multiple skin punctures, when appropriate. Otherwise, blood samples will be collected by 
direct venipuncture. 
The total volume of blood including that collected for eligibility and safety purposes should not 
exceed 313 mL for the whole study.  
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Further details regarding the proper collection, preparation, labeling, storage, and shipment of 
plasma samples for PK analysis will be provided by inVentiv in the lab manual. 
9.9 
Subject Monitoring 
Subjects will be monitored throughout the study by the clinical staff for adverse events. In each 
period, the Principal Investigator or Sub-Investigator will be on site for drug administration and 
until 8 hours after administration of the study medication to the last subject. A Principal 
Investigator or Sub-Investigator will also be on call for the remainder of the study. If necessary, a 
physician, either at the clinic or in a nearby hospital will administer treatment for any AEs. A 
crash cart or emergency bag containing the necessary rescue material and appropriate 
medications will be available in the clinic to allow for rapid intervention in case of emergency. 
Safety parameters, including laboratory results and ECG, will be assessed by the Principal 
Investigator or delegate, using local laboratories acceptance ranges criteria for biomedical 
laboratory as suggested guidelines in making the medical assessment. 
Scheduled safety measurements will be repeated according to appropriate ranges or upon request 
from a physician. Any abnormal repeated measurement will be evaluated by a physician and 
repeated if judged necessary. Further action may be taken upon physician's request. 
Subjects will be advised to notify their health care professional(s) (e.g., physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study on a new formulation of 
diazepam before taking any medicines or undergoing any medical procedure. 
9.9.1 
Vital Signs 
Vital signs (BP, RR, HR ) and digital oxygen monitoring will be measured in a sitting position 
(except for safety reasons) at screening and at study exit. Oral temperature will be measured at 
screening and at study exit. 
Vital signs and digital oxygen monitoring will be measured before dosing and approximately 0.5, 
1, 1.5, 2, 4, and 8 hours post-dose (and beyond if clinically indicated). 
Vital signs will also be measured approximately 12 and 24 hours post-dose.  
When vital signs measurements coincide with a blood draw, they should preferably be performed 
a few minutes before the blood collection whenever possible. 
9.9.2 
ECG 
Supine ECG will be performed at screening and study exit. Continuous ECG monitoring will be 
performed from approximately 1 hour prior to dosing until 8 hours post-dose (and extended if 
clinically indicated). 
9.9.3 
Physical Examination 
A physical examination will be performed at screening and study exit. The physical examination 
includes at least the following components: HEENT (head, eyes, ears, nose, and throat), neck, 
chest and lungs, cardiovascular, abdomen, skin, and musculoskeletal evaluation.   
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A brief neurologic examination will be performed at screening and study exit. The neurologic 
assessment involves at least the following evaluation: mental status, cranial nerves, motor 
system, sensory system, cerebellar disorder, gait, and reflexes. 
9.9.4 
DBF Application Site Inspection 
The Investigator or designee will make a visual inspection of the oral mucosa at screening. The 
application site will also be inspected prior to DBF administration and approximately 6 and 
24 hours after administration. Assessments of the oral mucosa (normal/abnormal) will be 
conducted by the Principal Investigator/Sub-Investigator or a trained nurse.  
Abnormalities observed before dosing will be recorded and evaluated regarding exclusion 
criteria but will not be considered AEs. Any post-dose abnormalities will be reported as AEs and 
followed until resolution. 
9.9.5 
Drug and Alcohol Screen 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, PCP, MDMA, methadone) and an alcohol breath test will 
be performed at screening and before dosing of each period. 
9.9.6 
Pregnancy Test 
A urine pregnancy test will be performed at screening and at study exit, and a serum pregnancy 
test will be performed at check-in of each period. 
9.9.7 
Laboratory Assessments 
9.9.7.1 
Hematology 
Hematology will be performed at screening and at study exit. The following will be assessed: 
complete blood count with differential, hemoglobin, hematocrit and platelet count. 
9.9.7.2 
Biochemistry 
Biochemistry will be performed at screening and at study exit. The following will be assessed: 
albumin, alkaline phosphatase, AST, ALT, urea, calcium, chloride, glucose, phosphorus, 
potassium, creatinine, sodium, total bilirubin, CK, lactate dehydrogenase, uric acid, total protein, 
magnesium, bicarbonates, and ammonia. 
9.9.7.3 
Serology 
Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV antigen and antibody detection will 
be performed at screening. 
9.9.7.4 
Urinalysis 
Urinalysis will be performed at screening and at study exit. The following will be assessed: 
macroscopic examination, pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, 
nitrite, and leukocytes. Unless otherwise specified, microscopic examination will be performed 
on abnormal findings. 
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9.10 Study Exit Procedures 
Physical examination, brief neurologic examination, hematology, biochemistry, urinalysis, vital 
signs (blood pressure, heart rate, respiratory rate), oral temperature, digital oxygen monitoring, 
ECG, urine pregnancy test, and AE monitoring will be performed on the last study day. If not 
possible, all efforts will be made to complete study exit procedures within 14 days after the last 
participation of the subject in the study. 
