Clinical trial NCT03428360
Conditions: Epilepsy
Keywords: Seizure
Sponsor: Aquestive Therapeutics
Start date: 2018-01-23; Completion date: 2020-06-25
Enrollment: 149 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 3, multicenter, open-label study of chronic, intermittent use of study drug (DBF) is designed to evaluate the safety and tolerability of the buccal formulation of diazepam in children, adolescents and adults with intermittent, stereotypic episodes of frequent seizure activity (eg, seizure clusters) that are distinct from the subject's usual seizure pattern.

Detailed description:
The Primary objective of the study is to assess the safety and tolerability of DBF (study drug) administered a minimum of 3 times to subjects with epilepsy for the treatment of seizures over a minimum 6-month period.

Secondary objectives:

* To evaluate the usability of study drug as assessed by the ability of caregivers/subjects to administer study drug based on the Instructions for Use (IFU).
* To evaluate the Quality of Life (QoL) of the subjects during the study drug treatment period as assessed by use of age-appropriate epilepsy scales over a minimum 6-month period.

Arms: arm 1: Male or female subjects between the ages of 2 and 65 years who had an established diagnosis of epilepsy exhibited by motor seizures with clear alteration of awareness, and while on a regimen of anti-epileptic medication(s), still experienced bouts of seizures (frequent breakthrough seizures, eg, seizure clusters) and who, in the opinion of the Investigator, could need benzodiazepine intervention for seizure control at least 1 time a month on average. Subjects must have been on at least 1 concomitant anti-epileptic drug at screening.
Interventions: intervention 1: Diazepam Buccal Soluble Film 5, 7.5,10, 12.5,15 or 17.5 mg with individual dose determined according to age and weight category
Intervention descriptions: intervention 1: The subjects in this study administered DBF themselves or with the help of a caregiver, (trained by the study site staff in study drug administration and documentation) in the same setting as they typically used the diazepam rectal gel or other rescue medication, without the presence of study staff.

Protocol documents:
Prot_000.pdf: 
NCT 03428360
Protocol Title:
An Open-Label, Safety and Tolerability Study of 
Chronic Intermittent Use of Diazepam Buccal Soluble 
Film (DBSF) in Pediatric, Adolescent and Adult Subjects 
with Epilepsy
Protocol Date:  02 March 2020


Aquestive Therapeutics 
Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
Page 1 of 132 
CLINICAL STUDY PROTOCOL 
Protocol Number: 42-1703 
Protocol Title: An Open-Label, Safety and Tolerability Study of Chronic Intermittent 
Use of Diazepam Buccal Soluble Film (DBSF) in Pediatric, Adolescent and Adult 
Subjects with Epilepsy 
IND Number: 
129068 
Name of Product: 
Diazepam Buccal Film (formerly referred to as 
Diazepam Buccal Soluble Film) 
Phase of Development: 
3 
Indication: 
Treatment and management of selected, refractory 
subjects with epilepsy who are on stable regimens of 
antiepileptic drugs and who require intermittent use of 
diazepam to control bouts of increased seizure activity 
Sponsor: 
Gary Slatko, MD 
Senior Vice President, Chief Medical Officer 
Aquestive Therapeutics 
(Formerly known as MonoSol Rx) 
30 Technology Drive 
Warren, NJ 07059 USA 
Tel: 908-941-1900 
Fax: 908-561-1209 
Protocol Version: 
Amendment 2 
Amendment 2 Date: 
02 March 2020 
Original Protocol Date: 
31 July 2017 
Amendment 1 Date: 
11 September 2018 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Aquestive Therapeutics, 
Inc. Any unauthorized copying or use of this document is prohibited. 


Aquestive Therapeutics 
Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
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PROTOCOL AMENDMENT: SUMMARY OF CHANGES 
Previous Protocol Versions 
 
Protocol 
Date 
Original 
31 July 2017 
Amendment 1 
11 September 2018 
Protocol 42-1703 Amendment 2 
Date of Amendment: 02 March 2020 
Amendment Summary 
The Protocol 42-1703 is being amended to: 1) update Diazepam Buccal Soluble Film to 
Diazepam Buccal Film for consistency with current nomenclature; 2) include updated 
Instructions for Use of the Investigative Product; 3) include plans for the end-date of the 
study; 4) include modifications to the weight-adjusted regimen for children who may 
enter this study after participating Pediatric Epilepsy Monitoring Unit (EMU) study 
160325 and who have taken study drug in the past and 5) incorporate edits based on the 
protocol clarification letter dated 11 September 2018. 
Following is a summary of content-oriented changes made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
 
Section 
Revision 
Rationale 
Throughout 
Diazepam Buccal Soluble Film has been 
changed to Diazepam Buccal Film 
The generic name of the 
Investigative Product has been 
updated for consistency with 
current nomenclature. 
Appendix A 
New Instructions for Use of Diazepam Buccal 
Film 
The Instructions for Use of 
Diazepam Buccal Film were 
updated in January 2020. 
Section 1 
Synopsis 
Section added to the Study Design Screening 
description: The last Screening Visit is 28 
February 2020. 
Study Design Schema updated to include 
projected end-dates. 
Baseline Visit (Study Day 1): Sentence added: 
The last Baseline Visit/Study Day 1 will occur 
no later than 06 March 2020. 
Study Final/Completion/Early Withdrawal Visit 
Sentence added: The last subject Study 
Completion Visit/Visit 5 is projected for 02 
September 2020. 
Last Subject Last Telephone Contact : Section 
added and reads: The last subject follow-up 
telephone contact will occur in October 2020. 
The planned end date for this 
study is 09 October 2020. The 
last screening visit is 28 
February 2020. The last 
enrollment visit will occur no 
later than 06 March 2020. Thus, 
the last planned Visit 5 will be 
02 September 2020 and the last 
planned follow up telephone 
contact will be completed by 09 
October 2020. Subjects who are 
ongoing at the enrollment end- 
date, who are benefitting from 
the use of DBF, and who would 
like to stay on study, will be 
allowed to continue until study 
end. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Section 
Revision 
Rationale 
Section 1 
Synopsis 
Continued → 
Treatment Duration in the description of Study 
Final/Completion/Early Withdrawal Visit, text 
added: The Sponsor has elected to extend the 
duration of treatment beyond 6 months under a 
similar schedule of visits. Enrollment end-date 
is 06 March 2020. However, all ongoing 
subjects at the enrollment end-date who are 
benefitting from the use of DBF and would like 
to stay on study, will be allowed to do so until 
study end. Last subject/last contact telephone 
call is projected for 09 October 2020. 
Study end dates continued → 
Section 6.1 
Screening Period: Sentence added: The last 
Screening Visit is 28 February 2020. 
Baseline Visit (Study Day 1) Sentence added: 
The last Baseline Visit/Study Day 1 will occur 
no later than 06 March 2020. 
New text added in the description of Study 
Design: The planned end date for this study is 
09 October 2020. Thus, the last screening visit 
is 28 February 2020. 
The last Baseline Visit/Study Day 1 will occur 
no later than 06 March 2020. The last planned 
Study Completion Visit/Visit 5 will be 02 
September 2020 and the last planned follow-up 
telephone contact will be completed by 09 
October 2020. Subjects who are ongoing on 28 
February 2020, who are benefitting from the use 
of DBF, and who would like to stay on study, 
will be allowed to continue until study end. 
New text added in section describing the 
Final/Completion or Early Withdrawal Visit 
The last subject Study Completion Visit/Visit 5 
is projected for 02 September 2020. 
New text added in section describing the 
Telephone contact 30-37 days after the 
Final/Completion Visit The last subject follow- 
up telephone contact will occur in October 
2020. 
Figure 1; 
Section 6.1 
Study Schema updated to include projected end- 
dates 
Section 9.2.6 
Introductory sentence added to this section: The 
last subject Final/Completion Visit is projected 
for September 2020. 
Section 9.2.7 
Introductory sentence added to this section: The 
last subject telephone follow-up contact is 
projected to occur in October 2020. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
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Section 
Revision 
Rationale 
Table 6 
Footnotes added to the Schedule of 
Assessments: 
To the Visit 1/Screening column: Screening end 
date is 28 February 2020. 
To the Visit 2/Day 1 column: The last Baseline 
Visit/Study Day 1 will occur no later than 06 
March 2020 
To the Visit 5 (Final Visit) column: The last 
planned Study Completion Visit/Visit 5 will be 
in September 2020. 
To the Follow-up/Telephone Contact Column: 
The last subject telephone contact will occur in 
October 2020. 
Study end dates continued → 
Section 4.6 
Rationale included in this section for the use of 
the weight-based dose regimen in pediatric 
subjects from Study 160325 who roll over into 
the current Study 42-1703. 
Population pharmacokinetic 
modeling has demonstrated that 
diazepam exposure following 
DBF (like Diastat rectal gel) is 
dependent on body size. For this 
reason, the DBF dose for 
subjects entering Study 42-1703 
from the Study 160325 
performed in pediatric subjects 
with epilepsy < 17 years and 
have received DBF as part of 
the Study 160325 will be 
determined using the weight- 
based dosing regimen employed 
in Study 160325. 
Subjects enrolled directly into 
Study 42-1703 and who are 
naive to DBF will be dosed 
according to the 42-1703 
protocol dose regimen (Table 4). 
After receiving their first dose 
of DBF, these subjects will be 
re-evaluated by the Investigator 
and, according to Investigator's 
judgment, may be moved to 
Table 5 for dose determination. 
Subjects already enrolled and 
dosed in Study 42-1703 
according to the 42-1703 
protocol dose regimen (Table 4) 
may be moved to Table 5 for 
dose determination after re- 
evaluation by the Investigator 
and, according to Investigator's 
judgment. 
Subjects who enter Study 
42-1703 from the pediatric 
Epilepsy Monitoring Unit Study 
160325 will be dosed according 
Section 6.1 
Sentence add to the description of overall study 
design: Study drug dosing is determined first 
according to age group and then by body weight 
within age group (Table 4) for subjects who 
entered into the present study 42-1703 never 
having received DBF as study drug before and 
Table 5 for rollover subjects from the pediatric 
EMU study 160325). 
Section 8.1 
Inclusion of Table 5 (Calculated Prescribed 
Dose of Study Drug for Subjects < 17 Years of 
Age Entering Study 42-1703 from Study 
160325 ) 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Section 
Revision 
Rationale 
the dosing regimen in Table 5 
after evaluation by the 
Investigator. 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 1 
Synopsis 
Study Design and 
Treatment 
Duration 
Section 6.1 
Section 9.2.3 
Section 9.2.6 
Section 1 : 
Treatment Duration statement added: The 
Sponsor has elected to extend the duration of 
treatment beyond 6 months under a similar 
schedule of visits. This policy is intended to 
continue for the period that the study remains 
open. 
Study Final/Completion/Early Withdrawal Visit 
The Sponsor has elected to extend the duration 
of treatment beyond 6 months under a similar 
schedule of visits. This policy is intended to 
continue for the period that the study remains 
open. 
The Sponsor has elected to 
extend the duration of treatment 
beyond 6 months under a 
similar schedule of assessments. 
This policy is intended to 
continue for the period that the 
study remains open. 
Section 6.1 
Section 6.1 Description of Overall Study Design 
and Plan; sentence amended: The duration of 
the study per subject will be a minimum of 6 
months. 
Final/Completion or Early Withdrawal Visit 
• 
For those subjects who have exceeded 6 
months on study with at least 3 uses of 
DBF, the subject may complete the study 
at the 6-month visit (Visit 5) per the 
protocol, or the subject may continue as 
described below. 
• 
For those subjects who have at least 6 
months on study with less than 3 uses of 
DBF, the subject may complete the study 
at the 6-month visit (Visit 5) per the 
protocol, or the subject may continue as 
described below. 
Extension of Study Beyond Month 6 
The duration of treatment is being extended 
beyond 6 months under a similar schedule of 
visits. This policy is intended to continue for the 
period while the study remains open. 
At the discretion of the Principal Investigator 
and the subject, caregiver or guardian as 
applicable, a subject may continue in the study 
beyond the 6-month visit under a similar 
schedule of assessments, while the study is 
open. No Medical Monitor approval is required 
for subjects with 3 or more uses. The subject 
may continue in the study while the study 
remains open. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 6.1 
Continued→ 
In order to continue: 
• 
The subject should be using the 
Investigational Product. 
• 
The subject is receiving benefit from 
the Investigational Product. 
• 
The subject is tolerating the 
Investigational Product. 
• 
The subject wishes to continue in the 
study. 
The Sponsor has elected to 
extend the duration of treatment 
beyond 6 months under a 
similar schedule of assessments. 
This policy is intended to 
continue for the period that the 
study remains open. 
Continued→ 
For subjects who continue beyond Month 6 
(Visit 5), subsequent visits will occur every 3 
months (± 14 days) while the study remains 
open. 
If a subject has not had 3 uses of DBF at the 6- 
month visit (Visit 5), or any visit after that, the 
Investigator should strongly consider the 
likelihood of the subject using DBF and whether 
the subject should continue in the study. The 
Investigator may consult with the Medical 
Monitor, if needed, to assess on a case-by-case 
basis the likelihood of achieving 3 uses of DBF 
by continuing the subject on study. If the 
assessment concludes that achieving 3 uses of 
study drug is likely, the subject’s participation 
can be extended with a similar schedule of 
assessments. If the assessment concludes that 
achieving 3 uses use of the study drug is not 
likely, the study will be considered complete for 
the subject. The sponsor may elect to end study 
  participation for non-users prior to end of study.  
Section 9.2.3 
Treatment Period Clinical Site Visits; text 
added: The Sponsor has elected to extend the 
duration of the study beyond 6 months under a 
similar schedule of visits. The policy is intended 
to continue for the period while the study 
remains open. 
Section 9.2.6 
Final / Completion or Early Withdrawal Visit; 
sentence added: The 6-month visit will serve as 
the study Final/Completion site visit. The 
Sponsor has elected to extend the study beyond 
6 months under a similar schedule of visits. 
Table 6 Schedule 
of Assessments 
Note added to the table for 6-month visit (Visit 
5): The Sponsor has elected to extend the 
duration of treatment beyond 6 months under a 
similar schedule of visits. This policy is 
intended to continue for the period that the 
study remains open. See Section 6.1 
Final/Completion or Early Withdrawal Visit for 
criteria and methods. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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  tests at study visits will be at 
Section 7.1 
Inclusion 
Criterion #5 
 
Section 7.2 
Exclusion 
criterion #7 
 
Section 9.2.1 
Screening; 
Section 9.2.3; 
Section 9.2.6 
Table 6 Schedule 
of Assessments; 
Table 8 
Laboratory 
Assessments 
Footnote states: If the subject is unable to 
provide a urine sample, the option to use only 
serum pregnancy test will be according to 
Investigator judgment. 
Changed to read: Lactating female or positive 
urine and serum pregnancy test (β-hCG) at 
screening for female subjects of childbearing 
potential 
Change in the assessment of urine and serum 
pregnancy test in female subjects 12 years of 
age to read: Urine and serum pregnancy test in 
female subjects of childbearing potential 
Table note added to clarify this process 
As with other missing/unobtainable protocol- 
mandated assessments, the site must document 
the reason why the urine sample could not be 
obtained from the subject (e.g., subject is 
incontinent, subject is incapable of supplying a 
urine sample on request, etc.) in the source 
documents and via the eCRF. 
Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine 
pads, etc. are not acceptable methods of 
obtaining a urine sample for this study. The 
Sponsor does not advocate use of a urinary 
catheter 
Investigator's discretion. 
The reason the urine pregnancy 
testing could not be completed 
should be documented in the 
source documents and Case 
Report Form. 
 
 
 
 
 
 
If a protocol-required urine 
sample cannot be obtained from 
the subject (at any study visit), 
the Investigator will ensure an 
accurate and thorough review is 
conducted by the Investigator 
with the subject and/or subject's 
caregiver/study partner/legally 
authorized representative. 
This review should include, as 
applicable, a Physical Exam, 
Review of Systems/Symptoms 
(ROS), Past Medical History, 
Concomitant Medications 
(including last known diazepam 
use), any new or ongoing AEs, 
sexual activity history, 
pregnancy/menstrual cycle 
status and illicit drug use. This 
is extremely important during 
the screening/eligibility visit as 
the urine sample is a key 
component/assessment in 
determining a host of inclusion 
and exclusion criteria. 
 
 
Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 1 
Clinical laboratory tests (hematology, serum 
To clarify that urine and serum 
Synopsis 
chemistry, urinalysis, and urine and serum 
pregnancy testing will be 
Clinical 
pregnancy tests for female subjects of 
performed for female subjects of 
laboratory tests; 
childbearing potential): 
childbearing potential. 
Site Visit at 3 
If the subject is unable to provide a urine 
However, if the subject is 
Months and 6 
sample, the option to use only the serum 
unable to provide a urine sample 
Months After 
pregnancy test will be at the Investigator's 
or is incontinent, the option to 
Study Day 1;
discretion 
perform only serum pregnancy 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
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Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 9.2.1, 
Section 9.2.2, 
Section 9.2.3, 
Section 9.2.6 
Text added to clarify the process 
If a subject cannot provide a urine sample for 
drug screen or, if in the judgment of the 
Investigator, the subject's exposure to drugs of 
abuse is limited as determined by the medical 
history, incapacity, etc., the site must document 
in the source documents the reason that the 
assessment is not completed. If the subject 
cannot provide a urine sample for routine 
analysis, the site must document in the source 
documents the reason that the assessment is not 
completed. Urine samples obtained using a 
urine collection bag are acceptable. Urine- 
soaked diapers, urine pads, etc. are not 
acceptable methods of obtaining a urine sample 
for this study. The Sponsor does not advocate 
use of a urinary catheter 
As with other 
missing/unobtainable protocol- 
mandated assessments, the site 
must document the reason why 
the urine sample could not be 
obtained from the subject (e.g. 
subject is incontinent, subject is 
incapable of supplying a urine 
sample on request, etc.) in the 
source documents and via the 
eCRF. 
Urine samples obtained using a 
urine collection bag are 
acceptable. Urine-soaked 
diapers, urine pads, etc. are not 
acceptable methods of obtaining 
a urine sample for this study. 
The Sponsor does not advocate 
use of a urinary catheter. 
Table 8 
Addition to the table: If a subject cannot provide 
a urine sample for drug screen, an accurate and 
thorough review should be conducted by the 
Investigator with the subject and/or subject’s 
caregiver/study partner/Legally Authorized 
Representative. This review should include, as 
applicable, a Physical Exam, Review of 
Systems/Symptoms (ROS), Past Medical 
History, Concomitant Medications (including 
last known diazepam use), any new or ongoing 
adverse events, sexual activity history, 
pregnancy/menstrual cycle status and illicit drug 
use. 
Section 11.9 
Laboratory 
Assessments 
Text above include in text of this section along 
with additional instructions: 
As with other missing/unobtainable protocol- 
mandated assessments, the site must document 
the reason why the urine sample could not be 
obtained from the subject (e.g., subject is 
incontinent, subject is incapable of supplying a 
urine sample on request, etc.) in the source 
documents and via the eCRF. 
Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine 
pads, etc. are not acceptable methods of 
obtaining a urine sample for this study. The 
Sponsor does not advocate use of a urinary 
catheter 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 1 
Synopsis 
Site Visit at 3 
Months and 6 
Months After 
Study Day 1 
Description of 
age-appropriate 
scales 
Section 6.1 
Treatment Period 
Clinical Site 
Visits 
Text added to clarify this process. 
The QoL and C-SSRS should be completed in 
appropriately aged subjects. These assessments 
may be omitted as applicable if a subject's 
cognitive status does not allow the subject to 
personally complete the assessment. The site 
must document in the source documents the 
reason that these assessments cannot be 
completed (e.g., unable to perform test due to 
incapacity, etc.). 
The Quality of Life (QoL) scale, 
Columbia-Suicide Severity 
Rating Scale and Gustatory 
assessment should be completed 
according to the schedule of 
assessments in appropriately 
aged subjects. These 
assessments may be omitted as 
applicable if a subject's 
cognitive status does not allow 
the subject to personally 
complete the assessment. The 
site must document in the 
source documents the reason 
that these assessments cannot be 
completed (e.g., unable to 
perform test due to incapacity, 
etc.). 
Section 9.2.1 Screening Assessments 
Section 9.2.2 Baseline Assessments 
Section 9.2.3 Treatment Period Clinical Site Visits 
Section 9.2.6 Final / Completion or Early Withdrawal 
Table 6 Schedule of Assessments 
Section 11.4 Quality of Life Assessments 
Section 11.5 Columbia Suicide Severity Rating Scale 
Section 11.7 Gustatory Sense Assessment 
Table 6 Schedule 
of Assessments; 
Table 8 
Laboratory 
Assessments 
Section 9.2.1 
Screening; 
Section 9.2.2; 
Section 9.2.3; 
Section 9.2.6; 
Table note added to clarify this process: The 
Alcohol Breath Test should be completed 
according to the schedule of assessments in 
subjects 17 years of age and older (and in 
subjects < 17 years of age at the Investigator's 
discretion). If a subject cannot complete the 
assessment or, if in the judgment of the 
Investigator, the subject's exposure to alcohol is 
limited as determined by the medical history, 
incapacity, etc., the site must document in the 
source documents the reason that the assessment 
is not completed. 
Text added: The Alcohol Breath Test should be 
completed according to the schedule of 
assessments in subjects 17 years of age and 
older (and in subjects < 17 years of age at the 
Investigator's discretion). If a subject cannot 
complete the assessment or, if in the judgment 
of the Investigator, the subject's exposure to 
alcohol is limited as determined by the medical 
history, incapacity, etc., the site must document 
in the source documents the reason that the 
assessment is not completed. 
The Alcohol Breath Test should 
be completed according to the 
schedule of assessments in 
subjects 17 years of age and 
older (and in subjects < 17 years 
of age at the Investigator's 
discretion). If a subject cannot 
complete the assessment or, if in 
the judgment of the Investigator, 
the subject's exposure to alcohol 
is limited as determined by the 
medical history, incapacity, etc., 
the site must document in the 
source documents the reason 
that the assessment is not 
completed. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Section 1 
Synopsis: Age- 
appropriate QoL 
scales 
Text revised to clarify this process 
Age-appropriate QoL scales; 
PedsQL 3.0 Epilepsy Module PedsQL Parent 
Proxy Report (ages 2 to 4 years); 
To clarify the age ranges for 
each Quality of Life scale and to 
identify the person who 
completes the assessment. 
Peds QL 3.0 Epilepsy Module Parent Proxy 
Report (ages 5 to 7 years) 
PedsQL 3.0 Epilepsy Module Parent Proxy 
Report (ages 8 to 10 years) 
QOLIE-AD-48 Version 1 (ages 11 to 17 years) 
QOLIE-31-P Version 2 (18 years and older) 
Section 1 
Text added: The QoL and C-SSRS should be 
Synopsis: Age- 
completed in appropriately aged subjects. These 
appropriate QoL 
assessments may be omitted as applicable if a 
scales 
subject's cognitive status does not allow the 
Continued 
subject to personally complete the assessment. 
The site must document in the source 
documents the reason that these assessments 
cannot be completed (e.g., unable to perform 
test due to incapacity, etc.). 
Table 7 Age- 
Table modified to include who completes each 
Defined Quality 
assessment listed in Table 7 
of Life 
(parent/guardian/caregiver or the subject) 
Assessment 
Modules 
Section 5.2.1 
Primary 
Endpoints; 
Table 6 Schedule 
of Assessments; 
Section 9.2.1 
Screening; 
Section 9.2.2 
Baseline; 
Section 9.2.3 
Treatment Period 
Clinical Site 
Visits; 
Section 9.2.6 
Final/Completion 
or Early 
Withdrawal Visit; 
Section 12.4.1 
Primary Safety 
Endpoints; 
Section 12.4.1.3 
Vital Signs 
Note added to include this clarification. 
If a subject is unable to provide an oral 
temperature as they are unable to retain an oral 
thermometer in position with their mouth 
closed, a tympanic, axillary, or temporal 
(forehead) temperature may be taken. In this 
case, the method should be recorded in the 
source documents. 
To clarify that body temperature 
requires oral temperature; 
however, many subjects are 
unable to provide an oral 
temperature as they are unable 
to retain an oral thermometer in 
position with their mouth 
closed. For these subjects, a 
tympanic, axillary, or temporal 
(forehead) temperature may be 
taken. In this case, the method 
should be recorded in the source 
documents. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
Page 11 of 132 
 
 
Section 
Revision 
Rationale 
Revisions made to implement Protocol Clarification Letter dated 11 September 2018 
Table 6 Schedule 
of Assessments 
Corrected to read: 12-lead ECG testing is 
performed at Screening, Baseline, and at all 
onsite visits including the Final Visit. When 
performed on days of blood draws, ECG should 
be completed prior to blood collection. 
Correction of footnote 
Appendix F 
Quality of Life in 
Epilepsy for 
Adolescents 
QOLIE-48 
(VERSION 1.0) 
Note added to reflect the correct date and the 
extra page has been deleted. 
To clarify that the QOLIE AD 
48 version should reflect the 
version date as 04 Jan 18 – NOT 
03 Jan 18. Page 5 of 6 is 
included twice 




Aquestive Therapeutics 
Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
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Page 13 of 132 
 
 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, any future 
amendments, and with any other study conduct procedures provided by 
Aquestive Therapeutics. 
• Not to implement any changes to the protocol without written agreement from 
Aquestive Therapeutics and prior review and written approval from the 
Institutional Review Board (IRB) except where necessary to eliminate an 
immediate hazard to subjects. 
• That I am thoroughly familiar with the appropriate use of the study drug, as 
described in this protocol and any other information provided by Aquestive 
Therapeutics including, but not limited to, the current Investigator’s Brochure 
(IB). 
• That I am aware of, and will comply with, good clinical practice (GCP) and 
all applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed 
about the Aquestive Therapeutics study drug and of their study-related duties 
and functions as described in the protocol. 
 
  
 
Signature: 
  
 Date: 
Name (print): 
  
 
Site Number: 
  
 


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Diazepam Buccal Film 
Protocol Number 42-1703 
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CONTACT LIST 
 
Sponsor: 
Gary Slatko MD 
Senior Vice President, Chief Medical Officer 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 USA 
Sponsor’s Responsible Medical 
Consultant: 
Allen H. Heller MD MPH 
Principal, Pharma Study Design LLC 
(Consultant to Aquestive Therapeutics) 
Sponsor’s Responsible Study Manager: 
Frances Ekweonu 
Clinical Trial Manager, Clinical Operations 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 USA 
Telephone: 1-219-762-8112 x 410 
Contract Research Organization (CRO) 
Study Manager: 
Jeanette George 
Senior Project Manager 
Syneos Health (formerly inVentiv Health) 
1030 Sync Street 
Morrisville, NC 27560 USA 
Telephone: 1-919-536-8330 
CRO Medical Monitor: 
Marcel Reichert MD 
Medical Director 
Syneos Health (formerly inVentiv Health) 
202 Carnegie Center 
Princeton, NJ 08540 USA 
Telephone (Direct): 1-408-320-4191 
Telephone (Mobile):1- 650-554-1706 
Facsimile:1- 650-264-3569 
CRO Safety (Pharmacovigilance) 
Reporting: 
Syneos Health Global Safety & 
Pharmacovigilance 
Telephone Hotline: 1-888-750-8020 
Facsimile: 1-866-856-1649 
Clinical Laboratory: 
Covance Central Laboratory Services 
8211 Scicor Drive 
Indianapolis, IN 46214 USA 
Telephone: 1-888-268-2623 or 1-317-217-1200 


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Diazepam Buccal Film 
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1. 
SYNOPSIS 
 
Title of Study 
An Open-Label, Safety and Tolerability Study of Chronic Intermittent 
Use of Diazepam Buccal Soluble Film (DBSF) in Pediatric, Adolescent, 
and Adult Subjects with Epilepsy 
Protocol Number 
42-1703 
Investigator/Study 
Sites 
Approximately 20 United States (US) study sites are projected 
Phase of 
Development 
3 
Objectives: 
Primary objective 
• 
To assess the safety and tolerability of DBF (study drug) 
administered a minimum of 3 times to subjects with epilepsy for 
the treatment of seizures over a minimum 6-month period. 
Secondary objectives 
• 
To evaluate the usability of study drug as assessed by the ability of 
caregivers/subjects to administer study drug based on the 
Instructions for Use (IFU) 
• 
To evaluate the Quality of Life (QoL) of the subjects during the 
study drug treatment period as assessed by use of age-appropriate 
epilepsy scales over a minimum 6-month period. 
Study Design 
This is a Phase 3 multicenter, open-label, long-term safety and 
tolerability study conducted in male and female pediatric (2 to 12 years 
old), adolescent (13 to 16 years old), and adult subjects (17 to 65 years 
old) with a clinical diagnosis of epilepsy who have bouts of increased 
seizure activity (e.g., Acute Repetitive Seizures [ARS], frequent 
breakthrough seizures, seizure clusters, or cluster seizures) and who are 
on chronic intermittent use of a rescue medication (e.g., Diastat® 
AcuDial™ or other benzodiazepine). 
Subjects who have completed the Phase 2 studies 160325 (Pediatric) or 
160326 (Adult) which enrolled subjects with a similar diagnosis may 
screen for enrollment into this Phase 3 study when they come in for the 
follow-up visit after the last treatment period in the Phase 2 study 
(rollover subjects). These rollover subjects will be screened for 
enrollment using inclusion/exclusion criteria of this protocol (42-1703). 
The Screening visit for the Phase 3 study can be conducted on the day 
of the follow-up visit for the Phase 2 study. 
Subjects who initially consented and enrolled in the study under version 
1 of the protocol dated 31 July 2017 may come in at their next 
scheduled site visit, reconsent under the amended protocol and be 
dispensed a new container of DBF based upon the revised mg/kg 
dosing. The subjects do not need to come in for unscheduled visit. 


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Screening: Screening for enrollment eligibility can occur within 1 to 28 
days prior to study entry. Before the performance of any study-related 
procedure, written informed consent will be obtained from the subject or 
subject’s legally authorized representative and oral and/or written assent 
will be obtained from the subject as required by the Institutional Review 
Board (IRB). 
As a part of screening, potential subjects and caregivers will be advised 
that electronic diaries will be used by subjects and/or caregivers to 
document seizures, use of study drug, adverse events (AEs), and 
changes in concomitant medication to determine their 
ability/willingness to comply with this procedure. 
Subjects may be re-screened during the study per Investigator judgment 
after consultation with and approval by the Medical Monitor. 
The last Screening Visit is 28 February 2020. 
The duration of the study per subject will be a minimum of 6 months: 
Mandatory Site Visit 
Within 14 days post 
first study drug use 
Telephone Contact 
Study Completion 
Baseline Visit ǂ 
Months 1 and 2 
Site Visit 
Visit § 
Telephone Contact # 
Study Day 1 
Month 1     Month 2 
Month 3 
Month 6 
Month 7 
± 7 days     ± 7 days 
± 14 days 
± 14 days 
Day 210 – Day 217 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
ǂ Date for last Baseline Visit/Study Day 1 no later than 06 March 2020. 
§ Planned date for last Study Completion Visit/Visit 5 is 02 September 2020. 
# Planned date for last Telephone Contact is 09 October 2020. 
Subjects who are ongoing on 28 February 2020, who are benefitting from the use of DBSF, and who would like to stay on 
study, will be allowed to continue until study end. 
Baseline Visit (Study Day 1)-Conducted after completion of 
screening and confirmation of eligibility for study enrollment-based 
compliance with protocol Inclusion and Exclusion criteria: The last 
Baseline Visit/Study Day 1 will occur no later than 06 March 2020. 
Training will be performed by the study team on study drug 
administration and the use of the electronic study diary. The training 
will be reinforced at all subsequent study visits/contacts. 
Study drug dosing will be administered away from the study site by the 
subject, with the assistance of a caregiver as appropriate. 
Administration and usability of study drug will be recorded at home in 
the electronic diary after each use of study drug. The electronic diary 
will also be used at home to capture seizure history and changes in 
health and medications. 
Subjects/caregivers will be instructed to call the site when the first 
seizure prompts study drug administration. A study site visit will occur 
within 14 days after this first use. 


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Site Visit Following the First Seizure Prompting Study Drug 
Administration: 
A study site visit will be conducted within 14 days after the first study 
drug dosing. 
The subject or caregiver (if needed) will document the seizure and study 
drug administration in the electronic study diary AND call the study site 
after the first use of study drug. 
Based on subject diagnosis and history (Inclusion Criteria), it is 
expected that subjects will have a minimum of 3 uses of the study drug 
within the 6 months treatment period. 
Telephone Contact at 1 Month and 2 Months After Study Day 1: 
The study site staff will telephone the subjects at approximately 1 and 2 
months ± 7 days after the baseline visit to check on the subject’s health 
and seizure status, reinforce training on study drug administration and 
diary documentation, determine if study drug was used, and to address 
concerns. 
Site Visit at 3 Months and 6 Months After Study Day 1: A study site 
visit will be conducted every 3 months ± 14 days over the minimum 6- 
month course of treatment. 
At the Month 3 visit, the subjects (and their caregivers as appropriate) 
will have a review of the number of study drug uses, study drug 
usability assessment, seizure-control status, use of the study diary, AEs, 
concomitant medications, and subject/caregiver training. Subjects will 
undergo assessment of oral mucosal health, gustatory assessment, vital 
signs, physical and neurological examination, collection of blood and 
urine samples for clinical laboratory testing, 12-lead ECG, age- 
appropriate Quality of Life (QoL) and Columbia Suicide Severity 
Rating Scale (C-SSRS) assessments. 
The QoL and C-SSRS should be completed in appropriately aged 
subjects. These assessments may be omitted as applicable if a subject's 
cognitive status does not allow the subject to personally complete the 
assessment. The site must document in the source documents the reason 
that these assessments cannot be completed (e.g., unable to perform test 
due to incapacity, etc.). 
For all age groups, height and weight will be measured and body mass 
index (BMI; kg/m2) recorded. 
Urine and serum pregnancy testing will be performed at for female 
subjects of childbearing potential. If the subject is unable to provide a 
urine sample, the option to use only the serum pregnancy test will be at 
the Investigator's discretion. The reason that urine pregnancy screen 
could not be completed should be documented in the source documents 
and the Case Report Form. 


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Study Final/Completion/Early Withdrawal Visit. A Final Visit after 
the end of the study drug treatment period or early withdrawal will 
occur for the subject to undergo final study assessments, return unused 
study drug, and return the study diary. 
The last subject Study Completion Visit/Visit 5 is projected for 02 
September 2020. 
The subjects will have a review of AEs in relation to study drug 
treatment and severity, concomitant medication review, assessment of 
vital signs, body height and weight, physical and neurological status, 
C-SSRS assessment, 12-lead ECG, and assessments of tolerability, 
usability, and seizure-control status. The unused study drug will be 
returned, and study diary will be collected. 
Urine and serum pregnancy testing will be performed for female 
subjects of childbearing capacity. If the subject is unable to provide a 
urine sample, the option to use only the serum pregnancy test will be at 
the Investigator's discretion. 
Telephone contact 30-37 days after the Final Visit: For subjects 
completing the study at 6 months, the 6-month visit serves as the 
Final/Completion Visit. The Investigator or designee will conduct a 
follow-up phone call with the subject at 30-37 days after the Final Visit 
to check on subject status and collect AE information. 
Last Subject Last Telephone Contact: The last subject follow-up 
telephone contact will occur in October 2020. 
Selection of Subjects 
Approximately 120 subjects are expected to be screened in order to have 
a minimum of 100 eligible subjects (50 adult and 50 
pediatric/adolescent) enrolled. The enrollment should include at least 20 
subjects in the 6 to 11-year-old group and 20 subjects in the 12 to 
16-year-old group. 
Subjects may be re-screened during the study per Investigator judgment 
after consultation with and approval by the Medical Monitor. 
Inclusion Criteria: Subjects must meet all the following criteria in order 
to be included in the study: 
1. Female or male between 2 and 65 years of age, inclusive 
2. Written informed consent to participate in the study from the 
subject or subject’s legally authorized representative and oral 
and/or written assent will be obtained from the subject as required 
by the Institutional Review Board (IRB) prior to the performance 
of any study-related procedure 
3. Caregiver, if needed for subject, provides written informed 
consent and is able to administer study drug in the event of a 
seizure. 


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4. Subject has an established diagnosis of epilepsy with motor 
seizures with clear alteration of awareness, and while on a 
regimen of anti-epileptic medication(s), still experiences bouts of 
seizures (frequent break through seizures, e.g., ARS or seizure 
clusters) and who, in the opinion of the Investigator, may need 
benzodiazepine intervention for seizure control at least 1 time a 
month on average. Subject must be on at least 1 concomitant anti- 
epileptic drug (AED) at screening. 
The study is open to subjects who, in the opinion of the 
Investigator, would benefit from the study drug. Concomitant 
prescription for a benzodiazepine for rescue (including diazepam) 
at screening or ongoing, or concomitant use of a benzodiazepine 
ongoing as a part of the subject’s daily antiepileptic drug regimen 
does not exclude a subject from eligibility. Subjects are to be 
encouraged to use study drug when a benzodiazepine rescue 
treatment is needed. However, treatment decisions are to be 
guided in all cases according to the Investigator’s judgment as to 
the optimal treatment in the interest of the subject’s care and 
welfare. Participation in this study is never a basis for the 
withholding of any treatment considered to be indicated in the 
interest of the subject. 
5. Female subjects have negative serum and urine pregnancy test at 
screening.a Female subjects of childbearing potential (not 
surgically sterile or less than 2 years postmenopausal) must have 
a partner who is sterile, agrees to abstinence, be practicing double 
barrier contraception or using a Food and Drug Administration 
(FDA) approved contraceptive (e.g., licensed hormonal or barrier 
methods) for greater than 2 months prior to screening visit and 
commit to an acceptable form of birth control for the duration of 
the study and for 30 days after the study. 
a 
If the subject is unable to provide a urine sample, the option to 
use only the serum pregnancy test will be at the Investigator's 
discretion. 
6. No clinically significant abnormal findings on the ECG (QTcF 
[Fridericia's Correction Formula] ≤ 450 msec for males and QTcF 
≤ 470 msec for females). 
7. Subject and caregiver (if applicable) must be willing to comply 
with all study visits and all required study procedures (including 
the use of the electronic diary). NOTE: Nonverbal and cognitively 
impaired subjects are eligible to participate in the study. 


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Exclusion Criteria: Subjects meeting any of the following criteria are 
ineligible to participate in this study: 
1. A history of clinically significant gastrointestinal, 
renal/genitourinary, hepatic, hematologic, dermatologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or 
cardiovascular disease, or any other clinically significant 
abnormalities, such as physical examination, vital signs, 
laboratory tests or ECG at Screening or Baseline which in the 
opinion of the Investigator require further investigation or 
treatment or which may interfere with study procedures or safety 
or other medical conditions (e.g., cardiac, respiratory, 
gastrointestinal, psychiatric, renal disease) which are not 
adequately and stably controlled, or which in the opinion of the 
Investigator could affect the subject’s safety or interfere with the 
study assessments or any other condition which, in the opinion of 
the Investigator, would jeopardize the safety of the subject. 
2. Subject has had a significant traumatic injury, major surgery or 
open biopsy within 30 days prior to study screening. 
3. Subject has a recent history of suicide attempt (defined as an 
active, interrupted, or aborted attempt with the past five years) or 
reports suicidal ideation in the past six months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of 
the C-SSRS performed at the Screening Visit. . 
NOTE: If a subject cannot complete the assessment, the site must 
document this. 
4. A history of allergic or adverse responses to diazepam or any 
other benzodiazepine. 
5. Participation in another clinical trial other than Aquestive 
Therapeutics Phase 2 studies 160325 and 160326 within 30 days 
prior to screening. Participation in an observational (non- 
interventional) study is not an exclusion provided there are no 
scheduling conflicts with this study. 
6. Received any other investigational medication (unless it can be 
documented that the subject received only placebo) or device 
within 8 weeks or 5 half-lives (whichever is longer) before 
assignment to study drug treatment. 
7. Lactating female or positive urine and serum pregnancy test 
(β-hCG) at screening for female subjects ≥ 12 years of age.a 
a 
If the subject is unable to provide a urine sample, the option to 
use only the serum pregnancy test will be at the Investigator's 
discretion. 


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8.   In subjects 17 years of age and older (and in subjects < 17 years 
of age at the Investigator’s discretion), positive blood screen for 
human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), hepatitis C, or a positive test result for drugs of abuse or 
alcohol, except marijuana use for medicinal indications. When 
marijuana is or was used for medicinal indications in the opinion 
of the Investigator, it is not considered as drug abuse and the 
subject can be enrolled in states where marijuana is legal, even if 
the marijuana metabolites are positive in the urine. NOTE: In 
such a case, the marijuana product will be recorded as a 
concomitant medication. 
Planned Sample Size: Approximately 120 subjects with epilepsy will be screened in order to 
have a minimum of 100 eligible subjects (50 adult and 50 
pediatric/adolescent) enrolled in the 6-month (24-week) study period. 
The enrollment should include at least 20 subjects in the 6 to 11-year- 
old group and 20 subjects in the 12 to 16-year-old group. 
Investigational 
Therapy: 
Study drug dosing is determined according to age group and body 
weight within age group during each study site visit where subjects are 
dispensed 5, 7.5, 10. 12.5, 15, or 17.5 mg study drug. 
Dosing occurs away from the study site by the subject or caregiver. 
Investigators can make dosing adjustments after the first administration 
and at subsequent visits. The Investigator may choose to adjust the dose 
upward or downward by 1 dose level depending on clinical response to 
study drug. 
For all age groups, the height and weight will be measured and recorded 
at all study visits. Subjects with body weights in the range 112 to 134 kg 
(247 to 295 pounds) may participate in the study at the discretion of the 
investigator. 
Treatment Duration: 
• Screening Period: A minimum of 1 and a maximum of 28 days prior 
to enrollment 
Subjects may be re-screened during the study per Investigator 
judgment after consultation with and approval by the Medical 
Monitor. 
• Baseline Visit/Study Day 1: Conducted after completion of screening. 
• Study Drug Treatment Period: Upon completion of the Baseline visit, 
the subject enters a 6-month minimum period of potential study drug 
treatment. 
− 
Study site visits occur every 3 months (± 14 days) after the 
Baseline Visit (Study Day 1/Visit 2) for a minimum of 6 months. 
− 
Subjects/caregivers will be instructed to call the site after the 
first seizure for which study drug is administered. A study site 
visit will occur within 14 days after this first use. 


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− 
The study site staff will telephone the subjects at approximately 
1 and again at 2 months after the date of the Baseline Visit 
(Study Day 1/Visit 2) to check on the subject’s health and 
seizure status, reinforce training on study drug administration 
and diary documentation, determine if study drug was used, and 
to address concerns. 
• Study Final/Completion/Early Withdrawal Visit: A Final Visit at 
Month 6 of the study drug treatment period or early withdrawal will 
occur for the subject to undergo final study assessments, return 
unused study drug, and return the study diary. 
If a subject has experienced 3 uses of study drug, study participation 
will be complete. For those subjects who have not experienced 3 uses 
of study drug, the Investigator and the Medical Monitor will assess 
on a case-by-case basis the likelihood of achieving 3 uses of study 
drug by continuing the subject on study for an additional 3 months. If 
the assessment concludes use of the study drug is not likely, the 
study will be considered complete for the subject. The sponsor may 
elect to end study participation for non-users prior to end of study. 
• For subjects completing the study at 6 months, the 6-month visit 
serves as the Final Visit. The Investigator or designee will conduct a 
follow-up phone call with the subject at 30-37 days after the Final 
Visit to check on subject status and collect any reporting information 
should any SAE have occurred. 
The Sponsor has elected to extend the duration of treatment beyond 6 
months under a similar schedule of visits. This policy is intended to 
continue for the period that the study remains open. 
Enrollment end-date is 06 March 2020. However, all ongoing subjects 
at the enrollment end-date who are benefitting from the use of DBF and 
would like to stay on study, will be allowed to do so until study end. 
Last subject/last contact telephone call is projected for 09 October 2020. 
Criteria for 
Evaluation: 
Safety Assessments: 
At each study visit, the following assessments will be completed: 
• Documentation and assessment of AEs over the time elapsed 
between visits (serious and non-serious to include time of onset and 
resolution, severity, relationship to study treatment) 
• Concomitant medications review 
• Vital signs (blood pressure, heart rate, respiration rate, oral 
temperature) 
• Body height and weight 
• Symptom-driven physical and neurological examination except at 
screening and baseline (Day 1) when a complete physical and 
neurological examination is required 


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• C-SSRS: if a subject cannot complete the questionnaire, the site must 
document this. 
• Clinical laboratory tests (hematology, serum chemistry, urinalysis, 
and urine and serum pregnancy tests for female subjects of 
childbearing potential) 
If the subject is unable to provide a urine sample, the option to use 
only the serum pregnancy test will be at the Investigator's discretion. 
If a protocol-required urine sample cannot be obtained from the subject 
(at any study visit), the site must document the reason why the urine 
sample could not be obtained from the subject (e.g., subject is 
incontinent, subject is incapable of supplying a urine sample on request, 
etc.) in the source documents and via the eCRF. Urine samples 
obtained using a urine collection bag are acceptable. Urine-soaked 
diapers, urine pads, etc. are not acceptable methods of obtaining a urine 
sample for this study. The Sponsor does not advocate use of a urinary 
catheter 
• Review of electronic diary which will capture the occurrence of 
seizures, use of study drug, usability assessment, study drug 
placement (left or right) for each seizure cluster treated, AE 
information, and any changes in medication. This information can be 
review directly in the subject’s electronic diary or via the Engage 
Portal database. 
Tolerability Assessments: 
At each study site visit: 
• Oral examination for assessment of oral mucosa 
• Gustatory sense assessment in subjects 12 years of age and older by 
trained Investigator or other trained site personnel using the labeled 
Magnitude Scale (gLMS) and commercially available test strips from 
Burghart Messtechnik 
• Age-appropriate QoL scales; 
PedsQL 3.0 Epilepsy Module PedsQL Parent Proxy Report (ages 2 to 
4 years); 
Peds QL 3.0 Epilepsy Module Parent Proxy Report (ages 5 to 7 
years) 
PedsQL 3.0 Epilepsy Module Parent Proxy Report (ages 8 to 10 
years) 
QOLIE-AD-48 Version 1 (ages 11 to 17 years) 
QOLIE-31-P Version 2 (18 years and older) 
Non-verbal and cognitively impaired subjects are eligible to 
participate in the study. If a subject cannot complete the assessment 
(ie, non-verbal subjects), the site must document this. 
The QoL and C-SSRS should be completed in appropriately aged 
subjects. These assessments may be omitted as applicable if a subject's 
cognitive status does not allow the subject to personally complete the 
assessment. The site must document in the source documents the reason 


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that these assessments cannot be completed (e.g., unable to perform test 
due to incapacity, etc.). 
Administration and Usability Assessments 
At each study site visit, the study team will review the Usability 
Assessments documented in the electronic diary. 
• Review diary for documentation of study drug use 
− 
Handling and administration of study drug, based on the 
Instructions for Use 
− 
Successful buccal insertion of study drug 
o Successful placement and adherence of the study drug 
against the buccal mucosa (inner cheek) 
− 
Oral cavity placement and retention 
o Study drug swallowed prior to sticking to inner cheek 
o Study drug spit out or blown out by subject after 
administration 
Training 
At each study site visit: 
• Use of electronic diary reinforced 
• Retraining of subjects/caregivers: when to administer study drug, 
how to open study drug package, and how to administer study drug 
based on the supplied Instructions for use 
Analysis Population: 
Safety Population: includes all subjects who receive at least 1 dose of 
study drug 
Study Endpoints: 
Primary endpoints 
• Treatment-emergent adverse event (TEAE) assessment including 
relationship to study drug and severity 
• C-SSRS assessment; if a subject cannot complete the assessment, the 
site must document this. 
• Vital signs (blood pressure, heart rate, respiration rate, oral 
temperature) 
• Laboratory analyses (hematology, serum chemistry, urinalysis) 
• Pathological change in oral mucosa as measured by an oral 
examination 
• Gustatory sense changes in subjects 12 years and older as measured 
by the general Labeled Magnitude Scale (gLMS) using commercially 
available Burghart Messtechnik taste test strips 
Secondary endpoints 


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• Quality of Life (QoL) assessments by use of age-appropriate epilepsy 
scales; if a subject cannot complete the assessment, the site must 
document this. 
• Assessment of usability by subject and/or caregiver 
− 
Handling and administration of study drug, based on the 
Instructions for Use 
− 
Successful buccal insertion of study drug 
o Successful placement and adherence of the study drug 
against the buccal mucosa (inner cheek) 
− 
Oral cavity placement and retention 
o Study drug swallowed prior to sticking to inner cheek 
o Study drug spit out or blown out by subject after 
administration 
• 12-lead ECGs 
• Use of concomitant medications 
• Physical and neurological examinations 
• Body height and weight; BMI (kg/m2) 
Statistical Methods 
and Planned 
Analyses: 
All analyses will be descriptive, and no formal statistical testing will be 
performed. 
All summaries will be done for all subjects combined as well as by age 
group (pediatric, adolescent, adult). Pediatric and adolescent might be 
combined as one group for summary purpose. 
An interim analysis is planned to obtain a snapshot of targeted Tables, 
Figures, and Listings and summary of the preliminary safety 
information. 
The statistical evaluation will be performed using the Statistical 
Analysis Software (SAS®) Version 9.3 or higher (SAS Institute, Cary, 
NC). 
All data will be listed and summary tables provided. Summary statistics 
will be presented by age group and overall. For continuous variables, 
data will be summarized with number of subjects (n), mean, standard 
deviation (SD), median, minimum (min), and maximum (max). For 
categorical variables, data will be tabulated with the number and 
proportion (percentage) of subjects for each category. 


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2. 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT: SUMMARY OF CHANGES ................................. 2 
PROTOCOL APPROVAL ...................................................................................... 12 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ........................................ 13 
CONTACT LIST................................................................................................14 
1. 
SYNOPSIS ......................................................................................15 
2. 
TABLE OF CONTENTS .................................................................26 
LIST OF TABLES .............................................................................................31 
LIST OF FIGURES ............................................................................................31 
3. 
LIST OF ABBREVIATIONS ..........................................................32 
4. 
INTRODUCTION ...........................................................................35 
4.1. 
Background on Treatment and Management of Individuals with 
Refractory Epilepsy .........................................................................35 
4.2. 
Diazepam .........................................................................................35 
4.2.1. 
Mechanism of Action ......................................................................36 
4.2.2. 
Metabolism and Elimination ............................................................36 
4.2.3. 
Pharmacokinetics ............................................................................36 
4.3. 
Diastat® AcuDial™ ...........................................................................36 
4.4. 
Diazepam Buccal Film (DBF) .........................................................37 
4.5. 
Background on Diazepam Buccal Film (DBF) ................................37 
4.5.1. 
Nonclinical Studies ..........................................................................38 
4.5.2. 
Clinical Studies ................................................................................39 
4.5.2.1. 
Safety in Clinical Studies .................................................................39 
4.5.2.2. 
Pharmacokinetics in Clinical Studies ...............................................40 
4.6. 
Rationale for the Dose Regimen of Diazepam Buccal Film .............44 
4.7. 
Clinical Risks/Benefits of Study Drug .............................................45 
4.7.1. 
Managing Clinical Risks/Benefits in the Current Study .................. 45 
4.7.2. 
Overdosage Information Derived from Diastat® AcuDial™ 
Prescribing Information ...................................................................45 
5. 
STUDY OBJECTIVES AND ENDPOINTS ...................................... 47 
5.1. 
Study Objectives ..............................................................................47 
5.1.1. 
Primary Objective ............................................................................47 
5.1.2. 
Secondary Objectives ......................................................................47 


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5.2. 
Study Endpoints ............................................................................. 47 
5.2.1. 
Primary Endpoints .......................................................................... 47 
5.2.2. 
Secondary Endpoints ...................................................................... 48 
6. 
INVESTIGATIONAL PLAN ........................................................ 49 
6.1. 
Description of Overall Study Design and Plan ............................... 49 
6.2. 
Rationale for Study Design ............................................................ 53 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................. 55 
7.1. 
Inclusion Criteria ............................................................................ 55 
7.2. 
Exclusion Criteria ........................................................................... 56 
7.3. 
Withdrawal, Removal, and Replacement of Subjects ..................... 57 
7.4. 
Follow-up for Drug Discontinuation/Subject Withdrawal from Study 
..........................................................................................................   58 
8. 
TREATMENTS ............................................................................. 59 
8.1. 
Details of Study Treatment ............................................................. 59 
8.1.1. 
Controlled Substance Documentation ............................................ 61 
8.1.2. 
Description of Study Drug ............................................................. 62 
8.2. 
Labelling, Maintenance and Retention of Study Drug ................... 62 
8.3. 
Dosage Schedule ............................................................................ 63 
8.4. 
Study Treatment Assignment ......................................................... 64 
8.5. 
Treatment Accountability and Compliance .................................... 64 
8.6. 
Prior and Concomitant Illnesses and Medications .......................... 65 
8.6.1. 
Prior and Concomitant Illnesses ..................................................... 65 
8.6.2. 
Prior and Concomitant Medications ............................................... 65 
9. 
STUDY PROCEDURES ................................................................ 66 
9.1. 
Subject Informed Consent .............................................................. 71 
9.2. 
Procedures by Study Visit or Period............................................... 71 
9.2.1. 
Screening ........................................................................................ 71 
9.2.2. 
Baseline (Study Day 1) ................................................................... 73 
9.2.3. 
Treatment Period Clinical Site Visits ............................................. 76 
9.2.4. 
Treatment Period (Remote Study Drug Administration) ................ 78 
9.2.4.1. 
Food and Fluid Intake .................................................................... 78 
9.2.4.2. 
Dosing ............................................................................................ 78 
9.2.5. 
Treatment Period Scheduled Telephone Contact with Subjects ...... 79 


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9.2.6. 
Final / Completion or Early Withdrawal Visit ............................... 79 
9.2.7. 
Telephone Contact 30-37 Days After the Final Visit ..................... 81 
9.2.8. 
Unscheduled Visits ......................................................................... 82 
10. 
EFFICACY ASSESSMENTS ........................................................ 83 
11. 
SAFETY ASSESSMENTS ............................................................ 84 
11.1. 
Vital Signs ...................................................................................... 84 
11.2. 
Body Height and Weight ................................................................ 84 
11.3. 
Physical and Neurological Examinations ....................................... 84 
11.4. 
Quality of Life Assessments ........................................................... 84 
11.5. 
Columbia Suicide Severity Rating Scale ........................................ 85 
11.6. 
Oral Mucosa Health Assessment .................................................... 86 
11.7. 
Gustatory Sense Assessment .......................................................... 86 
11.8. 
Electrocardiograms ......................................................................... 86 
11.9. 
Laboratory Assessments ................................................................. 87 
11.10. 
Adverse Events ............................................................................... 88 
11.10.1. 
Anticipated Adverse Events for this Study and Precautions ........... 88 
11.10.1.1. List of Anticipated Adverse Events for this Study ......................... 88 
11.10.1.2. Cautionary Statements .................................................................... 89 
11.10.2. 
Collection and Documentation of Adverse Events ......................... 89 
11.10.3. 
Serious Adverse Events and Reporting .......................................... 91 
11.10.3.1. Serious Adverse Events .................................................................. 91 
11.10.3.2. Reporting Serious Adverse Events ................................................. 91 
11.10.4. 
Pregnancy ....................................................................................... 92 
11.10.5. 
Overdose......................................................................................... 92 
12. 
STATISTICAL ANALYSIS .......................................................... 94 
12.1. 
Determination of Sample Size ........................................................ 94 
12.2. 
Analysis Population ........................................................................ 94 
12.3. 
Demographic and Baseline Characteristics .................................... 94 
12.4. 
Safety Analysis ............................................................................... 94 
12.4.1. 
Primary Safety Endpoints ............................................................... 94 
12.4.1.1. 
Adverse Events ............................................................................... 94 
12.4.1.2. 
C-SSRS Assessment ....................................................................... 95 
12.4.1.3. 
Vital Signs ...................................................................................... 96 


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12.4.1.4. 
Laboratory Analyses ........................................................................96 
12.4.1.5. 
Oral Mucosa Examination ...............................................................96 
12.4.1.6. 
Gustatory Sense Assessment............................................................96 
12.4.2. 
Secondary Safety Endpoints ............................................................96 
12.4.2.1. 
Electrocardiograms ..........................................................................96 
12.4.2.2. 
Concomitant Medications ................................................................96 
12.4.2.3. 
Other Safety Assessments ................................................................96 
12.4.3. 
Secondary Tolerability Endpoint .................................................... 96 
12.4.3.1. 
Quality of Life Assessment ..............................................................96 
12.4.4. 
Secondary Usability Endpoint ........................................................ 97 
12.4.4.1. 
Oral Cavity Insertion and Retention Assessment .............................97 
12.5. 
Interim Analysis ..............................................................................97 
12.6. 
Data Monitoring Committee ............................................................97 
13. 
STUDY MANAGEMENT .................................................................. 98 
13.1. 
Approval and Consent .....................................................................98 
13.1.1. 
Regulatory Guidelines .................................................................... 98 
13.1.2. 
Institutional Review Board/Independent Ethics Committee .............98 
13.1.3. 
Informed Consent ............................................................................98 
13.2. 
Data Handling ..................................................................................98 
13.3. 
Source Documents ...........................................................................99 
13.4. 
Record Retention .............................................................................99 
13.5. 
Monitoring .......................................................................................99 
13.6. 
Quality Control and Quality Assurance .......................................... 99 
13.7. 
Protocol Amendment and Protocol Deviation ................................100 
13.7.1. 
Protocol Amendment .....................................................................100 
13.7.2. 
Protocol Deviations ....................................................................... 100 
13.8. 
Ethical Considerations ................................................................... 100 
13.9. 
Financing and Insurance ................................................................ 100 
13.10. 
Publication Policy / Disclosure of Data ......................................... 101 
14. 
REFERENCES .............................................................................. 102 
15. 
APPENDICES ............................................................................... 104 
APPENDIX A. PLACEMENT DIAGRAM FOR AQUESTIVE 
THERAPEUTICS BUCCAL SOLUBLE FILM ............................... 105 


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APPENDIX B.  STUDY DRUG INSTRUCTIONS FOR USE ....................... 106 
APPENDIX C. PEDSQL™ EPILEPSY MODULE PARENT REPORT FOR 
TODDLERS (AGES 2-4) .............................................................. 109 
APPENDIX D. PEDSQL™ EPILEPSY MODULE PARENT REPORT FOR 
YOUNG CHILDREN (AGES 5-7) ................................................ 111 
APPENDIX E. PEDSQL™ EPILEPSY MODULE PARENT REPORT FOR 
CHILDREN (AGES 8-10) ............................................................. 114 
APPENDIX F. QUALITY OF LIFE IN EPILEPSY FOR ADOLESCENTS 
QOLIE-48 (VERSION 1.0) ........................................................... 117 
APPENDIX G. PATIENT-WEIGHTED QUALITY OF LIFE IN EPILEPSY: 
QOLIE-31-P .................................................................................. 123 


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LIST OF TABLES 
Table 1: 
Study 162013 - Dose-Proportionality of DBF at Doses of 5, 10, and 
15 mg ...............................................................................................41 
Table 2: 
Study 162021: Ratios (DBF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUCt, AUC∞, and 
Cmax - PK Population .......................................................................42 
Table 3: 
Details of Investigative Product ...................................................... 59 
Table 4: 
Calculated Prescribed Dose of Study Drug for Subjects Who Have 
Not Received Diazepam Administered as DBF in the Past ..............60 
Table 5: 
Calculated Prescribed Dose of Study Drug for Subjects < 17 Years of 
Age Entering Study 42-1703 from Study 160325 ............................61 
Table 6: 
Schedule of Assessments .................................................................67 
Table 7: 
Age-Defined Quality of Life Assessment Modules ..........................85 
Table 8: 
Laboratory Assessments ..................................................................87 
Table 9: 
Classification of Adverse Events by Intensity ..................................90 
Table 10: Classification of Adverse Events by Relationship to Study Drug.....90 
 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema ..................................................................................50 


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3. 
LIST OF ABBREVIATIONS 
NOTE: The term “patient” is used in this protocol when text is around individuals with 
epilepsy in the general public. The term “subject” is used when text is around individuals 
with epilepsy in this and other clinical trials. 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ARS 
Acute Repetitive Seizures 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
AUC 
Area Under the Curve 
BMI 
Body mass index (kg/m2) 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CRA 
Clinical Research Associate 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
Confidence Interval 
Cmax 
Maximum concentration 
CNS 
Central Nervous System 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
DBF 
Diazepam Soluble Buccal Film 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMU 
Epilepsy Monitoring Unit 
FDA 
Food and Drug Administration 
GABA 
γ-aminobutyric acid 
GABAA 
GABA receptors of the A-type 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HCG 
Human chorionic gonadotropin 


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Abbreviation 
Definition 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 
HEENT 
Head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFU 
Instructions For Use 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
max 
maximum 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
QOL 
Quality of Life 
RBC 
Red blood cell 
RLD 
Reference Listed Drug 
RR 
Respiratory rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time of maximum concentration 


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Abbreviation 
Definition 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 
US 
United States 


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4. 
INTRODUCTION 
4.1. 
Background on Treatment and Management of Individuals 
with Refractory Epilepsy 
Acute repetitive seizures (ARS) comprising 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 anywhere 
from minutes to hours.[1] When these seizures occur outside a hospital, the patient is 
often transported to an acute care facility for treatment to prevent prolonged seizures.[2] 
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.[3,4,5] 
In these cases, the primary goals of the treatment are seizure cessation and prevention of 
seizure recurrence.[1] 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.[6] 
Outpatient treatment for these types of seizures may reduce emergency medical 
intervention, decrease seizure duration, prevent general deterioration due to the repeated 
seizures and improve the quality of life of these patients. While rectal diazepam gel is 
currently available in the United States (US), a portion of the population does not benefit 
from this treatment partly because the rectal route of administration is inappropriate or 
unacceptable.[7] Therefore, there is an unmet medical need for an effective treatment 
with a rapid onset of action that is easily administered in the outpatient setting. 
4.2. 
Diazepam 
Diazepam is a long-acting "classical" benzodiazepine that enhances the effect of 
γ-aminobutyric acid (GABA) at the (GABA)-A receptor and demonstrates anticonvulsant 
properties. It is commonly used to treat a range of conditions including seizures, anxiety, 
alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, 
trouble sleeping, and restless legs syndrome.[8] It 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.[9] 
Intravenous diazepam is a first-line treatment for status epilepticus.[9] 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.[9] However, 
diazepam is effective when used intermittently for the prevention of repeated seizures. 
Like other benzodiazepines, diazepam administration may cause sedation, anxiolysis, and 
amnesia.[9] 


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4.2.1. 
Mechanism of Action 
Although the precise mechanism by which diazepam exerts its anti-seizure effects is 
unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures 
through an interaction with γ-aminobutyric acid (GABA) receptors of the A-type 
(GABAA). GABA, the major inhibitory neurotransmitter in the central nervous system, 
acts at this receptor to open the membrane channel allowing chloride ions to flow into 
neurons [10]. Entry of chloride ions causes an inhibitory potential that reduces the ability 
of neurons to depolarize to the threshold potential necessary to produce action potentials. 
Excessive depolarization of neurons is implicated in the generation and spread of 
seizures. It is believed that diazepam enhances the actions of GABA by causing GABA 
to bind more tightly to the GABAA receptor. 
4.2.2. 
Metabolism and Elimination 
Diazepam is extensively metabolized to one major active metabolite 
(desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam 
(temazepam) and 3-hydroxy-N-diazepam (oxazepam) [11]. 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 [12]. 
 