9.11 Data Collection and Evaluation 
All clinical raw data will be recorded promptly, accurately, and legibly as e-source data or 
indelibly on paper (e.g. ECG readings). A detailed list of the type (electronic or paper) and 
location for all source data will be included in the Trial Master File. All raw data will be 
conserved in order to maintain data integrity. A physician and/or the clinical staff will assume 
the responsibility of ensuring the completeness and accuracy of the clinical data. 
9.12 Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or a delegate may withdraw any subject 
from the study for one of the reasons described below: 
• 
safety reason; 
• 
non-compliance with protocol requirements; 
• 
significant protocol deviation; 
• 
positive alcohol breath test;  
• 
positive drug screen (except for subjects using prescribed marijuana and THC containing 
products as AED treatment);  
• 
positive pregnancy test. 
Positive result to the urine benzodiazepine screen (urine drug screen) in Period 2 and Period 3 
may derive from residual concentrations from study drug administered in the previous period(s). 
Therefore, it is not required that subjects with a positive result to that test in Period 2 and Period 
3 be withdrawn from the study. Continued subject participation in the study will be evaluated by 
the Principal Investigator. 
Subjects experiencing emesis within 4 hours following DBF adminsitration will be evaluated on 
a case-by-case basis by the Principal Investigator/Sub-Investigator, the CRO PK Scientist, and 
the Sponsor, and a decision on their continued participation will be made.  Subjects experiencing 
a bowel movement within 4 hours following DRG administration or clinically significant leakage 
of the rectal gel within 4 hours post-dose will be evaluated on a case-by-case basis by the 
Principal Investigator/Sub-Investigator, the CRO PK Scientist, and the Sponsor, and a decision 
on their continued participation will be made.  All decisions will be made prior to the 
bioanalytical laboratory commencing bioanalysis. 
Subjects who withdraw or are withdrawn from the study after dosing will not be replaced. 
However, in the event that the number of drop-outs exceeds initial expectations, subjects who 
withdraw or are withdrawn might be replaced at the discretion of the Sponsor. Such replacement 
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resulting in dosing of more subjects than planned in this protocol would be documented in a 
protocol amendment. 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or a delegate agrees that the subject is fine and can be discharged. As soon as subject 
withdrawal is confirmed, blood sampling will be stopped.  Study exit procedures will be 
performed at the time of withdrawal from the study or as soon as possible thereafter.  
9.13 Adverse Events 
9.13.1 Adverse Event Recording and Follow-up 
Subjects will be instructed to inform clinical personnel of any untoward medical symptoms 
and/or events that may arise during the course of the study. AEs/SAEs will be collected and 
documented from the signing of the ICF until at least 10 days following the last study drug 
administration, and as observed or reported spontaneously by study participants.  
Prior to subsequent dosing, subjects will be questioned concerning symptoms that may have 
occurred after the previous administration of the study drug. The incidence, seriousness, severity, 
duration, and relation to study drug of all AEs will be recorded. 
9.13.1.1 
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) 
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. 
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9.13.1.2 
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. 
9.13.1.3 
Assessing Relationship to Study Drug 
The Investigator will assess the relationship of all AEs to the drug, using the following scale: 
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. 
The Investigator or designee will be present from approximately 30 minutes prior to each dosing 
until at least 8 hours post-dose for each subject. The Investigator or designee will remain on-call 
throughout the duration of each study subject’s visit. 
9.13.1.4 
Follow-up of AEs 
Any AEs, whether serious or non-serious, will be monitored throughout the study and followed 
to resolution or for up to 2 weeks after the last PK blood draw, after which the Investigator will 
decide the course of action. 
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9.13.2 Procedures for Reporting Adverse Events 
Subjects will be instructed to inform clinical personnel of AEs that may arise during the course 
of the study. Treatment of any AEs will be administered under the direction of the Investigator. 
All symptoms will be recorded by clinical 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 serum pregnancy test at all 
treatment visits. Following administration of study drug, any known cases of pregnancy in 
female subjects will be reported until the subject completes or withdraws from the study. The 
pregnancy will be reported immediately by faxing/emailing a completed Pregnancy Report to the 
Sponsor’s safety representative, Syneos Health Safety & Pharmacovigilance 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’s safety representative, Syneos Health 
Safety & Pharmacovigilance 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 emailing/faxing a completed SAE form to the Sponsor’s safety representative, 
Syneos Health Safety & Pharmacovigilance within 24 hours of knowledge of the event.  
SAEs will also be reported to the Sponsor’s safety representative, Syneos Health Safety and 
Pharmacovigilance via e-mail (preferred) or fax within 24 hours of first knowledge by the 
Investigator. The notification must be directed to: 
Syneos Health Safety and Pharmacovigilance  
Fax Number: +1 866 856 1649  
Email: SafetyPV@syneoshealth.com 
 