4.2.3. 
Pharmacokinetics 
Per the prescribing information, rectal administration of a 15 mg dose of Diastat® 
AcuDial™ rectal gel produces peak plasma concentrations in 1.5 hours, with absolute 
bioavailability of 90% relative to Valium® injectable. The volume of distribution of 
diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half- 
life of diazepam and desmethyldiazepam following administration of a 15 mg dose of 
diazepam rectal gel was found to be about 46 hours (coefficient of variation [CV] = 43%) 
and 71 hours (Coefficient of Variation [CV] = 37%), respectively. Both diazepam and its 
major active metabolite desmethyldiazepam bind extensively to plasma proteins 
(95-98%). 
 
4.3. 
Diastat® AcuDial™ 
Although the Diastat® AcuDial™ rectal gel formulation is considered generally safe and 
effective, the route of administration is less than ideal. The mechanics of administering a 
rectal gel can be a difficult, time-consuming, and embarrassing experience for both 
patient and care-givers alike. For example, the patient or care-giver must first remove 


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articles of clothing and then place the patient in an appropriate position. The Diastat® 
AcuDial™ rectal gel syringe tip is inserted into the rectum to a specific depth and the gel 
expressed into the rectal vault. However, improper technique can lead to patient injury 
and leakage of gel from the rectum can result in incomplete dosing and the need for an 
additional dose to compensate for any loss. Additionally, the attitude of some patients 
toward a rectal route of drug administration is unfavorable which may negatively impact 
compliance to treatment.[13] Each of these factors has a potential influence on patient 
morbidity. Persistent seizure activity is associated with worse outcomes across a 
spectrum of precipitating conditions.[14,15] 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.[16] 
 
4.4. 
Diazepam Buccal Film (DBF) 
The new route of diazepam administration is via buccal soluble film. Buccal soluble 
diazepam 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 treatment 
and greater subject and caregiver acceptance with improved compliance may be 
expected. 
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 all 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. 
4.5. 
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 


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that are characteristic for each subject and deemed by the prescriber to be the kind of 
seizure for which a benzodiazepine would be administered (Diastat® AcuDial™ rectal gel 
Prescribing Information). 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.[13] 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.[14,15] 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.[15] 
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 
gastrointestinal (GI) tract may be possible due to swallowing of the saliva. It is expected 
that that 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. 
 
4.5.1. 
Nonclinical Studies 
Mechanism of Action: Although the precise mechanism by which diazepam exerts its 
anti-seizure effects is unknown, animal and in vitro studies suggest that diazepam acts to 
suppress seizures through an interaction with GABA receptors of the A-type (GABAA). 
GABA, the major inhibitory neurotransmitter in the central nervous system, acts at this 
receptor to open the membrane channel allowing chloride ions to flow into neurons. 
Entry of chloride ions causes an inhibitory potential that reduces the ability of neurons to 
depolarize to the threshold potential necessary to produce action potentials. Excessive 
depolarization of neurons is implicated in the generation and spread of seizures. It is 
believed that diazepam enhances the actions of GABA by causing GABA to bind more 
tightly to the GABAA receptor. 
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 


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(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. 
 
4.5.2. 
Clinical Studies 
As of 18 July 2018, 6 DBF studies in healthy volunteers have been completed: two 
bioavailability/bioequivalence studies (Study numbers 1899 and 1900), a dose- 
proportionality study (Study number 162013), a fasting pivotal bioavailability study in 
comparison with Diastat® gel (Study number 162021) and two food effect studies (high 
and moderate fat) in healthy subjects (Study numbers 162022 and 172018). 
 
4.5.2.1. 
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 from double-blind, placebo-controlled studies and open label studies 
with 573 subjects exposed to diazepam rectal gel.[11] 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%). 
In the 6 completed DBF studies, there have been a total of 154 subjects enrolled and 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. 
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 DBF; 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. 
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. 
In all studies to date, somnolence followed by dizziness were the most frequently 
reported TEAE, consistent with the known pharmacologic action of diazepam. 
Somnolence has also been the most frequent AE reported for Diastat. 


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The frequency of AEs increased in a dose-related manner with DBF. 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. 
An increased frequency of AEs following dosing in a fasted state was observed in the two 
food effect studies. 
Overall, the administration of DBF was safe and well tolerated in healthy subjects 
following a single oral dose of 5mg through 20 mg under various 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. 
 
4.5.2.2. 
Pharmacokinetics in Clinical Studies 
Pharmacokinetics: Per the prescribing information, 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, Coefficient of 
Variation (CV) =43% and 71 hours (CV=37%), respectively. Both diazepam and its 
major active metabolite desmethyldiazepam bind extensively to plasma proteins 
(95-98%). 
 
4.5.2.2.1. 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 enrolment 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, DMSF 5 mg was bioequivalent to 
Diastat® AcuDial™ rectal gel 5 mg with respect to area under the plasma concentration- 
time curve from time 0 (prior to administration of medication) to time t (the time of the 
last quantifiable concentration) [AUCt] and AUC extrapolated to infinity (AUC∞). This 
was evidenced by the 90% confidence interval (CI) for the ratio of geometric means was 
within the acceptable range of 80-125%. For the maximum observed plasma 
concentration (Cmax), the ratio of geometric means was 1.07 (90% CI: 87.1-131.5%). The 
median time to reach Cmax (Tmax) was 0.67 hours for DBF (range 0.33-1.50 hours) and 
0.25 hours for the Diastat® AcuDial™ rectal gel (range 0.15-1.00 hours). The difference 
in Tmax values was not statistically significant. 
Study 1900 compared DBF 20 mg to Diastat® AcuDial™ rectal gel 20 mg. Evaluable data 
from 10 subjects who completed both treatments showed that the extent of the absorption 
of DBF 20 mg was comparable to Diastat® 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® 


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AcuDial™ rectal gel (range 0.25-2.00 hours). The difference in Tmax values was not 
statistically significant. Examination of the mean plasma curves for DSBF and Diastat® 
AcuDial™ showed that although the Cmax was higher for the DSBF relative to Diastat® 
AcuDial™, the pharmacokinetics were comparable in terms of rapid rate of absorption, 
duration of plateau, and the rate of elimination. 
 
4.5.2.2.2. 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 DBF at doses of 5, 10, and 15 
mg. A total of 30 subjects were randomized and dosed in the study. Analysis of the 
pharmacokinetic data confirmed that DBF is dose-proportional over the dose range 5 mg 
to 15 mg (Table 1). The criteria for dose proportionality were met for diazepam since for 
both comparisons (A/B: DBF 5 mg/DBF 10 mg and C/B: DBF 15 mg/DBF 10 mg), the 
geometric mean 90% CI of the ratios of Least-Squares means from the analysis of 
variance (ANOVA) of the ln-transformed AUCt, AUC∞, and Cmax were within the 
acceptable range 80-125%. 
Table 1: 
Study 162013 - Dose-Proportionality of DBF at Doses of 5, 10, and 
15 mg 
 
Geometric Mean 
90% CI3 
Parameter1 
Treatment Comparisons 
Ratio2 
Lower 
Upper 
AUCt 
DBF 5 mg (A) – DBF 10 mg (B) 
103.53% 
99.51% 
107.72% 
AUC∞ 
DBF 5 mg (A) – DBF 10 mg (B) 
104.08% 
99.43% 
108.96% 
Cmax 
DBF 5 mg (A) – DBF 10 mg (B) 
104.57% 
97.92% 
111.67% 
AUCt 
DBF 15 mg (C) – DBF 10 mg (B) 
101.94% 
97.62% 
106.44% 
AUC∞ 
DBF 15 mg (C) – DBF 10 mg (B) 
103.64% 
98.52% 
109.02% 
Cmax 
DBF 15 mg (C) – DBF 10 mg (B) 
98.84% 
92.36% 
105.78% 
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; DBF= Diazepam Buccal Film. 
1 Dose normalized to 10 mg 
2 Calculated using least-squares means according to the formula eDIFFERENCE X 100 
3 90% Geometric Mean Confidence Interval using ln-transformed data. 
 
4.5.2.2.3. 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 DBF 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™. 


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Pharmacokinetic parameters (Cmax, AUCt, and AUC∞) were compared pairwise. DBF 
15 mg with each of the three doses of the rectal gel (Table 2). The results suggest that the 
dose of DBF expected to match the diazepam Cmax following 20 mg Diastat® 
AcuDial™gel is lower than 12.5 mg (closer to 11 mg); the dose expected to match the 
diazepam Cmax following a 12.5 mg dose of Diastat® AcuDial™gel is lower than 9 mg; 
and the dose of DBF expected to match the diazepam Cmax following a 5 mg dose of 
Diastat® AcuDial™gel is lower than 5 mg (closer to 4 mg). 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 DMSF 
compared with Diastat® AcuDial™ gel is 118% to 128%. 
Table 2: Study 162021: Ratios (DBF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUCt, AUC∞, and 
Cmax - PK Population 
 
Treatment 
Geometric 
Geometric 
90% Geometric CI2 
Comparison 
N 
Parameter 
LSM A 
LSM B 
Ratio1 
Lower 
Upper 
DBF 15 mg (A) 
24 
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 
DBF 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 
DBF 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; DBF= Diazepam Buccal Film; 
LSM = Least-Squares Mean 
1 Calculated least-squares means according to the formula: e(Difference) x 100 
2 90% Geometric Mean Confidence Interval using ln-transformed data 
 
4.5.2.2.4. Food Effect Studies 
Aquestive Therapeutics conducted two food effect studies (Study 162022 in 
Section 4.5.2.2.4.1 and Study 172018 in Section 4.5.2.2.4.2 ). Results for a high fat meal 
were consistent across the two studies. 


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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). 
4.5.2.2.4.1. Study 162022 
Study 162022 was a single-dose, open-label, two-period, randomized two-sequence 
crossover study with DBF 15 mg administered under fasted conditions and within 
30 minutes following a high-fat meal. The washout period between doses was 28 days. 
The study was conducted with 18 healthy male and female subjects aged 18 to 62 years, 
inclusive. 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. 
 
4.5.2.2.4.2. Study 172018 
Study 172018 was a four-period, randomized four-sequence crossover study in 24 male 
and female adults with four treatments: (A) DBF 15 mg fasted, administered upright; (B) 
DBF 15 mg fasted, administered reclining; DBF 15 mg within 30 minutes following a 
standardized high-fat meal, administered reclining; and DBF 15 mg within 30 minutes of 
a standardized moderate-fat meal, administered reclining. 
The primary objective was to assess the effect of a moderate-fat meal on the diazepam 
PK profile. A secondary objective was to assess the effect of administration of DBF with 
the subject reclining on his/her side (application site downward) for 15 minutes after 
application. This was based on aligning treatment administration with the typical posture 
assumed by subjects in a postictal state and the Sponsor’s interest in investigating 
whether position affected diazepam PK following administration of DBF. 
Analysis comprised pairwise comparisons of Treatment C (high-fat meal, reclining) and 
Treatment D (moderate-fat meal, reclining) with Treatment B (fasting, reclining) as well 
as a comparison between Treatment B (fasting, reclining) with Treatment A (fasting, 
upright). 
Overall, 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 Cmaxor AUC. Diazepam profiles (reclining versus upright) met bioequivalence 
criteria for the upright and fasting condition. There was no difference in Tmax, p = 0.4979. 


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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). 
4.6. 
Rationale for the Dose Regimen of Diazepam Buccal Film 
As described above, the data from Study 162013 and Study 162021 demonstrate that 
DBF is dose-proportional over the studied dose-range, while Diastat® AcuDial™ is less 
than dose-proportional with respect to Cmax. Also, as described above, the data from 
Study 162022 and Study 172018 demonstrate that food taken within 30 minutes prior to 
dosing affects the rate (but not the extent) of absorption of diazepam administered as 
DBF. Accordingly, Aquestive used population PK modeling to select a dosing regimen to 
compensate for the differences in PK between DBF and Diastat® AcuDial™ (Table 4; 
Section 8.1). 
Using data from Study 162013, Study 162021, and Study 172018, population PK 
modeling was used to model the PK profiles for DBF and Diastat® AcuDial™ under 
fasted and fed conditions (DBF). In brief, the recommended DBF dose for each weight 
class as defined in the Diastat® AcuDial™ 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® AcuDial™, 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 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® 
AcuDial™. 
Population PK modeling using data from healthy adults demonstrated that diazepam 
exposure following DBF (like Diastat) is dependent on body size. In the adult population, 
it was demonstrated that a weight-based dose regimen based on modeling produced 
exposures that were uniform across weight classes and these exposures in higher weight 
subjects following a 17.5 mg dose were no higher than exposures observed in lower 
weight subjects following a 12.5 mg dose. Thus, the weight adjusted regimen is not 
expected to incur any additional safety risks related to Cmax. In fact, the weight-adjusted 
regimen increases the likelihood that subjects receive relatively consistent exposure to 
diazepam across weight categories. 
For this reason, the DBF dose for pediatric subjects entering the current study from study 
160325 and who have received diazepam administered as study drug in the past will be 


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determined using the regimen employed in study 160325 (Table 5).The proposed dosing 
regimen, under conditions of a moderate fat meal, is expected to produce Cmax values 
similar to the Cmax expected following the labeled dose of Diastat. 
4.7. 
Clinical Risks/Benefits of Study Drug 
4.7.1. 
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. The 
data suggest that study drug and Diastat® AcuDial™ are approximately bioequivalent at 
the 5 mg dose, and that Cmax values for study drug exceed Cmax from Diastat® AcuDial™ 
as the dose increases beyond 5 mg. 
In this study, dose is based on age and weight category (Section 4.5.2.2 and Section 8.3). 
Note that subjects are to be weighed at screening and at each study visit, and dose 
dispensed will be adjusted depending on age and weight category at that visit 
(Section 8.3). Study drug dosing is determined first according to age group and then by 
body weight within age group. The Investigator may make adjustments as medically 
indicated. For all age groups, the height, weight, and body mass index (BMI; kg/m2) will 
be measured and recorded at all study visits. The rationale for the dose regimen for DBF 
is explained in Section 4.6. 
The subjects in this study will be administering study drug themselves or with the help of 
a caregiver, (trained by the study site staff in study drug administration and 
documentation) in the same setting as they typically use the diazepam rectal gel or other 
rescue medication, without the presence of study staff. The study design includes study 
site visits to monitor safety and tolerability, assess subject/caregiver use of study drug 
through review of subject/caregiver diaries, ensure adequate supply of study drug dose, 
and reinforce subject/caregiver training on the use of study drug, with a focus on safety 
and correct study conduct. Since the dosing is weight based, the subjects’ drug inventory 
will be reviewed at each study visit and reissued with the correct dosage, based on body 
weight. 
 
4.7.2. 
Overdosage Information Derived from Diastat® AcuDial™ Prescribing 
Information 
According to the prescribing information for Diastat® AcuDial™ rectal gel (December 
2016), previous reports of diazepam overdosage have shown that manifestations of 
diazepam overdosage include somnolence, confusion, coma, and diminished reflexes. 
Respiration, pulse, and blood pressure should be monitored, as in all cases of drug 
overdosage, although, in general, these effects have been minimal. General supportive 
measures should be employed, along with intravenous fluids, and an adequate airway 
maintained. Hypotension may be combated by the use of levarterenol or metaraminol. 
Dialysis is of limited value. 
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete 
or partial reversal of the sedative effects of benzodiazepines and may be used in 
situations when an overdose with a benzodiazepine is known or suspected. Prior to the 


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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. Subjects treated with 
flumazenil should be monitored for re-sedation, respiratory depression and other residual 
benzodiazepine effects for an appropriate period after treatment. The prescriber should be 
aware of a risk of seizure in association with flumazenil treatment, particularly in long- 
term benzodiazepine users and in cyclic antidepressant overdose. Caution should be 
observed in use of flumazenil in epileptic subjects treated with benzodiazepines. The 
complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, 
and PRECAUTIONS, should be consulted prior to use. 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
To assess the safety and tolerability of DBF (study drug) administered a minimum of 3 
times to subjects with epilepsy for the treatment of seizures over a minimum 6-month 
period. 
5.1.2. 
Secondary Objectives 
• To evaluate the usability of study drug as assessed by the ability of 
caregivers/subjects to administer study drug based on the Instructions for Use 
(IFU). 
• To evaluate the Quality of Life (QoL) of the subjects during the treatment 
period as assessed by use of age-appropriate epilepsy scales over a minimum 
6-month period. 
Data from this study is intended to support a 505 (b)(2) New Drug Application for the 
test product. 
5.2. 
Study Endpoints 
5.2.1. 
Primary Endpoints 
The primary endpoints of this study are obtained during study visits by a trained Principal 
Investigator, sub-investigator, or study nurse. 
• TEAE assessment, including relationship to treatment with study drug and 
severity. 
• Columbia Suicide Severity Rating Scale (C-SSRS) assessment: If a subject 
cannot complete the assessment, the site must document this. 
• Vital signs (blood pressure, heart rate, respiration rate, oral temperature) 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a tympanic, 
axillary, or temporal (forehead) temperature may be taken. In this case, the 
method should be recorded in the source documents. 
• Laboratory analyses (hematology, serum chemistry, and urinalysis) 
• Pathological change in oral mucosa as measured by an oral examination 
• Gustatory sense changes as measured by the general Labeled Magnitude Scale 
(gLMS) using commercially available Burghart Messtechnik test strips in 
cognitively appropriate subjects 12 years of age and older 


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5.2.2. 
Secondary Endpoints 
Secondary endpoints are: 
• Quality of Life (QoL) assessments by use of age-appropriate epilepsy scales; 
if a subject cannot complete the assessment, the site must document this. 
• Assessment of usability by subject and/or caregiver 
− Handling and administration of study drug, based on the Instructions for 
Use (IFU) 
− Successful buccal insertion of study drug 
o Successful placement and adherence of the study drug against the 
buccal mucosa (inner cheek) 
− Oral cavity placement and retention 
o Study drug swallowed prior to sticking to inner cheek 
o Study drug spit out or blown out by subject after administration 
• 12-lead electrocardiograms (ECGs) 
• Use of concomitant medications 
• Physical and neurological examinations 
• Body height and weight; BMI (kg/m2) 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Description of Overall Study Design and Plan 
This Phase 3, multicenter, open-label, long-term safety and tolerability study of chronic, 
intermittent use of DBF (study drug). 
The study population will be male and female children (2 to 12 years old), adolescents 
(13 to 16 years old), and adults (17 to 65 years old) with a clinical diagnosis of epilepsy 
and with bouts of increased seizure activity, ARS, frequent breakthrough seizures, seizure 
clusters, or cluster seizures and who are on chronic, intermittent use of a rescue 
medication (e.g., Diastat® AcuDial™ or other benzodiazepine). 
It is expected that approximately 120 subjects (∼60 children and adolescents and ∼60 
adults) will be screened and approximately 100 subjects (50 children and adolescents and 
50 adults) are expected to enroll. The enrollment should include at least 20 subjects in the 
6- to 11-year-old group and 20 subjects in the 12- to 16-year-old group. 
Subjects who initially consented and enrolled in the study under version 1 of the protocol 
dated 31 July 2017 may come in at their next scheduled site visit, reconsent under the 
amended protocol and be dispensed a new container of DBF based upon the revised 
mg/kg dosing in Table 4. The subjects do not need to come in for unscheduled visit. 
In addition to direct enrollment of subjects from screening, subjects who have completed 
the Phase 2 clinical trials (Study 160325 [Pediatric] and Study 160326 [Adult]) may 
screen and enroll (i.e., rollover subjects) into this Phase 3 long-term safety study when 
they come for their follow-up visit in the Phase 2 study. Seizure diary used during the 
Phase 2 studies will be reviewed at screening for this rollover subjects. Rollover subjects 
will be assessed using Protocol 42-1703 inclusion/exclusion criteria. The Phase 3 study 
Screening visit can be done on the same day as the Phase 2 study follow-up visit. 
The duration of the study per subject will be a minimum of 6 months (Figure 1). Subject 
study visits will occur at Baseline, within 14 days after the first seizure prompting study 
drug administration, and approximately every 3 months (± 14 days) over the course of the 
study. All visits are calculated from the time of the Baseline Visit/Study Day 1. 
The planned end date for this study is 09 October 2020. Thus, the last screening visit is 
28 February 2020. 
The last Baseline Visit/Study Day 1 will occur no later than 06 March 2020. The last 
planned Study Completion Visit/Visit 5 will be 02 September 2020 and the last planned 
follow-up telephone contact will be completed by 09 October 2020. Subjects who are 
ongoing on 28 February 2020, who are benefitting from the use of DBF, and who would 
like to stay on study, will be allowed to continue until study end. 


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Figure 1: 
Study Schema 
 
 
 
Baseline Visit ǂ 
Telephone Contact 
Months 1 and 2 
 
Site Visit 
Study Completion 
Visit § 
 
Telephone Contact # 
Study Day 1 
Month 1 
± 7 days 
Month 2 
± 7 days 
Month 3 
± 14 days 
Month 6 
± 14 days 
Month 7 
Day 210 – Day 217 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
ǂ Date for last Baseline Visit/Study Day 1 no later than 06 March 2020. 
§ Planned date for last Study Completion Visit/Visit 5 is 02 September 2020. 
# Planned date for last Telephone Contact is 09 October 2020. 
 
Subjects who are ongoing on 28 February 2020, who are benefitting from the use of DBSF, and who would like to stay on 
study, will be allowed to continue until study end. 
 
The study site visits will be conducted to assess protocol-defined safety variables 
(Section 5.2). 
Administration and usability of study drug will be recorded at home in the electronic 
diary after each use of study drug. The electronic diary will also be used at home to 
capture seizure history and changes in health and medications. 
The study drug dose will be tailored to the subject’s age and body weight, as described in 
Section 8.1, and adjusted throughout the study period if changes in body weight call for 
dose modification. For all age groups, the height and weight will be recorded at all study 
visits. Study drug dosing is determined first according to age group and then by body 
weight within age group. Subjects with weights in the range 112 to 134 kg (247 to 295 
pounds) may be allowed to participate in the study at the discretion of the Investigator. 
Table 4 provides the calculated prescribed DBF dose for DBF naive subjects (i.e., those 
who entered into the present study 42-1703 never having received DBF as study drug 
before). The Investigator is encouraged to use Table 5 for dose determination after 
subjects have received their first dose of DBF based on subject response to the study drug 
dose and the Investigator's judgment. Subjects already enrolled in the present study 42- 
1703 and dosed according to the guidelines in Table 4 can also be moved to dosing 
according to Table 5 after evaluation of subject response to the study drug dose and the 
Investigator's judgment. Table 5 will be used for dose-determination for subjects who 
enter the present study 42-1703 from the pediatric EMU study 160325 after Investigator 
review and evaluation of the subject's dose and response in the EMU study. 
Study drug will be administered away from the study site, by the subject or, if applicable. 
by a caregiver, both trained in study drug administration and documentation using the 
electronic diary. This is expected to be in the home most often but could also occur in a 
non-clinical environment outside of the home. The subject and/or caregiver will be: 
• able to recognize the occurrence of a qualifying event that for the individual 
subject is characteristic and is deemed by the investigator to be a kind for 
which benzodiazepine would ordinarily be administered acutely 
 
Within 14 days post 
 


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• trained by the study team to administer the study drug following the 
Instructions For Use (IFU; Appendix B) 
Investigators will be allowed to make adjustments to subjects’ anti-epileptic drug 
regimens throughout the study, with the aim to control seizures, and reduce increased 
bouts of seizure frequency, as will be expected in the general practice of medicine. 
Screening Period: The last Screening Visit is 28 February 2020. Screening for 
enrollment eligibility can occur within 1 to 28 days prior to study entry. Before the 
performance of any study-related procedure, written informed consent will be obtained 
from the subject or subject’s legally authorized representative and oral and/or written 
assent will be obtained from the subject as required by the Institutional Review Board 
(IRB). 
As a part of screening, potential subjects and caregivers will be advised that electronic 
diaries will be used by subjects and/or caregivers to document seizures, use of study drug, 
AEs, changes in concomitant medication to determine their ability/willingness to use the 
electronic diary during treatment. Training on the use of the diary will not be performed 
until the baseline visit. 
Subjects may be re-screened during the study per Investigator judgment after consultation 
with and approval by the Medical Monitor. 
Baseline Visit (Study Day 1) – conducted after completion of screening and 
confirmation of eligibility for study enrollment determined by compliance with protocol 
Inclusion (Section 7.1) and Exclusion (Section 7.2) criteria. During the baseline visit at 
the study site, the subjects will undergo baseline assessments and subjects/caregivers will 
receive training in study drug administration and use of electronic diary, and receive their 
study drug supply with documentation materials (IFU [Appendix B]). 
The last Baseline Visit/Study Day 1 will occur no later than 06 March 2020. 
Subjects/caregivers will be instructed to call the site when the first seizure prompts study 
drug administration. A study site visit will occur within 14 days after this first use. 
See Section 9.2.2 for the detailed list of procedures scheduled for Study Day 1. 
Treatment Period Clinical Site Visits: Upon completion of the Baseline visit, the 
subject enters a 6-month minimum period of study drug treatment with an expectation 
that the subject will use the study drug at least 3 times over the 6-month period. 
The study site visits will be conducted within 14 days after the first study drug dosing and 
then approximately every 3 months (± 14 days) after the Baseline Visit (Study Day 
1/Visit 2). 
See Section 9.2.3 for a detailed list of procedures scheduled for the site visit following 
the first seizure prompting study drug administration. 
Subjects will bring their diary and their supply of study drug to each study site visit. 
Subjects’ height and weight (without shoes and with empty pockets) will be obtained at 
each site visit for determination of study drug dose (Section 8). The subject diary will be 
reviewed, and subject/caregiver training will be reinforced (Section 9.2.2). Review of 


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study diary use will include the number of study drug uses, study drug usability 
assessment, seizure-control status, AEs, and concomitant medications. 
Subjects will undergo assessment of oral mucosal health, gustatory assessment, vital 
signs, physical and neurological examination, collection of blood and urine samples for 
clinical laboratory testing, 12-lead ECG, age-appropriate Quality of Life (QoL) and 
Columbia Suicide Severity Rating Scale (C-SSRS) assessments. 
The QoL and C-SSRS should be completed in appropriately aged subjects. These 
assessments may be omitted as applicable if a subject's cognitive status does not allow 
the subject to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., unable to 
perform test due to incapacity, etc.). 
See Section 9.2.3 for a detailed list of procedures scheduled for the planned visits during 
the treatment period. 
Scheduled Telephone Contact at 1 Month and 2 Months After Study Day 1: The 
study site staff will telephone the subjects at approximately 1 and 2 months ± 7 days after 
the baseline visit to check on the subject’s health and seizure status, determine if study 
drug was used reinforce training on study drug administration and diary documentation, 
and to address concerns. 
See Section 9.2.5 for a detailed list of procedures scheduled for the planned telephone 
contacts at Month 1 and Month 2. 
Final/Completion or Early Withdrawal Visit 
The last subject Study Completion Visit/Visit 5 is projected for 02 September 2020. 
• For those subjects who have exceeded 6 months on study with at least 3 uses 
of DBF, the subject may complete the study at the 6-month visit (Visit 5) per 
the protocol, or the subject may continue as described below. 
• For those subjects who have at least 6 months on study with less than 3 uses 
of DBF, the subject may complete the study at the 6-month visit (Visit 5) per 
the protocol, or the subject may continue as described below. 
Subjects who prematurely withdraw from the study for any reason should undergo a final 
visit as well. If the Early Withdrawal Visit is not done, the reason(s) will be recorded in 
the eCRF. Assessments/procedures performed at the final visit are the same as those 
performed during Treatment Period Clinical Site Visits. In addition: 
• Unused study drug will be returned, and the electronic study diary will be 
collected. For subjects completing the study at 6 months, the 6-month visit 
serves as the Final/Completion Visit. 
See Section 9.2.6 for a detailed list of procedures scheduled for the final study visit. 
Telephone contact 30-37 days after the Final/Completion Visit: 
The last subject follow-up telephone contact will occur in October 2020. 


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For subjects completing the study at 6 months, the Investigator or designee will conduct a 
follow-up phone call with the subject at 30-37 days after the Final Visit to check on 
subject status and collect reporting information, should any AE/serious adverse event 
(SAE) have occurred. 
See Section 9.2.7 for a detailed list of procedures scheduled for the telephone contact 
performed 30-37 days after the Final/Completion visit for subjects completing the 6- 
month visit. 
Extension of Study Beyond Month 6: 
The duration of treatment is being extended beyond 6 months under a similar schedule of 
visits. This policy is intended to continue for the period while the study remains open. 
At the discretion of the Principal Investigator and the subject, caregiver or guardian as 
applicable, a subject may continue in the study beyond the 6-month visit under a similar 
schedule of assessments, while the study is open. No Medical Monitor approval is 
required for subjects with 3 or more uses. The subject may continue in the study while 
the study remains open. 
In order to continue: 
• The subject is using the Investigational Product 
• The subject is receiving benefit from the Investigational Product 
• The subject is tolerating the Investigational Product 
• The subject wishes to continue in the study 
If a subject has had 3 or more uses of DBF, subjects may complete the study at the 6- 
month visit (Visit 5) per protocol or the subject may continue as described above. 
If a subject has not had 3 uses of DBF at the 6-month visit (Visit 5), or any visit after that, 
the Investigator should strongly consider the likelihood of the subject using DBF and 
whether the subject should continue in the study. The Investigator may consult with the 
Medical Monitor, if needed, to assess on a case-by-case basis the likelihood of achieving 
3 uses of DBF by continuing the subject on study. If the assessment concludes that 
achieving 3 uses of study drug is likely, the subject’s participation can be extended with a 
similar schedule of assessments. If the assessment concludes that achieving 3 uses use of 
the study drug is not likely, the study will be considered complete for the subject. 
 
6.2. 
Rationale for Study Design 
The subjects in this study will be administering study drug themselves or with the help of 
a caregiver (trained by study site staff in study drug administration and documentation) in 
the same setting as they typically use the diazepam rectal gel or other rescue mediation, 
without the presence of study staff. The study design includes study site visits to monitor 
safety and tolerability, assess subject/caregiver use of study drug through review of 
electronic diaries, ensure adequate supply of study drug dose, and reinforce 
subject/caregiver training on the use of study drug, with a focus on safety and correct 
study conduct. Since dosing is weight-based, the subject’s drug inventory will be 


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reviewed at each study visit and investigative product (IP) will be dispensed with the 
correct dosage, based on age and body weight. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Male and female subjects with a clinical diagnosis of epilepsy with bouts of increase 
seizure activity (e.g., ARS, frequent breakthrough seizures, seizure clusters or cluster 
seizures) will be screened. Subjects may be re-screened during the study per Investigator 
judgment after consultation with and approval by the Medical Monitor. Approximately 
120 subjects are expected to be screened in order to have a minimum of 100 enrolled 
subjects (50 adult and 50 pediatric/adolescent subjects). The enrollment should include at 
least 20 subjects in the 6 to 11-year-old group and 20 subjects in the 12 to 16-year-old 
group. 
In addition to direct enrollment from screening, subjects who have completed the Phase 2 
clinical trials (Study 160325 [Pediatric] and Study 160326 [Adult]) may screen and enroll 
(i.e., rollover subjects) into this Phase 3 long-term safety study when they come for their 
follow-up visit in the Phase 2 study. Seizure diary used during the Phase 2 studies will be 
reviewed at screening for this rollover subjects. Rollover subjects will be assessed using 
Protocol 42-1703 inclusion/exclusion criteria. The Phase 3 study Screening visit can be 
done on the same day as the Phase 2 study follow-up visit. 
 
7.1. 
Inclusion Criteria 
Subjects must meet all the following criteria in order to be included in the study: 
1. Female or male between the ages of 2 and 65 years, inclusive 
2. Written informed consent to participate in the study from the subject or subject’s 
legally authorized representative and oral and/or written assent will be obtained 
from the subject as required by the Institutional Review Board (IRB) prior to the 
performance of any study-related procedure 
3. Caregiver, if needed for subject, provides written informed consent and is able to 
administer study drug in the event of a seizure 
4. Subject has an established diagnosis of epilepsy with motor seizures with clear 
alteration of awareness, and while on a regimen of anti-epileptic medication(s), still 
experiences bouts of seizures (frequent break through seizures, e.g., ARS or seizure 
clusters) and who, in the opinion of the Investigator, may need benzodiazepine 
intervention for seizure control at least 1 time a month on average. Subject must be 
on at least 1 concomitant anti-epileptic drug (AED) at screening. 
The study is open to subjects who, in the opinion of the Investigator, would benefit 
from use of study drug. Concomitant prescription for a benzodiazepine for rescue 
(including diazepam) at screening or ongoing, or concomitant use of a 
benzodiazepine ongoing as a part of the subject’s daily antiepileptic drug regimen 
does not exclude a subject from eligibility. Subjects are to be encouraged to use 
study drug when a benzodiazepine rescue treatment is needed. However, treatment 
decisions are to be guided in all cases according to the Investigator’s judgment as to 
the optimal treatment in the interest of the subject’s care and welfare. Participation 
in this study is never a basis for the withholding of any treatment considered to be 
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5. Female subjects have negative serum and urine pregnancy test at screening1. 
Female subjects of childbearing potential (not surgically sterile or less than 2 years 
postmenopausal) must have a partner who is sterile, agrees to abstinence, be 
practicing double barrier contraception or using an FDA-approved contraceptive 
(e.g., licensed hormonal or barrier methods) for greater than 2 months prior to 
screening visit and commit to an acceptable form of birth control for the duration of 
the study and for 30 days after the final study visit. 
6. No clinically significant abnormal findings on the ECG (QTcF [Fridericia’s 
Correction Formula] ≤ 450 msec for males and QTcF ≤ 470 msec for females) 
7. Subject and caregiver (if applicable) must be willing to comply with all study visits 
and all required study procedures (including the use of electronic diary). NOTE: 
Non-verbal and cognitively impaired subjects are eligible to participate in the study. 
7.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible to participate in this study: 
1. A history of clinically significant gastrointestinal, renal/genitourinary, hepatic, 
hematologic, dermatologic, endocrine, oncologic, pulmonary, immunologic, 
psychiatric, or cardiovascular disease, or any other clinically significant 
abnormalities, such as physical examination, vital signs, laboratory tests or ECG at 
Screening or Baseline which in the opinion of the Investigator require further 
investigation or treatment or which may interfere with study procedures or safety or 
other medical conditions (e.g., cardiac, respiratory, gastrointestinal, psychiatric, 
renal disease) which are not adequately and stably controlled, or which in the 
opinion of the Investigator could affect the subject’s safety or interfere with the 
study assessments or any other condition which, in the opinion of the Investigator, 
would jeopardize the safety of the subject. 
2. Subject has had a significant traumatic injury, major surgery, or open biopsy within 
30 days prior to screening 
3. Subject has a recent history of suicide attempt (defined as an active, interrupted, or 
aborted attempt with the past five years) or reports suicidal ideation in the past six 
months as indicated by a positive response (“Yes”) to either Question 4 or Question 
5 of the C-SSRS performed at the Screening Visit. 
NOTE: If a subject cannot complete the assessment, the site must document this. 
4. A history of allergic or adverse responses to diazepam or any other benzodiazepine. 
5. Participation in another clinical trial other than Aquestive Therapeutics Phase 2 
studies 160325 and 160326 within 30 days prior to screening. Participation in an 
observational (non-interventional) study is not an exclusion provided there are no 
scheduling conflicts with this study. 
 
 
 
1 If the subject is unable to provide a urine sample, the option to use only serum pregnancy test will be 
according to Investigator judgment. 


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6. Received any other investigational medication (unless it can be documented that the 
subject received only placebo) or device within 8 weeks or 5 half-lives (whichever 
is longer) before assignment to study drug treatment. 
7. Lactating female or positive urine and serum pregnancy test (β-hCG) at screening 
for female subjects of childbearing potential.1 
8. In subjects 17 years of age and older (and in subjects < 17 years of age at the 
Investigator’s discretion), positive blood screen for human immunodeficiency virus 
(HIV), hepatitis B surface antigen (HBsAg), hepatitis C, or a positive test result for 
drugs of abuse or alcohol, except marijuana use for medicinal indications. When 
marijuana is or was used for medicinal indications in the opinion of the 
Investigator, it is not considered as drug abuse and the subject can be enrolled in 
states where marijuana is legal, even if the marijuana metabolites are positive in the 
urine. NOTE: In such a case, the marijuana product will be recorded as a 
concomitant medication. 
 
7.3. 
Withdrawal, Removal, and Replacement of Subjects 
A subject may voluntarily withdraw or be withdrawn from the study at any time for 
reasons including, but not limited to, the following: 
• progressive disease 
• unacceptable toxicity or AE 
• intercurrent illness: a condition, a condition, injury, or disease unrelated to the 
primary diagnosis that became apparent during treatment with study drug and 
necessitated the subject's termination from the study 
• general or specific changes in the subject's condition that renders him/her 
ineligible for further treatment with study drug according to the 
inclusion/exclusion criteria 
• subject or caregiver withdrawal of consent: At any time, a subject's 
participation in the study may terminate at his/her request or on the basis of 
the Investigator's clinical judgment. The reason for subject withdrawal will be 
noted on the electronic case report form (eCRF) 
• protocol deviation: The subject's findings or conduct failed to meet the 
protocol entry criteria or failed to adhere to the protocol requirements (e.g., 
drug noncompliance, failure to return for defined number of visits), and the 
deviation in the judgment of the Principal Investigator and/or the Sponsor 
warrants premature termination from the study. 
• lost to follow-up: The subject stopped coming for visits, and study personnel 
were unable to contact the subject. After two documented telephone contacts 
and a certified letter, the subject will be withdrawn as lost to follow-up. 
 
 
1 If the subject is unable to provide a urine sample, the option to use only the serum pregnancy test will be 
according to Investigator judgment. 


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This study may be terminated at the discretion of the Sponsor or any regulatory agency. 
An Investigator may elect to discontinue or stop the study at his or her site for any reason 
including safety or low enrollment. 
7.4. 
Follow-up for Drug Discontinuation/Subject Withdrawal from 
Study 
If a subject discontinues study treatment with study drug and is withdrawn from the study 
for any reason, the study site must promptly notify the clinical research associate (CRA). 
The date and the reason for study discontinuation must be recorded on the eCRF. 
Subjects who withdraw prematurely are to be scheduled and attend an Early Withdrawal 
Visit, if possible, and complete all assessments. 
In the event that a subject discontinues prematurely from the study due to a TEAE or 
serious TEAE, the TEAE or serious TEAE will be followed until it resolves (returns to 
normal or baseline values) or stabilizes, or until it is judged by the Investigator to be no 
longer clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. 


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8. 
TREATMENTS 
8.1. 
Details of Study Treatment 
Basic information about the study treatment with study drug is provided in Table 3. 
Table 3: 
Details of Investigative Product 
 
Preparations to be Administered 
Test Product (Generic) 
Trade Name 
diazepam 
Manufacturer 
Aquestive Therapeutics 
(formerly known as MonoSol Rx LLC) 
Dose(s) 
5, 7.5, 10, 12.5, 15, 17.5 mg (age and weight based)a 
Route 
buccal mucosa 
Formulation 
buccal mucosa soluble film 
Buccal Soluble Film Strength 
5, 7.5, 10, 12.5, 15, 17.5 mg (fasting or fed condition) 
a Where there is overlap in body weight with age, the age-adjustment takes precedence. Investigator may 
make adjustments as medically indicated. 
 
 
The DBF dose will be determined according to age and weight category in a manner 
analogous to the Diastat® AcuDial™ label [11] (Table 4). The rationale for the dose 
regimen of the test product is provided in Section 4.5.2.2. 
The dose levels specified in Table 4 are intended as the starting dose for subjects who 
have not received diazepam administered as DBF in the past. The Investigator may 
choose to adjust the dose upward or downward by 1 dose level depending on clinical 
response to study drug. The Investigator is encouraged to use Table 5 for dose 
determination after subjects have received their first dose of DBF based on subject 
response to the study drug dose and the Investigator's judgment. 
Subjects who initially consented and enrolled in the study under version 1 of the protocol 
dated 31 July 2017 may come in at their next scheduled site visit, reconsent under the 
amended protocol and be dispensed a new container of DBF based upon the revised 
mg/kg dosing in Table 4. The subjects do not need to come in for unscheduled visit. . 
These subjects already enrolled in the present study 42-1703 and dosed according to the 
guidelines in Table 4 can also be moved to dosing according to Table 5 after evaluation 
of subject response to the study drug dose and the Investigator's judgment. 
For subjects entering this study after participating in the Pediatric EMU Study 160325, 
who have taken DBF in the past, the Investigator will begin dosing according to dosing 
regimen derived from population pharmacokinetic modeling provided in Table 5 after 
Investigator review and evaluation of the subject's dose and response in the EMU study. 
See also the rationale for the modified pediatric dose regimen for these subjects entering 
Study 42-1703 from Study 160325 in Section 4.6. 


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Table 4: 
Calculated Prescribed Dose of Study Drug for Subjects Who Have 
Not Received Diazepam Administered as DBF in the Past 
 
Weight (kg)a 
Protocol-Specified Dose (mg)b 
Age 2 – 5 Years 
6 to 10 
5 
11 to 15 
7.5 
16 to 20 
7.5 
21 to 25 
10 
26 to 30 
12.5 
31 to 35 
12.5 
36 to 44 
12.5 
Age 6 – 11 Years 
10 to 16 
5 
17 to 25 
7.5 
26 to 33 
7.5 
34 to 41 
10 
42 to 50 
12.5 
51 to 58 
12.5 
59 to 74 
12.5 
Age 12 – 16 Years 
14 to 25 
5 
26 to 37 
7.5 
38 to 50 
7.5 
51 to 62 
10 
63 to 75 
12.5 
76 to 87 
12.5 
88 to 111c 
12.5 
ADULTS 
Age 17 Plus Years 
14 to 25 
5 
26 to 37 
7.5 
38 to 50 
10 
51 to 62 
12.5 
63 to 75 
15 
76 to 87 
15 
88 to 111c 
17.5 
a Dose of study drug expected to provide Cmax equal to Cmax for Diastat® dose. 
b Where there is overlap in body weight with age, the age-adjustment takes precedence. Investigator may 
make adjustments as medically indicated. 
c Subjects with body weights in the range 112 to 134 kg (247 to 295 pounds) may participate in the study at 
the discretion of the investigator. 


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Table 5: 
Calculated Prescribed Dose of Study Drug for Subjects < 17 Years of 
Age Entering Study 42-1703 from Study 160325 
 
Weight (kg) 
Protocol-Specified Dose (mg) 
Age 2–5 Years 
6 to 10 
5 
11 to 15 
7.5 
16 to 20 
10 
21 to 25 
12.5 
26 to 30 
15 
31 to 35 
15 
36 to 44 
17.5 
Age 6–11 Years 
10 to 16 
5 
17 to 25 
7.5 
26 to 33 
10 
34 to 41 
12.5 
42 to 50 
15 
51 to 58 
15 
59 to 74 
17.5 
Age 12–16 Years 
14 to 25 
5 
26 to 37 
7.5 
38 to 50 
10 
51 to 62 
12.5 
63 to 75 
15 
76 to 87 
15 
88 to 111 
17.5 
 
8.1.1. 
Controlled Substance Documentation 
The study drug DBF is designated as a Schedule IV controlled substance with abuse 
potential by the US Controlled Substances Act (21 Code of Federal Regulations [CFR] 
§1308). Because the study drug is a controlled substance, drug supplies at the study sites 
must be kept in a secure, double-locked, substantially constructed enclosure with 
restricted access. 
Prior to shipment of study drug to the study site, the Investigator must provide the 
Sponsor with a copy of a controlled substance license that clearly identifies the registrant 


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and address of the registrant. Study drug supplies will be shipped to the registrant and 
address noted on the certificate. 
8.1.2. 
Description of Study Drug 
The study drug, DBF, contains the active ingredient diazepam incorporated into a 
polymer-based film matrix utilizing Aquestive Therapeutics PharmFilm® technology. 
For the purposes of this study, with a population ranging in age from 2 to 65 years, the 
investigational product will be provided at the following strengths: 5 mg, 7.5 mg, 10 mg, 
12.5 mg, 15 mg, and 17.5 mg. 
The film is intended for application to the inner aspect of the cheek where the film 
immediately adheres and begins to hydrate. During the hydration process, the drug, along 
with associated solubility enhancers, are rapidly released onto the buccal mucosa for 
dissolution and absorption. The study drug doses up to 20 mg were tested in a pilot 
clinical study (Study 1900). The inactive ingredient composition, the film dimensions, 
and the manufacturing process selected for study drug are based on the information 
gained from the development of the study drug and other film products produced by 
Aquestive Therapeutics (ZUPLENZ® 4 and 8 mg and SUBOXONE® 2 mg/0.5 mg, 4 
mg/1 mg, 8 mg/2 mg, and 12 mg/3mg Sublingual Films). The study drug is a green 
rectangular film. 
The primary package used for study drug is a polyester/foil laminate provided by Amcor 
Flexibles (Madison, WI). The material (product code RFE-013) is a multi-layer 
composite consisting of (1) a 12.2-micron layer of polyethylene phthalate, (2) a 
25.4-micron layer of low-density polyethylene, (3) an 8.9-micron layer of aluminum foil, 
and (4) a 38.1-micron layer of low-density polyethylene, and is heat sealed at the edges. 
Each pouch contains one study drug film. 
8.2. 
Labelling, Maintenance and Retention of Study Drug 
It is the responsibility of the Sponsor to ensure that all drug supplies provided for the 
study are manufactured under current Good Manufacturing Practices (cGMP) and are 
suitable for human use. The Sponsor will supply an authorized clinical supplies vendor 
with a sufficient quantity of the study formulation(s) to allow completion of this study, 
including some spares for replacement drugs. The clinical supply vendor will ship the 
packaged and labeled study drugs for each participating investigator to the Pharmacy or 
Investigator at the address specified on the Drug Enforcement Agency Controlled 
Substance certificate. 
The study drugs will be sent to the Site Pharmacy already packed in individual unit-dose 
packages. Each unit-dose pouch will be labeled in English containing the Sponsor name 
(MonoSol Rx [now Aquestive Therapeutics])1, Protocol Number, Drug Name, Strength, 
Kit Identification Number, Subject Number, Lot Number, Route of Administration, 
Quantity of Dosage Units and a statement “Caution: New Drug – Limited by Federal Law 
to investigational use and the kit label will include at minimum Sponsor Name and 
Address, Drug Name, Strength, Quantity of Pouches, Route of Administration, Lot 
 
1 Some labels will retain the original name MonoSol Rx. 


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Number, Kit Identification Number, Protocol Number, Subject Number, Investigator 
Name, Directions for Use, Storage Conditions, and a statement ‘Keep out of reach of 
children’. 
Upon receipt of the study drugs, the Investigator, Pharmacist, or designee will inspect the 
shipment to ensure study drugs are received in good condition. Study drug receipt and 
condition will be promptly registered in the Interactive Web Response System (IWRS). 
The Investigator, Pharmacist, or designee will ensure records of receipt and dispensing of 
study drugs supplied are maintained for the duration of the study. 
The Investigator or designee will log into the IWRS to register the subject’s visit and 
have the study drug kit numbers assigned to the subject. Only these kits will be removed 
from inventory. At study visit 2 (Baseline visit) a starter kit containing 6 doses of one 
strength of study drug will be dispensed to each subject. 
At each subsequent study visit, a 3-month supply of study drug will be dispensed to each 
subject. Doses will be in individual labeled pouches inside a labeled container. Each 
container will hold either 15 or 23 pouches of the same dose of DBF. The decision of 
which quantity container is to be dispensed will be based on investigator estimation of 
whether or not the subject will need a 2nd dose of study drug for a seizure episode. Each 
subject will receive a new container with either 15 or 23 pouches at each visit. The 
subject should bring back the container with empty (used) and unused pouches at their 
next study visit. The container will not be re-dispensed. 
At the completion of the study, all unused study drug, will be retained by the Study Site 
until the authorization to return or destroy is received from the Sponsor. 
8.3. 
Dosage Schedule 
Dosing will occur away from the study site and administered by the subject or caregiver, 
if applicable. The dosing time will be triggered by occurrence of a qualifying event that 
for the individual subject is characteristic and is deemed by the prescriber to be of a kind 
for which a benzodiazepine would ordinarily be administered acutely. The subject and/or 
caregiver will administer the study drug as described in the IFU, see Appendix B. The 
actual date and time of film placement will be documented in the electronic diary by the 
subject or caregiver and in the eCRF by the study site staff during study visits. 
A second dose, when required, may be given within 4 to 12 hours after the first dose, as 
previously discussed between the investigator and subject/caregiver. No more than one 
episode every 5 days and no more than 5 episodes per month should be treated with study 
drug or with any other product containing diazepam (e.g., Diastat® AcuDial™) except as 
instructed by a physician. 
Based on subject diagnosis and history (Inclusion Criteria), it is expected that subjects 
will have a minimum of 3 uses of the study drug within the 6 months treatment period. 
If a subject has experienced 3 uses of study drug, study participation will be complete at 
Month 6. For those subjects who have not experienced 3 uses of study drug, the 
Investigator and the Medical Monitor will assess on a case-by-case basis the likelihood of 
achieving 3 uses of study drug by continuing the subject on study for an additional 3 


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months. If the assessment concludes use of the study drug is not likely, the study will be 
considered complete for the subject. The sponsor may elect to end study participation for 
non-users prior to end of study. 
8.4. 
Study Treatment Assignment 
Subjects will be assigned to treatment with study drug with the use of IWRS. There will 
be no subject randomization; however, each study drug kit will have a kit number which 
will be documented. The Investigator may adjust the study drug dose as medically 
appropriate, in accordance with guidelines provided in Section 8.1. 
8.5. 
Treatment Accountability and Compliance 
The pharmacist or other designated individual will maintain records of study treatment 
with study drug delivered to the study site, the inventory at the site, the distribution to and 
use by each subject, and the return of materials to the clinical supply vendor for storage 
or disposal. These records should include dates, quantities, batch/serial numbers, 
expiration dates, in clinic temperature log, and unique code numbers assigned to the 
product and study subjects. 
At each visit after initiation of treatment with study drug, site staff will record 
compliance of subjects with their assigned regimen. Subjects will be instructed to bring 
their diaries and study drug containers with unused/partially used/empty pouches back for 
inspection at each study visit. Subjects are to be reminded of the importance of 
compliance with their assigned regimen, with an emphasis on taking their study drug 
timed to occur during a qualifying seizure when it is safe to do so and maintaining the 
prescribed minimum interval between doses. 
Investigators will maintain records that document adequately that the subjects were 
provided with the correct study drug treatment kits and will reconcile the products 
received from the drug dispensing center. Study drug will not be returned to the clinical 
supplies vendor until accountability has been fully monitored. 
Unused medication must be returned at each visit, as compliance will be assessed by 
soluble film counts. Noncompliance is defined: 
• taking more than 2 doses for a single episode 
• treating a second episode in less than 5 days 
• treating more than 5 episodes per month 
• unaccounted for doses 
Discontinuation for noncompliance is at the Investigator’s discretion and is to be noted 
on the eCRF. 
Study drugs may be administered by a caregiver (including group home or school 
personnel) trained to assist with study drug administration. 


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8.6. 
Prior and Concomitant Illnesses and Medications 
8.6.1. 
Prior and Concomitant Illnesses 
Investigators should document all surgeries and prior significant illnesses that the subject 
has experienced prior to screening. Additional illnesses present at the time when 
informed consent is given and up to the time of first dosing are to be regarded as 
concomitant illnesses. Illnesses first occurring or detected during the study and/or 
worsening of a concomitant illness during the study are to be documented as AEs on the 
eCRF. For subjects completing the Aquestive Therapeutics Phase 2 studies, this 
information will be collected. 
 
8.6.2. 
Prior and Concomitant Medications 
All medications and other treatments taken by the subject during the study, including 
those treatments initiated prior to the start of the study, must be recorded on the eCRF. 
Medications taken by or administered to the subject for 30 days before screening will be 
recorded in the eCRF. After the baseline visit, concomitant medication will be reviewed 
on a case by case basis to determine further participation in the study. Any treatment or 
therapy that is taken by or administered to the subject during the course of the study must 
be recorded in the eCRF. The entry must include the dose, regimen, route, indication, and 
dates of use. 
Subjects who test positive for tetrahydrocannabinol (THC) at screening can continue with 
screening if the Principal Investigator is able to affirm that the use of a medical marijuana 
product is part of the subject’s treatment plan as recommended by a physician for 
treatment of a medical condition(s), and hence the marijuana product shall be recorded as 
a concomitant medication. This is applicable in states where medical marijuana use is 
legal. 


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9. 
STUDY PROCEDURES 
Table 6 outlines the timing of procedures and assessments to be performed throughout 
the study. All site visits and telephone contacts are calculated from the time of the 
Baseline Visit/Study Day 1 with the exception of the Final/Completion/Early Withdrawal 
Visit which is calculated from the time of the 6-month visit. 
See Section 11 for additional details of study procedures. 
NOTE: The schedule of procedures and assessments in this table assumes the subjects 
has experienced 3 uses of study drug over the minimum 6-month study period. For those 
subjects who have not experienced 3 uses of study drug, the Investigator and the Medical 
Monitor will assess on a case-by-case basis the likelihood of achieving 3 uses of study 
drug by continuing the subject on study for an additional 3 months. Thus, for these 
subjects who continue on study, the Day 180 (Month 6) visit would entail all procedures 
and assessments performed at the Day 90 (Month 3) visit including: 
• review training subject/caregiver on timing of study drug administration and use 
of electronic diary 
• review of study drug administration (IFU) 
• providing a new supply of study drug 
If the assessment concludes use of the study drug is not likely, the Sponsor may elect to 
end study participation for non-users prior to end of study 


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Table 6: 
Schedule of Assessments 
 
Study Period 
Screeninga 
Baselineb 
Study Drug Treatmentc 
(Study drug dosing administered away from the study site) 
Follow-up 
Visit 
Visit 1¶ 
Visit 2† 
Visit 3 
Telephone 
Contact 
Visit 4 
Visit 5 
(Final)# 
Telephone Contact ǂ 
Study Day 
Day -1 
to -28 
Day 1 
within 14 days post 
first study drug dose 
Day 30, Day 
60 
Day 90 
Day 180 
Month 7 
(Day 210 – Day 217) 
Informed Consent/Assentd 
× 
Demographye 
× 
Inclusion/Exclusion Criteria 
× 
× 
Training Subject/Caregiver on Study 
Drug Administration (IFU) and Use of 
Electronic Diaryf 
× 
× 
× 
× 
× 
Medical/Disease Historyg 
× 
× 
Concomitant Medication Review 
× 
× 
× 
× 
× 
× 
Vital Signs (blood pressure, heart rate, 
respiration rate, oral temperature)h 
× 
× 
× 
× 
× 
Body Height and Weighti 
× 
× 
× 
× 
× 
Complete Physical and Neurological 
Examinationj 
× 
Symptom Driven Physical and 
Neurological Examinationk 
× 
× 
× 
× 
C-SSRSl ¶¶ 
× 
× 
× 
× 
× 
Oral Mucosa Examinationm 
× 
× 
× 
× 
× 
12-lead ECGn 
× 
× 
× 
× 
× 
Urine and Serum Pregnancy Tests o 
× 
× 
× 
× 
× 


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Study Period 
Screeninga 
Baselineb 
Study Drug Treatmentc 
(Study drug dosing administered away from the study site) 
Follow-up 
Visit 
Visit 1¶ 
Visit 2† 
Visit 3 
Telephone 
Contact 
Visit 4 
Visit 5 
(Final)# 
Telephone Contact ǂ 
Study Day 
Day -1 
to -28 
Day 1 
within 14 days post 
first study drug dose 
Day 30, Day 
60 
Day 90 
Day 180 
Month 7 
(Day 210 – Day 217) 
Collect Samples for Complete Blood 
Count, Blood Chemistry, Urinalysis, 
Urine Drug Screen, Breath Alcohol 
Testsp †† 
× 
× 
× 
× 
× 
Gustatory Sense Assessment q ¶¶ 
× 
× 
× 
× 
Review Instances of At Home Study 
Drug Use with Subject r 
× 
x 
× 
x 
Quality of Life by age appropriate 
epilepsy scaless ¶¶ 
× 
× 
× 
× 
× 
Collect/Review Caregiver/Subject 
Diaryt 
× 
× 
× 
Supply Study Drug 
× 
× 
× 
×u 
Collect/Count Study Drug 
× 
× 
× 
Adverse Events Evaluationu 
×u 
×u 
× 
× 
× 
× 
× 
Study Site will telephone subjectsv 
× 
× 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale: ECG = electrocardiogram; IFU = Instructions for Use; NIH = National Institutes of Health; 
SAE=serious adverse event; WOCBP=women of childbearing potential. 
¶ Screening end date is 28 February 2020. 
† The last Baseline Visit/Study Day 1 will occur no later than 06 March 2020. 
# The last planned Study Completion Visit/Visit 5 will be in September 2020. 
ǂ The last subject telephone follow-up contact will occur in October 2020. The Sponsor has elected to extend the duration of treatment beyond 6 months under a similar 
schedule of visits. This policy is intended to continue for the period that the study remains open. See Section 6.1 Final/Completion or Early Withdrawal Visit for 
criteria and methods. 
¶¶ The QoL, C-SSRS, and Gustatory assessments should be completed in appropriately aged subjects. These assessments may be omitted as applicable if a 
subject's cognitive status does not allow the subject to personally complete the assessment. The site must document in the source documents the reason that 
these assessments cannot be completed (e.g., unable to perform test due to incapacity, etc.). 