The following Sponsor personnel are to be contacted on the occurrence of a SAE: 
Allen H. Heller, MD, MPH  
Pharma Study Design LLC  
Office phone: 203-389-2324 
24-hour phone: 908 300 7986 
 
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9.14 Reportable Disease 
In the case a subject has or manifested any clinical signs characteristic of a reportable disease or 
condition (e.g., HIV, Hepatitis B or C), it is the responsibility of the Principal Investigator to 
notify the public health department of the State of Florida by telephone or fax, as soon as 
possible and within the appropriate timelines. 
10. Study Termination 
The study may be terminated by the Principal Investigator following consultation with the 
Sponsor, by the Sponsor or by the regulatory authorities. Following a decision to discontinue the 
trial, the Principal Investigator will immediately inform the active study subjects and the 
IRB/IEC responsible for this trial, stating the reasons for discontinuation of the study and, 
furthermore, advise them in writing of any potential risks to the health of study subjects or other 
persons. It is the Sponsor’s responsibility to report the premature termination of the study to the 
regulatory authority(ies), when required by the applicable regulatory requirement(s).  
11. Analytical Methodology 
Each plasma sample for PK analysis will be aliquoted in 2 samples. One set of aliquots from all 
subjects will be delivered to the analytical facility packed on a sufficient amount of dry ice so 
that the samples remain frozen for at least 72 hours. Once the initial set has been confirmed to 
have been received by the analytical facility, the second set of aliquots will then be delivered, if 
requested. 
All shipments will be accompanied by an inventory list and delivered to the following address:  
 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Attn: Sample Management 
Tel.: 1-418-527-4000 
Fax: 1-418-527-3456  
E-mail: DL-SamplesControllerQuebec@syneoshealth.com 
 