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††The Alcohol Breath Test should be completed according to the schedule of assessments in subjects 17 years of age and older (and in subjects < 17 years of age 
at the Investigator's discretion). If a subject cannot complete the assessment or, if in the judgment of the Investigator, the subject's exposure to alcohol is 
limited as determined by the medical history, incapacity, etc., the site must document in the source documents the reason that the assessment is not completed. 
If a subject cannot provide a urine sample for drug screen, the same policy applies. If a subject cannot provide a urine sample or, if in the judgment of the 
Investigator, the subject's exposure to drugs of abuse is limited as determined by the medical history, incapacity, etc., the site must document in the source 
documents the reason that the assessment is not completed. If the subject cannot provide a urine sample for routine analysis, the site must document in the 
source documents the reason that the assessment is not completed. Urine samples obtained using a urine collection bag are acceptable. Urine-soaked diapers, 
urine pads, etc. are not acceptable methods of obtaining a urine sample for this study. The Sponsor does not advocate use of a urinary catheter. 
a Screening evaluation is to be conducted for all direct enrolling subjects within 28 days before the baseline visit. Rollover subjects may consent and undergo 
screening during their final visit of their Phase 2 trial, thus eliminating an additional screening visit. Subjects may be re-screened during the study per 
Investigator judgment after consultation with and approval by the Medical Monitor. 
b The Baseline visit includes a battery of assessments, as well as training in study drug administration and documentation and supply of study drug and study 
logs. 
c Study site visits will be conducted at Baseline, within 14 days after the first study drug dose, and approximately every 3 months until completion 6 months or 
Discontinuation. The study site staff will telephone the subjects at approximately 1 and 2 months ± 7 days after baseline to check on status, reinforce training 
on study drug administration and diary documentation, and address any concerns. 
d Before the performance of any study-related procedure, written informed consent will be obtained from the subject or subject’s legally authorized 
representative and oral and/or written assent will be obtained from the subject as required by the Institutional Review Board (IRB). 
e Age, weight, height, gender, ethnicity and race at screening; Body weight and height will be measured at every site visit. Study drug dosage based on age and 
body weight. Duration of epilepsy history is documented. 
f Training of subject/caregiver (as applicable) on the use of the electronic diary; use of the diary will be reviewed at each visit/contact to ensure 
subjects/caregivers understand and are comfortable with using the electronic diary. 
g Review/record medical history. 
h Vital signs include body temperature, respiration rate, heart rate, systolic and diastolic blood pressure measurements. All vital signs will be measured after the 
subject has been resting in a sitting position for at least 5 minutes. Blood pressure measurements are to be taken in the same arm (if possible) for the duration 
of the study. If a subject is unable to provide an oral temperature as they are unable to retain an oral thermometer in position with their mouth closed, a 
tympanic, axillary, or temporal (forehead) temperature may be taken. In this case, the method should be recorded in the source documents. 
i Body height and weight is obtained for all subjects at screening to document body mass index (kg/m2). Body weight (without shoes and with empty pockets) 
will be recorded whenever vital signs are recorded, and height (without shoes) will be recorded at all study site visits to calculate weight-based study drug 
dosage. 
j Complete physical examination: head, eyes, ears, nose, and throat (HEENT), heart, lungs, abdomen, skin, cervical and axillary lymph nodes, neurological and 
musculoskeletal systems. 
k Symptom-driven Physical and Neurological examinations will be conducted at the First/Day 1 visit, at the Final/Completion or Early Withdrawal visit, and as 
clinically indicated during the study. 
l C-SSRS; If a subject cannot complete the assessment, the site must document this. 
m Oral mucosal health assessment will be performed by the Investigator or trained Study nurse at all study site visits. In addition, any mucosal or tongue 
lacerations encountered during the study are recorded in the diary. 
n 12-lead ECG testing is performed at Screening, Baseline, and at all onsite visits including the Final Visit. When performed on days of blood draws, ECG 
should be completed prior to blood collection. 


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o Serum and/or urine pregnancy test for females of childbearing potential. If the subject is unable to provide a urine sample, the option to use only the serum 
pregnancy test will be at the Investigator's discretion. The reason that urine pregnancy testing could not be completed should be documented in the source 
documents and CRF. Females with positive pregnancy tests cannot be dosed. 
p Hematology testing includes Full and differential blood count, hematocrit, hemoglobin, RBC morphology, mean corpuscular volume, platelet count, RBC 
count and WBC with differential. Albumin, ALT, AST ALP, BUN, creatinine, creatine kinase, Na, K, Cl, Ca, glucose, protein, total protein, total bilirubin, 
uric acid will be performed. For urinalysis, dipstick is acceptable. Microscopic analyses if clinically indicated. 
q Gustatory sense assessment will be administered to cognitively-appropriate subjects 12 years and older at all site visits. The general Labeled Magnitude Scale 
(gLMS) will remain as the evaluation scale for gustation (taste) testing; however, commercially available test strips from Burghart Messtechnik will replace 
the liquid taste solutions described as part of the NIH Toolbox Regional Taste Intensity Test. 
r Study drug will be self-administered or with the assistance of a caregiver, as applicable. The dosing is administered remote from the study site, usually in the 
home setting, according to the IFU (see Appendix B) 
s Quality of life will be assessed at all study site visits by age appropriate epilepsy scales (Section 11.4). If a subject cannot complete the assessment, the site 
must document this. 
t Use of an electronic diary will be reviewed with the subject/caregiver (as applicable) to determine their ability/willingness to use the electronic diary during 
treatment. 
u Adverse events should be recorded. At the screening visit, this applies only to rollover subjects from the Phase 2 studies. For all other subjects, adverse events 
observed/reported after provision of informed consent/assent are recorded. Subjects must be followed for AEs for 30 days after the last study drug treatment 
administration or until all drug related toxicities have resolved, whichever is later. 
v The study site staff will telephone the subjects at approximately 1 and 2 months ± 7 days after the baseline visit to check on the subject’s health and seizure 
status, reinforce training on study drug administration and diary documentation, and to address concerns. The investigator or designee will conduct a follow-up 
phone call with the subject at 30-37 days after the Final Visit to check on subject status and collect reporting information, should any SAE have occurred. 


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9.1. 
Subject Informed Consent 
Before the performance of any study-related procedure, written informed consent will be 
obtained from the subject or subject’s legally authorized representative and oral and/or 
written assent will be obtained from the subject as required by the IRB. 
Subjects who initially consented and enrolled in the study under version 1 of the protocol 
dated 31 July 2017 may come in at their next scheduled site visit, reconsent under the 
amended protocol and be dispensed a new container of DBF based upon the revised 
mg/kg dosing in Table 4. The subjects do not need to come in for unscheduled visit. 
9.2. 
Procedures by Study Visit or Period 
Assessments are to be performed as outlined in the following by-visit subsections. 
 
9.2.1. 
Screening 
The Screening visit (Visit 1) will occur within 1 to 28 days prior to Study Day 1. 
Subjects who have completed the Phase 2 studies 160325 (Pediatric) or 160326 (Adult) 
which enrolled subjects with a similar diagnosis may screen for enrollment into this 
Phase 3 study when they come in for the follow-up visit after the last treatment period in 
the Phase 2 study (rollover subjects). These rollover subjects will be assessed for 
enrollment using inclusion/exclusion criteria of this protocol (42-1703). In addition to the 
Follow-up clinical laboratory assessments for the Phase 2 studies, clinical laboratory 
screen for this Phase 3 study includes HIV, HBsAg, and hepatitis C in subjects 17 years 
of age and older (and in subjects < 17 years of age at the Investigator’s discretion). 
The following procedures will be performed: 
• Obtain written informed consent/assent (Section 9.1) 
• Record medical/medication history and demographic information based on the 
interview with the potential subject 
• For rollover subjects from the Phase 2 studies described above, AEs will be 
documented/assessed (Section 11.10). 
• Obtain vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR], 
oral temperature). All vital signs will be measured after the subject has been 
resting in a sitting position for at least 5 minutes. Blood pressure 
measurements are to be taken in the same arm (if possible) for the duration of 
the study. 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a tympanic, 
axillary, or temporal (forehead) temperature may be taken. In this case, the 
method should be recorded in the source documents. 
• Obtain height and body weight (without shoes and with empty pockets) 
• Obtain a 12-lead ECG; ECG should be completed prior to any blood 
collection. 


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• Perform a complete physical and neurological examination, including 
examination of the oral cavity to verify there are no significant lesions, recent 
prophylactic procedures, mouth jewelry, dentures, braces, or piercings in the 
mouth or tongue that in the opinion of the Investigator would likely interfere 
with successful completion of the dosing procedure. 
• Advise potential subjects and caregivers that electronic diaries will be used by 
subjects and/or caregivers to document seizures, use of study drug, adverse 
events (AEs), changes in concomitant medication to determine their 
ability/willingness to comply with this procedure. 
• C-SSRS; Baseline Screening 
C-SSRS should be completed according to the schedule of assessments in 
appropriately aged subjects. These assessments may be omitted as applicable 
if a subject's cognitive status does not allow the subject to personally 
complete the assessment. The site must document in the source documents 
the reason that these assessments cannot be completed (e.g., unable to 
perform test due to incapacity, etc.). 
• Quality of Life (QoL) assessment by use of age-appropriate epilepsy scales 
(Appendix C through Appendix G). If a subject cannot complete the 
assessment, the site must document this along with the reason. 
QoL assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Collect blood and urine samples for hematology, chemistry, urinalysis and 
screening for drugs of abuse. Perform breath alcohol test. Urine and serum 
pregnancy test in female subjects of childbearing potential. A complete listing 
of all tests to be performed is provided in Section 11.9. 
If the subject is unable to provide a urine sample, the option to use only the 
serum pregnancy test will be according to Investigator judgment. 
The Alcohol Breath Test should be completed according to the schedule of 
assessments in subjects 17 years of age and older (and in subjects < 17 years 
of age at the Investigator's discretion). If a subject cannot complete the 
assessment or, if in the judgment of the Investigator, the subject's exposure to 
alcohol is limited as determined by the medical history, incapacity, etc., the 
site must document in the source documents the reason that the assessment is 
not completed. 
If a subject cannot provide a urine sample for drug screen or, if in the 
judgment of the Investigator, the subject's exposure to drugs of abuse is 
limited as determined by the medical history, incapacity, etc., the site must 
document in the source documents the reason that the assessment is not 


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completed. If the subject cannot provide a urine sample for routine analysis, 
the site must document in the source documents the reason that the 
assessment is not completed. Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine pads, etc. are not acceptable 
methods of obtaining a urine sample for this study. The Sponsor does not 
advocate use of a urinary catheter. 
• Principal Investigator’s/Sub-Investigator’s review of Inclusion/Exclusion 
criteria (Section 7.1 and Section 7.2) and all screening results/data to assess 
eligibility. 
NOTE: Subjects may be re-screened during the study per Investigator judgment after 
consultation with and approval by the Medical Monitor. 
9.2.2. 
Baseline (Study Day 1) 
The baseline period begins after the subject has successfully completed screening, within 
to 28 days after the screening visit. This is Day 1 for the subject in the study. The 
following procedures will be performed: 
• Review of Inclusion/Exclusion criteria 
• Review medical/medication history 
• Obtain vital signs (BP, HR, RR, oral temperature). All vital signs will be 
measured after the subject has been resting in a sitting position for at least 5 
minutes. Blood pressure measurements are to be taken in the same arm (if 
possible) for the duration of the study. 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a tympanic, 
axillary, or temporal (forehead) temperature may be taken. In this case, the 
method should be recorded in the source documents. 
• Obtain height and body weight (without shoes and with empty pockets) 
• Collect blood and urine samples for hematology, chemistry, urinalysis and 
screening for drugs of abuse. Perform breath alcohol test; urine and serum 
pregnancy test in female subjects of childbearing potential. A complete listing 
of all tests to be performed is provided in Section 11.9. 
If the subject is unable to provide a urine sample, the option to use only the 
serum pregnancy test will be according to Investigator judgment. 
The Alcohol Breath Test should be completed according to the schedule of 
assessments in subjects 17 years of age and older (and in subjects < 17 years 
of age at the Investigator's discretion). If a subject cannot complete the 
assessment or, if in the judgment of the Investigator, the subject's exposure to 
alcohol is limited as determined by the medical history, incapacity, etc., the 
site must document in the source documents the reason that the assessment is 
not completed. 


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If a subject cannot provide a urine sample for drug screen or, if in the 
judgment of the Investigator, the subject's exposure to drugs of abuse is 
limited as determined by the medical history, incapacity, etc., the site must 
document in the source documents the reason that the assessment is not 
completed. If the subject cannot provide a urine sample for routine analysis, 
the site must document in the source documents the reason that the 
assessment is not completed. Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine pads, etc. are not acceptable 
methods of obtaining a urine sample for this study. The Sponsor does not 
advocate use of a urinary catheter. 
• Perform symptom-driven physical examination, including examination of the 
oral cavity to verify there are no significant lesions, recent prophylactic 
procedures, mouth jewelry, dentures, braces, or piercings in the mouth or 
tongue that in the opinion of the Investigator would likely interfere with 
successful completion of the dosing procedure. 
• Perform limited neurological examination. 
• Gustatory sense assessment using the general labeled Magnitude Scale and 
commercially available Burghart Messtechnik taste test strips in cognitively- 
appropriate subjects 12 years and older. 
Gustatory sense assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• C-SSRS, since last visit. If a subject cannot complete the assessment, the site 
must document this along with the reason on the eCRF. 
C-SSRS assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Perform 12-lead ECG; ECG should be completed prior to any blood 
collection. 
• Quality of Life (QoL) assessment by use of age-appropriate epilepsy scales 
(Appendix C through Appendix G). If a subject cannot complete the 
assessment, the site must document this along with the reason. 
QoL assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 


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documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Review and record AEs 
• A starter kit containing 6 doses of one strength of study drug will be dispensed 
to each subject. The DBF dose will be determined according to age and 
weight category in a manner analogous to the Diastat® AcuDial™ label [11] 
(Table 4). 
• Subjects/caregivers will be instructed to call the site when the first seizure 
prompts study drug administration. A study site visit will occur within 14 days 
after the first study drug dosing. 
• Training of subjects/caregivers on drug administration and documentation in 
the electronic diary ensuring that subjects/caregivers understand: 
1. The guidelines on when to use study drug 
2. How to store study drug and how to obtain additional study drug if 
needed before the next scheduled visit 
3. How to administer study drug including review of Instructions for Use 
(IFU) 
4. Where to record information in the electronic diary 
a. Record assigned seizure type A, B, C, and D in the “Seizure Type 
Diary” 
b. Record seizures in the “Seizure Calendar” section of the diary; 
recording seizure type, number, and date 
c. Seizures other than those defined at baseline can be recorded in the 
“Change in Health” section 
d. Record each attempt to use study drug in the “Study Drug 
Administration and Usability” section 
e. Record study drug placement and disposition after application in the 
“Study Drug Administration and Usability” section 
f. Log of AEs and changes in health will be recorded in the “Change in 
Health” section. Any buccal mucosa or tongue lacerations 
encountered during the study will be recorded in the “Change in 
Health” section. 
g. Changes/additions to concomitant medications will be recorded in the 
“New Medications” section. 
Electronic diaries will be preprogrammed to transmit subject-entered data to the 
electronic diary database (Engage Portal) whenever the diary is connected to WiFi. Study 
center staff will monitor the electronic diary Engage Portal to ensure that subjects are 
recording medication use (following the Baseline/Day 1 visit), and that the data are being 
transmitted to the data base. Study center staff will follow up with subjects/caregivers as 
necessary to counsel them on completion of the electronic diaries. Study center staff will 
review the data entries with the subjects/caregivers at the study visits and ask 


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subjects/caregivers to fill in any missing study drug administration and usability 
questionnaires to the best of their recollection, if necessary. 
9.2.3. 
Treatment Period Clinical Site Visits 
Upon completion of the Baseline visit, the subject enters a 6-month minimum period of 
potential study drug treatment with an expectation that the subject will use the study drug 
at least 3 times over the 6-month period. Study site visits occur every 3 months (± 14 
days) after the Baseline Visit (Study Day 1/Visit 2) for a minimum of 6 months. 
The study visits will be conducted within 14 days after the first study drug dosing and 
then approximately every 3 months for a minimum of 6 months. The Sponsor has elected 
to extend the study beyond 6 months under a similar schedule of visits. The policy is 
intended to continue for the period while the study remains open. 
The following procedures will be performed at the study during the study drug treatment 
period. Additional details with frequency are listed in Table 6, Schedule of Assessments: 
• Review and record concomitant medications 
• Obtain vital signs (BP, HR, RR, oral temperature). All vital signs will be 
measured after the subject has been resting in a sitting position for at least 5 
minutes. Blood pressure measurements are to be taken in the same arm (if 
possible) for the duration of the study. 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a tympanic, 
axillary, or temporal (forehead) temperature may be taken. In this case, the 
method should be recorded in the source documents. 
• Obtain height and body weight (without shoes and with empty pockets) 
• Collect blood and urine samples for hematology, chemistry, urinalysis and 
screening for drugs of abuse. Perform breath alcohol test. Urine and serum 
pregnancy test in females of childbearing potential. A complete listing of all 
tests to be performed is provided in Section 11.9. 
If the subject is unable to provide a urine sample, the option to use only the 
serum pregnancy test will be according to Investigator judgment. 
The Alcohol Breath Test should be completed according to the schedule of 
assessments in subjects 17 years of age and older (and in subjects < 17 years 
of age at the Investigator's discretion). If a subject cannot complete the 
assessment or, if in the judgment of the Investigator, the subject's exposure to 
alcohol is limited as determined by the medical history, incapacity, etc., the 
site must document in the source documents the reason that the assessment is 
not completed. 
If a subject cannot provide a urine sample for drug screen or, if in the 
judgment of the Investigator, the subject's exposure to drugs of abuse is 
limited as determined by the medical history, incapacity, etc., the site must 
document in the source documents the reason that the assessment is not 


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completed. If the subject cannot provide a urine sample for routine analysis, 
the site must document in the source documents the reason that the 
assessment is not completed. Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine pads, etc. are not acceptable 
methods of obtaining a urine sample for this study. The Sponsor does not 
advocate use of a urinary catheter. 
• Perform symptom-driven physical examination, including examination of the 
oral cavity to verify there are no significant lesions, recent prophylactic 
procedures, mouth jewelry, dentures, braces, or piercings in the mouth or 
tongue that in the opinion of the Investigator would likely interfere with 
successful completion of the dosing procedure. 
• Perform limited neurological examination. 
• C-SSRS, since last visit. If a subject cannot complete the assessment, the site 
must document this along with the reason on the eCRF. 
C-SSRS assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Perform 12-lead ECG; ECG should be completed prior to any blood 
collection. 
• Obtain age-appropriate QoL assessment; Appendix C (PedsQL™ Epilepsy 
Module Parent Report for Toddlers (Ages 2-4); Appendix E (PedsQL™ 
Epilepsy Module Parent Report for Children (Ages 8-10); Appendix F 
(Quality of Life in Epilepsy for Adolescents QOLIE-48). 
QoL assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Oral mucosal health assessment will be performed by the Investigator or other 
trained site personnel. In addition, any mucosal or tongue lacerations 
encountered during the study are recorded in the diary. 
• Gustatory sense assessment by a trained Investigator, sub-investigator, or 
study nurse using commercially available test strips from Burghart 
Messtechnik in cognitively appropriate subjects 12 years of age and older. 
Gustatory sense assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 


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to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Review subject/caregiver diary for drug administration and usability and 
provide training as described in Section 9.2.1. 
• Dispense a new 3-month supply of study drug based on body weight and 
supportive documentation as needed. NOTE: where there is an overlap in age 
and weight criteria, the age-adjustment takes precedence (Table 4). 
Investigator may make adjustments as medically indicated (Section 8.1). 
• Review and record AEs 
9.2.4. 
Treatment Period (Remote Study Drug Administration) 
The study drug Treatment Period is for a minimum of 6 months after baseline (Day 1). 
The subjects will administer the study drug as needed with help of their caregiver, if 
applicable, to treat their recurring seizures as they would have with Diastat® AcuDial™, 
or other prescribed benzodiazepine. The subject or caregiver will document all 
procedures as trained (Section 9.2.2). Subjects and/or caregivers will perform the 
following: 
• Monitor and record seizures, using seizure calendar in electronic diary 
• Dose with study drug and record use in electronic diary 
• Complete diary documentation as instructed at the Baseline/Day 1 visit 
(Section 9.2.2) 
• Record any AEs in the electronic diary 
• Record any changes in concomitant medication in the electronic diary 
• Store study drug in a safe place with limited access (Section 0) 
• Bring unused study drug, empty pouches, and electronic diary to all study site 
visits 
9.2.4.1. 
Food and Fluid Intake 
Food and water will be allowed ad libitum at all times, except during the study drug 
application. Per dosing instructions, the subject should refrain from eating or drinking 
during study drug dosing until full dissolution of study drug has been confirmed by visual 
inspection. 
9.2.4.2. 
Dosing 
Dosing will occur away from the study site. The subject or caregiver will administer the 
study drug as described in the IFU. The actual time of study drug film placement will be 
documented in the study diary. 
A second dose, when required, may be given within 4 to 12 hours after the first dose, as 
previously discussed between the investigator and subject/caregiver. No more than 5 


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episodes per month or one episode every 5 days should be treated with study drug or with 
any other product containing diazepam (e.g., Diastat® AcuDial™) except as instructed by a 
physician. 
The DBF dose will be determined according to age and weight category in a manner 
analogous to the Diastat® AcuDial™ label [11] (Table 4). The rationale for the dose 
regimen of the test product is provided in Section 4.5.2.2. 
The adjustment of study drug dose by body weight and dispensing of study drug is done 
at each study visit with use of IWRS assigning the appropriate kit number. Where there is 
overlap in body weight with age, the age-adjustment takes precedence. The Investigator 
may also make adjustments as medically indicated. 
 
9.2.5. 
Treatment Period Scheduled Telephone Contact with Subjects 
Study site staff will telephone subjects approximately 1 and 2 months ± 7 days after the 
Baseline Visit (Study Day 1/Visit 2) to query the subject/caregiver regarding study drug 
administration, diary use, seizures, AEs, changes in concomitant medication, to reinforce 
training, and to address concerns. 
If subject has had qualifying seizures for which study drug was not taken, the site should 
determine if the subject chose to use a different rescue (eg, Diastat ® in lieu of study drug 
and the reasons why and brought back in for a study visit). The site should discuss with 
the medical monitor the appropriateness of the subject’s inclusion in the study. 
If the subject has not had any qualifying seizures within this timeframe, the site should 
discuss with the Medical Monitor the appropriateness of the subject’s inclusion in the 
study. 
9.2.6. 
Final / Completion or Early Withdrawal Visit 
The 6-month visit will serve as the study Final/Completion site visit . The Sponsor has 
elected to extend the study beyond 6 months under a similar schedule of visits. 
The last subject Final/Completion Visit is projected for September 2020. 
Prior to the subject’s return for the 6-month visit, site personnel will review the subject’s 
status with respect to use of study drug. If a subject has experienced 3 uses of study drug, 
study participation will be complete. For those subjects who have not experienced 3 uses 
of study drug, the Investigator and the Medical Monitor will assess on a case-by-case 
basis the likelihood of achieving 3 uses of study drug by continuing the subject on study 
for an additional 3 months. If considered likely, the subject’s participation can be 
extended for another 90 days with a similar schedule of assessments. If the assessment 
concludes use of the study drug is not likely, the study will be considered complete for 
the subject. The sponsor may elect to end study participation for non-users prior to end of 
study. 
Subjects who prematurely withdraw from the study for any reason should undergo a Final 
Visit as well. If the Early Withdrawal Visit is not done, the reason(s) will be recorded in 
the eCRF. 


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The following procedures will be performed. Additional details are listed in Table 6, 
Schedule of Assessments. 
• Review and record concomitant medications 
• Obtain vital signs (BP, HR, RR, oral temperature). All vital signs will be 
measured after the subject has been resting in a sitting position for at least 5 
minutes. Blood pressure measurements are to be taken in the same arm (if 
possible) for the duration of the study. 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a tympanic, 
axillary, or temporal (forehead) temperature may be taken. In this case, the 
method should be recorded in the source documents. 
• Obtain height and body weight (without shoes and with empty pockets) 
• Collect blood and urine samples for hematology, chemistry, urinalysis and 
screening for drugs of abuse. Perform breath alcohol test. Urine and serum 
pregnancy test in females of childbearing potential. A complete listing of all 
tests to be performed is provided in Section 11.9. 
If the subject is unable to provide a urine sample, the option to use only the 
serum pregnancy test will be according to Investigator judgment. 
The Alcohol Breath Test should be completed according to the schedule of 
assessments in subjects 17 years of age and older (and in subjects < 17 years 
of age at the Investigator's discretion). If a subject cannot complete the 
assessment or, if in the judgment of the Investigator, the subject's exposure to 
alcohol is limited as determined by the medical history, incapacity, etc., the 
site must document in the source documents the reason that the assessment is 
not completed. 
If a subject cannot provide a urine sample for drug screen or, if in the 
judgment of the Investigator, the subject's exposure to drugs of abuse is 
limited as determined by the medical history, incapacity, etc., the site must 
document in the source documents the reason that the assessment is not 
completed. If the subject cannot provide a urine sample for routine analysis, 
the site must document in the source documents the reason that the 
assessment is not completed. Urine samples obtained using a urine collection 
bag are acceptable. Urine-soaked diapers, urine pads, etc. are not acceptable 
methods of obtaining a urine sample for this study. The Sponsor does not 
advocate use of a urinary catheter. 
• Perform symptom-driven physical examination, including examination of the 
oral cavity to verify there are no significant lesions, recent prophylactic 
procedures, mouth jewelry, dentures, braces, or piercings in the mouth or 
tongue that in the opinion of the Investigator would likely interfere with 
successful completion of the dosing procedure. 


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• Perform gustatory sense assessment using the general labeled Magnitude 
Scale and commercially available Burghart Messtechnik taste test strips in 
cognitively-appropriate subjects 12 years and older. 
Gustatory sense assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Administer C-SSRS, since the last visit. If a subject cannot complete the 
assessment, the site must document this along with the reason on the eCRF. 
C-SSRS assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's cognitive status does not allow the subject 
to personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Perform 12-lead ECG; ECG should be completed prior to any blood 
collection. 
• Obtain age-appropriate QoL assessment; Appendix C (PedsQL™ Epilepsy 
Module Parent Report for Toddlers (Ages 2-4); Appendix E (PedsQL™ 
Epilepsy Module Parent Report for Children (Ages 8-10); Appendix F 
(Quality of Life in Epilepsy for Adolescents QOLIE-48). 
QoL assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be 
omitted as applicable if a subject's (or parent's/guardian's/caregiver's) 
cognitive status does not allow the subject (or parent/guardian/caregiver) to 
personally complete the assessment. The site must document in the source 
documents the reason that these assessments cannot be completed (e.g., 
unable to perform test due to incapacity, etc.). 
• Review subject/caregiver diary for drug administration and usability and 
provide training as described in Section 9.2.1. 
• Review and record AEs 
• Review study drug 
• Return unused drug 
9.2.7. 
Telephone Contact 30-37 Days After the Final Visit 
The last subject telephone follow-up contact is projected to occur in October 2020. 
The Investigator or designee will conduct a follow-up phone call with the subject at 30- 
37 days after the Final Visit to check on subject status and collect AE information. 


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9.2.8. 
Unscheduled Visits 
The Investigator may at his/her discretion arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up, or an AE considered by 
the Investigator to be possibly related to the use of study drug. The unscheduled visit 
page in the eCRF must be completed. 


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10. 
EFFICACY ASSESSMENTS 
Not applicable. 


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11. 
SAFETY ASSESSMENTS 
Safety assessments are performed at each study visit/contact, as specified in the Schedule 
of Assessments, Table 6. 
11.1. 
Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, systolic and diastolic blood 
pressure measurements) will be measured, recorded, and evaluated at the visits indicated 
in the Schedule of Assessments. All vital signs will be measured after the subject has 
been resting in a sitting position for at least 5 minutes. Blood pressure measurements are 
to be taken in the same arm (if possible) for the duration of the study. 
Vital sign measurements will be repeated if clinically significant or machine/equipment 
errors occur. Out-of-range BP, RR or HR measurements will be repeated at the 
Investigator’s discretion. Any confirmed, clinically significant vital sign measurements 
must be recorded as AEs. 
11.2. 
Body Height and Weight 
Body weight (without shoes, and empty pants pockets) will be recorded whenever vital 
signs are recorded, and height (without shoes) will be recorded at all study site visits, to 
calculate weight-based study drug dosage. 
11.3. 
Physical and Neurological Examinations 
A complete physical examination (head, eyes, ears, nose, and throat [HEENT], heart, 
lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and 
musculoskeletal systems) will be performed at Screening Visit 1. Physical examinations 
will be performed by medically qualified site personnel. In addition, medical history will 
be recorded at screening, including smoking history, if applicable. 
A symptom-driven physical examination to verify continued subject eligibility and to 
follow up any change in medical history will be performed at the visits indicated in the 
Schedule of Assessments. Symptom-driven limited physical and neurological 
examinations will be performed at First, Early Withdrawal / Completion Visit, and as 
clinically indicated at any study visit. All changes not present at baseline or described in 
the past medical history and identified as clinically noteworthy must be recorded as AEs. 
11.4. 
Quality of Life Assessments 
Age-appropriate QoL assessments will be performed at all study site visits (Table 7). 
QoL administration should be delayed if a subject has experienced a simple or complex 
seizure within the previous 4 hours, or a generalized tonic-clonic seizure within the 
previous 24 hours. 
If a subject moves from one age range to the next while participating in the study, 
continued to use the same scale throughout the study. Do not switch to the next QoL 
module. 


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Table 7: 
Age-Defined Quality of Life Assessment Modules 
 
Scale Name 
Corresponding Age 
Ranges in This Studya 
Who Completes the Assessment 
PedsQL 3.0 Epilepsy Module 
2-4 years 
Parent/Guardian/Caregiver 
PedsQL Parent Proxy Report (Ages 2-4 
years) 
PedsQL 3.0 Epilepsy Module 
5-7 years 
Parent/Guardian/Caregiver 
PedsQL Parent Proxy Report (Ages 5-7 
years) 
PedsQL 3.0 Epilepsy Module 
8-12 years 
Parent/Guardian/Caregiver 
PedsQL Parent Proxy Report (Ages 8-12 
years) 
QOLIE-AD-48 (Version 1) 
11-17 years 
Self-assessment 
QOLIE-31-P (Version 2) 
18 years and older 
Self-assessment 
a Please note this column indicates the age range for each Scale to be applied in this study. 
Non-verbal and cognitively impaired subjects are eligible to participate in the study. The 
Quality of Life assessments should be personally completed by the subject using non- 
verbal methods with assistance of site staff trained for these assessments. If the scales are 
not able to be completed, the site must document this. 
Quality of Life assessment should be completed according to the schedule of assessments 
in appropriately aged subjects. These assessments may be omitted as applicable if a 
subject's cognitive status does not allow the subject to personally complete the 
assessment. The site must document in the source documents the reason that these 
assessments cannot be completed (e.g., unable to perform test due to incapacity, etc.). 
11.5. 
Columbia Suicide Severity Rating Scale 
The C-SSRS, which assesses suicidal behavior and ideation, will be administered at each 
study visit. Qualified, trained staff will administer the C-SSRS, Baseline-Screening 
version at screening, and the C-SSRS, Since Last Visit version will be administered at 
Baseline and all subsequent visits. Subjects with Type 4 (active suicidal ideation with 
some intent to act, without specific plan) or Type 5 (active suicidal ideation with specific 
plan and intent) suicidal ideation during the study will be discontinued from the study and 
referred to a mental health professional. 
The C-SSRS assessment should be completed according to the schedule of assessments in 
appropriately aged subjects. These assessments may be omitted as applicable if a 
subject's cognitive status does not allow the subject to personally complete the 
assessment. The site must document in the source documents the reason that these 
assessments cannot be completed (e.g., unable to perform test due to incapacity, etc.). 


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11.6. 
Oral Mucosa Health Assessment 
A checklist was developed to use in the assessment of the health of the oral mucosa with 
sporadic, yet chronic use of study drug. During site initiation, use of the oral mucosa 
examination checklist will be reviewed with the clinical investigators and other medically 
qualified study personnel. 
The examiner will make an illumination-assisted visual inspection of the oral mucosa at 
Screening, and at all study site visits. Mucosal irritation and any injuries to the oral cavity 
(e.g., tongue or mucosa laceration, broken tooth, bleeding) will be recorded using criteria 
specified in a checklist in the eCRF. Any de novo post-dose mucosal irritation or other 
abnormality will be reported as an AE of special interest and will be followed until 
resolution. 
 
11.7. 
Gustatory Sense Assessment 
A gustatory (sense of taste) assessment using commercially available taste test strips from 
Burghart Messtechnik, in subjects 12 years and older, will be conducted by trained 
Investigator or other trained site personnel. 
The general Labeled Magnitude Scale (gLMS) will be used as the evaluation scale 
(ranging from “no sensation at all” to “strongest sensation of any kind”) using 
commercially available taste test strips from Burghart Messtechnik The taste strips are 
statistically well-correlated with the NIH Toolbox Regional Taste Intensity Test 
solutions.[17] The test takes approximately 6 minutes to administer. The subject must not 
eat or drink for 30 minutes prior to completing the taste test. 
The assessment will be performed during all study site visits. 
Gustatory sense assessment should be completed according to the schedule of 
assessments in appropriately aged subjects. These assessments may be omitted as 
applicable if a subject's cognitive status does not allow the subject to personally complete 
the assessment. The site must document in the source documents the reason that these 
assessments cannot be completed (e.g., unable to perform test due to incapacity, etc.). 
11.8. 
Electrocardiograms 
A 12-lead resting ECG will be obtained at the visits indicated in the Schedule of 
Assessments (Table 6). When performed on days of blood draws, ECG should be 
completed prior to blood collection. 
At Screening, the Investigator will examine the ECG traces for signs of cardiac disease 
that could exclude the subject from the study. An assessment of normal or abnormal will 
be recorded and if the ECG is considered abnormal, the abnormality will be documented 
on the eCRF. ECGs will be repeated at Baseline and 6 months after dosing, and at the 
Study Final/Completion or Early Withdrawal Visit, and at any study site visit if clinically 
significant abnormalities are observed or artifacts are present. 


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11.9. 
Laboratory Assessments 
Laboratory assessment samples listed below in Table 8 will be obtained at the visits 
indicated in the Schedule of Assessments (Table 6). 
Table 8: 
Laboratory Assessments 
 
Hematology 
Serum Chemistry 
Urine Analysis 
(dipstick) 
Full and differential blood count 
Albumin 
pH 
Hematocrit (Hct) 
Alanine aminotransferase (ALT) 
Protein 
Hemoglobin (Hb) 
Alkaline phosphatase (ALP) 
Glucose 
Red blood cell (RBC) morphology 
Aspartate aminotransferase (AST) 
Ketone bodies 
Mean corpuscular volume (MCV) 
Blood urea nitrogen (BUN) or Urea 
Indicators of blood and 
WBCs 
Nitrites 
Specific gravity 
Platelet count 
Creatinine 
RBC count 
Creatine kinase 
White blood cell (WBC) count with 
differential 
Electrolytes (Na, K, Cl, Ca) 
Urine human chorionic 
gonadotropin (HCG) in 
pre-menopausal females 
only 
Urobilinogen 
Glucose 
Protein 
Total bilirubin 
Uric Acid 
Serology: At screening (in subjects 17 years of age and older) tests for HIV, HBsAg, and HCV. Test 
positive for any of these tests is exclusionary. These may be collected in subjects < 17 years of age at the 
Investigator’s discretion. 
Pregnancy Tests: Both serum and urine pregnancy tests will be performed in all female subjects of 
childbearing potential; if the subject is unable to provide a urine sample, the option to use only the serum 
pregnancy test will be according to Investigator judgment. 
Breath Alcohol Test: The Alcohol Breath Test should be completed according to the schedule of 
assessments in subjects 17 years of age and older (and in subjects < 17 years of age at the Investigator's 
discretion). If a subject cannot complete the assessment or, if in the judgment of the Investigator, the 
subject's exposure to alcohol is limited as determined by the medical history, incapacity, etc., the site 
must document in the source documents the reason that the assessment is not completed. 
Urine Tests for Drugs of Abuse: amphetamines, phencyclidine, cocaine, opiates, benzodiazepines, 
tetrahydrocannabinol; if a subject cannot provide a urine sample for drug screen, an accurate and 
thorough review should be conducted by the Investigator with the subject and/or subject’s 
caregiver/study partner/Legally Authorized Representative. This review should include, as applicable, a 
Physical Exam, Review of Systems/Symptoms (ROS), Past Medical History, Concomitant Medications 
(including last known diazepam use), any new or ongoing adverse events, sexual activity history, 
pregnancy/menstrual cycle status and illicit drug use. 
Blood and urine samples will be analyzed at a central laboratory facility. Urine samples 
will be analyzed by dipstick, and a microscopic analysis will be performed if the results 
of dipstick indicate abnormalities to be further investigated. All laboratory reports must 
be reviewed, signed, and dated by the Investigator. A legible copy of all reports must be 
filed with both the subject's eCRF and medical record (source document) for that visit. 
Any laboratory test result considered by the Investigator to be clinically significant 


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should be considered an AE (clinically significant AEs include those that require an 
intervention). Clinically significant abnormal values occurring during the study will be 
followed until repeat test results return to normal, stabilize, or are no longer clinically 
significant. 
If/When a protocol-required urine sample cannot be obtained from the subject (at any 
study visit), the Investigator should in lieu ensure that an accurate and thorough review 
be conducted by the Investigator with the subject and/or subject’s caregiver/study 
partner/Legally Authorized Representative. This review should include, as applicable, a 
Physical Exam, Review of Systems/Symptoms (ROS), Past Medical History, 
Concomitant Medications (including last known diazepam use), any new or ongoing 
adverse events, sexual activity history, pregnancy/menstrual cycle status and illicit drug 
use. This is extremely important during the screening/eligibility visit as the urine sample 
is a key component/assessment in determining a host of inclusion and exclusion criteria. 
As with other missing/unobtainable protocol-mandated assessments, the site must 
document the reason why the urine sample could not be obtained from the subject (e.g., 
subject is incontinent, subject is incapable of supplying a urine sample on request, etc.) 
in the source documents and via the eCRF. 
Urine samples obtained using a urine collection bag are acceptable. Urine-soaked diapers, 
urine pads, etc. are not acceptable methods of obtaining a urine sample for this study. The 
Sponsor does not advocate use of a urinary catheter. 
11.10. 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during 
the study or, if present at screening, worsens during the study, regardless of the suspected 
cause of the event. All medical and psychiatric conditions (except those related to the 
indication under study) present at screening will be documented in the medical history 
eCRF. Changes in these conditions and new symptoms, physical signs, syndromes, or 
diseases should be noted on the AE eCRF during the rest of the study. Symptoms present 
at screening in rollover subjects whose screening visit is also their final visit of the Phase 
2 study will be recorded as AEs (Table 6). Clinically significant laboratory abnormalities 
should also be recorded as AEs. Surgical procedures that were planned before the subject 
enrolled in the study are not considered AEs if the conditions were known before study 
inclusion; the medical condition should be reported in the subject’s medical history. 
Additionally, anticipated AEs for this study population, listed below, must be reported by 
Investigators to the Sponsor but will not be expedited on an individual basis. Instead 
these AEs will be reviewed in aggregate every three months by Syneos Health 
responsible group or Data and Safety Monitoring Board (DSMB). This aggregate review 
may result in an expedited safety report. 
 
11.10.1. 
Anticipated Adverse Events for this Study and Precautions 
 
11.10.1.1. List of Anticipated Adverse Events for this Study 
The most frequent adverse event reported to be related to Diastat®AcuDial™ in the two 
double-blind, placebo-controlled studies was somnolence (23%). Less frequent adverse 


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events were headache (≤ 5%), diarrhea (≤ 4%), ataxia (≤ 3%), dizziness (≤ 3%), euphoria 
(≤ 3%), incoordination (≤ 3%), rash (≤ 3%), vasodilatation (≤ 2%), and asthma (≤ 2%). 
The majority of adverse events were mild to moderate in severity and transient in nature. 
Adverse events reported elsewhere were dose related and included fatigue, drowsiness, 
muscle weakness, ataxia, occasional dizziness, dysarthria, slurred speech, headache, 
paradoxical reactions, confusion, emotional poverty, decreased alertness, depression, and 
increased or decreased libido (Valium® package insert 2015). 
In the pilot study drug bio-equivalence bio-availability studies, the most frequently 
reported adverse event was somnolence. In Study1899, there were 7 occurrences of 
somnolence in 7 subjects while taking 5 mg study drug and there were 10 occurrences of 
somnolence in 10 subjects while taking 5 mg Diastat®AcuDial™ rectal gel. In Study 
1900, there were 12 occurrences of somnolence in 12 subjects while taking 20 mg study 
drug and there were 11 occurrences of somnolence in 11 subjects while taking 20 mg 
Diastat®AcuDial™ rectal gel. 
11.10.1.2. Cautionary Statements 
Due to the Central Nervous System (CNS) depressant effect of diazepam, any subject or 
subject taking it should be cautioned not to operate dangerous machinery or motor 
vehicles or engage in activities requiring mental alertness until they have returned to their 
baseline level of functioning. Additionally, there is the potential for a synergistic CNS 
depressant effect when diazepam is used simultaneously with alcohol or other CNS 
depressants including barbiturates, anxiolytics, sedatives, anti-depressants, hypnotics, 
anti-epileptic drugs, phenothiazines, skeletal muscle relaxants, anti-histamines, narcotic 
analgesics and anesthetics. 
Although study drug will not be used on a chronic daily basis, as noted in the preceding 
sections, diazepam is a Schedule IV controlled substance and can produce drug 
dependence. Caution should be used in any subject with a history, however remote, of 
alcohol or drug abuse or dependence. Diazepam may interact with disulfiram, cimetidine, 
ketoconazole, fluvoxamine, fluoxetine, diltiazem or omeprazole resulting in increased 
plasma levels of diazepam. Subjects who have taken diazepam concomitantly with these 
medications or within 5 half-lives of the respective drug, should be observed closely for 
evidence of enhanced benzodiazepine response (e.g., increased or prolonged sedation 
(Valium® PI). 
 
11.10.2. 
Collection and Documentation of Adverse Events 
Subjects/caregivers will be instructed to report AEs at each study visit. All AEs are to be 
followed until resolution or until a stable clinical endpoint is reached. Any de novo post- 
dose mucosal irritation or other abnormality will be reported as an AE of special interest 
and will be followed until resolution (see Section 11.6 ). 
Each AE is to be documented on the eCRF with reference to date of onset, duration, 
frequency, severity, relationship to study drug, action taken with study drug, treatment of 
event, and outcome. Furthermore, each AE is to be classified as being serious or 
non-serious. Changes in AEs and resolution dates are to be documented on the eCRF. 


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For the purposes of this study, the period of observation for collection of AEs extends 
from the time the subject gives informed consent until the Final Visit. Follow-up of the 
AE, even after the date of therapy discontinuation, is required if the AE persists until the 
event resolves or stabilizes at a level acceptable to the Investigator. The Investigator or 
designee will conduct a follow-up phone call with the subject at 30-37 days after the 
Final Visit to check on subject status and collect reporting information, should any SAE 
have occurred. 
Specific guidelines for classifying AEs by intensity and relationship to study drug are 
given in Table 9 and Table 10. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be recorded. If the intensity category changes 
over a number of days, then the changes should be recorded separately (with distinct 
onset dates). 
Table 9: 
Classification of Adverse Events by Intensity 
 
MILD 
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
MODERATE 
An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
SEVERE 
An event that prevents normal everyday activities 
Table 10: 
Classification of Adverse Events by Relationship to Study Drug 
 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to drug administration, unlikely to be attributed to current 
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 reasonable 
time sequence 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 adverse events which are judged to be clearly 
and incontrovertibly due to extraneous causes (disease, environment, etc.) 
and do not meet the criteria for drug relationship listed for the above- 
mentioned conditions. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the event should be recorded. If the intensity category changes 
over a number of days, then the changes should be recorded separately (with distinct 
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11.10.3. 
Serious Adverse Events and Reporting 
 
11.10.3.1. Serious Adverse Events 
An AE is considered “serious” if, in the view of either the Investigator or the Sponsor, it 
meets 1 or more of the following criteria: 
• is fatal 
• is life-threatening 
• 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/birth defect 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered 
serious adverse events (SAEs) if they are thought to jeopardize the subject and/or require 
medical or surgical intervention to prevent one of the outcomes defining a SAE. Since 
SAEs are critically important for the identification of significant safety problems, it is 
important to take into account both the Investigator’s and the Sponsor’s assessment. If 
either the Sponsor or the Investigator believes that an event is serious, the event must be 
considered serious and evaluated by the Sponsor for expedited reporting. 
 
11.10.3.2. Reporting Serious Adverse Events 
An SAE occurring during the study or 30 days of stopping the study drug treatment must 
be reported to the Syneos Pharmacovigilance Group and will be communicated to the 
Sponsor. Any such SAE due to any cause, whether or not considered related to the study 
drug, must be reported within 24 hours of occurrence or when the Investigator becomes 
aware of the event. Notification can be made using the dedicated fax line or telephone 
line for the Syneos Pharmacovigilance Group: 
 
Syneos Pharmacovigilance Fax Number: 
+1-866-856-1649 
Syneos Pharmacovigilance Telephone Number: 
+1-888-750-8020 
 
Email In case of emergency or fax failure the report can also be submitted by email to 
saereceipt.international@syneoshealth.com 
If the Investigator contacts the Syneos Pharmacovigilance Group by telephone, then a 
written report must follow within 24 hours and is to include a full description of the event 
and sequelae in the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE electronic eCRF. Preliminary reports 
of SAEs must be followed by detailed descriptions later on, including clear and 
anonymized photocopies of hospital case reports, consultant reports, autopsy reports, and 
other documents when requested and applicable. SAE reports must be made whether or 
not the Investigator considers the event to be related to the investigational drug. 


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Appropriate remedial measures should be taken to treat the SAE, and the response should 
be recorded. Clinical, laboratory, and diagnostic measures should be employed as needed 
in order to determine the etiology of the problem. The Investigator must report all 
additional follow-up evaluations to the Syneos Pharmacovigilance Group within 10 
calendar days. All SAEs will be followed until the Investigator and Sponsor agree the 
event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
subject’s participation in the study is to be followed until it either resolves, stabilizes, 
returns to baseline values (if a baseline value is available), or is shown to not be 
attributable to the study drug or procedures. 
 
11.10.4. 
Pregnancy 
Female subjects of childbearing potential must not be pregnant or breast feeding and 
must have a negative pregnancy test at Screening. 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 
phone and by faxing/emailing a completed Pregnancy Report to the Sponsor (or 
designee) within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the Investigator will follow the subject until completion 
of the pregnancy and must assess the outcome in the shortest possible time but not more 
than 30 days after completion of the pregnancy. The Investigator should notify the 
Sponsor (or designee) of the pregnancy outcome by submitting a follow-up Pregnancy 
Report. If the outcome of the pregnancy meets the criteria for immediate classification of 
an SAE (e.g., spontaneous or therapeutic abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator will report the event by phone and by faxing a completed SAE form to the 
Sponsor (or designee) within 24 hours of knowledge of the event. 
 
11.10.5. 
Overdose 
The Investigator must immediately notify the Sponsor of any occurrence of overdose 
with study drug. Previous reports of diazepam overdose have shown that manifestations 
of diazepam overdose include somnolence, confusion, coma, and diminished reflexes. 
Respiration rate, pulse and blood pressure should be monitored, as in all cases of drug 
overdose, although, in general, these effects have been minimal. General supportive 
measures should be employed, along with intravenous fluids, and an adequate airway 
maintained. Hypotension may be combated by the use of levarterenol or metaraminol. 
Dialysis is of limited value. Flumazenil, a specific benzodiazepine-receptor antagonist, is 
indicated for the complete or partial reversal of the sedative effects of benzodiazepines 
and may be used in situations when an overdose with a benzodiazepine is known or 
suspected. Prior to the administration of flumazenil, necessary measures should be 
instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as 
an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. 
Subjects 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 


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flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic 
antidepressant overdose. Caution should be observed in use of flumazenil in epileptic 
subjects treated with benzodiazepines. The complete flumazenil package insert, including 
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, should be consulted 
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12. 
STATISTICAL ANALYSIS 
All analyses will be descriptive, and no formal statistical testing will be performed. All 
summaries will be done for all subjects combined, as well as by age group (pediatric, 
adolescent, adult). Pediatric and adolescent subjects might be combined as 1 group for 
summary purpose. 
The statistical evaluation will be performed using the Statistical Analysis Software 
(SAS®) Version 9.3 or higher (SAS Institute, Cary, NC). All data will be listed, and 
summary tables will be provided. Summary statistics will be presented by age group and 
overall. For continuous variables, data will be summarized with the number of subjects 
(n), mean, standard deviation (SD), median, min, and max. For categorical variables, data 
will be tabulated with the number and proportion of subjects for each category. 
A separate statistical analysis plan (SAP) will provide further details regarding the 
summary statistics to be provided. The SAP will serve as a compliment to the protocol 
and supersedes it in case of differences. 
12.1. 
Determination of Sample Size 
A maximum of 120 subjects with epilepsy will be screened, with about 50 pediatric and 
adolescent and about 50 adult subjects planned. A minimum of 100 subjects is expected 
to be enrolled. This sample size is based on practical reason instead of statistical 
consideration. The enrollment should include at least 20 subjects in the 6 to 11-year-old 
group and 20 subjects in the 12 to 16-year-old group. 
12.2. 
Analysis Population 
Safety Population: all subjects administered at least 1 dose of study drug. The Safety 
Population is used for all data summaries. 
12.3. 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized descriptively by 
age group and overall. Subject demographic baseline disease characteristics include age, 
race, gender, weight (kg), height (cm), BMI (kg/m2), and duration of epilepsy. 
12.4. 
Safety Analysis 
12.4.1. 
Primary Safety Endpoints 
 
12.4.1.1. Adverse Events 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA version 20.0, or later). The incidence of TEAEs (adverse events with onset 
dates on or after administration of study drug) will be included in incidence tables. 
Events with missing onset dates will be included as study drug treatment-emergent. If a 
subject experiences more than 1 occurrence of the same AE, the occurrence with the 
greatest severity and the closest association with the study drug will be used in the 
summary tables. SAEs and AEs causing discontinuation will be tabulated. All AEs will 


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be listed by subject, along with information regarding onset, duration, relationship and 
severity to study drug, action taken with study drug, treatment of event, and outcome. 
Exploratory analysis of possible correlation between AEs and exposure might be 
performed, in addition to other variables such as age, gender, cognitive status, 
concomitant medications: 
• Documentation and assessment of TEAEs (serious and non-serious; time, 
incidence and severity, relationship to study drug treatment) over the time 
elapsed between visits. 
• Review of the caregiver/subject electronic diary which captures the 
occurrence of seizures and location of study drug placement for each cluster 
treated. In addition, the subject or caregiver documents any adverse effects 
• Documentation and assessment of AEs (serious and non-serious; time, 
incidence and severity, relationship to study drug treatment) over the time 
elapsed between visits 
• Assessment of safety measures at end of study vs baseline: 
− Vital signs (BP, HR, RR, oral temperature) 
If a subject is unable to provide an oral temperature as they are unable to 
retain an oral thermometer in position with their mouth closed, a 
tympanic, axillary, or temporal (forehead) temperature may be taken. In 
this case, the method should be recorded in the source documents. 
− Body height and weight 
− Electrocardiogram (12-lead ECG) 
− Clinical laboratory tests (hematology, serum chemistry, urinalysis) 
− Assessment of oral mucosa by oral examination 
− Physical and Neurological examination 
− C-SSRS 
− Age-defined QoL assessments 
• Pathological change in oral mucosa as measured by an oral examination 
• Gustatory changes as measured by the by the general Labeled Magnitude 
Scale (gLMS) using commercially available taste test strips from Burghart 
Messtechnik 
Descriptive summaries will be provided for change in oral mucosa and gustation at each 
visit. 
12.4.1.2. C-SSRS Assessment 
Frequency and severity of suicidality using the C-SSRS will be summarized at each visit. 


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12.4.1.3. Vital Signs 
Vital signs (BP, HR, RR, oral temperature) will be summarized for each visit. If a subject 
is unable to provide an oral temperature as they are unable to retain an oral thermometer 
in position with their mouth closed, a tympanic, axillary, or temporal (forehead) 
temperature may be taken. In this case, the method should be recorded in the source 
documents. 
12.4.1.4. Laboratory Analyses 
Clinical laboratory data will be summarized using descriptive statistics at each visit 
separately for hematology, serum chemistry, urinalysis and drug screen, see Table 8. For 
hematology and serum chemistry laboratory tests, numbers of subjects with values 
outside limits of the normal range at each visit will be summarized. 
12.4.1.5. Oral Mucosa Examination 
Pathological change in oral mucosa as measured by an illuminated oral examination will 
be summarized at each visit. 
12.4.1.6. Gustatory Sense Assessment 
Gustatory sense changes as measured by the general Labeled Magnitude Scale (gLMS) 
using commercially available taste test strips from Burghart Messtechnik will be 
summarized at each visit. 
12.4.2. 
Secondary Safety Endpoints 
 
12.4.2.1. Electrocardiograms 
Summary tables will be provided for 12-lead ECG results obtained for all study visits. 
 
12.4.2.2. Concomitant Medications 
Summary tables will be provided for concomitant medications initiated after 
administration of study drug. 
12.4.2.3. Other Safety Assessments 
Summaries will be provided for other safety assessments for all study visits: 
• physical and neurological examinations – descriptive summaries will be 
provided 
• body height and weight and BMI (kg/m2) – summary tables will be provided 
12.4.3. 
Secondary Tolerability Endpoint 
 
12.4.3.1. Quality of Life Assessment 
Quality of Life assessment by age appropriate use of epilepsy scales will be summarized 
at all study visits for the 6-month period. 


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12.4.4. 
Secondary Usability Endpoint 
 
12.4.4.1. Oral Cavity Insertion and Retention Assessment 
Attempt is defined as the process of placing the study drug against the buccal mucosa in 
the oral cavity. Categorical explanations will be capture for attempt failures and will be 
presented in data listings. 
Descriptive summaries will be provided for the following variables: 
• Handling and administration of study drug, based on IFU 
− Ability to open packaging and remove study drug 
− Successful study drug buccal insertion 
o Successful insertion will be defined as the process of placing the 
study drug against the buccal mucosa 
o Categorical explanations will be captured for unsuccessful 
insertion 
• Oral cavity placement and retention assessment 
− Study drug is swallowed prior to sticking to inner check 
− Study drug spit out or blown out by subject after administration 
12.5. 
Interim Analysis 
An interim analysis is planned to obtain a snapshot of targeted Tables, Figures, and 
Listings and summary of the preliminary safety information. 
12.6. 
Data Monitoring Committee 
Not applicable. 


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13. 
STUDY MANAGEMENT 
13.1. 
Approval and Consent 
13.1.1. 
Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration 
of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the Code of Federal Regulations (CFR), and in compliance with 
GCP guidelines. 
 
13.1.2. 
Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted Investigational 
Review Board/Investigational Ethics Committee (IRB/IEC). Approval is required for the 
study protocol, investigational drug brochure, protocol amendments, Informed Consent 
Forms (ICFs), and subject information sheets. 
 
13.1.3. 
Informed Consent 
For each study subject, written informed consent will be obtained prior to any protocol 
related activities. As part of this procedure, the Principal Investigator (PI) or one of 
his/her associates must explain orally and in writing the nature, duration, and purpose of 
the study, and the action of the drug in such a manner that the subject and/or the subject’s 
parent(s) or legally authorized representative are aware of the potential risks, 
inconveniences, or adverse effects that may occur. The subject and/or the subject’s 
parent(s) or legally authorized representative should be informed that the subject may 
withdraw from the study at any time, and the subject and/or the subject’s parent(s) or 
legally authorized representative will receive all information that is required by local 
regulations and International Conference on Harmonization (ICH) guidelines. Verbal 
and/or written assent will be obtained from the subject as required by the IRB. The PI 
will provide the Sponsor or its representative with a copy of the IRB/IEC approved ICF 
prior to the start of the study. 
 
13.2. 
Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from 
source documents should be consistent with the source documents, or the discrepancies 
must be explained. 
Clinical data will be entered on eCRFs for transmission to the Sponsor. Data on eCRFs 
transmitted via the web-based data system must correspond to and be supported by 
source documentation maintained at the study site, unless the study site makes direct data 
entry to the databases for which no other original or source documentation is maintained. 
In such cases, the study site should document which eCRFs are subject to direct data 
entry and should have in place procedures to obtain and retain copies of the information 
submitted by direct data entry. All study forms and records transmitted to the Sponsor 
must carry only coded identifiers such that personally identifying information is not 


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transmitted. The primary method of data transmittal is via the secure, internet-based 
electronic data capture (EDC) system maintained by Syneos Health. Access to the EDC 
system is available to authorized users via the study’s Internet web site, where an 
assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of Data 
Clarification Forms. The eCRFs will be considered complete when all missing and/or 
incorrect data have been resolved. 
13.3. 
Source Documents 
Source documents are considered to be all information in original records and certified 
copies of original records of clinical findings, observations, data, diaries or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
13.4. 
Record Retention 
Study records and source documents must be preserved for at least 15 years after the 
completion or discontinuation of/withdrawal from the study or 2 years after the last 
approval of a marketing application in an ICH region, whichever is the longer time 
period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 
164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation). The Investigator shall ensure that study subjects and/or the subject’s parents 
or legally authorized representatives authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to 
the Sponsor. 
 
13.5. 
Monitoring 
The study will be monitored to ensure that it is conducted and documented properly 
according to the protocol, GCP, and all applicable regulatory requirements. 
On-site monitoring visits will be made at appropriate times during the study. Clinical 
monitors must have direct access to source documentation in order to check the 
completeness, clarity, and consistency of the data recorded in the eCRFs for each subject. 
The Investigator will make available to the clinical monitor source documents and 
medical records necessary to complete eCRFs. In addition, the Investigator will work 
closely with the clinical monitor and, as needed, provide them appropriate evidence that 
the conduct of the study is being done in accordance with applicable regulations and GCP 
guidelines. 
13.6. 
Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control 
activities of this study; however, responsibility for the accuracy, completeness, and 


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reliability of the study data presented to the Sponsor lies with the Investigator generating 
the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to 
ensure that the study is being conducted in compliance with the protocol, Standard 
Operating Procedures, GCP, and all applicable regulatory requirements. Audits will be 
independent of and separate from the routine monitoring and quality control functions. 
Quality assurance procedures will be performed at study sites and during data 
management to assure that safety and efficacy data are adequate and well documented. 
13.7. 
Protocol Amendment and Protocol Deviation 
13.7.1. 
Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications 
of confusing wording, changes in study personnel, and minor modifications that have no 
impact on the safety of subjects or the conduct of the study will be classed as 
administrative amendments and will be submitted to the IRB/IEC for information only. 
The Sponsor will ensure that acknowledgement is received and filed. Amendments that 
are classed as substantial amendments must be submitted to the appropriate Regulatory 
Authorities and the IRBs/IECs for approval. 
 
13.7.2. 
Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. 
Protocol deviations and/or violations and the reasons they occurred will be included in 
the clinical study report. Reporting of protocol deviations to the IRB/IEC and in 
accordance with applicable Regulatory Authority mandates is an Investigator 
responsibility. 
13.8. 
Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration 
of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR, and in compliance with GCP guidelines. 
IRBs/IECs will review and approve this protocol and the ICF. All subjects are required 
to give written informed consent prior to participation in the study. 
13.9. 
Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This 
agreement will be documented in a financial agreement that will be signed by the 
Investigator (or the institution signatory) and the Sponsor (or its designee). 
The Investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice. The Sponsor will provide insurance coverage for the 
clinical study as required by national regulations. 


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13.10. 
Publication Policy / Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study 
agreement. Intellectual property rights (and related matters) generated by the Investigator 
and others performing the clinical study will be subject to the terms of a clinical study 
agreement that will be agreed between the Institution and the Sponsor or their designee. 
With respect to such rights, the Sponsor or its designee will solely own all rights and 
interests in any materials, data, and intellectual property rights developed by Investigators 
and others performing the clinical study described in this protocol, subject to the terms of 
any such agreement. In order to facilitate such ownership, Investigators will be required 
to assign all such inventions either to their Institution or directly to the Sponsor or its 
designee, as will be set forth in the clinical study agreement. 