Clinical personnel will notify the analytical laboratory prior to shipment by phone, fax or e-mail. 
The Bioanalytical Division of inVentiv will analyze diazepam and nordiazepam in plasma 
samples using a validated method.  
Analyst and Watson LIMS (Laboratory Information Management System) will be used at 
different steps of the analysis. 
Samples from subjects included in the pharmacokinetic population (see section 12.2.2) and from 
subjects who were withdrawn from the study due to adverse events or vomiting episodes will be 
analyzed. 
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12. Pharmacokinetic and Statistical Analyses 
Pharmacokinetic analysis will be performed using Phoenix® WinNonlin®, which is validated for 
bioequivalence/bioavailability studies by inVentiv. Inferential statistical analyses will be 
performed using SAS® according to FDA guidelines. 
12.1 Pharmacokinetics 
The following pharmacokinetic parameters will be calculated by standard non-compartmental 
methods for diazepam and nordiazepam:  
1) AUC0-t: area under the concentration-time curve from time zero to the last non-zero 
concentration 
2) AUC0-inf: area under the concentration-time curve from time zero to infinity 
(extrapolated) 
3) Cmax: maximum observed concentration  
4) Residual area: calculated as 100*(1- AUC0-t /AUC0-inf) 
5) Tmax: time of observed Cmax 
6) T½ el: elimination half-life 
7) Kel: elimination rate constant  
8) Cl/F: Apparent Total Clearance (L/hr) estimated from dose/AUC0-inf 
9) Vd/F: Apparent Volume of distribution (L) estimated from Cl/Kel (β) 
10) Cl/F/kg: Apparent Total Clearance/kg (L/hr) estimated from dose/kg/AUC0-inf 
11) Vd/F/kg: Apparent Volume of distribution/kg (L) estimated from Cl/Kel (β)/kg 
12.2 Analysis Populations 
12.2.1 Safety Population 
The safety population is defined as all subjects who received at least one dose of the study 
medication. 
12.2.2 Pharmacokinetic Population 
The pharmacokinetic population will include all subjects completing at least Period 1 and 
Period 2 with no significant violation of study restrictions, and for whom the pharmacokinetic 
profile can be adequately characterized. Any subject who completes only one period will be 
presented in the concentrations and pharmacokinetic tables but excluded from descriptive 
statistics and ANOVA. 
A violation of the requirement to maintain a stable regimen of AEDs or a stable regimen of other 
concomitant drugs with the potential to influence diazepam pharmacokinetics will be considered 
a significant violation of study restrictions.  A change of drug in the prescribed AED regimen 
and/or change in the dose of a prescribed AED will be considered a departure from a stable 
regimen.  Any subject who does not maintain a stable AED regimen in the course of the study 
will be presented in the concentrations and pharmacokinetic tables but excluded from descriptive 
statistics and ANOVA.  For cases in which a departure from a stable AED regimen is a matter of 
judgment, the decision will be made by the Principal Investigator/Sub-Investigator and/or by the 
CRO PK Scientist in consultation with the Sponsor prior to bioanalysis.   
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Any subject with diazepam or nordiazepam pre-dose concentrations will be presented in the 
concentrations and pharmacokinetic tables but excluded from descriptive statistics and ANOVA 
if the pre-dose concentration is greater than 5% of the Cmax value for that analyte of that period 
for that subject. 
Subjects withdrawn due to vomiting episodes as per criterion established under section 9.12 or 
due to adverse events will be presented but excluded from the statistical analyses (i.e., 
descriptive statistics and ANOVA). 
Data from subjects who experienced emesis during the sampling interval and who were not 
withdrawn as per criterion established under section 9.12 may be evaluated after completion of 
the pharmacokinetic analysis. Any subject who experienced emesis within 2 times median Tmax 
of the current study (based on the reference product) will be excluded from the statistical 
analysis (i.e., descriptive statistics and ANOVA). 
12.3 Statistical Analyses 
Demographic parameters will be summarized descriptively. Treatment-emergent adverse events 
will be summarized descriptively by treatment for all subjects who were dosed (safety 
population). No inferential statistical analysis of safety data is planned. 
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales. Descriptive statistics (arithmetic and geometric means, standard deviation 
[SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) of the 
plasma concentrations versus time and the pharmacokinetic parameters will be presented for the 
Test and the Reference products for each weight category as well as irrespective of weight 
category. 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be performed on 
untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, AUC0-inf, Cmax, Cl/F, Cl/F/kg, 
Vd/F, and Vd/F/kg at the alpha level of 0.05. Factors incorporated in the model will include: 
Sequence, Subject(Sequence), Period, and Treatment. Tmax will be analyzed using an additional 
non-parametric test (Wilcoxon signed-rank test). 
12.3.1 Treatment Comparison DBF (Test) versus DRG (Reference) Following a 
Moderate-Fat Meal 
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax  for the Test 
product versus the Reference product (Treatment A/Treatment B) irrespective of weight 
category. The 90% confidence interval for the ratio of geometric means, based on least-squares 
means from the ANOVA of the ln-transformed data will also be calculated. Intra and inter-
subject coefficient of variation will be estimated.  
12.3.2 Treatment Comparison DBF (Test) versus DRG (Reference) Following Different 
Meal Conditions 
An exploratory pair-wise analysis comparing DBF following a high-fat meal (Treatment C) with 
DRG following a moderate-fat meal (Treatment B) will be conducted and reported. 
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The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax for Treatment C 
versus Treatment B, irrespective of weight category. The 90% confidence interval for the ratio of 