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14. 
REFERENCES 
1. Cereghino JJ. Identification and treatment of acute repetitive seizures in children 
and adults. Curr Treat Options Neurol. 2007;9:249-255. 
2. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970- 
976. 
3. Sankar R, Rho JM. Do seizures affect the developing brain? Lessons from the 
laboratory. J Child Neurol. 2007;22:21S-9S. 
4. Bergen DC. Do seizures harm the brain? Epilepsy Curr. 2006;6:117-118. 
5. Lowe MN, Palmer KJ, Wilde MI. Management of acute repetitive seizures: 
defining the role of rectal diazepam gel. Dis Manage Health Outcomes. 2000;8:355- 
368. 
6. Glauser TA. Designing practical evidence-based treatment plans for children with 
prolonged seizures and status epilepticus. J Child Neurol. 2007;22:38S-46S. 
7. Fisgin T, Gurer Y, Tezic T, et al. Effects of intranasal midazolam and rectal 
diazepam on acute convulsions in children: prospective randomized study. J Child 
Neurol. 2002;17:123-126. 
8. Calcaterra, NE; Barrow, JC. Classics in chemical neuroscience: diazepam (valium). 
ACS Chemical Neuroscience. 2014;5 (4): 253-260. 
9. Riss J, Cloyd J, Gates J, Collins S (August 2008). "Benzodiazepines in epilepsy: 
pharmacology and pharmacokinetics". Acta Neurologica Scandinavica. 118 (2): 69- 
86. 
10. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor 
subtypes and addiction. Trends Neurosci. 2011;34(4):188-197 
11. Diastat® AcuDial™ label, FDA approved on December 16, 2014, available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2013/013263s092lbl.pdf. Revised 
12/16. Accessed August 10, 2018. 
12. Dean L. Diazepam Therapy and CYP2C19 Genotype In: Pratt V, McLeod H, Dean 
L, editors. Medical Genetics Summaries [Internet]. Bethesda MD: National Center 
for Biotechnology Information (US); 2016. Accessed 10 August 2018. Available 
from: https://www.ncbi.nlm.nih.gov/books/NBK379740/ 
13. Tatum WO. Adult patient perceptions of emergency rectal medication for refractory 
seizures. Epilepsy & Behavior. 2002;3:535-538. 
14. Haut SR, Lipton RB, LeValley AJ, et al. Identifying seizure clusters in patients with 
epilepsy. Neurology. 2005 October 25; 65(8): 1313–1315. 
15. Marawar R, Basha M, Mahulikar A, et al. Updates in refractory status epilepticus. 
Crit Care Res Pract. 2018;2018:9768949. doi: 10.1155/2018/9768949. 
16. Kapur J, Macdonald R. Rapid Seizure-Induced Reduction of Benzodiazepine and 
Zn2+ Sensitivity of Hippocampal Dentate Granule Cell GABAA Receptors. J. 
Neurosci. 1997; 17(19): 7532-7533. 


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17. Coldwell SE, Mennella JA, Duffy VB, Pelchat ML, Griffith JW, Smutzer G, et al. 
Gustation assessment using the NIH Toolbox. Neurology. 2013;80(11 Suppl 
3):S20-4. doi: 10.1212/WNL.0b013e3182872e38. 


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15. 
APPENDICES 


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APPENDIX A. Placement Diagram for Aquestive Therapeutics Buccal 
Soluble Film 
 
Test Drug: Placement against the buccal mucosa (either side can be against mucosa): 
MonoSol Rx film is to be centered against the inner aspect of the right or left cheek, as 
illustrated by the Figure below. Film may be placed without regard to the location of 
the parotid duct. 
Ensure film is completely adhered to the mucosal surface. 
Note: Figure is for illustrative purposes and not drawn to scale. 
 
Figure: Test Drug: Placement of Aquestive Therapeutics Buccal Soluble Film against 
the buccal mucosa of the mouth. 


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Appendix B. 
Study Drug Instructions for Use 
This Instructions for Use contains information on how to use diazepam buccal soluble 
film. This information does not take the place of talking to your healthcare provider 
(study investigator) about your medical condition or your treatment. Ask your 
healthcare provider (study investigator) if you have any questions about how to use 
diazepam buccal soluble film the right way. 
Important Information You Need to Know Before Using Diazepam Buccal Film: 
• For buccal use (place film on inside of cheek) 
• Before using diazepam buccal film, make sure your healthcare provider shows 
you the right way to use it. If treatment is unable to be given and there is 
concern, call for emergency medical help right away. 
 
 
Preparing to Use Diazepam buccal film 
• Ensure hands are clean and dry before handling film so the film does not stick to 
your fingers. 
Step 1. Open Pouch and Remove Film from Pouch 
• Fold foil pouch along the side with vertical slit. While folded over, note where the 
vertical slit is and carefully tear down the side of the pouch at the slit to open 
pouch. 
• Remove diazepam buccal soluble film from foil pouch. 
Each foil pouch contains one dose of diazepam buccal film. 


Aquestive Therapeutics 
Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
Page 107 of 132 
 
 
Step 2. Place One Film on Inside of Cheek 
• Stretch either cheek open with one hand and place one film flat against the cheek 
with your other hand. Do not rub film into cheek with your finger. 
• Remove fingers from the cheek. 
• If the film is spit or blown out immediately, attempt to give another dose using a 
new film. 
• Do not give diazepam buccal film with liquids. 
Step 3. Allow Film to Dissolve 
• Diazepam buccal soluble film will stick to the inside of the cheek and begin to 
dissolve. 
• The mouth can be closed or remain open while waiting. 
• Saliva may be swallowed normally as the film dissolves. 
• If the film is accidentally swallowed or chewed there is no need to give a 
replacement dose. 
 
 
What to do after diazepam buccal soluble film has been used: 
• Note time diazepam buccal soluble film was given in your electronic 
diary. 
• Continue to observe the person. 
• Your doctor may prescribe a second dose of diazepam buccal 
soluble film. If a second dose is needed, take it 4 hours to 12 hours 
after the first dose of diazepam buccal soluble film is taken. 


Aquestive Therapeutics 
Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
Page 108 of 132 
 
 
 
 
Wash your hands after administering diazepam buccal soluble film. 
Place the empty foil pouch back in the hard case or cardboard carton. Bring the case 
containing unused/partially used and empty pouches with you to your next study visit. 
 
 
Call for emergency medical help if any of the following occur: 
• There is an increase in seizure frequency that does not stop after using 
diazepam buccal soluble film as instructed by your healthcare provider. 
• Seizure behavior is different from other episodes. 
• The frequency or severity of the seizure is alarming. 
• Either color or breathing is alarming. 
• The person is having unusual or serious problems. 
 
Please remember to fill out the electronic diary with each use of diazepam buccal 
soluble film. 
 
 
How to store diazepam buccal soluble film 
 
• Store at room temperature 68° to 77°F (20°C to 25°C); excursions 
permitted to 59°C to 86°F (15°C to 30°C) 
• Keep diazepam buccal film in foil pouch until ready to use. 
• Use immediately after opening foil pouch. 
• Keep diazepam buccal soluble film out of the reach of children. 
 
Disposing of diazepam buccal film 
 
• 
Any films that were spit out or not used after opening should be flushed 
down the toilet or placed in the sink and rinsed with water until no 
longer visible. 
 
Manufactured by: 
Aquestive Therapeutics 
30 Technology Dr. 
Warren, NJ 07059 
Revision Date: 01/2020 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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APPENDIX C. PedsQL™ Epilepsy Module Parent Report for Toddlers 
(AGES 2-4) 
 


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Amendment 2 
02 March 2020 
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APPENDIX D. PedsQL™ Epilepsy Module Parent Report For Young 
Children (AGES 5-7) 
 
 
 
 
 
 
 


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Amendment 2 
02 March 2020 
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APPENDIX E. PedsQL™ Epilepsy Module Parent Report for Children 
(AGES 8-10) 
 
 
 
 
 
 
 
 


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Amendment 2 
02 March 2020 
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Protocol Number 42-1703 
Amendment 2 
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APPENDIX F. Quality of Life in Epilepsy for Adolescents QOLIE-48 
(VERSION 1.0) 
 
 
Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
Page 118 of 132 
 
 
 
 
 
 
 
Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
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Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
Confidential 
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Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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Should read version date as 04 Jan 2018 instead of 03 Jan 2018. 


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Diazepam Buccal Film 
Protocol Number 42-1703 
Amendment 2 
02 March 2020 
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APPENDIX G. Patient-Weighted Quality of Life in Epilepsy: 
QOLIE-31-P 
 
 
 
 
 
 
 


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Amendment 2 
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SAP_001.pdf: 
NCT 03428360
Statistical Analysis Plan (SAP)  
SAP Date: 11 August 2020
For
Protocol Title:   An Open-Label, Safety and Tolerability Study of Chronic 
Intermittent Use of Diazepam Buccal Soluble Film (DBSF) in Pediatric, 
Adolescent and Adult Subjects with Epilepsy
Amendment 2 Protocol Date: 02 March 2020


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics (Formerly known as MonoSol Rx) 
Protocol Number: 42-1703 
Protocol Title: An Open-Label, Safety and Tolerability Study of Chronic Intermittent Use of Diazepam 
Buccal Soluble Film (DBSF) in Pediatric, Adolescent and Adult Subjects with Epilepsy 
Protocol Version and Date: Amendment 2 (dated 02 March 2020) 
Amendment 1 (dated 11 September 2018) 
Original Protocol Date: 31 July 2017 
Syneos Health Project Code: 17MO1R0003 
Authors: Priya D’Silva, Senior Biostatistician 
Jit Mitra, Biostatistician 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Aquestive Therapeutics. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Aquestive Therapeutics. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics Committees 
or duly authorized representatives of a national regulatory authority under the condition that they are 
requested to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos 
Health should be notified promptly. 
SAP Version: 2.0 dated August 11, 2020 
This document is confidential. 
Page 1 of 33 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 2 of 33 
 
 
 
Revision History 
 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
03-Jan-2019 
Priya D’Silva 
Initial Release Version 
2.0 
11-Aug-2020 
Jit Mitra 
Updates made on Sponsor’s request 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 3 of 33 
natur
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
Jit Mitra, 
Biostatistitian 
13-Aug-2020
Name, Title 
Developing Biostatistician 
Sig 
Date (DD-Mmm- 
YYYY) 
Priya Diana D’Silva, 
Senior Biostatistitian 
PriyaDiana 
Signature 
14-Aug-20
Name, Title 
Lead Biostatistician 
Date (DD-Mmm- 
YYYY) 
Aquestive Therapeutics Approval 
Frances Ekweonu 
Name, Title Clinical Operations Manager 
Signature 
Aquestive Therapeutics 
Aug 13th 2020 
Date (DD-Mmm- 
YYYY) 
Gary Slatko MD, Chief Medical Officer 
August 13, 2020 
Name, Title 
Aquestive Therapeutics 
Signature 
Date (DD-Mmm- 
YYYY) 
Signature 
Name, Title 
Aquestive Therapeutics 
Date (DD-Mmm- 
YYYY) 
Signature 
Name, Title 
Aquestive Therapeutics 
Date (DD-Mmm- 
YYYY) 
N/A
N/A


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 4 of 33 
 
 
 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals ................................................................................................................................... 3 
Glossary of Abbreviations ................................................................................................... 6 
Purpose .............................................................................................................................. 7 
Study Objectives ................................................................................................................. 8 
 
 
 
 
 
 
 
 
 
Endpoints .......................................................................................................................... 14 
Analysis Sets .................................................................................................................... 15 
General Aspects for Statistical Analysis ........................................................................... 16 
 
 
 
 
 
 
Subject Characteristics ..................................................................................................... 18 
 
 
 
 
 
Analysis of Safety ............................................................................................................. 20 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 5 of 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Analyses ............................................................................................................... 25 
Changes from Analysis Planned in Protocol .................................................................... 26 
 
 
 
 
Programming Considerations ............................................................................................ 27 
 
 
 
 
 
 
 
 
 
 
Quality Control .................................................................................................................. 33 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 6 of 33 
 
 
Glossary of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ATC 
Anatomical Therapeutic Chemical 
ARS 
Acute Repetitive seizures 
BMI 
Body Mass index 
BP 
Blood pressure 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
C-SSRS 
Columbia Suicidal Severity Rating Scale 
DBSF 
Diazepam Buccal Soluble Film 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practice 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
IWRS 
Interactive Web Response System 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N/A 
Not Applicable 
NA 
Not Applicable 
PT 
Preferred Term 
QC 
Quality Control 
QTc 
Corrected QT Interval 
QOL 
Quality of Life 
RR 
Respiratory rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
WHO 
World Health Organization 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 7 of 33 
 
 
 
Purpose 
 
The purpose of this statistical analysis plan (SAP) is to ensure that the statistical methodologies that will be 
used, and the data listings, summary tables and figures which will be produced, are complete and 
appropriate to allow valid conclusions regarding the study objectives. The timing of the final SAP is after 
the finalization of the protocol and prior to the database lock. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality control 
of all tables, figures and listings. 
 
Timings of Analyses 
This SAP is amended after three interim analysis, which are already completed based on the SAP version 
1.0 dated 03-Jan-2019. 
 
The primary analysis of safety and efficacy is planned after all subjects complete the final study visit or 
terminate early from the study. Unless otherwise specified, the analysis includes all data collected in the 
database through the time of the database lock. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 8 of 33 
 
 
 
Study Objectives 
 
Primary Objective 
The primary objective of this study is: 
 
• 
To assess the safety and tolerability of DBSF (study drug) administered a minimum of 3 times to 
subjects with epilepsy for the treatment of seizures over a minimum 6-month period. 
 
Secondary Objective(s) 
The secondary objectives of this study are: 
 
• 
To evaluate the usability of study drug as assessed by the ability of caregivers/subjects to 
administer study drug based on the Instructions for Use (IFU). 
 
• 
To evaluate the Quality of Life (QoL) of the subjects during the treatment period as assessed by 
use of age-appropriate epilepsy scales over a minimum 6-month period. 
 
Data from this study is intended to support a 505 (b)(2) New Drug Application for the test product. 
 
Subject Selection 
Male and female subjects with a clinical diagnosis of epilepsy with bouts of increase seizure activity (e.g., 
ARS, frequent breakthrough seizures, seizure clusters or cluster seizures) will be screened. Subjects may 
be re-screened during the study per Investigator judgment after consultation with and approval by the 
Medical Monitor. Approximately 120 subjects are expected to be screened in order to have a minimum of 
100 enrolled subjects (50 adult and 50 pediatric/adolescent subjects). The enrollment should include at 
least 20 subjects in the 6 to 11-year-old group and 20 subjects in the 12 to 16-year-old group. 
 
In addition to direct enrollment from screening, subjects who have completed the Phase 2 clinical trials 
(Study 160325 [Pediatric] and Study 160326 [Adult]) may screen and enroll (i.e., rollover subjects) into this 
Phase 3 long-term safety study when they come for their follow-up visit in the Phase 2 study. Seizure diary 
used during the Phase 2 studies will be reviewed at screening for this rollover subjects. Rollover subjects 
will be assessed using Protocol 42-1703 inclusion/exclusion criteria. The Phase 3 study Screening visit can 
be done on the same day as the Phase 2 study follow-up visit. 
 
Inclusion Criteria 
Subjects must meet all the following criteria in order to be included in the study: 
I-01. Female or male between the ages of 2 and 65 years, inclusive 
I-02. Written informed consent to participate in the study from the subject or subject’s legally authorized 
representative and oral and/or written assent will be obtained from the subject as required by the 
Institutional Review Board (IRB) prior to the performance of any study-related procedure 
 
I-03. Caregiver, if needed for subject, provides written informed consent and is able to administer study 
drug in the event of a seizure 
 
I-04. Subject has an established diagnosis of epilepsy with motor seizures with clear alteration of 
awareness, and while on a regimen of anti-epileptic medication(s), still experiences bouts of seizures 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 9 of 33 
 
 
 
(frequent break through seizures, e.g., ARS or seizure clusters) and who, in the opinion of the 
Investigator, may need benzodiazepine intervention for seizure control at least 1 time a month on 
average. Subject must be on at least 1 concomitant anti-epileptic drug (AED) at screening. 
 
The study is open to subjects who, in the opinion of the Investigator, would benefit from use of study 
drug. Concomitant prescription for a benzodiazepine for rescue (including diazepam) at screening or 
ongoing, or concomitant use of a benzodiazepine ongoing as a part of the subject’s daily antiepileptic 
drug regimen does not exclude a subject from eligibility. Subjects are to be encouraged to use study 
drug when a benzodiazepine rescue treatment is needed. However, treatment decisions are to be 
guided in all cases according to the Investigator’s judgment as to the optimal treatment in the interest 
of the subject’s care and welfare. Participation in this study is never a basis for the withholding of any 
treatment considered to be indicated in the interest of the subject. 
 
I-05. Female subjects have negative serum and urine pregnancy test at screening (If the subject is unable 
to provide a urine sample, the option to use only serum pregnancy test will be according to 
Investigator judgment). Female subjects of childbearing potential (not surgically sterile or less than 2 
years postmenopausal) must have a partner who is sterile, must have a partner who is sterile, agrees 
to abstinence, be practicing double barrier contraception or using an FDA-approved contraceptive 
(e.g., licensed hormonal or barrier methods) for greater than 2 months prior to screening visit and 
commit to an acceptable form of birth control for the duration of the study and for 30 days after the 
final study visit. 
 
I-06. No clinically significant abnormal findings on the ECG (QTcF [Fridericia’s Correction Formula] ≤ 450 
msec for males and QTcF ≤ 470 msec for females) 
 
I-07. Subject and caregiver (if applicable) must be willing to comply with all study visits and all required 
study procedures (including the use of electronic diary). 
 
NOTE: Non-verbal and cognitively impaired subjects are eligible to participate in the study. 
 
Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible to participate in this study: 
 
E-01. A history of clinically significant gastrointestinal, renal/genitourinary, hepatic, hematologic, 
dermatologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, 
or any other clinically significant abnormalities, such as physical examination, vital signs, laboratory 
tests or ECG at Screening or Baseline which in the opinion of the Investigator require further 
investigation or treatment or which may interfere with study procedures or safety or other medical 
conditions (e.g., cardiac, respiratory, gastrointestinal, psychiatric, renal disease) which are not 
adequately and stably controlled, or which in the opinion of the Investigator could affect the subject’s 
safety or interfere with the study assessments or any other condition which, in the opinion of the 
Investigator, would jeopardize the safety of the subject. 
 
E-02. Subject has had a significant traumatic injury, major surgery, or open biopsy within 30 days prior to 
screening 
 
E-03. Subject has a recent history of suicide attempt (defined as an active, interrupted, or aborted attempt 
with the past five years) or reports suicidal ideation in the past six months as indicated by a positive 
response (“Yes”) to either Question 4 or Question 5 of the C-SSRS performed at the Screening Visit. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 10 of 33 
 
 
 
NOTE: If a subject cannot complete the assessment, the site must document this. 
 
E-04. A history of allergic or adverse responses to diazepam or any other benzodiazepine. 
 
E-05. Participation in another clinical trial other than Aquestive Therapeutics Phase 2 studies 160325 and 
160326 within 30 days prior to screening. Participation in an observational (non-interventional) study 
is not an exclusion provided there are no scheduling conflicts with this study. 
 
E-06. Received any other investigational medication (unless it can be documented that the subject received 
only placebo) or device within 8 weeks or 5 half-lives (whichever is longer) before assignment to 
study drug treatment. 
 
E-07. Lactating female or positive urine and serum pregnancy test (β-hCG) at screening for female subjects 
≥ 12 years of age (If the subject is unable to provide a urine sample, the option to use only serum 
pregnancy test will be according to Investigator judgment). 
 
E-08. In subjects 17 years of age and older (and in subjects < 17 years of age at the Investigator’s 
discretion), positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg), hepatitis C, or a positive test result for drugs of abuse or alcohol, except marijuana 
use for medicinal indications. When marijuana is or was used for medicinal indications in the opinion 
of the Investigator, it is not considered as drug abuse and the subject can be enrolled in states where 
marijuana is legal, even if the marijuana metabolites are positive in the urine. 
 
NOTE: In such a case, the marijuana product will be recorded as a concomitant medication. 
 
Determination of Sample Size 
A maximum of 120 subjects with epilepsy will be screened, with about 50 pediatric and adolescent and 
about 50 adult subjects planned. A minimum of 100 subjects is expected to be enrolled. This sample size 
is based on practical reason instead of statistical consideration. The enrollment should include at least 20 
subjects in the 6 to 11-year-old group and 20 subjects in the 12 to 16-year-old group. 
 
Treatment Assignment 
This is an open label study. Subjects will be assigned to treatment with study drug with the use of IWRS. 
There will be no subject randomization; however, each study drug kit will have a kit number which will be 
documented. The Investigator may adjust the study drug dose as medically appropriate, in accordance with 
guidelines. 
 
Administration of Study Medication 
Study drug dosing is determined according to age group and body weight within age group during each 
study site visit where subjects are dispensed 5, 7.5, 10, 12.5, 15, or 17.5 mg study drug. Dosing occurs 
away from the study site by the subject or caregiver. 
 
Investigators can make dosing adjustments after the first administration and at subsequent visits. The 
Investigator may choose to adjust the dose upward or downward by 1 dose level depending on clinical 
response to study drug. For all age groups, the height and weight will be measured and recorded at all 
study visits. Subjects with body weights in the range 112 to 134 kg (247 to 295 pounds) may participate in 
the study at the discretion of the investigator. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 11 of 33 
 
 
 
Dosing will occur away from the study site and administered by the subject or caregiver, if applicable. The 
dosing time will be triggered by occurrence of a qualifying event that for the individual subject is 
characteristic and is deemed by the prescriber to be of a kind for which a benzodiazepine would ordinarily 
be administered acutely. The subject and/or caregiver will administer the study drug as described in the 
IFU. The actual date and time of film placement will be documented in the electronic diary by the subject or 
caregiver and in the eCRF by the study site staff during study visits. 
 
A second dose, when required, may be given within 4 to 12 hours after the first dose, as previously 
discussed between the investigator and subject/caregiver. No more than one episode every 5 days and no 
more than 5 episodes per month should be treated with study drug or with any other product containing 
diazepam (e.g., Diastat® AcuDial™) except as instructed by a physician. 
 
Based on subject diagnosis and history (Inclusion Criteria), it is expected that subjects will have a minimum 
of 3 uses of the study drug within the 6 months treatment period. 
 
If a subject has experienced 3 uses of study drug, study participation will be complete at Month 6. For those 
subjects who have not experienced 3 uses of study drug, the Investigator and the Medical Monitor will 
assess on a case-by-case basis the likelihood of achieving 3 uses of study drug by continuing the subject 
on study for an additional 3 months. If the assessment concludes use of the study drug is not likely, the 
study will be considered complete for the subject. The sponsor may elect to end study participation for non- 
users prior to end of study. 
Study Procedures and Flowchart 
 
Study Period 
Screeninga 
Baselineb 
Study Drug Treatmentc 
(Study drug dosing administered away 
from the study site) 
Follow-up 
Visit 
Visit 1 
Visit 2 
Visit 3 
Telephone 
Contact 
Visit 4 
Visit 5 
(Final) 
Telephone 
Contact 
Study Day 
Day -1 
to -28 
Day 1 
within 14 
days post 
first study 
drug dose 
Day 30, Day 
60 
Day 90 
Day 
180 
Month 7 
(Day 210 – 
Day 217) 
Informed Consent/Assent d 
x 
Demography e 
x 
Inclusion/Exclusion Criteria 
x 
x 
Training Subject/Caregiver 
on Study Drug 
Administration and Use of 
Electronic Diary f 
x 
x 
x 
x 
x 
Medical/Disease History g 
x 
x 
Concomitant Medication 
Review 
x 
x 
x 
x 
x 
x 
Vital Signs (blood pressure, 
heart rate, respiration rate, 
oral temperature)h 
x 
x 
x 
x 
x 
Body Height and Weight i 
x 
x 
x 
x 
x 
Complete Physical and 
Neurological Examination j 
x 
Symptom Driven Physical 
and Neurological 
Examinationk 
x 
x 
x 
x 
C-SSRS l 
x 
x 
x 
x 
x 
Oral Mucosa Examination m 
x 
x 
x 
x 
x 
12-lead ECG n 
x 
x 
x 
x 
x 
Urine and Serum Pregnancy 
Tests o 
x 
x 
x 
x 
x 
Collect Samples for 
Complete Blood Count, 
x 
x 
x 
x 
x 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 12 of 33 
 
 
 
Blood Chemistry, Urinalysis, 
Urine Drug Screen, Breath 
Alcohol Testsp 
Gustatory Sense 
Assessmentq 
x 
x 
x 
x 
Review Study Drug 
Administration (IFU) r 
x 
x 
x 
x 
Quality of Life by age 
appropriate epilepsy scales s 
x 
x 
x 
x 
x 
Collect/Review 
Caregiver/Subject Diary t 
x 
x 
x 
Supply Study Drug 
x 
x 
x 
Collect/Count Study Drug 
x 
x 
x 
x 
Adverse Events Evaluation u 
x 
x 
x 
x 
x 
x 
x 
Study Site will telephone 
subjects v 
x 
x 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale: ECG = electrocardiogram; IFU = Instructions for Use; NIH = National 
Institutes of Health; 
SAE=serious adverse event; WOCBP=women of childbearing potential. 
a Screening evaluations are to be conducted for all direct enrolling subjects within 28 days before the baseline visit. Rollover subjects 
may consent and undergo screening during their final visit of their Phase 2 trial, thus eliminating an additional screening visit. Subjects 
may be re-screened during the study per Investigator judgment after consultation with and approval by the Medical Monitor. 
b The Baseline visit includes a battery of assessments, as well as training in study drug administration and documentation and supply 
of study drug and study logs. For rollover subjects, the assessments and training and supply can be completed during the final visit of 
their Phase 2 trial. 
c Study site visits will be conducted at Baseline, within 14 days after the first study drug dose, and approximately every 3 months until 
completion 6 months or Discontinuation. The study site staff will telephone the subjects at approximately 1 and 2 months +- 7 days after 
baseline to check on status, reinforce training on study drug administration and diary documentation, and address any concerns. d 
Before the performance of any study-related procedure, written informed consent will be obtained from the subject or subject’s legally 
authorized representative and oral and/or written assent will be obtained from the subject as required by the Institutional Review Board 
(IRB). 
eAge, weight, height, gender, ethnicity and race at screening; Body weight and height will be measured at every site visit. Study drug 
dosage based on age and body weight. Duration of epilepsy history is documented. 
f Training of subject/caregiver (as applicable) on the use of the electronic diary; use of the diary will be reviewed at each visit/contact 
to ensure subjects/caregivers understand and are comfortable with using the electronic diary. 
h Vital signs include body temperature, respiration rate, heart rate, systolic and diastolic blood pressure measurements. All vital signs 
will be measured after the subject has been resting in a sitting position for at least 5 minutes. Blood pressure measurements are to 
be taken in the same arm (if possible) for the duration of the study. 
i Body height and weight is obtained for all subjects at screening to document body mass index (kg/m2). Body weight (without shoes 
and with empty pockets) will be recorded whenever vital signs are recorded, and height (without shoes) will be recorded at all study 
site visits to calculate weight-based study drug dosage. 
j Complete physical examination: head, eyes, ears, nose, and throat (HEENT), heart, lungs, abdomen, skin, cervical and axillary lymph 
nodes, neurological and musculoskeletal systems. 
k Symptom-driven Physical and Neurological examinations will be conducted at the First/Day 1 visit, at the Final/Completion or Early 
Withdrawal visit, and as clinically indicated during the study. 
l C-SSRS; If a subject cannot complete the assessment, the site must document this. 
m Oral mucosal health assessment will be performed by the Investigator or trained Study nurse at all study site visits. In addition, any 
mucosal or tonguelacerations encountered during the study are recorded in the diary. 
n 12-lead ECG testing is performed at Screening, Baseline, and at approximately 6 months or Final Visit. When performed on days of 
blood draws, ECG should be completed prior to blood collection. 
O Serum and/or urine pregnancy test for females > 12 years of age. If the subject is unable to provide a urine sample, the option to 
use only the serum pregnancy test will be according to Investigator judgment. Females with positive pregnancy tests cannot be dosed. 
p Hematology testing includes Full and differential blood count, hematocrit, hemoglobin, RBC morphology, mean corpuscular volume, 
platelet count, RBC count and WBC with differential. Albumin, ALT, AST ALP, BUN, creatinine, Creatine kinase, Na, K Cl, Ca, Glucose, 
Protein, Total Protein, Total bilirubin Uric Acid will be performed. For urinalysis, dipstick is acceptable. Microscopic analyses if clinically 
indicated. 
q Gustatory sense assessment will be administered to cognitively-appropriate subjects 12 years and older at all site visits. The general 
Labeled Magnitude Scale (gLMS) will remain as the evaluation scale for gustation (taste) testing; however, commercially available 
test strips from Burghart Messtechnik will replace the liquid taste solutions described as part of the NIH Toolbox Regional Taste Intensity 
Test. 
r Study drug will be self-administered or with the assistance of a caregiver, as applicable. The dosing is administered remote from the 
study site, usually in the home setting, according to the IFU 
s Quality of life will be assessed at all study site visits by age appropriate epilepsy scales. If a subject cannot complete the assessment, 
the site must document this. 
t Use of an electronic diary will be reviewed with the subject/caregiver (as applicable) to determine their ability/willingness to use the 
electronic diary during treatment. 


St ati sti c al  A n al y si s  Pl a n  
S p o n s or  N a m e:  A q u e sti v e  T h er a p e uti c s;  Pr ot o c ol  N u m b er:  4 2 -1 7 0 3  
S y n e o s  H e alt h  
T hi s  d o c u m e nt  i s c o nfi d e nti al.  
S A P  V er si o n:  2. 0  d at e d  A u g u st  1 1,  2 0 2 0  
P a g e  1 3  of  3 3  
 
 
 
u A d v er s e e v e nt s s h o ul d b e r e c or d e d. S u bj e ct s m u st b e f oll o w e d f or A E s f or 3 0 d a y s aft er t h e l a st st u d y dr u g tr e at m e nt a d mi ni str ati o n  
or u ntil  all  dr u g r el at e d  t o xi citi e s h a v e r e s ol v e d, w hi c h e v er  i s l at er. 
v T h e st u d y sit e st aff will t el e p h o n e t h e s u bj e ct s at a p pr o xi m at el y 1 a n d 2 m o nt h s  7 d a y s aft er t h e b a s eli n e vi sit t o c h e c k o n t h e  
s u bj e ct’ s h e alt h a n d s ei z ur e st at u s, r ei nf or c e tr ai ni n g o n st u d y dr u g a d mi ni str ati o n a n d di ar y d o c u m e nt ati o n, a n d t o a d dr e s s c o n c er n s.  
T h e i n v e sti g at or or d e si g n e e will c o n d u ct a f oll o w -u p p h o n e c all wit h t h e s u bj e ct at 3 0 -3 7 d a y s aft er t h e Fi n al Vi sit t o c h e c k o n s u bj e ct  
st at u s  a n d c oll e ct  r e p orti n g i nf or m ati o n, s h o ul d a n y  S A E h a v e  o c c urr e d.  


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 14 of 33 
 
 
 
Endpoints 
 
Primary Endpoint 
The primary endpoints of this study are obtained during study visits by a trained Principal Investigator, sub- 
investigator, or study nurse. 
 
• 
TEAE assessment, including relationship to treatment with study drug and severity. 
 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) assessment: If a subject cannot complete the 
assessment, the site must document this. 
 
• 
Vital signs (blood pressure, heart rate, respiration rate, oral temperature) 
 
• 
Laboratory analyses (hematology, serum chemistry, and urinalysis) 
 
• 
Pathological change in oral mucosa as measured by an oral examination 
 
• 
Gustatory sense changes as measured by the general Labeled Magnitude Scale (gLMS) using 
commercially available Burghart Messtechnik test strips in cognitively appropriate subjects 12 years 
of age and older 
 
Secondary Endpoints 
Secondary endpoints are: 
 
• 
Quality of Life (QoL) assessments by use of age-appropriate epilepsy scales; if a subject cannot 
complete the assessment, the site must document this. 
 
• 
Assessment of usability by subject and/or caregiver 
 
o 
Handling and administration of study drug, based on the Instructions for Use (IFU) 
o 
Successful buccal insertion of study drug 
 
Successful placement and adherence of the study drug against the buccal mucosa 
(inner cheek) 
o 
Oral cavity placement and retention 
 
Study drug swallowed prior to sticking to inner cheek 
 
Study drug spit out or blown out by subject after administration 
 
• 
12-lead electrocardiograms (ECGs) 
 
• 
Use of concomitant medications 
 
• 
Physical and neurological examinations 
 
• 
Body height and weight; BMI (kg/m2) 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 15 of 33 
 
 
 
Analysis Sets 
 
All Enrolled Subjects 
This set represents all subjects that are passed screening and entered into the database. All Enrolled 
Subjects will be used for all subject disposition presentation. 
 
Safety Analysis Set 
This set will include all subjects administered at least 1 dose of study drug which is captured in the eCRF. 
The Safety Analysis Set will be used for all data summaries and listings other than subject disposition. 
 
Additionally dose information will be captured in the eDiaries but that information will not be used to 
determine Safety Analysis Set. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 16 of 33 
 
 
 
General Aspects for Statistical Analysis 
 
General Methods 
• 
Statistical methodology and analyses are in accordance with the principles outlined by the 
International Conference on Harmonization (ICH) E9 guidelines. All statistical analyses will be 
done using SAS statistical software version 9.4 or higher. 
 
• 
Subject listings of all data represented in the electronic CRF (eCRF) will be provided. 
Measurements from subjects excluded from the pre-defined analysis populations or extra 
measurements (such as unscheduled or repeat assessments) will not be included in summary 
tables unless specified otherwise, but will be included in the subject listings. In general, the subject 
listings will be sorted by age-group, subject number, visit and assessment date and time (if 
applicable). Data captured in electronic Diaries (eDiaries) will not be listed unless and otherwise 
directed in the corresponding section. 
 
• 
Unless otherwise specified, continuous/quantitative variables will be summarized using descriptive 
statistics which will include the number of subjects with data to be summarized (n), mean, standard 
deviation (SD), median, minimum and maximum. The same number of decimal places as in the 
raw data will be presented when reporting minimum and maximum, 1 more decimal place than in 
the raw data will be presented when reporting mean and median, and 2 more decimal places than 
in the raw data will be presented when reporting SD. 
 
• 
All categorical/qualitative data will be presented using frequency counts and percentage. The total 
number of subjects in the relevant population with non-missing data (N) will be used as the 
denominator for percentage calculations, unless stated otherwise in the table shell. All percentage 
will be presented as 1 decimal point, unless otherwise specified. Percentage equals to 100 will be 
presented as 100% and percentage will not be presented for 0 frequencies. 
 
• 
In the case of multiple or repeat assessments at a scheduled visit, the record closest to the planned 
assessment day will be selected for the summary. If 2 records are equidistant from the target day, 
then the later record will be selected. All assessments will be listed. 
 
• 
Unless otherwise specified, all tables will be produced by age-group and overall as column 
headers. Adverse event tables will be repeated for by onset dose and overall as column headers. 
 
Key Definitions 
Baseline: Unless otherwise specified, the baseline value is the last non-missing measurement or 
assessment prior to Study Day 1 study drug administration. It can be taken as the measurement on the 
Baseline Visit (i.e. Visit 2) and if missing taken as the measurement on the Screening Visit (i.e. Visit 1). 
 
Study Day: Study Day is the number of days since the first study drug administration, which is counted as 
Study Day 1. Study day is calculated as Date of Assessment - Date of First Dosing + (1, if Date of 
Assessment is on or after first dosing; 0, otherwise). 
 
Onset Dose and Onset Day: Onset Dose and Onset Day is the dose and day of dose immediately prior 
to the event or assessment (since dose may change over time). Onset Dose and Onset Day (calculated as 
Date of Event or Assessment - Date of dose immediately prior to the event or assessment + 1) will be blank 
if it is prior to first study drug administration. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 17 of 33 
 
 
 
Missing Data 
No imputation will be done for the missing data. 
 
Visit Windows 
In general, all safety data will be summarized by scheduled visits based on the scheduled events indicated 
in section 3.7. The visits indicated on the eCRF (i.e. eCRF visit) will be used as the analysis visits for 
analysis of most parameters. 
Pooling of Centres 
Pooling of investigative sites is not applicable for this study. 
 
Subgroups 
No subgroup analysis will be done for this study. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 18 of 33 
 
 
 
Subject Characteristics 
 
Subject Disposition and Withdrawals 
A listing of disposition, by age-group and subject identification number, presenting the Screen 
Result/Baseline Date, Protocol Version, whether apart of Enrolled Set and Safety Set, Status as completed 
or withdrawn, Days in Study as date of last available visit - date of baseline visit + 1, Number of doses as 
captured in eCRF and eDiary, and if withdrawn, the Reason and the Date. 
The following frequencies (number and percent) will be displayed in the subject disposition table, by age- 
group and overall: Subjects Screened, Subjects failed Screening, Subjects passed Screening, Subjects in 
the Enrolled Set, Subjects passed Screening but not Enrolled, Subjects in the Safety Analysis Set. Also the 
same will be calculated for Completed and Withdrawn categorized by <180 and ≥180 days in the study and 
hence number of doses taken (as captured in eCRF) categorized by 0, 1-2 and ≥3 doses. For withdrawn 
subjects reason for non completion will be summarized. 
The analyses of disposition will be based on the All Enrolled Subjects. 
 
Demographic and Other Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized descriptively by age group and 
overall. Subject demographic baseline disease characteristics will include age, race, gender, weight (kg), 
height (cm), BMI (kg/m2), and duration of epilepsy (in years). BMI will be calculated as: BMI (kg/m2) = 
Weight(kg)/[Height(cm)/100]2. 
All of the above will be listed. The summary and listing will use Safety Analysis Set. 
 
Protocol Deviation 
All protocol deviations will be listed by age-group, subject identification number and start date. All protocol 
deviations will be classified into a number of general categories and further into Major and Minor type of 
deviations. 
Medical History 
All medical histories will be listed by age-group, subject identification number and start date. Medical 
Histories will be coded into system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.1 or later and will be listed along with verbatim terms. Medical histories 
related to epilepsy will be flagged using MedDRA High Level Group Terms as Seizures (incl subtypes) and 
System organ class as Nervous system disorders. 
Medication 
Prior Medication: Prior Medication is categorized as any medication which started before first study dose. 
 
Concomitant Medication: Concomitant Medication is categorized as any medication which started after 
first study dose or (started before the study drug but continued during study drug). 
The following table can be utilized to determine prior and concomitant medications. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 19 of 33 
 
 
 
Medication start (↓) 
/end (→) date 
< first 
drug 
intake 
≥ first 
drug 
intake 
All cases 
where 
year is 
missing or 
ongoing is 
ticked 
Month and Day is missing 
Only Day is missing 
Year of 
Medication < 
Year of first 
drug intake 
Year of 
Medication ≥ 
Year of first 
drug intake 
Month-Year 
of Medication 
< Month-Year 
of first drug 
intake 
Month-Year 
of Medication 
≥ Month-Year 
of first drug 
intake 
< first drug intake 
P 
PC 
PC 
P 
PC 
P 
PC 
≥ first drug intake 
C 
C 
C 
C 
 
All cases where year is 
missing 
P 
PC 
PC 
P 
PC 
P 
PC 
Month 
and Day 
is 
missing 
Year of 
Medication < 
Year of first 
drug intake 
P 
PC 
PC 
P 
PC 
P 
PC 
Year of 
Medication ≥ 
Year of first 
drug intake 
C 
C 
C 
PC 
Only 
Day is 
missing 
Month-Year 
of Medication 
< Month-Year 
of first drug 
intake 
P 
PC 
PC 
P 
PC 
P 
C 
Month-Year 
of Medication 
≥ Month-Year 
of first drug 
intake 
C 
C 
C 
C 
P=Prior medication, C=Concomitant medication 
 
All Prior and concomitant medications will be coded into Anatomical Therapeutic Chemical (ATC) 
Classification and preferred term using World Health Organization Drug Dictionary Enhanced (WHO DDE) 
Version June 2016 , format B2 or later. 
Summary (number and percent) tables will be provided for each prior and concomitant medications by ATC 
class and preferred term and further classified into age group and overall. Additionally, Summary of 
Concomitant Medications with Benzodiazepine and Summary of Concomitant Medications: Anti-epileptic 
Drugs will be produced. Antiepileptic drug to be identified by ATC code N03 for ANTIEPILEPTICS and 
further branched into chemical classes and preferred terms. Concomitant Medications with Benzodiazepine will 
be identified by ATC code as N03AE for Benzodiazepine derivatives and further to be branched as 
Scheduled use (medications that are prescribed chronically or they are given on a known schedule such 
as a daily basis (once/day or twice/day etc), weekly, monthly) and Rescue use (medications that are used 
for rescue and the terms could be “prn”, “as needed”, or “rescue”). 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 20 of 33 
 
 
 
Analysis of Safety 
 
The safety set will be based on all subjects who received at least one study treatment. Safety parameters 
will be presented by age-group and overall. Additionally Adverse event tables will be repeated by onset 
doses and overall. All listings will be provided by age group, Subject identification number, and if applicable, 
Visit, Onset Dose (mg) and Collection Date (day). 
Safety will be assessed through descriptive summaries and/or listings of adverse events, laboratory test 
results, ECGs, body weight, physical examination findings and vital signs. 
Extent of Exposure 
A summary table will be utilized to show descriptive statistics (sample size, mean, median, SD, Min and 
Max) of Duration (Days) on Study, Doses (Number Received) on Study as captured in eCRF, Doses 
(Number Received) on Study as Captured in eDiary. 
Subjects’ treatment exposure will be listed with the drug administration per visit. If not administered then 
the reason for not administration of the drug will be presented in listing. The number of doses and study 
duration will already be listed in subject dispostion listing and will not be repeated here. 
Type of Seizures treated will be listed as captured in eCRF. 
 
Drug Accountibility in terms of Amount of Drug (in Pouch) Dispensed, Taken and Returned along with dates 
and reason for the Drug not Returned will be listed. 
 
Adverse Events 
Definitions 
Treatment-Emergent Adverse Event: An AE will be considered a treatment-emergent adverse event 
(TEAE) if the AE starts or worsens after first dose of study medication. The following table will be utilized 
to dermine a TEAE: 
 
AE Start Date 
AE End Date 
Rule on AE End Date 
Rule on AE Start Date 
TEAE 
Not missing 
AE Start Date 
< Treatment Start Date 
N 
AE Start Date 
≥ Treatment Start Date 
Y 
Partly missing 
Not missing 
AE End Date 
< Treatment Start Date 
N 
AE End Date 
≥ Treatment Start Date 
non missing part of AE Start Date 
< Treatment Start Date 
N 
non missing part of AE Start Date 
≥ Treatment Start Date 
Y 
Partly missing 
non missing part of AE End 
Date 
< Treatment Start Date 
N 
non missing part of AE End 
Date 
≥ Treatment Start Date 
non missing part of AE Start Date 
< Treatment Start Date 
N 
non missing part of AE Start Date 
≥ Treatment Start Date 
Y 
Totally Missing or 
Ongoing 
non missing part of AE Start Date 
< Treatment Start Date 
N 
non missing part of AE Start Date 
≥ Treatment Start Date 
Y 
Totally 
Missing 
Not missing 
AE End Date 
< Treatment Start Date 
N 
AE End Date 
≥ Treatment Start Date 
Y 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 21 of 33 
 
 
 
AE Start Date 
AE End Date 
Rule on AE End Date 
Rule on AE Start Date 
TEAE 
Partly missing 
non missing part of AE End 
Date 
< Treatment Start Date 
N 
non missing part of AE End 
Date 
≥ Treatment Start Date 
Y 
Totally Missing or 
Ongoing 
Y 
 
Serious Adverse Event: A serious adverse event is any AE that meets any of the following criteria: 
 
○ 
is fatal 
○ 
is life-threatening 
○ 
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/birth defect 
Adverse Event of special interest: An AE of special interest(AESI) will be categorized as: 
 
a) Oral Irritation Safety related AESI – include the following (but not limited to): 
Buccal Mucosal Swelling, Mouth Ulceration, Injuries to Oral Cavity (such as Tongue or 
Mucosa Laceration, Broken Tooth, Bleeding), Erythema, Stomatitis, Gingivitis, Xerostomia, 
Staining, Dysphagia, Dysgeusia, Burning, Stinging, Tingling 
b) Abuse related AESI – include the following: 
Euphoria, Euphoric Mood, Feeling of Relaxation, Anger, Dissociative Effects, 
Hallucinations, Psychosis, Changes in Mood, Impaired Cognition, Attention, Psychomotor 
Effects, Inappropriate Affect, Overdose and Misuse 
Relationship of an Adverse Event with DBF: An AE will be categorized as Possible, Probable, Unlikely 
and Unrelated in terms of relationship with DBF. Further an AE will be termed as related to DBF if it is 
categorized as Possible, Probable or the relationship is missing. 
Intensity of an Adverse Event: An AE will be categorized as Mild, Moderate and Severe in terms of it’s 
intensity. Further an AE will be termed as severe if it is categorized as Severe or the intensity is missing. 
 
Reporting 
Adverse event terms recorded on the eCRF will be mapped to preferred terms and system organ classes 
using the MedDRA dictionary. MedDRA version 19.1 or above should be used for coding. 
All AE summary tables will be will be presented by age-group and overall and will be repeated by onset 
doses and overall. All listings will be provided by age group, Subject identification number, Onset Dose 
(mg) and Event Date (day). 
An overall summary of AEs and TEAEs reporting the number of subjects with adverse events and the 
number of adverse events will be presented. The following categories will be included in this overall 
summary: 
 
○ 
Any AE 
○ 
Any TEAE 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 22 of 33 
 
 
 
○ 
Any Serious TEAE 
○ 
Any Related TEAE 
○ 
Any Severe TEAE 
○ 
Any Severe and Related TEAE 
○ 
Any Serious and Related TEAE 
○ 
Any AESI 
○ 
Any AE leading to Study Drug Discontinuation 
○ 
Any Related AE leading to Study Drug Discontinuation 
○ 
Any Serious AE leading to Study Drug Discontinuation 
○ 
Any Serious and Related AE leading to Study Drug Discontinuation 
○ 
Any AE leading to Death 
○ 
Any Related AE leading to Death 
The number and percentage of subjects and events by system organ class and preferred term will be 
calculated (by age-group and overall and repeated by onset doses and overall) and sorted by descending 
frequency of subjects and then descending frequency of events for each system organ class and preferred 
term within the overall column. Each subject is counted once to each of the incidence rates, regardless of 
the number of occurrences. These are: 
 
○ 
Summary of TEAE 
○ 
Summary of Serious TEAE 
○ 
Summary of Related TEAE 
○ 
Summary of Severe TEAE 
○ 
Summary of Severe and Related TEAE 
○ 
Summary of Serious and Related TEAE 
○ 
Summary of AESI 
○ 
Summary of AE leading to Study Drug Discontinuation 
○ 
Summary of Related AE leading to Study Drug Discontinuation 
○ 
Summary of Serious AE leading to Study Drug Discontinuation 
○ 
Summary of Serious and Related AE leading to Study Drug Discontinuation 
○ 
Summary of AE leading to Death 
○ 
Summary of Related AE leading to Death 
○ 
Summary of TEAEs by Relationship with DBF 
○ 
Summary of TEAEs by Intensity 
Listings of all Adverse Events, Serious Adverse Events, Adverse Events of Special Interest, Adverse Events 
leading to Study drug discontinuation and Adverse Events leading to death will be presented. 
Laboratory Evaluations 
Clinical laboratory data will be summarized using descriptive statistics (sample size, mean, median, SD, 
Min and Max) will be presented for the baseline and all post baseline visits for hematology and serum 
chemistry only. Descriptive statistics for change from baseline for on-study measurements will also be 
presented for each parameter. 
For both hematology and serum chemistry laboratory tests, Low, normal, and high classifications will be 
applied to determine whether the laboratory test value was below (low), within (normal), or above (high) its 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 23 of 33 
 
 
 
reference range. For both separate tables will be utilized to show frequencies (number and percent) at 
baseline and post-baseline visits as Low, Normal, High and Missing and for post baseline visits shifts from 
baseline will also be shown for each parameters. 
For Urinalysis frequencies (number and percent) of subjects will be shown by visit and shifts from baseline 
for each parameter. 
Separate listings will be produced for hematology, serum chemistry, Urinalysis and all other laboratory 
testing (including Serology, Pregnancy Tests, Breath Alcohol Test, Urine Tests for Drugs of Abuse and if 
any thing which is other than Hematology, Blood Chemistry, Urinalysis). 
Vital Signs and ECG 
Descriptive statistics (sample size, mean, median, SD, Min and Max) for each vital sign and ECG parameter will 
be presented by overall for the baseline and all post baseline visits in separate tables. Descriptive statistics 
for change from baseline for on-study measurements will also be presented for each parameter. 
Corresponding listings of all vital signs and ECG results will be provided by age group, Subject identification 
number, Visit, Onset Dose (mg) and Collection Date (day). 
 
Physical and Neurological Examination 
Listings of all physical and neurological examination results will be provided by age group, Subject 
identification number, Visit, Onset Dose (mg) and Collection Date (day). 
For both separate tables will be utilized to show frequencies (number and percent) at baseline as Normal, 
Abnormal and Not Done or Missing and for post baseline visits as Change Or Abnormality, No Change Or 
Abnormality and Not Done or Missing. 
Other Safety 
Oral Mucosa Examination 
All Oral mucosa examination will be listed. No summary statistics will be provided. 
 
Gustatory Labeled Magnitude Scale (gLMS) sense Assessments 
All Gustatory Labeled Magnitude Scale (gLMS) sense Assessments will be listed. Also it will be tabulated 
as frequencies(number and percent) of subjects at each of baseline and post-baseline visits and shifts from 
baseline to post-baseline visits by categories No sensation/ Barely detectable/ Weak/ Moderate/ Strong/ 
Very strong/ Strongest imaginable sensation/ Missing. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
All Columbia Suicide Severity Rating Scale (C-SSRS) will be listed. Also it will be tabulated as 
frequencies(number and percent) of subjects at each of baseline and post-baseline visits by categories. 
Quality of Life in Epilepsy Inventory Assessments 
Following listings for Quality of Life in Epilepsy Inventory Assessments will be produced: 
 
• 
Quality of Life in Epilepsy Inventory Assessments questions 
• 
Quality of Life in Epilepsy Inventory Assessments (Scores) for PedsQL: Epilepsy Module Adult 
Report for Toddlers (Age Category : Infants(2-4 years)) 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 24 of 33 
 
 
 
• 
Quality of Life in Epilepsy Inventory Assessments (Scores) for PedsQL: Epilepsy Module Parent 
Report for Young Child (Age Category : Younger Children(5-7 years)) 
• 
Quality of Life in Epilepsy Inventory Assessments (Scores) for PedsQL: Epilepsy Module Parent 
Report for Children (Age Category : Older Children(8-10 years)) 
• 
Quality of Life in Epilepsy Inventory Assessments (Scores) for QOLIE-AD-48 (Age Category : 
Adolescents(11-17 years)) 
• 
Quality of Life in Epilepsy Inventory Assessments (Scores) for QOLIE-31-P (Age Category : 
Adults(18 years or more)) 
 
A summary table by Type/Group (Maximum Score) with descriptive statistics (sample size, mean, median, 
SD, Min and Max) will be presented for the baseline and all post baseline visits. Same descriptive statistics 
will be calculated for change from baseline in the same table. This table will be done by Infant(as 2-4 years), 
Younger Child(as 5-7 years), Older Child(as 8-10 years), Adolescent(as 11-17 years) and Adult(as 18 years 
or more) as column headers and not by the usual columns proposed for safety tables. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 25 of 33 
 
 
 
Interim Analyses 
 
This SAP amendment is based on the experience of the previous three interim analysis and in order to 
better representation the data. This SAP amendment will be applicable only for the final analysis and no 
other interim analysis. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 26 of 33 
 
 
 
Changes from Analysis Planned in Protocol 
 
Analysis of Usability data 
Analysis of Usability data which is captured in the eDiaries are removed from this SAP amendment. 
 
Analysis of Adverse events of special interest 
Some adverse events of special interest are defined in this SAP based on the experiences in the previous 
interim analyses and other studies with DBF. 
Concomitant medications of interest 
Concomitant Medications with Benzodiazepine (by Scheduled and Rescue use) and Concomitant 
Medications with Anti-epileptic Drugs are included in this SAP. 
Epilepsy related Medical History 
Rules have been difined to identify Epilepsy related Medical History which are of interest. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 27 of 33 
 
 
 
Programming Considerations 
 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output will 
adhere to the following specifications. 
Format of Output 
Unless otherwise specified, all computer-generated output should be produced in landscape mode. 
Required margins: at least 1.25 inches on top (the binding margin [or left for portrait output]), at least 1 inch 
on right, left, and bottom. All output should have the sponsor name, protocol number, the type of delivery, 
and page number. Tables/listings/figures should be internally paginated in relation to total length (i.e., page 
number should appear sequentially as page n of N, where N is the total number of pages in the table). 
 
a) Output numeration will conform to International Conference on Harmonisation (ICH) 
recommendations. The study population should be identified immediately following the title. 
 
b) Column headings should be in initial upper-case characters. 
 
c) For numeric variables, include “unit” in column or row headings where appropriate. 
 
d) Footnotes should be single spaced, but separated by at least a double space from the bottom line 
of the table. The notes are aligned vertically by the left vertical border of the table. 
 
e) If the categories are not ordered (e.g., race), then only those categories for which there is at least 
1 subject represented in 1 or more groups should be included. 
 
f) 
An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more subjects. 
 
g) Listings should be sorted by cohorts and subject numbers. 
 
h) In a listing, display the subject number only once for the subject with multiple records. If a subject’s 
records run into multiple pages, display the subject number once for every page. 
 
Format of Data 
a) Unless otherwise specified for continuous variables, the estimated mean, standard deviation and 
median for a set of values should be printed out to 1 more significant digit than the individual units 
of measurement. The minimum and maximum should report the same significant digits as the 
original values. 
 
b) Data in columns of a table should be formatted as follows: 
 
• 
Alphanumeric values are left-justified. 
 
• 
Whole numbers (e.g., counts) are right-justified. 
 
• 
Numbers containing fractional portions are decimal aligned. 
 
c) Unless otherwise specified, percentage values should be printed with 1 digit to the right of the 
decimal point (e.g., 12.8%, 5.4%). Less-than signs “<0.1%” should be printed when values are >0 
and <0.1% (not 0%). 
 
d) Missing data should be represented on subject listings as either a hyphen (“-“) with a corresponding 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 28 of 33 
 
 
 
footnote (“- = unknown or not evaluated”), or as “NA,” with the footnote “NA = not applicable,” 
whichever is appropriate. 
 
e) Dates should be printed in SAS® date9.format (“DDMMMYYYY”: 23MAR2020). Missing portions 
of     dates     should     be     represented     on     subject     listings     as     dashes (--MAR2020). 
Dates that are missing because they are not applicable for the subject are output as “NA”, unless 
otherwise specified. 
 
f) 
Time should be printed in SAS® TOD5.format (“HH:MM”: 17:30). Missing portions of time should 
be represented on subject listings as dashes (--:30). Times that are missing because they are not 
applicable for the subject are output as “NA”, unless otherwise specified. 
 
General Considerations 
• 
One SAS program can create several outputs, or a separate SAS program will be created for each 
output. 
 
• 
One output file can contain several outputs or each output will be stored in a separate file. 
 
• 
Output files will be delivered in Word format or portable document format pdf. 
 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
Table, Listing, and Figure Format 
General 
• 
All TFLs will be produced in landscape format on A4 (ISO 216 standard), unless otherwise 
specified. 
 
• 
All TFLs will be produced using the Times new Roman, size 10. 
 
• 
The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
 
• 
Headers and footers for figures will be in Times new Roman, size 10. 
 
• 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 
• 
TFLs will be in black and white (no color), unless otherwise specified 
 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 
• 
Only standard keyboard characters will be used in the TFLs. Special characters, such as non- 
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help display 
math symbols (e.g., μ). Certain subscripts and superscripts (e.g., m2) will be employed on a case- 
by-case basis. 
 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
• 
All output should have the following header at the top left of each page: 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 29 of 33 
 
 
 
• 
Aquestive Therapeutics; Protocol Number: 42-1703 
 
• 
Final Run and the system Date 
 
• 
All output should have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number should appear sequentially as page 
n of N, where N is the total number of pages in the table). 
 
• 
The date output was generated should appear along with the program name as a footer on each 
page. 
 
Aquestive Therapeutics 
Confidential 
 
Page n of N 
Protocol Number: 42-1703 
 
Final/Draft Output 
Display Titles 
• 
Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering 
is strongly recommended, but sponsor preferences are obtained before final determination a 
decimal system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. 
The analysis set are identified on the line immediately following the title. The title and table 
designation are single spaced. 
 
• 
Column headers. There will be 1 blank line between the last title and the solid line. 
 
Table x.y.z: First Line of Title (Analysis Set) 
Second Line of Title if Needed 
Column Headers 
• 
Column headings are displayed immediately below the solid line described above in initial upper- 
case characters. 
 
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column (if applicable). P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
• 
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis set. 
 
• 
The order of treatments in the tables and listings will be Placebo first in the case of placebo 
controlled studies and Active comparators first in the case of active comparator trials, followed by 
a total column (if applicable). 
 
Body of the Data Display 
11.4.5.1. General Conventions 
Data in columns of a table or listing are formatted as follows: 
 
• 
Alphanumeric values are left-justified; 
 
• 
Whole numbers (e.g., counts) are right-justified; and 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 30 of 33 
 
 
 
• 
Numbers containing fractional portions are decimal aligned. 
 
11.4.5.2. Table Conventions 
• 
Units will be included where available 
 
• 
If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
 
Severity Rating 
N 
Severe 
0 
Moderate 
8 
Mild 
3 
 
 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0%). 
 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented in 1 or more 
groups are included. 
 
• 
An Unknown or Missing category are added to each parameter for which information is not available 
for 1 or more subjects. 
 
• 
Unless otherwise specified, the estimated mean and median for a set of values are printed out to 
1 more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
N 
XX 
Mean 
XXX.X 
SD 
X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
If there is only 1 data point i.e. n=1 then only n and mean (=data) will be shown. If unavoidable 
show “-“(hyphen) in all other places. 
 
• 
P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 
• 
Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down 
to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal 
places. Unless otherwise noted, for all percentages, the number of subjects in the analysis set for 
the treatment group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% are presented as 100%, without 
decimal places. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 31 of 33 
 
 
 
• 
Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated are reported as “-”. 
 
• 
The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Describe details of this in 
footnotes or programming notes. 
 
• 
For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, describe in a footnote or programming note if the subject are included 
in the summary statistics for all relevant categories or just 1 category and the criteria for selecting 
the criteria. 
 
• 
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(cont.)” at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page. 
 
11.4.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
 
• 
Missing data are represented on subject listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “NA”, with the footnote “NA = not applicable”, 
whichever is appropriate. 
 
• 
Dates should be printed in SAS® date9.format (“DDMMMYYYY”: 23MAR2020). Missing portions 
of     dates     should     be     represented     on     subject     listings     as     dashes (--MAR2020). 
Dates that are missing because they are not applicable for the subject are output as “NA”, unless 
otherwise specified. 
 
• 
All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 
• 
Units will be included where available. 
 
• 
Full page utilization in sense of line numbers are expected. 
 
• 
If any of the selection within columns/subheaders are continuing into next page please mark (cont.) 
in the next page. 
 
11.4.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the footnotes. 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 32 of 33 
 
 
 
• 
All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote should start on a new line, where possible. 
 
• 
Subject specific footnotes are avoided, where possible. 
 
• 
Footnotes will be used sparingly and add value to the table, figure, or listing. If more than six lines 
of footnotes are planned, then a cover page is strongly recommended to be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each page. 
 
• 
The last line of the footnote section will be a standard source line that indicates the source listing(if 
table or figure), the name of the program used to produce the data display, the name of the ADaM 
dataset used, date the program was run, and the listing source (i.e., ‘Program : myprogram.sas 
ADaM: xxxxx Listing source: 16.x.y.z’) in following order: 
 
For tables and Figures: 
Data Source: Listing XXXX 
Program:XXXX.sas   ADaM: ADxxx 
Table Generation: ddmmmyyyy/hh:mm 
For Listings: 
Program:XXXX.sas 
ADaM: ADxxx 
Listing Generation: ddmmmyyyy/hh:mm 


Statistical Analysis Plan 
Sponsor Name: Aquestive Therapeutics; Protocol Number: 42-1703 
Syneos Health 
This document is confidential. 
SAP Version: 2.0 dated August 11, 2020 
Page 33 of 33 
 
 
 
Quality Control 
 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
SOP Developing Statistical Programs (3907) . 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (3908) describes the quality control procedures that are performed for all SAS programs and 
output. Quality control is defined here as the operational techniques and activities undertaken to verify that 
the SAS programs produce the output by checking for their logic, efficiency and commenting and by review 
of the produced output.”