geometric means, based on least-squares means from the ANOVA of the ln-transformed data 
will also be calculated. Intra and inter-subject coefficient of variation will be estimated.  
Additional analyses may be performed.  
Details of the pharmacokinetic and statistical analyses will be provided in the SAP. 
12.4 Safety and Tolerability Parameters and Analyses 
Demographic parameters will be summarized descriptively. 
Safety and tolerability to DBF will be evaluated through the assessment of AEs (i.e., seriousness, 
severity, relationship to the study drug, outcome, duration, and management), vital signs, clinical 
laboratory parameters and physical examination. Treatment-emergent AEs will be summarized 
descriptively by treatment for all subjects who were dosed (safety population). Changes from 
baseline values in vital signs, ECG, and clinical laboratory parameters will be evaluated. Safety 
and tolerability data will be reported using descriptive statistics. No inferential statistical analysis 
of safety data is planned. 
Details of the safety and tolerability analyses will be provided in the SAP. 
13. Final Report 
A final report including clinical, bioanalytical, and statistical sections will be the responsibility 
of inVentiv. 
In the event that the study is prematurely terminated, inVentiv will produce an abbreviated safety 
report. In such an event, raw data will not be submitted with the abbreviated report but will be 
archived at inVentiv, unless requested by the Sponsor. 
14. Regulatory Considerations and Quality Assurance 
14.1 Independent Ethics Committee Approval of Protocol and Other Study Documents 
The Investigator(s) agree to provide the IRB/IEC with all appropriate documents, including a 
copy of the protocol/amendments, ICFs, advertising text (if any), Investigator’s Brochure (if any) 
and any other written information provided to study subjects. The trial will not begin until the 
Investigators have obtained the IEC favourable written approvals for the above-mentioned study 
documents. A properly executed written ICF shall be read, signed, and dated by each subject 
prior to entering the trial or prior to performing any study procedure. The original signed and 
dated ICF will be kept by the Investigator and a copy will be given to the subject.  
In the event that the protocol is amended, the revised protocol must be approved by the IEC prior 
to its implementation, unless the changes involve only logistical or administrative aspects of the 
trial. If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
obtaining each subject’s consent. 
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The Investigators and the Sponsor’s representative must sign the protocol and its amendments (if 
any) before initiating the study. 
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
14.2 Compliance 
This study will be conducted in compliance with the protocol, GCP, GLP, and all applicable 
regulations, including the Federal Food, Drug and Cosmetic Act, U.S. applicable Code of 
Federal Regulations (title 21), and any IEC requirements relative to clinical studies. The study 
will also be conducted in compliance with the recommendations laid down in the most recent 
version of the Declaration of Helsinki, with the exception that registration of such Phase 1 trials 
in a publicly accessible database is not mandatory.    
14.3 Audits, Inspections and Monitoring 
All source documents and laboratory reports will be Quality Control reviewed to ensure accuracy 
and completeness. Adverse events will be reviewed and assessed for severity and causality by 
the Principal Investigator/Sub-Investigator.  
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor, and the CRO. The Sponsor is entitled to access information about the 
status of the study and to review the original documents of the study. 
15. Confidentiality 
This document contains trade secrets and commercial information that is confidential and may 
not be disclosed to third parties. Persons to whom this study protocol is disclosed must be 
informed that all the information herein is confidential and may not be further divulged. These 
restrictions will apply as well to all future communications if deemed privileged or confidential. 
Publication of the study results may only be allowed with written permission from the Sponsor. 
All information on a subject obtained during the conduct of the study will be kept confidential. 
Subjects will be identified by an anonymized identifier on all samples and study records 
provided to the Sponsor or designee. In compliance with ICH GCP, the Sponsor’s authorized 
representatives, monitor(s), auditor(s), IEC, and regulatory authority(ies) will be granted direct 
access to the subject’s original trial-related records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations. Consent from the subject for disclosure of such information will 
be obtained in writing in the ICF. In addition, should a subject requires medical care or 
hospitalization during the course of the study, the clinical site’s representatives may contact the 
treating physician with the subject’s consent, except that consent may not be requested if there is 
an emergency situation. If the results of the study are published, the subject’s identity will 
remain confidential. 
16. References 
1 Diazepam Buccal Film (DBF) Investigator's Brochure_4.0_XX Dec 2018 
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2 Physician’s Desk Reference (PDR). Diazepam – drug summary. http://www.pdr.net/drug-
summary/Valium-diazepam-2100. Accessed 01 October 2018. 
3 Diastat® AcuDial™ C-IV label, FDA revision date 12/2016, available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2013/013263s092lbl.pdf.  
4 Valium® (diazepam) label, FDA revision date 12/16/2016, available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2013/013263s092lbl.pdf. 
5 Bonate PL, Howard D. Pharmacokinetics in drug development: Problems and Challenges 
in Oncology. Switzerland: Springer; 2016. 
6 Bonate PL, Howard D. Pharmacokinetics in drug development: Problems and Challenges 
in Oncology. Switzerland: Springer; 2016. 
7 FDA Guidance for Industry – Food-Effect Bioavailability and Fed Bioequivlence 
Studies, 2002. 
 
 
 
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17. Appendix I – Diazepam PK Study Participant Questions  
 
SECTION 1 
 
Audience: 
 
Study Participants – Subjects Enrolled in Study 180323 
 
Timeframe:  
Prior to Dosing 
 
Areas of Interest: 
Current rescue medication, previous experience with Diastat (if any), 
preferred route of administration 
 
Questions: 
 
1) What is your current rescue medication treatment? 
 
A) Diastat 
B) Extra dose of usual maintenance medication 
C) Oral diazepam 
D) ER visit/call 911 
E) No treatment 
 
2) If you have used Diastat (diazepam rectal gel) in the past, how 
would you rate the experience in terms of ease of use for your 
caregiver? 
 
 
1  
very easy 
to use 
2  
easy, but with 
some 
limitations 
3  
neutral 
4  
somewhat 
difficult to 
use 
5  
very difficult 
to use 
 
 
 
 
3) How would your ideal rescue medication be taken? 
 
 
 
 
A) orally – via the mouth 
 
 
 
B) rectally 
 
 
 
C) nasally – as a nasal spray 
 
 
 
SECTION 2 
 
Audience: 
 
Study Participants – Subjects Enrolled in Study 180323 
 
Timeframe:  
Post Diazepam Buccal Film (DBF) Dosing 
 
Areas of Interest: 
Experience with DBF, perceptions of ease of use, comparison to Diastat 
experience, ability to self-administer 
 
 
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Questions: 
 
1) How would you rate the experience of taking DBF? 
 
 
1  
very easy  
2  
somewhat 
easy 
3  
neutral 
4  
somewhat 
difficult  
5  
very difficult  
 
 
 
 
2) Do you prefer DBF over DRG? 
 
A) yes 
B) no 
 
3) How willing would you be to use DBF in public following a seizure 
(at work, in a public setting, etc.)? 
 
 
1  
very willing 
2  
neutral 
3  
not willing 
 
4) Do you prefer DBF vs a medication that requires a device to use? 
 
A) yes 
B) no 
 
 
SECTION 3 
 
Audience: 
 
Study Administrators  
 
Timeframe:  
Post DBF Dosing 
 
Areas of Interest: 
Experience with DBF, ease of administration 
 
Questions: 
 
1) How would you rate the experience of administering DBF? 
 
 
1  
very easy  
2  
somewhat 
easy 
3  
neutral 
4  
somewhat 
difficult  
5  
very difficult  
 
 
 
 
2) Do you prefer to administer DBF over Diastat? 
 
A) yes 
B) no 
 
 
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3) How clear were the administration instructions for DBF? 
 
 
1  
very clear  
2  
somewhat 
clear 
3  
neutral 
4  
somewhat 
unclear  
5  
very unclear  
 
 
 
 
 
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18. Appendix II – Study Restrictions 
 
Restriction Period 
Item Restricted 
Examples 
6 months prior to first 
study drug administration 
until the last blood draw 
in the final study period 
Females: implanted, injected, or 
intravaginal hormonal contraceptive 
 
 
3 months prior to 
screening until the last 
blood draw in the final 
study period 
Marijuana and THC containing products 
other than as a prescribed AED 
 
30 days prior to first drug 
administration until the 
last blood draw in the 
final study period 
 
Enzyme-modifying drugs 
(Strong Inhibitors)  
Strong inhibitors of CYP 
enzymes (e.g. Cimetidine, 
fluoxetine, quinidine, 
erythromycin, ciprofloxacin, 
fluconazole, ketoconazole, 
diltiazem and HIV antivirals); 
Females: oral or transdermal hormonal 
contraceptives other than a continuous 
28-days treatment cycle  
 
Monoamine oxidase (MAO) inhibitors  
Note: until 14 days after the last study 
drug administration 
Phenelzine, tranylcypromine 
Phenothiazines 
Chlorpromazine 
Diazepam  and any benzodiazepines 
  
Prescription medication other than a 
prescribed drug that is part of a stable 
drug regimen* 
Prescription pills, topical 
systemic creams, inhalants, 
sprays. 
OTC medication other than an OTC drug 
that is part of a stable drug regimen* 
 
Note: Spermicidal/barrier contraceptive 
products may be permitted 
 
dietary and/or herbal supplements and/or 
teas 
Ricola, oral multivitamins 
Foods and/or beverages containing 
grapefruit, star fruit and/or pomelo 
Grapefruit, grapefruit juice, 
grapefruit candies, pomelo, 
star fruit, etc. 
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Restriction Period 
Item Restricted 
Examples 
48 hours prior to drug 
administration until after 
the last blood draw in 
each study period. 
Products containing 
caffeine/methylxanthines 
Coffee, tea, chocolate, caffeine-
containing soft drinks (e.g. 
Coke, Pepsi, Red Bull) 
Alcohol of any kind 
Wine, beer, liquor, cocktails 
Poppy seeds  
Note: 48 hours prior to drug 
administration in each period only 
Poppy seed cake, cookies, 
bagels 
*A stable drug regiment is defined as at least once a day administration from at least 30 days prior to the 
first study drug administration and with no changes expected in dosage regimen through the study (until 
the last PK sample). 
 
 
 
 
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19. Appendix III - Placement Diagram for Aquestive Therapeutics Buccal Film 
Test Drug: Placement against the buccal mucosa (either side of film can be placed against the 
buccal mucosa): 
Aquestive Therapeutics 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. 
 
 
 
 
 
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20. Appendix IV - Placement Diagram for DIASTAT® AcuDial™ Rectal Delivery System 
 
 
 
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